VOLUME 2 DISEASE CONTROL PRIORITIES • THIRD EDITION Reproductive, Maternal, Newborn, and Child Health DISEASE CONTROL PRIORITIES • THIRD EDITION Series Editors Dean T. Jamison Rachel Nugent Hellen Gelband Susan Horton Prabhat Jha Ramanan Laxminarayan Charles N. Mock Volumes in the Series Essential Surgery Reproductive, Maternal, Newborn, and Child Health Cancer Mental, Neurological, and Substance Use Disorders Cardiovascular, Respiratory, and Related Disorders HIV/AIDS, STIs, Tuberculosis, and Malaria Injury Prevention and Environmental Health Child and Adolescent Development Disease Control Priorities: Improving Health and Reducing Poverty DISEASE CONTROL PRIORITIES Budgets constrain choices. Policy analysis helps decision makers achieve the greatest value from limited available resources. In 1993, the World Bank published Disease Control Priorities in Developing Countries (DCP1), an attempt to systematically assess the cost-effec- tiveness (value for money) of interventions that would address the major sources of disease burden in low- and middle-income countries. The World Bank’s 1993 World Development Report on health drew heavily on DCP1’s findings to conclude that specific interventions against noncommunicable diseases were cost-effective, even in environments in which substantial burdens of infection and undernutrition persisted. DCP2, published in 2006, updated and extended DCP1 in several aspects, including explicit consideration of the implications for health systems of expanded intervention coverage. One way that health systems expand intervention coverage is through selected platforms that deliver interventions that require similar logistics but deliver interventions from different packages of conceptually related interventions, for example, against cardiovascular disease. Platforms often provide a more natural unit for investment than do individual interventions. Analysis of the costs of packages and platforms—and of the health improvements they can generate in given epidemiological environments—can help to guide health system investments and development. DCP3 differs importantly from DCP1 and DCP2 by extending and consolidating the concepts of platforms and packages and by offering explicit consideration of the financial risk protection objective of health systems. In populations lacking access to health insurance or prepaid care, medical expenses that are high relative to income can be impoverishing. Where incomes are low, seemingly inexpensive medical procedures can have catastrophic financial effects. DCP3 offers an approach to explicitly include financial protection as well as the distribution across income groups of financial and health outcomes resulting from policies (for example, public finance) to increase intervention uptake. The task in all of the DCP volumes has been to combine the available science about interventions implemented in very specific locales and under very specific conditions with informed judgment to reach reasonable conclusions about the impact of intervention mixes in diverse environments. DCP3 ’s broad aim is to delineate essential intervention packages and their related delivery platforms to assist decision makers in allocating often tightly constrained budgets so that health system objectives are maximally achieved. DCP3 ’s nine volumes are being published in 2015 and 2016 in an environment in which serious discussion continues about quantifying the Sustainable Development Goal (SDG) for health. DCP3 ’s analyses are well-placed to assist in choosing the means to attain the health SDG and assessing the related costs. Only when these volumes, and the analytic efforts on which they are based, are completed will we be able to explore SDG-related and other broad policy conclusions and generalizations. The final DCP3 volume will report those conclusions. Each individual volume will provide valuable, specific policy analyses on the full range of interventions, packages, and policies relevant to its health topic. More than 500 individuals and multiple institutions have contributed to DCP3. We convey our acknowledgments elsewhere in this volume. Here we express our particular gratitude to the Bill & Melinda Gates Foundation for its sustained financial support, to the InterAcademy Medical Panel (and its U.S. affiliate, the Institute of Medicine of the National Academy of Medicine), and to the External and Corporate Relations Publishing and Knowledge division of the World Bank. Each played a critical role in this effort. Dean T. Jamison Rachel Nugent Hellen Gelband Susan Horton Prabhat Jha Ramanan Laxminarayan Charles N. Mock VOLUME 2 DISEASE CONTROL PRIORITIES • THIRD EDITION Reproductive, Maternal, Newborn, and Child Health EDITORS Robert E. Black Ramanan Laxminarayan Marleen Temmerman Neff Walker © 2016 International Bank for Reconstruction and Development / The World Bank 1818 H Street NW, Washington, DC 20433 Telephone: 202-473-1000; Internet: www.worldbank.org Some rights reserved 1 2 3 4 19 18 17 16 This work is a product of the staff of The World Bank with external contributions. 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All queries on rights and licenses should be addressed to the Publishing and Knowledge Division, The World Bank, 1818 H Street NW, Washington, DC 20433, USA; fax: 202-522-2625; e-mail: pubrights@worldbank.org. ISBNs and DOIs: Softcover: Hardcover: ISBN: 978-1-4648-0348-2 ISBN: 978-1-4648-0347-5 ISBN (electronic): 978-1-4648-0368-0 DOI: 10.1596/978-1-4648-0348-2 DOI: 10.1596/978-1-4648-0347-5 Cover photo: Foune Kouyate waits to vaccinate her baby, Kadidia Goulibaly, at the Centre De Sante Communautaire De Banconi (ASACOBA), a health clinic in Bamako, Mali, on November 4, 2013. © Dominic Chavez/World Bank. Further permission required for reuse. Cover and interior design: Debra Naylor, Naylor Design, Washington, DC. Library of Congress Cataloging-in-Publication Data Names: Black, Robert E., editor. | Laxminarayan, Ramanan, editor. | Temmerman, Marleen, editor. | Walker, Neff, editor. Title: Reproductive, maternal, newborn, and child health / volume editors, Robert Black, Ramanan Laxminarayan, Marleen Temmerman, Neff Walker. Other titles: Disease control priorities ; v. 2. Description: Washington, DC : World Bank, 2016. | Series: Disease control priorities ; volume 2 | Includes bibliographical references and index. Identifiers: LCCN 2015038391| ISBN 9781464803475 (hc : alk. paper) | ISBN 9781464803482 (alk. paper) | ISBN 9781464803680 (e-book) Subjects: | MESH: Child Welfare. | Maternal Welfare. | Reproductive Health. | Child Mortality. | Developing Countries. | Infant Mortality. Classification: LCC RG940 | NLM WA 395 | DDC 362.1982--dc23 LC record available at http://lccn.loc.gov/2015038391 Contents Foreword xi Preface xiii Abbreviations xv 1. Reproductive, Maternal, Newborn, and Child Health: Key Messages of This Volume 1 Robert E. Black, Neff Walker, Ramanan Laxminarayan, and Marleen Temmerman PART 1 REPRODUCTIVE, MATERNAL, AND CHILD MORTALITY AND MORBIDITY AND THE UNMET NEED FOR FAMILY PLANNING 2. Burden of Reproductive Ill Health 25 Alex Ezeh, Akinrinola Bankole, John Cleland, Claudia Garcia-Moreno, Marleen Temmerman, and Abdhalah Kasiira Ziraba 3. Levels and Causes of Maternal Mortality and Morbidity 51 Véronique Filippi, Doris Chou, Carine Ronsmans, Wendy Graham, and Lale Say 4. Levels and Causes of Mortality under Age Five Years 71 Li Liu, Kenneth Hill, Shefali Oza, Dan Hogan, Yue Chu, Simon Cousens, Colin Mathers, Cynthia Stanton, Joy Lawn, and Robert E. Black 5. Levels and Trends in Low Height-for-Age 85 Gretchen A. Stevens, Mariel M. Finucane, and Christopher J. Paciorek PART 2 INTERVENTIONS TO IMPROVE REPRODUCTIVE HEALTH AND REDUCE MATERNAL AND CHILDHOOD MORBIDITY AND MORTALITY 6. Interventions to Improve Reproductive Health 95 John Stover, Karen Hardee, Bella Ganatra, Claudia García Moreno, and Susan Horton 7. Interventions to Reduce Maternal and Newborn Morbidity and Mortality 115 A. Metin Gülmezoglu, Theresa A. Lawrie, Natasha Hezelgrave, Olufemi T. Oladapo, João Paulo Souza, Marijke Gielen, Joy E. Lawn, Rajiv Bahl, Fernando Althabe, Daniela Colaci, and G. Justus Hofmeyr 8. Diagnosis and Treatment of the Febrile Child 137 Julie M. Herlihy, Valérie D’Acremont, Deborah C. Hay Burgess, and Davidson H. Hamer ix 9. Diarrheal Diseases 163 Gerald T. Keusch, Christa Fischer Walker, Jai K. Das, Susan Horton, and Demissie Habte 10. Vaccines for Children in Low- and Middle-Income Countries 187 Daniel R. Feikin, Brendan Flannery, Mary J. Hamel, Meghan Stack, and Peter M. Hansen 11. Management of Severe and Moderate Acute Malnutrition in Children 205 Lindsey Lenters, Kerri Wazny, and Zulfiqar A. Bhutta 12. Infant and Young Child Growth 225 Jai K. Das, Rehana A. Salam, Aamer Imdad, and Zulfiqar A. Bhutta 13. Very Early Childhood Development 241 Frances E. Aboud and Aisha K. Yousafzai PART 3 PLATFORMS FOR HEALTH CARE AND PUBLIC HEALTH INTERVENTIONS 14. Community-Based Care to Improve Maternal, Newborn, and Child Health 263 Zohra S. Lassi, Rohail Kumar, and Zulfiqar A. Bhutta 15. Innovations to Expand Access and Improve Quality of Health Services 285 Lori A. Bollinger and Margaret E. Kruk PART 4 ECONOMICS, PREVENTION, AND FINANCING OF CARE FOR PREGNANT WOMEN, MOTHERS, AND CHILDREN 16. Returns on Investment in the Continuum of Care for Reproductive, Maternal, Newborn, and Child Health 299 Karin Stenberg, Kim Sweeny, Henrik Axelson, Marleen Temmerman, and Peter Sheehan 17. Cost-Effectiveness of Interventions for Reproductive, Maternal, Neonatal, and Child Health 319 Susan Horton and Carol Levin 18. The Benefits of a Universal Home-Based Neonatal Care Package in Rural India: An Extended Cost-Effectiveness Analysis 335 Ashvin Ashok, Arindam Nandi, and Ramanan Laxminarayan 19. Health Gains and Financial Risk Protection Afforded by Treatment and Prevention of Diarrhea and Pneumonia in Ethiopia: An Extended Cost-Effectiveness Analysis 345 Stéphane Verguet, Clint Pecenka, Kjell Arne Johansson, Solomon Tessema Memirie, Ingrid K. Friberg, Julia R. Driessen, and Dean T. Jamison DCP3 Series Acknowledgments 363 Volume and Series Editors 365 Contributors 367 Advisory Committee to the Editors 371 Reviewers 373 Index 375 x Contents Foreword When I became the Deputy Director of the Child Survival future where we reach the highest attainable standard Partnership in 2004, I knew the task at hand was a chal- of health for all women, children, and adolescents. A lenging one. We were only four years into the Millennium new funding mechanism, The Global Financing Facility Development Goals (MDGs), but we already knew that in Support of Every Woman, Every Child, aims to bring moving the needle on maternal and child survival would together existing and new sources of financing for take more headway and greater advances. Since then, and “smart, scaled, and sustainable financing” to accelerate particularly since 2010, we have accelerated progress in efforts to end preventable maternal, newborn, and child an unprecedented manner, mobilized actors and part- deaths by 2030. ners, and improved our way of working. Strategy, financing, and delivery of services need to We have undergone an extraordinary transformation, be guided by the best available scientific knowledge on halving maternal and child mortality under the MDGs. the efficacy of interventions and the effectiveness of pro- As we transition to the Sustainable Development Goals grams. This volume of the Disease Control Priorities, third (SDGs), we are in a much better position to achieve the edition (DCP3) series, Reproductive, Maternal, Newborn, global and equitable progress we seek for all people. and Child Health, provides this rigorous knowledge base. Goal 3 of the 17 SDGs is “to ensure healthy lives and Readers now have at their fingertips the most relevant promote well-being for all at all ages.” This broad goal technical information on which interventions, pro- embraces the unfinished agenda of the MDGs and goes grams, service delivery platforms, and policies can best beyond—to virtually end preventable maternal, new- help all to reach the ambitious Global Goal 3 targets— born, and child deaths and to improve access to sexual maternal mortality rates lower than 70 maternal deaths and reproductive health, as well as access to medicines per 100,000 live births, neonatal mortality rates of 9 and vaccines. By moving toward this goal, we are work- per 1,000 live births, and stillbirth rates of 9 per 1,000 ing to protect the future and well-being of those closest total births. It is a source of great pride to know that my to us: our mothers, children, and communities. WHO team, led by Professor Dr. Marleen Temmerman, The 2010–15 Global Strategy for Women’s and Director of the Department of Reproductive Health and Children’s Health brought together hundreds of part- Research, contributed to this work. My team will con- ners around the Every Woman Every Child movement tinue its efforts to end preventable mortality worldwide to jointly achieve the ambitious goals for maternal and to achieve the three broad goals embraced by the and child health. Building on this progress, the United new Global Strategy—survive, thrive, and transform. Nations (UN) Secretary-General, in September 2015, We all have a role to play as we put this Global launched a follow-up roadmap for 2016–30 at the UN Strategy into practice in every corner of the globe. We General Assembly, The Global Strategy for Women’s, need everyone’s continued engagement, support, and Children’s, and Adolescents’ Health. The new strategy commitments. We have the knowledge, the tools, and aligns fully with the SDGs, embracing the vision of a the will. A transformation by 2030 is within our reach. Dr. Flavia Bustreo Assistant Director-General, Family, Women, and Children’s Health, World Health Organization xi Preface Reproductive, maternal, newborn, and child health of preventive and therapeutic interventions, as well (RMNCH) encompasses health concerns spanning the as cost-effectiveness of these interventions and health life course from adolescent girls to women before and system considerations for their implementation. The during pregnancy to newborns and older children. In volume gives particular attention to the efficient and recent years, it has been recognized that appropriately effective use of delivery platforms to provide pack- addressing these concerns requires organizing services ages of interventions—a framing that supports country in a continuum of care that encompasses these stages decision-making for universal health care. Despite our in the life course. The rationale for the organization objective of covering a broad range of RMNCH topics of the RMNCH volume is based on the link between in this volume, some topics of relevance to women and interventions at each stage and health effects at that stage children were found to fit better in other volumes. These and future stages, and consequently the need to deliver include surgical conditions, cancer, mental and develop- integrated, preventive, and therapeutic interventions for mental disorders, HIV/AIDS and sexually transmitted mothers and children. infections, malaria, injuries, and adolescent health and In considering interventions that span the RMNCH development. continuum, DCP3 has departed from the disease-specific RMNCH interventions have received significant framing of interventions that was followed in previous attention in low- and middle-income countries and editions. DCP1, published in 1993, largely focused on among international donors. The reasons for this include individual diseases and conditions with those regarding the high burden of disease and the evidence that many RNMCH. DCP1 referred to the “unfinished agenda” efficacious and cost-effective interventions are available that included major diseases, such as acute respiratory to dramatically reduce the burden of ill health. The infection, diarrhea, malaria, and poliomyelitis, as well promulgation of the Millennium Development Goals, as malnutrition, HIV/AIDS and sexually transmitted with their strong focus on RMNCH concerns, gave fur- infections, “excess fertility,” and maternal and perinatal ther impetus to implementation of the proven interven- health, but it did not include the broader issue of neo- tions. It has been important that review of the evidence natal health. In DCP2, published in 2006, nine of the 73 for new interventions and program approaches has con- chapters were on RMNCH, reflecting the broader scope tinued through academic journals such as The Lancet, of that edition including a greater emphasis on noncom- DCP, and other critical exercises that have identified municable diseases, health system strengthening, and the needs and opportunities in RMNCH. Substantial cross-cutting issues. success has been achieved with unprecedented declines The “unfinished agenda” of RMNCH continues to in maternal and child mortality and fertility; however, be as important today as it was in 1993. This volume problems remain, including large inequities among and contains 19 chapters that range from descriptions of the within low- and middle-income countries in health ser- current levels and causes of reproductive ill health, mater- vices and outcomes. nal and child morbidity and mortality, undernutrition, We intend for this volume to provide an update of the and compromised child development, to consideration evidence and help to shape what can be implemented xiii in integrated packages of services for reproductive We thank the following individuals who provided health, maternal and newborn health, and child health valuable assistance and comments in the development to achieve the new Sustainable Development Goals. of this volume: Brianne Adderley, Kristen Danforth, Alex In addition, we hope that consideration of delivery of Ergo, Victoria Fan, Mary Fisk, Glenda Gray, Rajat Khosla, interventions with greatest coverage and equity will pri- Nancy Lammers, Rachel Nugent, Rumit Pancholi, Helen oritize strengthening of the three interlinked platforms: Pitchik, Carlos Rossel, Lale Say, Rachel Upton, Kelsey communities, primary health centers, and hospitals. We Walters, and Gavin Yamey. We also thank the RMNCH now have the knowledge and means to fully address the Authors Group for the preparation of the chapters and unfinished agenda of RMNCH and must not miss the the reviewers organized by the National Academy of opportunity and the obligation to act. Medicine (formerly the Institute of Medicine). Robert E. Black Ramanan Laxminarayan Marleen Temmerman Neff Walker xiv Preface Abbreviations ACT artemisinin-based combination therapy AFHS Adolescent Friendly Health Services ANC antenatal care ARI acute respiratory infection ART antiretroviral therapy ASHA accredited social health activist BCG Bacille Calmette-Guérin BEP balanced protein energy BES balanced energy and protein supplementation BF breastfeeding BMI body mass index CBD community-based distribution CCM community case management CCT conditional cash transfer CEA cost-effectiveness analysis CF complementary feeding CFR case fatality rate CHERG Child Health Epidemiology Reference Group CHV community health volunteer CHW community health worker CI confidence interval CLTS Community-Led Total Sanitation CMAM community-based management of acute malnutrition CQI continuous quality improvement CRS congenital rubella syndrome CS cesarean section CSB corn-soy blend CYP couple-years of protection DALY disability-adjusted life year DHS demographic and health survey DPT diphtheria, pertussis, and tetanus DTP3 third dose of DTP EBF exclusive breastfeeding ECEA extended cost-effectiveness analysis ECV external cephalic version EED environmental enteric dysfunction xv EPI Expanded Program on Immunization FBF fortified blended flour FRP financial risk protection GAM global acute malnutrition Gavi Global Alliance for Vaccines and Immunization GBS Group B streptococcus GDP gross domestic product GNI gross national income HAZ height-for-age Z-score HBNC home-based neonatal care HEP health extension program HEW health extension worker HiB Haemophilus influenzae B HICs high-income countries HIV human immunodeficiency virus HR hazard ratio HSV-2 herpes simplex virus-2 IAP intrapartum antibiotic prophylaxis iCCM Integrated Community Case Management ICD International Classification of Diseases ICPD International Conference on Population and Development IDA iron deficiency anemia IIV inactivated influenza vaccine IMCI Integrated Management of Childhood Illness IMNCI Integrated Management of Neonatal and Childhood Illness IMPAC Integrated Management in Pregnancy and Childcare IPT intermittent preventive treatment ITN insecticide-treated bednet IU international unit IUD intrauterine device IUGR intrauterine growth restriction IYCF infant and young child feeding JE Japanese encephalitis LBW low birth weight LHWs Lady Health Workers LICs low-income countries LiST Lives Saved Tool LMICs low- and middle-income countries LNS lipid-based nutrient supplement LRI lower respiratory tract infections LYS life-year saved MAM moderate acute malnutrition MD mean difference MDG Millennium Development Goal MgSO4 magnesium sulphate MICs middle-income countries MMR maternal mortality ratio MNP multiple micronutrient powder MUAC mid-upper arm circumference NIMS Nutrition Impact Model Study NMR newborn mortality rate NPV net present value OHT One Health Tool xvi Abbreviations OOP out-of-pocket OPV oral polio vaccine ORS oral rehydration solution PBF performance-based financing PCV pneumococcal conjugate vaccination PPH postpartum hemorrhage PUFA polyunsaturated fatty acids QALY quality-adjusted life year RCT randomized controlled trial RDS respiratory distress syndrome RDT rapid diagnostic test RMNCH reproductive, maternal, newborn, and child health RR relative risk RUF ready-to-use food RUSF ready-to-use supplementary food RUTF ready-to-use therapeutic food SAM severe acute malnutrition SFP supplementary feeding program SGA small for gestational age STI sexually transmitted infection TFC therapeutic feeding center TFR total fertility rate UCTs unconditional cash transfers UHC universal health coverage UMICs upper-middle-income countries UN United Nations UNICEF United Nations Children’s Fund UPF universal public finance USAID United States Agency for International Development VLY value of a life-year saved WASH Water, sanitation, and hygiene WHO World Health Organization WHZ weight-for-height z-score YICSSG Young Infants Clinical Signs Study Group Abbreviations xvii Chapter 1 Reproductive, Maternal, Newborn, and Child Health: Key Messages of This Volume Robert E. Black, Neff Walker, Ramanan Laxminarayan, and Marleen Temmerman VOLUME SUMMARY • Progress could be accelerated by scaling up integrated packages of essential interventions across the contin- Reproductive, Maternal, Newborn, and Child Health uum of care for RMNCH. These interventions are (RMNCH) covers the health concerns and interven- highly cost-effective and result in benefit-cost ratios tions across the life course involving women before of 7–11 to 2035 (net present value in U.S. dollars of and during pregnancy; newborns, that is, the first benefits to costs). 28 days of life; and children to their fifth birthday. • Scaling up all interventions in the packages of The volume identifies 61 essential interventions and maternal and newborn health, plus folic acid before because of the timing of their delivery in the life pregnancy, and child health from the existing rate of course, groups them into three packages: 18 for repro- coverage to 90 percent would avert 149,000 mater- ductive health, 30 for maternal and newborn health, nal deaths; 849,000 stillbirths; 1,498,000 neonatal and 13 for child health, although some interventions, deaths; and 1,515,000 child deaths, representing the such as vaccines for immunization, have multiple impact in 2015 at current rates of pregnancy, birth, components. The volume considers the health system and mortality. needs for implementing these interventions in health • The reproductive health package is particularly service platforms in communities, in primary health important for providing contraceptive services. centers, and in hospitals and the cost-effectiveness of Addressing 90 percent of unmet need in 2015 would interventions for which data are available. This chapter reduce annual births by almost 28 million, which summarizes the volume and considers the poten- would consequently prevent 67,000 maternal deaths; tial impact and cost of scaling up proven interven- 440,000 neonatal deaths; 473,000 child deaths; and tions to reduce maternal, newborn, and child deaths 564,000 stillbirths from avoided pregnancies. and stillbirths. • Individual interventions that have the highest impact on deaths are provision of contraception; • The annual number of global maternal and child management of labor and delivery; care of pre- deaths has dropped markedly in the past 25 years, yet term births; treatment of severe infectious dis- the rate of reduction in many countries has been too eases, including pneumonia, diarrhea, malaria, and slow to achieve Millennium Development Goals 4 neonatal sepsis; and management of severe acute and 5 by 2015. malnutrition. Corresponding author: Robert E. Black, Johns Hopkins Bloomberg School of Public Health, rblack1@jhu.edu. 1 • The three packages of reproductive, maternal and new- child health has increased from US$2.7 billion in 2003 born, and child health interventions have an annual to US$8.3 billion in 2012, when there was an additional incremental cost of US$6.2 billion in low-income US$4.5 billion for reproductive health (Arregoces and countries, US$12.4 billion in lower-middle-income others 2015). A continued focus on RMNCH is needed countries, and US$8.0 billion in upper-middle- to address the remaining considerable burden of disease income countries. The average per capita cost of in LMICs from unwanted pregnancies; high maternal, these three packages is US$6.7, US$4.7, and US$3.9 newborn, and child mortality and stillbirths; high rates in low-, lower-middle-, and upper-middle-income of undernutrition; frequent communicable and non- countries, respectively. communicable diseases; and loss of human capacity. • These packages of interventions are delivered through Cost-effective interventions are available and can be three key service platforms: community workers and implemented at high coverage in LMICs to greatly health posts, primary health centers, and hospitals reduce these problems at an affordable cost. (first level and referral). Community and primary RMNCH encompasses health problems across the health center platforms could reduce 77 percent of life course from adolescent girls and women before maternal, newborn, and child deaths and stillbirths and during pregnancy and delivery, to newborns and that are preventable by these essential interventions children. An important conceptual framework is the in the maternal and newborn health and child health continuum-of-care approach in two dimensions. One packages. Hospitals contribute the remaining averted dimension recognizes the links from mother to child and deaths through more advanced management of com- the need for health services across the stages of the life plicated pregnancies and deliveries, severe infec- course. The other is the delivery of integrated preventive tious diseases, and malnutrition in these calculations. and therapeutic health interventions through service Contraceptive services are considered to be almost platforms ranging from the community to the primary entirely delivered at primary health centers. health center and the hospital. • Weaknesses in RMNCH delivery platforms, includ- This volume presents the levels and trends of RMNCH ing limited access to care, poor quality of services, indicators, proven interventions for prevention of mor- and shortages of health workers or medicines, are tality, costs of these interventions and potential health a major barrier to improving RMNCH outcomes. service delivery platforms, and system innovations. To overcome these weaknesses and expand access to Other volumes in the third edition of Disease Control RMNCH services, innovative delivery approaches Priorities also cover topics of importance to women and are being deployed, such as task-shifting to other children that are related to the RMNCH health services cadres of workers, household visitation, community packages (box 1.1). These topics include the following: mobilization and service delivery, financial incentives for households and health workers, and supervision • Trauma care; obstetric surgery; obstetric fistula; sur- and accreditation. gery for family planning, abortion, and postabortion care; and surgery for congenital anomalies (Volume 1, Essential Surgery) INTRODUCTION • Breast cancer, cervical cancer and precancer, child- Reproductive, maternal, newborn, and child health hood cancer, and cancer pain relief (Volume 3, (RMNCH) has been a priority for both governments Cancer) and civil society in low- and middle-income countries • Childhood mental and developmental disorders (LMICs). This priority was affirmed by world lead- (Volume 4, Mental, Neurological, and Substance Use ers in the Millennium Development Goals (MDGs) Disorders) that called for countries to reduce child mortality • Cardiovascular and respiratory disorders (Volume 5, by 67 percent and maternal mortality by 75 percent Cardiovascular, Respiratory, and Related Disorders) between 1990 and 2015. Although substantial progress • HIV/AIDS and other sexually transmitted infections, on these targets has been made, few countries achieved tuberculosis, and malaria (Volume 6, HIV/AIDS, the needed reductions. The United Nations (UN) STIs, Tuberculosis, and Malaria) Secretary-General’s Global Strategy for Women’s and • Road traffic injury and interpersonal violence Children’s Health, launched in 2010 and expanded in (Volume 7, Injury Prevention and Environmental 2015 to include adolescents, is an indication of the Health) continued global commitment to the survival and well- • Child (older than five years) and adolescent develop- being of women and children (Ban 2010). Annual offi- ment (the subject of the entire Volume 8, Child and cial development assistance for maternal, newborn, and Adolescent Development). 2 Reproductive, Maternal, Newborn, and Child Health Box 1.1 From the Series Editors of Disease Control Priorities, Third Edition Budgets constrain choices. Policy analysis helps offers an approach that explicitly includes financial decision makers achieve the greatest value from protection as well as the distribution across income limited available resources. In 1993, the World Bank groups of financial and health outcomes resulting published Disease Control Priorities in Developing from policies (for example, public finance) to increase Countries (DCP1), an attempt to systematically intervention uptake (Verguet, Laxminarayan, and assess the cost-effectiveness (value for money) of Jamison 2015). The task in all the volumes has been interventions that would address the major sources to combine the available science about interventions of disease burden in low- and middle-income coun- implemented in very specific locales and under very tries (Jamison and others 1993). The World Bank’s specific conditions with informed judgment to reach 1993 World Development Report on health drew reasonable conclusions about the impact of interven- heavily on DCP1’s findings to conclude that specific tion mixes in diverse environments. DCP3’s broad interventions against noncommunicable diseases aim is to delineate essential intervention packages— were cost-effective, even in environments in which such as the essential packages in this volume—and substantial burdens of infection and undernutrition their related delivery platforms. This information persist (World Bank 1993). will assist decision makers in allocating often tightly DCP2, published in 2006, updated and extended constrained budgets so that health system objectives DCP1 in several respects, including explicit consid- are maximally achieved. eration of the implications for health systems of DCP3’s nine volumes are being published in 2015 expanded intervention coverage (Jamison and oth- and 2016 in an environment in which serious dis- ers 2006). One way that health systems expand inter- cussion continues about quantifying the sustainable vention coverage is through selected platforms that development goal (SDG) for health (United Nations deliver interventions that require similar logistics 2015). DCP3’s analyses are well placed to assist in but address heterogeneous health problems. choosing the means to attain the health SDG and Platforms often provide a more natural unit for assessing the related costs. Only when these volumes, investment than do individual interventions, and and the analytic efforts on which they are based, are conventional health economics has offered little completed will we be able to explore SDG-related understanding of how to make choices across and other broad policy conclusions and generaliza- platforms. Analysis of the costs of packages and tions. The final DCP3 volume will report those con- platforms—and of the health improvements clusions. Each individual volume will provide they can generate in given epidemiological valuable specific policy analyses on the full range of environments—can help guide health system invest- interventions, packages, and policies relevant to its ments and development. health topic. The third edition is being completed. DCP3 differs substantively from DCP1 and DCP2 by extending Dean T. Jamison and consolidating the concepts of platforms and Rachel Nugent packages and by offering explicit consideration of the financial-risk-protection objective of health systems. Hellen Gelband In populations lacking access to health insurance or Susan Horton prepaid care, medical expenses that are high relative Prabhat Jha to income can be impoverishing. Where incomes are low, seemingly inexpensive medical procedures can Ramanan Laxminarayan have catastrophic financial consequences. DCP3 Charles N. Mock Reproductive, Maternal, Newborn, and Child Health: Key Messages of This Volume 3 LEVELS AND TRENDS IN RMNCH An estimated 74 million unintended pregnancies INDICATORS occurred in LMICs in 2012 (Sedgh, Singh, and Hussain 2014). Some of these ended by unsafe abortion, a major Reproductive Health cause of maternal morbidity and mortality (Singh, Poor reproductive health outcomes for women and Sedgh, and Hussain 2010). About 8.5 million women their children may result from a broad spectrum of worldwide suffer complications from unsafe abortions morbid conditions and adverse circumstances and annually (Singh, Darroch, and Ashford 2014). Regardless risk factors, such as unsafe sex leading to unwanted of legal status or policies on abortion, it can be fairly pregnancies and sexually transmitted infections, as stated that preventing unsafe abortion is critical and well as violence against women and girls. Because these that effective programming for reproductive health are sensitive matters and are often related to gender needs should be uncoupled from laws on the legal sta- inequality in a cultural and social context, measuring tus of abortion. The large effects of reducing unwanted and quantifying the burden of these conditions and pregnancies on maternal, neonatal, and child deaths and risk factors remains a challenge. This DCP3 volume stillbirths are estimated in a later section of this chapter. focuses on four conditions and risk factors that have Another hidden burden of reproductive health is significant impacts on reproductive health: unwanted infertility. In 2010, an estimated 48.5 million women pregnancies, unsafe abortions, infertility, and violence were involuntarily childless as a result of male or female against women. infertility, or both. This is especially concerning in In 2015, 12 percent of married or in-union women LMICs, where infertility can lead to severe stigmatiza- of reproductive age worldwide want to delay or tion, economic deprivation and denial of inheritance, avoid pregnancy but are not using any method of divorce, and social isolation (Chachamovich and others contraception. For example, women in Sub-Saharan 2010; Cui 2010). Africa are twice as likely to have an unmet need for As an extreme manifestation of social and gender family planning compared with the rest of the world inequality, violence against women and girls is often (UN 2015). The total fertility rate remains very high a hidden problem, with serious health consequences. in many countries in Sub-Saharan Africa (map 1.1, Women exposed to intimate partner violence are more panel a). likely to have poor pregnancy outcomes; acquire HIV Map 1.1 Total Fertility, Maternal Mortality Ratios, and Under-Five Mortality Rates by Country, 2015 a. Total Fertility (children per woman) 2010–15 IBRD 42133 | JANUARY 2016 1–1.9 2–2.9 3–3.9 4–4.9 5–5.9 >6 Data not available or not applicable Source: Based on UNPD 2015 (http://esa.un.org/unpd/wpp); map re-created based on WHO 2015. map continues next page 4 Reproductive, Maternal, Newborn, and Child Health Map 1.1 Total Fertility, Maternal Mortality Ratios, and Under-Five Mortality Rates by Country, 2015 (continued) b. Maternal Mortality Ratios, 2015 IBRD 42132 | JANUARY 2016 1–19 20–99 100–299 300–499 500–999 >1,000 Data not available or not applicable Source: Based on WHO 2015; map re-created based on WHO 2015. c. Under-Five Mortality per 1,000 Live Births, 2015 IBRD 42131 | JANUARY 2016 1–4.9 5–14.9 15–24.9 25–54.9 >55 Data not available or not applicable Source: Based on UN IGME 2015; map re-created based on WHO 2015. (in some regions), syphilis, chlamydia, or gonorrhea; 30 percent of women age 15–49 years in a relation- experience depression; or have alcohol abuse disor- ship experience physical or sexual violence by their ders (WHO, Department of Reproductive Health and intimate partner at some point in their lives (WHO, Research, London School of Hygiene and Tropical Department of Reproductive Health and Research, Medicine, and South African Medical Research London School of Hygiene and Tropical Medicine, Council 2013). Studies have found between 3 percent and South African Medical Research Council 2013). and 31 percent of women report partner violence dur- Tragically, many women do not seek help following ing pregnancy (Devries and others 2010). Worldwide, these events. Reproductive, Maternal, Newborn, and Child Health: Key Messages of This Volume 5 Maternal Mortality and Morbidity Perinatal, Neonatal, and Child Mortality Globally, the total number of maternal deaths The under-five mortality rate (U5MR), the probabil- decreased by 43 percent, from 532,000 in 1990 to ity of dying between a live birth and the fifth birthday, 303,000 in 2015, and the global maternal mortality is one of the most important measures of the health ratio declined by 44 percent, from 385 maternal of a population. Although MDG 4 was not achieved deaths per 100,000 live births in 1990 to 216 in globally, some high-mortality countries in South Asia 2015 (Alkema and others 2015). LMICs continue to and Sub-Saharan Africa have achieved this target account for 99 percent (302,000 out of 303,000) of (Afnan-Holmes and others 2015; Amouzou and oth- global maternal deaths. The highest risks of maternal ers 2012). The U5MR remains very high, especially death are in countries in South Asia and Sub-Saharan in many countries in Sub-Saharan Africa (map 1.1, Africa (map 1.1, panel b). Thus, while considerable panel c). progress has been made, particularly in recent years, The U5MR in 2015 is 42.5 per 1,000 live births, a the goal of reducing maternal mortality by 75 percent decline from 90.6 per 1,000 live births in 1990 (You by 2015 was not met. and others 2015). The U5MR fell by half or more from The risk of maternal death has two components: the 1990 to 2015 in all world regions. The UN estimates risk of getting pregnant, which is a risk related to fertility that only 24 of 82 low- or lower-middle-income coun- and its control or lack of control; and the risk of devel- tries achieved the MDG 4 target (You and others 2015). oping a complication and dying while pregnant, in labor, However, it is important to note that compared with or postpartum. Chapter 3 of this volume, on maternal historical trends, the reduction of U5MR has accelerated morbidity and mortality, focuses on the risk during since 2000, when the MDGs were approved (You and pregnancy, delivery, and postpartum, which is highest at others 2015). the time of delivery (Filippi and others 2016). The neonatal mortality rate is now widely followed as The most important causes of maternal death are an important population health measure because a large obstetric hemorrhage, hypertension, abortion, and proportion (45 percent in 2015) of the deaths in children sepsis (figure 1.1, panel a). The overall proportion of under age five years occurs in the first month of life. In HIV-related maternal deaths is highest in Sub-Saharan addition, the rate of stillbirths has received more atten- Africa (Say and others 2014). Most maternal deaths tion with the recognition of the large number of viable do not have well-defined medical causes, and given fetuses (2.6 million in 2015) who die after 28 weeks of that many occur in the community rather than health gestation, often at the time of delivery (Blencowe and facilities, determining the cause is challenging. Deaths others 2016). due to abortive outcomes (for example, ectopic preg- Of the 5.9 million deaths occurring after a live birth nancy, induced abortion, and miscarriage), obstructed before age five years, pneumonia, diarrhea, and neonatal labor, and indirect causes are of considerable pro- sepsis or meningitis are the leading infectious causes grammatic interest, but are particularly difficult to (figure 1.1, panel b). The leading single cause of child capture because of poor reporting resulting from lack deaths was complications from preterm birth, followed of knowledge and the sensitive nature of abortion and by pneumonia and intrapartum-related complications, maternal deaths in facilities. Deaths due to abortion formerly known as birth asphyxia. In the next 15 years, are often not reported to avoid stigma. Despite the with further implementation of proven health interven- availability of proven interventions, the persistence of tions, it is anticipated that the infectious causes of death deaths due to hemorrhage and hypertension are par- will decline more quickly than noninfectious causes (Liu ticularly concerning. and others 2014). The common causes of maternal morbidity in The proportion of global live births in Sub-Saharan the community vary by region; these causes include Africa is projected to increase from 24.9 percent anemia, preexisting hypertension or diabetes, depres- currently to 32.6 percent by 2030 because of the sion, and other mental health conditions. Prolonged region’s high fertility rate compared with other and obstructed labor is associated with a high burden of regions. If the current regional trends in child mor- morbidity and disability, including that due to obstetric tality are continued to 2030, global child deaths will fistula. The true extent of maternal morbidity is not fall to 4.4 million (Liu and others 2014). However, known because of difficulties in definition and mea- because of both the high number of births and high surement. The World Health Organization (WHO) is U5MR, Sub-Saharan Africa’s share of global child currently working with partners to develop standard deaths is expected to increase from 49.6 percent to definitions and tools to close this gap. 59.8 percent by 2030. 6 Reproductive, Maternal, Newborn, and Child Health Figure 1.1 Causes of Maternal and Child Deaths a. Causes of maternal death b. Causes of childhood (under five years) death Pneumonia 13% Preterm birth complications 16% Sepsis Intrapartum-related 11% Other disorders events 11% Hemorrhage 11% Hypertension 27% Sepsis 7% 14% Neonatal 45% Congenital abnormalities 5% Embolism Abortion 8% Other neonatal 3% Diarrhea disorders 3% Other 9% direct 4% Preexisting Pneumonia 3% medical Injury 6% Tetanus <1% Obstructed conditions labor 3% 15% Malaria 5% Diarrhea <1% HIV-related Congenital abnormalities Complications 5% 4% of delivery Other indirect 3% causes 7% Preterm birth Meningitis complications AIDS Measles Pertussis Intrapartum-related 2% 2% 1% 1% <1% events <1% Source: Say and others 2014. Source: Liu and others 2016. MATERNAL, FETAL, AND CHILD been published (Villar and others 2014). Compared with MALNUTRITION AND EARLY CHILD this standard, the estimated global prevalence of small- for-gestational-age births is about one-quarter lower DEVELOPMENT (Kozuki and others 2015). As neonates and infants, these Malnutrition includes both undernutrition and the babies have a higher risk of mortality than babies who growing problem of overweight, both important prob- were appropriate weight for gestational age, and this risk lems in women and children under age five years. In is similar using either the U.S. reference or the new inter- women of reproductive age (age 20–49 years), a body national standard (Kozuki and others 2015). They also mass index (BMI) of less than 18.5 kilograms weight/ have an increased risk of stunted linear growth (Black height in meters squared (kg/m2) is defined as under- and others 2013; Christian and others 2013). The risk of nutrition or excessive thinness, and a BMI of greater mortality with small-for-gestational age birth increases than or equal to 25 kg/m2 is considered overweight. if they are also premature. The prevalence of maternal undernutrition has fallen Compared with an international growth standard, it from almost 20 percent in Asia and Africa to about was estimated that in 2011 26 percent of children glob- 10 percent, which is still too high (Black and others ally had stunted linear growth (height-for-age of less 2013). The prevalence of overweight in women has than −2 standard deviations of the growth standard), steadily increased during the same period in all world totaling 165 million children (Black and others 2013). regions, reaching more than 50 percent in the Americas The prevalence of stunting has declined in LMICs since and in Oceania, 30 percent in Africa, and 20 percent in 1990, more in Asia and Latin America than in Africa. Asia (Black and others 2013). Deficiencies of iodine, Stunting prevalence has declined at similar rates in calcium, zinc, iron, and other essential vitamins and rural and urban areas but remains higher in rural areas minerals are also prevalent and have particular rele- (Stevens, Paciorek, and Finucane 2016). Severe wasting, vance to maternal and fetal health. which was estimated to affect 3 percent, or 19 million, Restriction of fetal growth, usually assessed by a low of the world’s children in 2011, requires urgent inter- weight for gestational age at birth, is due to poor mater- vention with therapeutic feeding and treatment of con- nal nutrition and other morbidity, infection, and toxic current infections (Lenters, Wazny, and Bhutta 2016). in-utero exposures (Das and others 2016). Compared to Of the micronutrient deficiencies, vitamin A and zinc a U.S. birthweight reference, more than a quarter of all deficiencies are associated with increased risk of mor- live births in LMICs, or 32.4 million babies, were born tality and infectious disease morbidity (Black and others small-for-gestational age (Black and others 2013). A new 2013; Das and others 2016). At the same time, over- international birthweight standard has subsequently weight (greater than 2 standard deviations of the growth Reproductive, Maternal, Newborn, and Child Health: Key Messages of This Volume 7 standard weight for height) has steadily increased since ESSENTIAL INTERVENTIONS ON 1990 to 7 percent, an increase of more than 50 percent, STILLBIRTHS AND MATERNAL, NEONATAL, affecting 43 million children. Fetal growth restriction, suboptimal breastfeeding, AND CHILD DEATHS stunting, wasting, and deficiencies of vitamin A and In this volume, we define three packages of interven- zinc, usually in combination with infectious diseases, tions across the RMNCH continuum with the greatest are important underlying causes of neonatal and child potential to reduce deaths and disability: reproductive deaths. These conditions have been estimated to be the health, maternal and newborn health, and child (age underlying causes of 45 percent of deaths in children 1–59 months) health. under age five years (Black and others 2013). We report on estimated morbidity and mortality Grantham-McGregor and International Child from 75 countries that include more than 95 percent of Development Committee (2007) estimate that a high the world’s maternal and child deaths, the countries that proportion of the world’s surviving children do had been monitored in the Countdown to 2015 initiative not reach their developmental potential, based on (Requejo and others 2015). Estimates are derived using rates of stunting and poverty. This poor devel- the Lives Saved Tool (LiST; box 1.2) by increasing the opment outcome has numerous causes, including coverage of each intervention to 90 percent from the antenatal and postnatal nutrition, exposure to vio- current level of coverage in each of these 75 countries lence, brain injuries or infections, and environments (Requejo and others 2015). with insufficient stimulation (Aboud and Yousafzai The deaths averted by individual interventions in 2016). Critical periods for brain development are the maternal and newborn health and the child health during fetal growth and in the first two years of life. packages are shown in figure 1.2. The immediate (for Micronutrient deficiencies in pregnancy have impor- 2015) impact on deaths of the individual interventions tant consequences, such as compromised mental and their combined effects if implemented together was development with iodine deficiency and neural tube estimated. For these estimates, the effects of folic acid defects with folic acid deficiency (Black and others supplementation in the reproductive health package 2013). Inadequate diets and high rates of infectious are considered, and these effects are combined with the diseases in the first two years of life lead to short maternal and newborn package for presentation. stature (stunting) and permanent deficits in cogni- A separate analysis was undertaken for family plan- tive and social development. Additional important ning services in the reproductive health package, in determinants of development in children are the which the provision of contraception is scaled up to amount and quality of household psychosocial stim- cover 90 percent of current unmet need (Walker, Tam, ulation (Singla, Kumbakumba, and Aboud 2015) and and Friberg 2013). Because this reduces the number the effects of maternal illness, including depression of pregnancies, we calculated the number of maternal, (Walker and others 2007). neonatal, and child deaths and stillbirths that would be prevented if the rates of mortality in 2015 had applied to these pregnancies and births. Estimates of the effects INTERVENTIONS TO REDUCE MATERNAL of other interventions such as human papillomavirus vaccination or targeted health care approaches for ado- AND CHILD MORBIDITY AND MORTALITY lescents are considered in other volumes (for example, The RMNCH volume identifies essential interventions, volume 3 Cancer and volume 8 Child and Adolescent based on their efficacy and appropriateness, to address Development). important health conditions. Tables 1.1–1.3 list these The impact is also considered for interventions pro- interventions in the least advanced service platform at vided by each of three platforms for health services (see which their delivery is possible. The three platforms tables 1.1–1.3). The community platform includes all represent services that can be provided by (1) com- interventions that can be delivered by a community- munity health workers or health posts; (2) primary based health worker with appropriate training and sup- health centers; or (3) hospitals, both first-level and port or by outreach services, such as child health days, referral. The interventions are grouped by the point immunizations, vitamin A, and other interventions. For at which they are needed in the continuum of care. ill children, the integrated community case management We also consider the nature of their delivery (urgent, (iCCM) approach is assumed to include diagnosis and continuing care, or routine care), which has important treatment of pneumonia, diarrhea, and malaria cases implications for the organization and responsibilities without danger signs that indicate the need for refer- of the health system. ral (Hamer and others 2012; Young and others 2012). 8 Reproductive, Maternal, Newborn, and Child Health Box 1.2 Lives Saved Tool The Lives Saved Tool (LiST) has been continually or size at birth) and cause-specific mortality developing since 2003. The initial version of the (neonatal, child mortality for those age 1–59 months, software was developed as part of the work for the maternal mortality, and stillbirths). The relation- Child Survival Series in The Lancet in 2003 (Jones ship between an input (change in intervention and others 2003). The original purpose of the coverage) and one or more outputs is specified as a program was to estimate the impact that scaling measure of the effectiveness of the intervention in up community-based interventions would have on reducing the probability of that outcome. The out- under-five mortality (Jones and others 2003). The come can be cause-specific mortality or a risk factor. Bill & Melinda Gates Foundation provided support The overarching assumption in LiST is that mortal- for the further development and maintenance of ity rates and cause-of-death structure will not the software as part of the work of the Child Health change except in response to changes in coverage of Epidemiology Reference Group (CHERG). At that interventions. point, the software was shifted into the free and pub- The roughly 70 separate interventions within LiST licly available Spectrum software package, to take (see tables 1.1–1.3) target stillbirths, neonatal mor- advantage of the demographic capabilities in that tality, mortality in children age 1–59 months, software and to provide links to other models for maternal mortality, or risk factors such as stunting family planning and AIDS (Stover, McKinnon, and and wasting, within the model. In LiST, interven- Winfrey 2010). Since that time, LiST has expanded tions can be linked to multiple outcomes, with some its scope to examine the impact of interventions interventions linked to multiple causes of death and on birth outcomes and stillbirths (Pattinson and risk factors. LiST allows the impact of scaling up others 2011), maternal mortality, and incidence of coverage of multiple interventions to be examined pneumonia and diarrhea (Bhutta and others 2013), simultaneously. as well as neonatal and child mortality. CHERG, along with its institutional sponsors, the LiST has been characterized as a linear, mathemati- WHO and UNICEF, developed rules of evidence to cal model that is deterministic (Garnett and others decide what interventions should be included in the 2011). It describes fixed relationships between model as well as how to develop the estimates of inputs and outputs that will produce the same out- effectiveness (Walker and others 2010). The assump- puts each time one runs the model. The primary tions used within LiST are drawn from various inputs in LiST are coverage of interventions with sources, but most of the evidence about effectiveness the condition that the quality of that intervention is of interventions is presented in three journal supple- sufficient to be effective, what is commonly referred ments (Fox and others 2011; Sachdev, Hall, and to as effective coverage. The outputs are changes in Walker 2010; Walker 2013). The set of assumptions population-level risk factors (such as wasting or and their sources can be found at the LiST website stunting rates, birth outcomes such as prematurity, (http://www.livessavedtool.org). The primary health center (PHC) platform is a facility training and supervision of community-based workers. with a doctor or a nurse midwife (or both), nurses and For LiST modeling, the effects of meeting the unmet support staff, as well as basic diagnostic and treatment need for contraceptives are considered to be delivered by capabilities. The PHC provides facility-based contracep- the PHC platform. For young infants and children, the tive services, including long-acting reversible contracep- Integrated Management of Childhood Illness approach tives (implants, intrauterine devices); surgical sterilization is assumed to be used at the PHC level (Bryce and others (vasectomy, tubal ligation); care during pregnancy and 2004). The hospital platform, consisting of both first- delivery for uncomplicated pregnancies; provision of level and referral hospitals, includes more advanced ser- medical care for adults and children, such as injectable vices for management of labor and delivery in high-risk antibiotics, that cannot be done in the community; and women or those with complications, including operative Reproductive, Maternal, Newborn, and Child Health: Key Messages of This Volume 9 Figure 1.2 Deaths Averted by Individual Interventions in the Maternal and Newborn Health and Child Health Packages Folic acid supplementation or fortification 48,172 – 26,384 Labor and delivery management 337,060 – 43,861 – 503,626 Care of premature babies 410,473 Syphilis detection and treatment 7,559 – 142,289 Treatment for sepsis and pneumonia in neonates 129,756 Promotion of breastfeeding 50,009 – 55,818 Neonatal resuscitation 99,905 Clean postnatal practices 91,491 MgSO4 - Management of preeclampsia and eclampsia 18,410 – 64,812 IPTp 13,766 – 1,024 – 1,258 – 50,064 Chlorhexidine 59,684 Clean birth practices 47,489 – 8,378 Balanced energy supplementation 50,614 – 2,965 Antibiotics for pPRoM 40,242 – 5,560 Immediate assessment and stimulation of newborns 45,449 Micronutrient supplementation 40,159 – 2,061 Induction of labor for pregnancies lasting 41+ weeks 40,058 Diabetes case management 22,364 Active management of the third stage of labor 20,381 PMTCT 287 – 15,980 Safe abortion services 14,633 Tetanus toxoid vaccination 14,172 – 154 Hypertensive disorder case management 13,055 Maternal sepsis case management 12,392 Calcium supplementation 5,294 Postabortion case management 3,833 Malaria case management of pregnant women 2,219 Antimalarials – Artemesinin compounds for malaria 207,436 Handwashing with soap 171,370 Oral antibiotics for pneumonia in children 161,832 Pneumococcal vaccine 132,440 Oral rehydration solution 11,306 – 102,485 Therapeutic feeding for severe wasting 104,389 Haemophilus influenzae b vaccine 100,064 ITN/IRS - Households protected against malaria 81,369 Zinc supplementation 79,106 Appropriate complementary feeding 58,618 Treatment for moderate acute malnutrition 53,839 Hygienic disposal of children’s stools 46,705 Rotavirus vaccine 39,043 Zinc – for treatment of diarrhea 29,639 Measles vaccine 21,869 DPT vaccine 15,020 Vitamin A supplementation 10,018 HIV treatment (ART and cotrimoxazole) 8,355 Vitamin A – for treatment of measles 7,411 Antibiotics – for treatment of dysentery 6,125 0 200,000 400,000 600,000 800,000 1,000,000 Neonatal deaths averted Child (age 1–59 months) deaths averted Maternal deaths averted Stillbirth deaths averted Note: ART = antiretroviral therapy; DPT = diphtheria, pertussis, tetanus; HIV = human immunodeficiency virus; IPTp = intermittent preventive treatment in pregnancy; ITN/IRS = insecticide-treated net/indoor residual spraying; MgSO4 = magnesium sulfate; PMTCT = prevention of mother-to-child transmission; pPRoM = preterm premature rupture of membranes. delivery, full supportive care for preterm newborns, and Some deaths are averted through provision of folic acid children with severe infection or severe acute malnutri- before conception and in early pregnancy, reducing both tion with infection. stillbirths and neonatal deaths by preventing fetal neural The reproductive health package, other than pro- tube defects, resulting in a reduction of stillbirths of vision of contraceptive services, consists primarily of 26,000 and neonatal deaths of 48,000 at the current rates educational interventions that are not expected to have a of fertility. These deaths are included in the maternal direct impact on deaths, but are important to encourage and newborn package for presentation in this chapter. behaviors to prevent infections, ensure proper nutrition The largest effect of the reproductive health package is of girls before pregnancy, or to seek care for antenatal or from the contraceptive services that prevent unintended delivery services at other levels. The effects of these prac- pregnancies. It is estimated that if 90 percent of current tices or treatments are included in LiST and are assigned unmet need for contraceptives had been met, 28 million to the level at which the practice or treatment occurs. births would have been prevented in 2015. This level of 10 Reproductive, Maternal, Newborn, and Child Health Table 1.1 Essential Interventions for Reproductive Health Delivery platforma First-level and referral Community workers or health post Primary health center hospitals Information 1. Sexuality education and education 2. Nutritional education and food supplementation 3. Promotion of care-seeking for antenatal care and delivery 4. Prevention of sexual and reproductive 1. Detection and treatment of sexual and tract infections reproductive tract infections 5. Prevention of female genital mutilation 2. Management of complications following (may be for daughters of women of female genital mutilation reproductive age) 6. Prevention of gender-based violence 3. Post-gender-based violence care (prevention of sexually transmitted infection and HIV, emergency contraception, support and counseling) 7. Information about cervical cancer and 4. Screening and treatment of precancerous 1. Management of screening lesions, referral of cancers cervical cancer Service 8. Folic acid supplementationb delivery 9. Immunization (human papillomavirus, hepatitis B) 10. Contraception: Provision of condoms 5. Tubal ligation, vasectomy, and insertion and 2. Management and hormonal contraceptivesb removal of long-lasting contraceptivesb of complicated contraceptive procedures Note: Red type denotes urgent care, blue type denotes continuing care, and black type denotes routine care. In this table, the community worker or health post consists of a trained and supported health worker based in or near communities working from home or a fixed health post. A primary health center is a health facility staffed by a physician or clinical officer and often a midwife to provide basic medical care, minor surgery, family planning and pregnancy services, and safe childbirth for uncomplicated deliveries. First-level and referral hospitals provide full supportive care for complicated neonatal and medical conditions, deliveries, and surgeries. HIV = human immunodeficiency virus. a. All interventions listed for lower-level platforms can be provided at higher levels. Similarly, each facility level represents a spectrum and diversity of capabilities. The column in which an intervention is listed is the lowest level of the health system in which it would usually be provided. b. The intervention effect was included in the Lives Saved Tool (LiST). Table 1.2 Essential Interventions for Maternal and Newborn Health Delivery platforma Community worker or health First-level and referral post Primary health center hospitals Pregnancy 1. Preparation for safe birth and newborn care; emergency planning 2. Micronutrient supplementationb 3. Nutrition educationb table continues next page Reproductive, Maternal, Newborn, and Child Health: Key Messages of This Volume 11 Table 1.2 Essential Interventions for Maternal and Newborn Health (continued) Delivery platforma Community worker or health First-level and referral post Primary health center hospitals 4. IPTpb 5. Food supplementationb 6. Education on family planning 1. Management of unwanted pregnancyb 7. Promotion of HIV testing 2. Screening and treatment for HIV and syphilisb 3. Management of miscarriage or incomplete abortion and postabortion careb 4. Antibiotics for pPRoMb 5. Management of chronic medical conditions (hypertension, diabetes mellitus, and others) 6. Tetanus toxoidb 7. Screening for complications of pregnancyb 8. Initiate antenatal steroids (as long as clinical 1. Antenatal steroidsb criteria and standards are met)b 9. Initiate magnesium sulfate (loading dose)b 2. Magnesium sulfateb 10. Detection of sepsisb 3. Treatment of sepsisb 4. Induction of labor posttermb 5. Ectopic pregnancy case managementb 6. Detection and management of fetal growth restrictionb Delivery 8. Management of labor and 11. Management of labor and delivery in low-risk 7. Management of labor and (woman) delivery in low-risk women women (BEmNOC) including initial treatment delivery in high-risk women, by skilled attendantb of obstetric and delivery complications prior to including operative delivery transferb (CEmNOC)b Postpartum 9. Promotion of breastfeedingb (woman) Postnatal 10. Thermal care for preterm 12. Kangaroo mother careb 8. Full supportive care for preterm (newborn) newbornsb newbornsb 11. Neonatal resuscitationb 12. Oral antibiotics for 13. Injectable and oral antibiotics for sepsis, 9. Treatment of newborn pneumoniab pneumonia, and meningitisb complications, meningitis, and other very serious infectionsb 14. Jaundice managementb Note: Red type denotes urgent care, blue type denotes continuing care, black type denotes routine care. In this table, the community worker or health post consists of a trained and supported health worker based in or near communities working from home or a fixed health post. A primary health center is a health facility staffed by a physician or clinical officer and often a midwife to provide basic medical care, minor surgery, family planning and pregnancy services, and safe childbirth for uncomplicated deliveries. First-level and referral hospitals provide full supportive care for complicated neonatal and medical conditions, deliveries, and surgeries. BEmNOC = basic emergency newborn and obstetric care; CEmNOC = comprehensive emergency newborn and obstetric care; HIV = human immunodeficiency virus; IPTp = intermittent preventive treatment in pregnancy; pPRoM = preterm premature rupture of membranes. a. All interventions listed for lower-level platforms can be provided at higher levels. Similarly, each facility level represents a spectrum and diversity of capabilities. The column in which an intervention is listed is the lowest level of the health system in which it would usually be provided. b. The intervention effect was included in the Lives Saved Tool (LiST). 12 Reproductive, Maternal, Newborn, and Child Health Table 1.3 Essential Interventions for Child Health Delivery platforma Community worker or health post Primary health center First-level and referral hospitals 1. Promote breastfeeding and complementary feedingb 2. Provide vitamin A, zinc, and food supplementationb 3. Immunizationsb,c 4. Cotrimoxazole for HIV-positive childrenb 1. Antiretroviral therapy for HIV-positive childrenb 5. Education on safe disposal of children’s stools and handwashingb 6. Distribute and promote use of ITNs or IRSb 7. Detect and refer severe acute malnutritionb 2. Treat severe acute malnutritionb 1. Treat severe acute malnutrition associated with serious infectionb 8. Detect and treat serious infections without 3. Detect and treat serious infections with 2. Detect and treat serious infections with danger signs (iCCMd); refer if danger signsb danger signs (IMCId)b danger signs with full supportive careb Note: Red type denotes urgent care, blue type denotes continuing care, black type denotes routine care. In this table, the community worker or health post consists of a trained and supported health worker based in or near communities working from home or a fixed health post. A primary health center is a health facility staffed by a physician or clinical officer and often a midwife to provide basic medical care, minor surgery, family planning and pregnancy services, and safe childbirth for uncomplicated deliveries. First-level and referral hospitals provide full supportive care for complicated neonatal and medical conditions, deliveries, and surgeries. HIV = human immunodeficiency virus; iCCM = integrated community case management; IMCI = integrated management of childhood illness; IRS = indoor residual spraying; ITN = insecticide-treated net. a. All interventions listed for lower-level platforms can be provided at higher levels. Similarly, each facility level represents a spectrum and diversity of capabilities. The column in which an intervention is listed is the lowest level of the health system in which it would usually be provided. b. The intervention effect was included in the Lives Saved Tool (LiST). c. Immunizations included in the standard package are those for diphtheria, pertussis, tetanus, polio, bacillus Calmette-Guerin, measles, hepatitis B, Haemophilus influenzae type b, pneumococcus, rotavirus. d. Components of iCCM are treatments for diarrhea, pneumonia, and malaria; and of IMCI are treatments of diarrhea, pneumonia, malaria, AIDS (acquired immune deficiency syndrome), other infections, and severe acute malnutrition. contraception, in turn, would reduce maternal deaths For stillbirths, 19 percent could be averted with the com- by 67,000, neonatal deaths by 440,000, child deaths by munity platform, 46 percent with the PHC platform, 473,000, and stillbirths by 564,000. Because about half and an additional 35 percent in hospitals. For maternal of unwanted pregnancies are ended in abortion, pre- deaths, 13 percent could be averted with the community venting these pregnancies would also reduce millions platform, 71 percent with the PHC platform, and the of abortions, more than half of which would have been remaining 16 percent with hospital care. For neonatal unsafe (Singh and others 2009). In addition, delayed deaths, the relative effects on level of services are differ- age of first pregnancy and avoidance of short interpreg- ent from maternal deaths, with a possible 48 percent of nancy intervals would reduce adverse birth outcomes newborn deaths averted with the community platform, such as preterm delivery. It is important to note that an additional 12 percent with the PHC platform, and a these potential deaths averted by preventing unplanned further 40 percent with hospital care. The interventions pregnancies cannot be added to the potential lives saved with the largest effects are labor and delivery manage- by the maternal and newborn and child health packages ment, care of preterm births, and treatment of neonatal (plus folic acid supplementation), which are estimated at sepsis and pneumonia (figure 1.2). the current rates of fertility and mortality. The child health package includes essential interven- The maternal and newborn package provides many tions across all three service platforms and together these interventions resulting in large effects on all of the mor- could avert 1,437,000 child deaths. The largest impact tality outcomes in the current year (figure 1.3). We esti- (93 percent of avertable child deaths) can be realized by mate that 2,574,000 deaths would be averted, including interventions in the community platform (figure 1.3), 149,000 maternal deaths, 849,000 stillbirths, 1,498,000 especially through immunizations and treatment of neonatal deaths, and 78,000 child deaths (figure 1.2). infectious diseases (figure 1.2). The PHC platform Reproductive, Maternal, Newborn, and Child Health: Key Messages of This Volume 13 Figure 1.3 Deaths Averted by Health Care Packages through Three Service Platforms 1,600,000 1,400,000 1,200,000 1,000,000 800,000 600,000 400,000 200,000 0 MN CH MN CH MN CH Community Primary health center Hospital Maternal deaths averted Stillbirths averted Neonatal deaths averted Child (age 1–59 months) deaths averted Source: Analyses using the Lives Saved Tool (LiST). Note: CH = child health package; MN = maternal and newborn package. results in additional effects on child deaths primarily tables 1.1–1.3); provided as continuing care such as for through treatment of severe infectious diseases and of chronic conditions (shown in blue in tables 1.1–1.3); or severe acute malnutrition (SAM). SAM can be managed if the service has to be available at all times and offered on an outpatient basis with therapeutic feeding but is as urgent care (shown in red in tables 1.1–1.3). Because placed in the PHC platform because of the need for ini- of the unpredictable nature of most life-threatening tial assessment and stabilization. The hospital platform conditions in maternal, newborn, and child health, such averts some additional deaths with full supportive care as complications of labor and delivery or acute illnesses, for very severe infectious diseases and malnutrition. most of the essential interventions must be available for Scaling up all interventions in the maternal and urgent care at all times of the day. newborn health and child health packages in 2015 would avert 149,000 maternal deaths, 849,000 stillbirths, 1,498,000 neonatal deaths, and 1,515,000 child deaths, a total of 4,011,000 deaths averted. Then, interven- COST-EFFECTIVENESS tions would result in a reduction in about half of the Individual RMNCH interventions, summarized estimated global 303,000 maternal deaths in 2015 and in figure 1.4, have been shown to be cost-effective also about half of the 5,900,000 global newborn and (Horton and Levin 2016). This volume explores the cost- child deaths (Alkema and others 2015; You and others effectiveness of packages of interventions that have not 2015). However, they would result in a reduction of only yet been scaled up across LMICs. It also reports on new about one-third of the 2,600,000 stillbirths (Blencowe results from extended cost-effectiveness analyses that and others, forthcoming). Well-functioning community look at financial-risk-protection outcomes in addition and PHC platforms could avert 77 percent of maternal, to the health outcomes that are part of traditional cost- newborn, and child deaths and stillbirths that are pre- effectiveness analyses. ventable by these essential interventions, with hospitals Expansion of coverage of the traditional Expanded contributing the remaining averted deaths through more Program on Immunization package of bacillus Calmette- advanced management of complicated pregnancies and Guerin; diphtheria, pertussis, and tetanus; measles; polio; deliveries and newborn and child conditions. and hepatitis B vaccines remains highly cost-effective, An additional consideration for the organization regardless of delivery modality. Introduction of pneu- of health services is whether the interventions can be mococcal and rotavirus vaccines at Gavi (the Global provided as scheduled routine care (shown in black in Vaccine Alliance) prices can avert deaths at a cost of less 14 Reproductive, Maternal, Newborn, and Child Health Figure 1.4 Cost-Effectiveness Ranges of Selected Interventions for Reproductive, Maternal, Neonatal, and Child Health for Cost per Death Averted (2012 U.S. dollars) Nutrition in pregnancy Cesarean section for obstructed labor IYCF (food and education) Vitamin A and zinc Pneumonia and diarrhea, multiple interventions Community management of severe acute malnutrition Safe abortion, LIC Women’s groups - prenatal and newborn care HiB vaccine lower-middle-income countries Home-based and community-based neonatal care HiB vaccine LIC Train TBAs for safer births Rotavirus vaccine lower-middle-income countriesa Treatment of severe malaria with artesunate Train GPs to do cesarean sections LIC Rotavirus vaccine LICa Pneumococcus vaccine LICa 1 10 100 1,000 10,000 100,000 Note: Some vaccine results are for lower-middle-income countries. If country group is not specified, results refer to low and lower-middle-income countries combined. GP = general practitioner; HiB = Haemophilus influenzae B; IYCF = infant and young child feeding interventions (education combined with food distribution to poorest); LIC = low-income country; TBA = traditional birth attendant. a. Cost-effectiveness of vaccines is sensitive to vaccine price. Rotavirus and pneumococcus vaccine costs to LICs are a fraction (for example, 5 percent) of the price paid by Gavi, the Vaccine Alliance to procure the vaccines; Gavi, in turn, receives prices that are more favorable than what upper-middle-income countries pay as a result of volume discounts and other factors. than US$100 per death (Horton and Levin 2016), but pneumococcal conjugate vaccine provides substan- these estimates do not include reduced out-of-pocket tially higher financial risk protection and saves more expenditures, improved financial risk protection for lives for the poor in Ethiopia than the current situ- households, or long-term benefits of improved cogni- ation. Financial risk protection associated with an tion and lifetime productivity (Barnighausen and others intervention is measured using the money-metric- 2014). Megiddo and others (2014) find that introduction equivalent value of insurance, which is simply what of a rotavirus vaccine in India was cost-saving and was an individual would pay as an insurance premium to estimated to avert 34.7 (95 percent uncertainty range ensure that they are fully protected against the disease [UR], 31.7–37.7) deaths and US$215,569 (95 percent or adverse health condition. UR, US$207,846–US$223,292) out-of-pocket expendi- India alone accounts for 28 percent of neonatal ture per 100,000 children under age five years. deaths globally. In 2011, India introduced a home- Chapters in this volume have calculated that home- based newborn care (HBNC) package to be delivered based management of maternal and neonatal care, by community health workers across rural areas of the including interventions to train traditional birth atten- country. Nandi and others (2015) estimate the disease dants for safer births (Sabin and others 2012), can and economic burdens averted by scaling up the HBNC be cost-effective with lower-end estimates of cost- among households in rural India. Compared with a effectiveness of less than US$1,000 per death averted. baseline of no coverage, providing the care package Scaling up midwifery services with referral when needed through the existing network of community health and family planning would cost US$2,200 per death workers could avert 48 (95 percent uncertainty range averted (Bartlett and others 2014). [UR] 34–63) incident cases of severe neonatal morbidity Using extended cost-effectiveness analysis (Verguet and 5 (95 percent UR 4–7) related deaths, save US$4,411 and others 2015), it was shown that investing in (95 percent UR US$3,088–US$5,735) in out-of-pocket the provision of universal public finance for pneu- treatment expenditure, and provide US$285 (95 percent monia treatment and for combined treatment with UR US$200–US$371) in insurance value per 1,000 live Reproductive, Maternal, Newborn, and Child Health: Key Messages of This Volume 15 births in rural India. Intervention benefits were greater COST OF SCALING UP ESSENTIAL for lower socioeconomic groups. INTERVENTIONS FOR REPRODUCTIVE, Investments that increase the supply and demand for RMNCH interventions can have long-lasting effects— MATERNAL, NEWBORN, AND CHILD HEALTH for example, the benefits of investments in nutrition can This volume estimates the annual cost of scaling up go beyond the immediate improvement in nutritional three service packages for reproductive health (family status by also improving cognitive development, school planning costs only), maternal and newborn health, performance, and future earnings (Victora and others and child health in 74 of the 75 Countdown coun- 2008; Walker and others 2007). tries (Sudan is not included because of lack of data). The economic and social benefits of a set of inte- These countries account for more than 95 percent grated RMNCH interventions include health and of the world’s maternal and child deaths. We estimate fertility impacts (Stenberg and others 2014). Some of the annual incremental costs of scaling up the three these benefits are strictly economic, reflected in higher packages described in table 1.1, based on per capita gross domestic product (GDP) from increased work- cost estimates from a global reproductive, maternal, force participation and higher productivity. Other newborn, and child health investment case (Stenberg benefits, denoted as social benefits, are not reflected in and others 2014). Using population estimates for conventional GDP measures. For example, the value of 2015 associated with the health impact shown in a child’s life saved does not depend only on his or her figure 1.3, the annual incremental cost is US$6.2 participation in the labor force when an adult. When billion in low-income countries, US$12.4 billion in taking into consideration the full-income approach lower-middle-income countries, and US$7.9 billion that goes beyond GDP to also capture these social in upper-middle-countries (table 1.4). Considering benefits, including from reducing morbidity and con- a longer time horizon of 2013 to 2035, the annual trolling fertility, the benefit-cost ratios indicate high incremental costs of scaling up the three packages returns on increased investment in RMNCH in most increases slightly depending on the country income countries, especially when benefits beyond the inter- groups, reflecting a larger target population, consistent vention period are included. For all LMICs considered with Stenberg and others (2014) and chapter 16 in this as a group, the benefit-cost ratio is 8.7 for the inter- volume (Stenberg and others 2016). These estimates vention period to 2035 at a 3 percent discount rate include health system strengthening costs, such as (Stenberg and others 2014; Stenberg and others 2016). program management, infrastructure needs, improved Table 1.4 Cost of Essential Reproductive Health (family planning only), Maternal and Newborn Health, and Child Health Packages by Country Income Group for 2015 and 2035 (million 2012 U.S. dollars, except per capita costs) Low-income Lower-middle-income Upper-middle-income Total cost per countries countries countries package Package 2015 2035 2015 2035 2015 2035 2015 2035 Reproductive health package costsa $562 $603 $520 $630 $151 $164 $1,233 $1,397 Cost per capita $0.6 $0.5 $0.2 $0.2 $0.1 $0.1 $0.2 $0.2 Maternal and newborn health $1,183 $1,268 $2,922 $3,542 $1,768 $1,923 $5,872 $6,733 package costsa Cost per capita $1.3 $1.0 $1.1 $1.1 $0.9 $0.9 $1.0 $1.0 Child health package costsa $4,484 $4,810 $8,838 $10,712 $6,060 $6,591 $19,382 $22,113 Cost per capita $4.8 $3.9 $3.4 $3.3 $2.9 $2.9 $3.5 $3.3 Total costs $6,229 $6,681 $12,406 $14,884 $7,979 $8,679 $26,614 $30,243 Total per capita costs $6.7 $5.4 $4.7 $4.6 $3.9 $3.9 $4.7 $4.5 Note: Estimates have been inflated to 2012 U.S. dollars using U.S. consumer price index data (World Bank World Development Indicators). a. Package costs include commodities, front-line health workers, and additional health system strengthening costs for scaling up services. 16 Reproductive, Maternal, Newborn, and Child Health governance, and health system information and logis- Table 1.5 Average Additional Modern Contraceptive tics systems. These costs account for 73 percent of total Users, Cost per Additional User, and Incremental Costs package costs in low-income countries, 50 percent in over the Period 2013–35 (2012 U.S. dollars) lower-middle-income countries, and 41 percent in Lower- Upper- upper-middle-income countries.1 Low- middle- middle- The child health package requires the greatest addi- income income income tional cost to scale up to 2035 with an additional US$22 countries countries countries Total billion per year. It includes a wide range of commodi- Additional ties and services to prevent and treat childhood illness, modern including immunization, malaria, and HIV. Scaling up contraceptive the maternal and newborn package requires an addi- users (million) 75 106 27 208 tional US$6.7 billion per year. The reproductive health Cost per package is the least costly to scale up and requires an additional user $15.8 $10.0 $24.4 $14 additional US$1.4 billion per year, covering commodi- ties and personnel costs of front-line workers delivering Incremental costs (US$ modern family planning methods associated with the million) $1,188 $1,065 $663 $2,916 greatest reductions in fertility. The estimate does not include the costs of educational interventions in the reproductive health package because these were not assumptions regarding the rate of scaling up and the available. One reproductive health package service, folic methods mix of modern family planning among the acid, is included in the maternal and newborn health target population. package in this chapter, while human papillomavirus Scaling up the three essential packages will require vaccination is included and costed in the package of an average additional investment of US$4.7 per person essential cancer services. per year in the 74 countries with 95 percent of the The cost of family planning is low at an average of global maternal and child mortality burden. It provides US$0.20 per capita per year and an annual incremental rates of return based on economic and social bene- cost of US$1.4 billion per year. However, because the fit that are up to nine times the investment by 2035 model only estimates the cost of adding an average (Stenberg and others 2016). The current (2015) cost 104 million new users for the period, we also estimated of the three packages, inclusive of health system costs, the cost of eliminating unmet need for all women who ranges from US$6.70 per capita in low-income settings desire to prevent a pregnancy, but do not currently use to US$4.80 and US$3.90 in lower-middle-income and effective contraceptive methods, by 2035 (Stenberg and upper-middle-income country settings. These estimates others 2014). In this scenario, 208 million additional may be higher or lower depending on the country con- users are reached during this period at a total cost of text and current levels of investment and commitment US$2.9 billion or US$14.0 per additional user (US$15.8 to health system strengthening. per additional user for low-, US$10.0 for lower-middle-, Results from the RMNCH investment case (Stenberg and US$24.4 for upper-middle-income countries) and others 2014) are complemented by new evidence (table 1.5). on individual interventions in reproductive, mater- For comparison, a recent study by the Guttmacher nal and newborn, and child health interventions also Institute (Singh, Darroch, and Ashford 2014) esti- presented in this volume. Although information on mates that meeting all women’s needs for modern empirical costs has grown substantially in the past contraceptives will cost US$5.3 billion per year more decade, it remains imperfect and lacks up-to-date data than current spending. Although the services included on relatively well-established interventions, such as are very similar to those included in our reproduc- vitamin A capsule distribution and family planning tive health package, the Guttmacher estimate covers where modern contraceptive coverage is low in spite of all LMICs rather than the 74 Countdown countries, high expressed unmet need. In emerging areas, such as includes the costs of improving the quality of care for maternal depression and intimate partner violence, few current family planning users, and includes costs of published studies are available. However, the literature scaling up services for an estimated 225 million women does support trends in relative costs across the essential with unmet need (Singh, Darroch, and Ashford 2014). packages and provides a wealth of information espe- In sum, differences between this and our estimate cially for child illness and for a variety of platforms. reflect differences in scope (all LMICs compared with For example, average unit costs (cost per beneficiary) only Countdown countries), methods, and underlying are lower for family planning interventions, antenatal Reproductive, Maternal, Newborn, and Child Health: Key Messages of This Volume 17 care visits, and normal deliveries at home or health chosen physicians every six months during a three-year centers with trained birth attendants. Costs per benefi- period to assess physicians’ quality indicators. Bonus ciary tend to increase with the complexity of the service payments were awarded if qualifying scores were met. (that is, treatment of obstetric or abortion complica- Outcomes of interest—including age-adjusted wasting, tions, treatment of severe acute child malnutrition, and C-reactive protein, hemoglobin level, parental self- a range of community-based nutrition interventions). reported health of children, and children under age five For example, breastfeeding support and prevention years hospitalized for diarrhea or pneumonia—were of micronutrient deficiencies are inexpensive com- not improved in intervention sites. Only two indicators pared with facility-based treatment of severe acute improved. Parental self-reported health of children malnutrition. Within packages, costs are also likely to increased by 7 percentage points and wasting declined vary depending on the context and condition—the by 9 percentage points. A Cochrane review suggests that prevention and treatment of malaria and diarrheal the quality of evidence is too poor to draw general con- disease are less expensive per child (US$20 to US$100) clusions about the effectiveness of pay for performance than treating pneumonia and meningitis, which more and notes that several studies arrive at contradictory often require inpatient admission (US$150 per visit, results (Witter and others 2012). or US$800 per child treated for pneumonia; US$300 Safe childbirth (intrapartum care) checklists have to US$500 for inpatient care treatment of meningitis been proposed as a way of reducing newborn deaths, and pneumonia). but there are gaps in the evidence base. The WHO childbirth safety checklist was developed to help reduce the major causes of these deaths (hemorrhage, infec- IMPROVING INTERVENTION UPTAKE AND tion, obstructed labor, and others) (Spector and oth- QUALITY ers 2013; Temmerman, Khosla, Bhutta, and Bustreo 2015; Temmerman, Khosla, Laski, and others 2015). Supply- and demand-side interventions to improve Since most deaths associated with childbirth occur intervention uptake and quality are increasingly used to within a 24-hour window and the major causes are ensure that essential RMNCH services are delivered with well described, checklists have promise for improv- quality and used appropriately. ing healthy delivery. Follow-up studies are currently underway that focus directly on health outcomes attrib- utable to the increase in these practices. The qual- Supply-Side Interventions ity of RMNCH services can also be improved using On the supply side, interest has been growing in the supportive supervision for front-line health workers, use of pay-for-performance, which rewards providers which is associated with small benefits for provider or health care organizations for achieving coverage or practice and knowledge (Bosch-Capblanch, Liaqat, and quality targets. One study in Rwanda shows a 23 percent Garner 2011). increase in facility delivery and larger increases in pre- Recent efforts have been made in task-shifting—an ventive care visits by young children in facilities enrolled innovative approach to increase the delivery of RMNCH in a payment plan compared with randomly selected services by reassigning certain tasks to community controls (Basinga and others 2011). workers. Lay community health workers are increasingly A study of performance-based financing in Rwanda being deployed to classify and treat childhood infectious in which the government implemented an incentive diseases, such as pneumonia, diarrhea, and malaria, and program in several districts to motivate providers to approaches such as iCCM for their management are improve the quality of care and increase service output expanding widely (Young and others 2012). A recent found no significant differences in the use of mater- WHO Guidance Panel on Task Shifting suggested that nal health services between intervention and control health workers could carry out many tasks related to sites (Priedeman Skiles and others 2013). Only facility maternal and newborn health, provided they received birth deliveries (p = 0.014) were 10 percentage points adequate training and support (WHO 2012). These per- higher for the intervention sites compared with con- sonnel include lay workers (for example, for promotion trols. Performance-based financing may be useful if of appropriate care-seeking behavior and antenatal care targeted at specific services, such as facility deliveries, during pregnancy, administration of misoprostol to pre- but only if service use was consistently low. Peabody vent postpartum hemorrhage, and promotion and sup- and others (2014) considered payment-for-performance port of breastfeeding), auxiliary nurses (for example, for incentives and child health outcomes in the Philippines administration of injectable contraceptives), auxiliary using clinical performance vignettes among randomly nurse midwives (for example, for neonatal resuscitation 18 Reproductive, Maternal, Newborn, and Child Health and insertion and removal of intrauterine devices), maternal mortality, and under-five mortality, providing nurses (for example, for administration of a loading a compelling case for integrated RMNCH interventions. dose of magnesium sulfate to prevent or treat eclamp- Most deaths from RMNCH conditions could be greatly sia), midwives (for example, for vacuum extraction reduced by scaling up integrated packages of interventions during childbirth), and associate clinicians (for example, across the continuum of care. Many of these interven- for manual removal of the placenta). tions, especially family planning, labor and delivery man- agement, promotion of breastfeeding, immunizations, improved childhood nutrition, and treatment of severe Demand-Side Interventions infectious diseases, are among the most cost-effective of Countries are increasingly relying on demand-side inter- all health interventions. Nevertheless, implementation ventions to expand coverage. Brazil’s Bolsa Família, research is still needed to adapt these interventions to launched in 2003, transfers payments to families on the the local health service context and achieve the great- condition that beneficiaries obtain health services (such est effects. The benefits of scaling up packages extend as vaccinations and prenatal care for pregnant women) beyond health to also include substantial economic and and that children maintain a minimum daily atten- social outcomes. Improved access and quality of care dance rate at school. The program was associated with a around childbirth can generate a quadruple return on 9.3 percent (p < 0.01) decline in the infant mortality rate investment by saving maternal and newborn lives and and a 24.3 percent (p < 0.01) decrease in the postneona- preventing stillbirths and disability. Furthermore, these tal mortality rate (Shei 2013). benefits extend beyond survival—for example, investing Lagarde, Haines, and Palmer (2009) conducted a sys- in early childhood nutrition and stimulation can reduce tematic review of conditional cash transfers (CCTs) in losses in cognitive development and adult capacity. low- and middle-income countries to see whether CCTs Strengthening health systems and improving data for improve access to and use of health care services as well decision making are, among others, key strategies to as health outcomes. Of the 11 CCT studies reviewed, 10 drive improvement, equity, and accountability. find significant positive effects on the outcome variable The 2015 UN Global Strategy for Women’s, being examined. Only the Janani Suraksha Yojana pro- Children’s, and Adolescents’ Health builds on evidence gram in India had no significant benefit, but its failure presented in this volume, as well as the need to focus to lower the maternal mortality rate likely stems from on critical population groups such as adolescents and beneficiaries’ lack of access to quality health care facil- those living in fragile and conflict settings; build the ities (Lim and others 2010). A 2009 Cochrane review resilience of health systems; improve the quality of finds that CCTs were associated with higher service use health services and equity in their coverage; and work and may be an effective approach to promoting use of with health-enhancing sectors on issues such as women’s frequently undervalued preventive interventions, such empowerment, education, nutrition, water, sanitation, as immunization (Lagarde, Haines, and Palmer 2009). and hygiene (Temmerman, Khosla, Bhutta, and Bustreo Removal of user fees can result in increased use of the 2015). The objectives of universal health coverage, targeted RMNCH service, sometimes by a large margin including public health interventions and preventive as (Lagarde and Palmer 2008; Ponsar and others 2011). well as curative services (Schmidt, Gostin, and Emanuel Although few rigorous evaluations have been conducted, 2015), and ensuring financial security and health equity vouchers have been linked to increases in use of facility are critical if the Sustainable Development Goals are to delivery and family planning (Bellows and others 2013; be achieved. A new vision and commitment to realize Bellows, Bellows, and Warren 2011). A meta-analysis of good health and human rights for all women, adoles- women’s participatory learning and action groups finds cents, and children needs to be articulated. that vouchers could potentially reduce maternal mortal- ity by 37 percent and newborn mortality by 23 percent (Prost and others 2013). ACKNOWLEDGMENTS The Bill & Melinda Gates Foundation provides finan- cial support for the Disease Control Priorities Network CONCLUSIONS project, of which this volume is a part. Carol Levin pro- Despite sizable recent reductions in child and maternal vided sections of the chapter on cost-effectiveness and deaths, the rate of mortality decline has been too slow cost of interventions. Doris Chou assisted with sections to achieve MDGs 4 and 5 globally. Particular regions, on reproductive health and maternal morbidity and especially Sub-Saharan Africa, have high rates of fertility, mortality, and Li Liu on child mortality. The following Reproductive, Maternal, Newborn, and Child Health: Key Messages of This Volume 19 individuals provided valuable assistance and comments N. Walker, and M. Temmerman. Washington, DC: on this chapter: Brianne Adderley, Rachel Nugent, World Bank. Lale Say, and Gavin Yamey. Members of the RMNCH Afnan-Holmes, H., M. Magoma, T. John, F. Levira, G. Msemo, Authors Group wrote chapters on which this initial and others. 2015. “Tanzania’s Countdown to 2015: An Analysis of Two Decades of Progress and Gaps for chapter draws. The group includes Frances Aboud, Reproductive, Maternal, Newborn, and Child Health, to Fernando Althabe, Ashvin Ashok, Henrik Axelson, Inform Priorities for post-2015.” The Lancet Global Health Rajiv Bahl, Akinrinola Bankole, Zulfiqar Bhutta, Lori 3 (7): e396–409. doi:10.1016/S2214-109X(15)00059-5. Bollinger, Deborah Hay Burgess, Doris Chou, John Alkema, L., D. Chou, D. Hogan, S. Zhang, A. B. Moller, and Cleland, Daniela Colaci, Simon Cousens, Valérie others. 2015. “Global, Regional, and National Levels and D’Acremont, Jai Das, Julia Driessen, Alex Ezeh, Daniel Trends in Maternal Mortality between 1990 and 2015, with Feikin, Veronique Filippi, Mariel Finucane, Christa Scenario-Based Projections to 2030: A Systematic Analysis Fischer Walker, Brendan Flannery, Ingrid Friberg, Bela by the UN Maternal Mortality Estimation Inter-Agency Ganatra, Claudia García-Moreno, Marijke Gielen, Group.” The Lancet. doi:10.1016/S0140-6736(15)00838-7. Wendy Graham, Metin Gulmezoglu, Demissie Habte, Amouzou, A., O. Habi, K. Bensaid, and Niger Countdown Mary J. Hamel, Davidson H. Hamer, Peter Hansen, Case Study Working Group. 2012. “Reduction in Child Mortality in Niger: A Countdown to 2015 Country Case Karen Hardee, Julie M. Herlihy, Natasha Hezelgrave, Study.” The Lancet 380 (9848): 1169–78. doi:10.1016 Justus Hofmeyr, Dan Hogan, Susan Horton, Aamer /S0140-6736(12)61376-2. Imdad, Dean Jamison, Kjell Arne Johansson, Jerry Arregoces, L., F. Daly, C. Pitt, J. Hsu, M. Martinez-Alvarez, and Keusch, Margaret Kruk, Rohail Kumar, Zohra Lassi, Joy others. 2015. “Countdown to 2015: Changes in Official Lawn, Theresa Lawrie, Ramanan Laxminarayan, Lindsey Development Assistance to Reproductive, Maternal, Lenters, Colin Mathers, Solomon Tessema Memirie, Newborn, and Child Health, and Assessment of Progress Arindam Nandi, Olufemi T. Oladapo, Shefali Oza, Clint between 2003 and 2012.” The Lancet Global Health 3 (7): Pecenka, Carine Ronsmans, Rehana Salam, Lale Say, e410–21. doi:10.1016/S2214-109X(15)00057-1. Peter Sheehan, Joao Paulo Souza, Meghan Stack, Karin Ban, K. 2010. “Global Strategy for Women’s and Children’s Stenberg, Gretchen Stevens, John Stover, Kim Sweeny, Health.” Partnership for Maternal, Newborn and Child Stéphane Verguet, Kerri Wazny, Aisha Yousafzai, and Health, New York, NY. Barnighausen, T., S. Berkley, Z. A. Bhutta, D. M. Bishai, Abdhalah Ziraba. M. M. Black, and others. 2014. “Reassessing the Value of Vaccines.” The Lancet Global Health 2 (5): e251–52. Bartlett, L., E. Weissman, R. Gubin, R. Patton-Molitors, and NOTES I. K. Friberg. 2014. “The Impact and Cost of Scaling up Midwifery and Obstetrics in 58 Low- and Middle-Income World Bank Income Classifications as of July 2014 are as fol- Countries.” PLoS One 9 (6): e98550. doi:10.1371/journal. lows, based on estimates of gross national income (GNI) per pone.0098550. capita for 2013: Basinga, P., P. J. Gertler, A. Binagwaho, A. L. Soucat, J. Sturdy, • Low-income countries (LICs) = US$1,045 or less and C. M. Vermeersch. 2011. “Effect on Maternal and Middle-income countries (MICs) are subdivided: Child Health Services in Rwanda of Payment to Primary • Lower-middle-income = US$1,046 to US$4,125 Health-Care Providers for Performance: An Impact • Upper-middle-income (UMICs) = US$4,126 to US$12,745 Evaluation.” The Lancet 377 (9775): 1421–28. doi:10.1016 • High-income countries (HICs) = US$12,746 or more. /S0140-6736(11)60177-3. Bellows, B., C. Kyobutungi, M. K. Mutua, C. Warren, and 1. For the maternal and newborn health package, health sys- A. Ezeh. 2013. “Increase in Facility-Based Deliveries tem costs are assumed to constitute 19 percent, 23 percent, Associated with a Maternal Health Voucher Programme in and 22 percent of the total package for low-, lower-middle, Informal Settlements in Nairobi, Kenya.”[Research Support, and upper-middle-income groups, respectively. For the Non-U.S. Gov’t]. Health Policy and Planning 28 (2): 134–42. child health package, they are 72 percent, 71 percent, doi:10.1093/heapol/czs030. and 76 percent of the total for low-, lower-middle, and Bellows, N. M., B. W. Bellows, and C. Warren. 2011. “Systematic upper-middle-income groups, respectively. Review: The Use of Vouchers for Reproductive Health Services in Developing Countries: Systematic Review.” Tropical Medicine and International Health 16 (1): 84–96. Bhutta, Z. A., J. K. Das, N. Walker, A. Rizvi, H. Campbell, REFERENCES and others. 2013. “Interventions to Address Deaths from Aboud, F. E., and A. Yousafzai. 2016. “Very Early Childhood Childhood Pneumonia and Diarrhoea Equitably: What Development.” In Disease Control Priorities (third edi- Works and at What Cost?” The Lancet 381 (9875): 1417–29. tion): Volume 2, Reproductive, Maternal, Newborn, and Black, R. E., C. G. Victora, S. P. Walker, Z. A. Bhutta, P. Christian, Child Health, edited by R. E. Black, R. Laxminarayan, and others. 2013. “Maternal and Child Undernutrition 20 Reproductive, Maternal, Newborn, and Child Health and Overweight in Low-Income and Middle-Income Grantham-McGregor, S., and International Child Development Countries.” The Lancet 382 (9890): 427–51. doi:10.1016 Committee. 2007. “Early Child Development in Developing /S0140-6736(13)60937-X. Countries. The Lancet 369 (9564): 824. doi:10.1016 Blencowe, H., S. Cousens, F. Bianchi Jassir, L. Say, D. Chou, and /S0140-6736(07)60404-8. others. 2016. “National, Regional, and Worldwide Estimates Hamer, D. H., E. T. Brooks, K. Semrau, P. Pilingana, of Stillbirth Rates in 2015, with Trends from 2000: A W. B. MacLeod, and others. 2012. “Quality and Safety of Systematic Analysis.” The Lancet Global Health. doi:http://dx Integrated Community Case Management of Malaria Using .doi.org/10.1016/S2214-109X(15)00275-2. Epub January 18. Rapid Diagnostic Tests and Pneumonia by Community Bosch-Capblanch, X., S. Liaqat, and P. Garner. 2011. “Managerial Health Workers.” Pathogens and Global Health 106 (1): Supervision to Improve Primary Health Care in Low- 32–39. doi:10.1179/1364859411Y.0000000042. and Middle-Income Countries.” Cochrane Database of Horton, S., and C. Levin. 2016. “Cost-Effectiveness of Systematic Reviews (9): CD006413. doi:10.1002/14651858 Interventions for Reproductive, Maternal, Newborn, .CD006413.pub2. and Child Health.” In Disease Control Priorities (third Bryce, J., C. G. Victora, J. P. Habicht, J. P. Vaughan, and edition): Volume 2, Reproductive, Maternal, Newborn, R. E. Black. 2004. “The Multi-Country Evaluation of the and Child Health, edited by R. E. Black, R. Laxminarayan, Integrated Management of Childhood Illness Strategy: N. Walker, and M. Temmerman. Washington, DC: Lessons for the Evaluation of Public Health Interventions.” World Bank. American Journal of Public Health 94 (3): 406–15. Jamison, D. T., J. G. Breman, A. R. Measham, G. Alleyne, Chachamovich, J. R., E. Chachamovich, H. Ezer, M. P. Fleck, M. Claeson, D. B. Evans, P. Jha, A. Mills, and P. Musgrove. D. Knauth, and E. P. Passos. 2010. “Investigating Quality 2006. Disease Control Priorities in Developing Countries, of Life and Health-Related Quality of Life in Infertility: (second edition). Washington, DC: World Bank and Oxford A Systematic Review.” Journal of Psychosomatic Obstetrics University Press. and Gynaecology 31 (2): 101–10. doi:10.3109/01674 Jamison, D. T., W. Mosley, A. Measham, and J. Bobadilla. 82X.2010.481337. 1993. Disease Control Priorities in Developing Countries, Christian, P., S. E. Lee, M. Donahue Angel, L. S. Adair, (first edition). Washington, DC: World Bank and Oxford S. E. Arifeen, and others. 2013. “Risk of Childhood University Press. Undernutrition Related to Small-for-Gestational Age and Jones, G., R. W. Steketee, R. E. Black, Z. A. Bhutta, S. S. Morris, Preterm Birth in Low- and Middle-Income Countries.” and Bellagio Child Survival Study Group. 2003. “How International Journal of Epidemiology 42 (5): 1340–55. Many Child Deaths Can We Prevent This Year?” The Lancet doi:10.1093/ije/dyt109 362 (9377): 65–71. Cui, W. 2010. “Mother or Nothing: The Agony of Infertility.” Kozuki, N., J. Katz, P. Christian, A. C. Lee, L. Liu, and others. Bulletin of the World Health Organization 88 (12): 881–82. 2015. “Comparison of US Birth Weight References and doi:10.2471/BLT.10.011210. the International Fetal and Newborn Growth Consortium Das, J. K., R. A. Salam, A. Imdad, Z. Lassi, and for the 21st Century Standard.” JAMA Pediatrics 169 (7): Z. A. Bhutta. 2016. “Infant and Young Child Growth.” e151438. doi:10.1001/jamapediatrics.2015.1438. In Disease Control Priorities (third edition): Volume 2, Lagarde, M., A. Haines, and N. Palmer. 2009. “The Impact of Reproductive, Maternal, Newborn, and Child Health, Conditional Cash Transfers on Health Outcomes and Use edited by R. E. Black, R. Laxminarayan, N. Walker, and of Health Services in Low and Middle Income Countries.” M. Temmerman. Washington, DC: World Bank. Cochrane Database of Systematic Reviews 7 (4). Devries, K. M., S. Kishor, H. Johnson, H. Stockl, L. J. Bacchus, Lagarde, M., and N. Palmer. 2008. “The Impact of User Fees and others. 2010. “Intimate Partner Violence during on Health Service Utilization in Low- and Middle-Income Pregnancy: Analysis of Prevalence Data from 19 Countries.” Countries: How Strong Is the Evidence?” Bulletin of the Reproductive Health Matters 18 (36): 158–70. doi:10.1016 World Health Organization 86 (11): 839–48. /S0968-8080(10)36533-5. Lenters, L., K. Wazny, and Z. Bhutta. 2016. “Management of Filippi, V., C. Ronsmans, D. Chou, L. Say, and W. Graham. Severe and Moderate Acute Malnutrition in Children.” 2016. “Levels and Causes of Maternal Morbidity and In Disease Control Priorities (third edition): Volume 2, Mortality.” In Disease Control Priorities (third edition): Reproductive, Maternal, Newborn, and Child Health, edited Volume 2, Reproductive, Maternal, Newborn, and Child by R. E. Black, R. Laxminarayan, N. Walker, and M. Health, edited by R. E. Black, R. Laxminarayan, N. Walker, Temmerman. Washington, DC: World Bank. and M. Temmerman. Washington, DC: World Bank. Lim, S. S., L. Dandona, J. A. Hoisington, S. L. James, M. C. Hogan, Fox, M. J., R. Martorell, N. Van den Broek, and N. Walker. and E. Gakidou. 2010. “India’s Janani Suraksha Yojana, a 2011. “Technical Inputs, Enhancements and Applications Conditional Cash Transfer Programme to Increase Births of the Lives Saved Tool (LiST).” BMC Public Health 11 in Health Facilities: An Impact Evaluation.” The Lancet 375 (Supplement 3). (9730): 2009–23. Garnett, G. P., S. Cousens, T. B. Hallett, R. Steketee, and Liu, L., K. Hill, S. Oza, D. Hogan, S. Cousens, and others. N. Walker. 2011. “Mathematical Models in the Evaluation 2016. “Levels and Causes of Mortality under Age Five.” of Health Programmes.” Review. The Lancet 378 (9790): In Disease Control Priorities (third edition): Volume 2, 515–25. doi:10.1016/S0140-6736(10)61505-X. Reproductive, Maternal, Newborn, and Child Health, edited by Reproductive, Maternal, Newborn, and Child Health: Key Messages of This Volume 21 R. E. Black, R. Laxminarayan, N. Walker, and M. Temmerman. Systematic Analysis.” The Lancet Global Health 2 (6): Washington, DC: World Bank. e323–333. doi:10.1016/S2214-109X(14)70227-X. Liu, L., S. Oza, D. Hogan, J. Perin, I. Rudan, and others. Schmidt, H., L. O. Gostin, and E. J. Emanuel. 2015. “Public 2014. “Global, Regional, and National Causes of Child Health, Universal Health Coverage, and Sustainable Mortality in 2000–13, with Projections to Inform Post- Development Goals: Can They Coexist?” The Lancet 386 2015 Priorities: An Updated Systematic Analysis.” [Research (9996): 928–30. doi:10.1016/S0140-6736(15)60244-6. Support, Non-U.S. Gov’t]. The Lancet 385 (9966): 430–40. Sedgh, G., S. Singh, and R. Hussain. 2014. “Intended and doi:10.1016/S0140-6736(14)61698-6. Unintended Pregnancies Worldwide in 2012 and Recent Megiddo, I., A. R. Colson, A. Nandi, S. Chatterjee, S. Prinja, Trends.” Studies in Family Planning 45 (3): 301–14. and others. 2014. “Analysis of the Universal Immunization doi:10.1111/j.1728-4465.2014.00393.x. Programme and Introduction of a Rotavirus Vaccine in Shei, A. 2013. “Brazil’s Conditional Cash Transfer Program India with IndiaSim.” Vaccine 32 (Suppl 1): A151–61. Associated with Declines in Infant Mortality Rates.” Health Nandi, A., A. R. Colson, A. Verma, I. Megiddo, A. Ashok, and Affairs (Millwood) 32 (7): 1274–81. R. Laxminarayan. 2015. “Health and Economic Benefits of Singh, S., J. Darroch, and L. Ashford. 2014. Adding It Up: The Scaling up a Home-Based Neonatal Care Package in Rural Costs and Benefits of Investing in Sexual and Reproductive India: A Modelling Analysis.” Health Policy and Planning. Health 2014. New York: Guttmacher Institute. doi:10.1093/heapol/czv113. Singh, S., G. Sedgh, and R. Hussain. 2010. “Unintended Pattinson, R., K. Kerber, E. Buchmann, I. K. Friberg, M. Belizan, Pregnancy: Worldwide Levels, Trends, and Outcomes.” and others. 2011. “Stillbirths: How Can Health Systems Studies in Family Planning 41 (4): 241–50. Deliver for Mothers and Babies?” The Lancet 377 (9777): Singh, S., D. Wulf, R. Hussain, A. Bankole, and G. Sedgh. 1610–23. 2009. Abortion Worldwide: A Decade of Uneven Progress. Peabody, J. W., R. Shimkhada, S. Quimbo, O. Solon, X. Javier, New York: Guttmacher Institute. and C. McCulloch. 2014. “The Impact of Performance Singla, D. R., E. Kumbakumba, and F. E. Aboud. 2015. “Effects Incentives on Child Health Outcomes: Results from a of a Parenting Intervention to Address both Maternal Cluster Randomized Controlled Trial in the Philippines.” Psychological Wellbeing and Child Development and Health Policy and Planning 29 (5): 615–21. Growth in Rural Uganda: A Community-Based, Cluster Ponsar, F., M. Van Herp, R. Zachariah, S. Gerard, M. Philips, Randomised Trial.” The Lancet Global Health 3 (8): e458–69. and G. Jouquet. 2011. “Abolishing User Fees for Children doi:10.1016/S2214-109X(15)00099-6. and Pregnant Women Trebled Uptake of Malaria-Related Spector, J. M., A. Lashoher, P. Agrawal, C. Lemer, G. Dziekan, Interventions in Kangaba, Mali.” Health Policy and Planning and others. 2013. “Designing the WHO Safe Childbirth 26 (Suppl 2): ii72–83. doi:10.1093/heapol/czr068. Checklist Program to Improve Quality of Care at Priedeman Skiles, M., S. L. Curtis, P. Basinga, and G. Angeles. Childbirth.” International Journal of Gynaecology and 2013. “An Equity Analysis of Performance-Based Financing Obstetetrics 122 (2): 164–68. in Rwanda: Are Services Reaching the Poorest Women?” Stenberg, K., H. Axelson, P. Sheehan, I. Anderson, Health Policy and Planning 28 (8): 825–37. A. M. Gulmezoglu, and others. 2014. “Advancing Social Prost, A., T. Colbourn, N. Seward, K. Azad, A. Coomarasamy, and Economic Development by Investing in Women’s and others. 2013. “Women’s Groups Practising Participatory and Children’s Health: A New Global Investment Learning and Action to Improve Maternal and Newborn Framework.” The Lancet 383 (9925): 1333–54. doi:10.1016 Health in Low-Resource Settings: A Systematic Review /S0140-6736(13)62231-X. and Meta-Analysis.” The Lancet 381 (9879): 1736–46. Stenberg, K., K. Sweeney, H. Axelson, M. Temmerman, and doi:10.1016/S0140-6736(13)60685-6. P. Sheehan. 2016. “Returns on Investment in the Continuum Requejo, J. H., J. Bryce, A. J. Barros, P. Berman, Z. Bhutta, and of Care for Reproductive, Maternal, Newborn, and Child others. 2015. “Countdown to 2015 and Beyond: Fulfilling Health.” In Disease Control Priorities (third edition): the Health Agenda for Women and Children.” The Lancet Volume 2, Reproductive, Maternal, Newborn, and Child 385 (9966): 466–76. doi:10.1016/S0140-6736(14)60925-9. Health, edited by R. E. Black, R. Laxminarayan, N. Walker, Sabin, L. L., A. B. Knapp, W. B. MacLeod, G. Phiri-Mazala, and M. Temmerman. Washington, DC: World Bank. J. Kasimba, and others. 2012. “Costs and Cost-Effectiveness Stevens, G., C. Paciorek, and M. Finucane. 2016. “Levels of Training Traditional Birth Attendants to Reduce and Trends in Low Height for Age.” In Disease Control Neonatal Mortality in the Lufwanyama Neonatal Survival Priorities (third edition): Volume 2, Reproductive, Study (LUNESP).” PLoS One 7 (4): e35560. doi:10.1371 Maternal, Newborn, and Child Health, edited by R. E. Black, /journal.pone.0035560. R. Laxminarayan, N. Walker, and M. Temmerman. Sachdev, H. P. S., A. Hall, and N. Walker, eds. 2010. “Development Washington, DC: World Bank. and Use of the Lives Saved Tool (LiST): A Model to Estimate Stover, J., R. McKinnon, and B. Winfrey. 2010. “Spectrum: the Impact of Scaling up Proven Interventions on Maternal, A Model Platform for Linking Maternal and Child Neonatal and Child Mortality.” Special issue of International Survival Interventions with AIDS, Family Planning Journal of Epidemiology 39 (Supplement 1). and Demographic Projections.” International Journal Say, L., D. Chou, A. Gemmill, O. Tuncalp, A. B. Moller, and of Epidemiology 39 (Suppl 1): i7–10. doi:10.1093/ije others. 2014. “Global Causes of Maternal Death: A WHO /dyq016. 22 Reproductive, Maternal, Newborn, and Child Health Temmerman, M., R. Khosla, Z. A. Bhutta, and F. Bustreo. 2015. International Journal of Epidemiology 39 (Suppl 1): i21–31. “Towards a New Global Strategy for Women’s, Children’s doi:10.1093/ije/dyq036. and Adolescents’ Health.” Review. BMJ 351: h4414. Walker, N., Y. Tam, and I. K. Friberg. 2013. “Overview of the doi:10.1136/bmj.h4414. Lives Saved Tool (LiST).” BMC Public Health 13 (Suppl 3): Temmerman, M., R. Khosla, L. Laski, Z. Mathews, and L. Say. S1. doi:10.1186/1471-2458-13-S3-S1. 2015. “Women’s Health Priorities and Interventions.” BMJ Walker, S. P., T. D. Wachs, J. M. Gardner, B. Lozoff, G. A. Wasserman, 351: h4147. doi:10.1136/bmj.h4147. and others. 2007. “Child Development: Risk Factors for UN (United Nations). 2015. The Millennium Development Adverse Outcomes in Developing Countries.” The Lancet 369 Goals Report 2015. New York: United Nations. http:// (9556): 145–57. doi:10.1016/S0140-6736(07)60076-2. www.un.org/millenniumgoals/2015_MDG_Report/pdf WHO (World Health Organization). 2012. WHO /MDG%202015%20rev%20(July%201).pdf. Recommendations: Optimizing Health Worker Roles UN IGME (Inter-Agency Group for Child Mortality to Improve Access to Key Maternal and Newborn Health Estimation). 2015. “Levels & Trends in Child Mortality: Interventions through Task Shifting. Geneva: WHO. Report 2015.” UN, New York. ———. 2015. Trends in Maternal Mortality: 1990 to 2015: UNPD (United Nations Population Division). 2015. “2015 Estimates by WHO, UNICEF, UNFPA, World Bank, and the World Population Prospects.” UN, New York. United Nations Population Division. Geneva: WHO. Verguet, S., Z. D. Olson, J. B. Babigumira, D. Desalegn, WHO, Department of Reproductive Health and Research, K. A. Johansson, and others. 2015. “Health Gains and London School of Hygiene and Tropical Medicine, Financial Risk Protection Afforded by Public Financing and South African Medical Research Council. 2013. of Selected Interventions in Ethiopia: An Extended Cost- Global and Regional Estimates of Violence against Women: Effectiveness Analysis.” The Lancet Global Health 3 (5): Prevalence and Health Effects of Intimate Partner Violence e288-296. doi:10.1016/S2214-109X(14)70346-8. and Non-Partner Sexual Violence. Geneva: WHO. Verguet, S., R. Laxminarayan, and D. T. Jamison. 2015. doi:http://www.who.int/reproductivehealth/publications/ “Universal Public Finance of Tuberculosis Treatment in violence/9789241564625/en/. India: An Extended Cost-Effectiveness Analysis.” Health Witter, S., A. Fretheim, F. L. Kessy, and A. K. Lindahl. 2012. Economics 24 (3): 318–32. “Paying for Performance to Improve the Delivery of Health Victora, C. G., L. Adair, C. Fall, P. C. Hallal, R. Martorell, Interventions in Low- and Middle-Income Countries.” and others. 2008. “Maternal and Child Undernutrition: Cochrane Database of Systematic Reviews 2: CD007899. Consequences for Adult Health and Human doi:10.1002/14651858.CD007899.pub2. Capital.” The Lancet 371 (9609): 340–57. doi:10.1016 World Bank. 1993. World Development Report 1993: Investing in /S0140-6736(07)61692-4. Health. Oxford: Oxford University Press. Villar, J., L. Cheikh Ismail, C. G. Victora, E. O. Ohuma, You, D., L. Hug, S. Ejdemyr, P. Idele, D. Hogan, and others. E. Bertino, and others. 2014. “International Standards 2015. “Global, Regional, and National Levels and Trends for Newborn Weight, Length, and Head Circumference in Under-5 Mortality between 1990 and 2015, with by Gestational Age and Sex: The Newborn Scenario-Based Projections to 2030: A Systematic Analysis Cross-Sectional Study of the INTERGROWTH-21st by the UN Inter-agency Group for Child Mortality Project.” The Lancet 384 (9946): 857–68. doi:10.1016 Estimation.” The Lancet 386 (10010): 2275–86. doi:10.1016 /S0140-6736(14)60932-6. /S0140-6736(15)00120-8. Walker, N. 2013. “Updates of Assumptions and Methods Young, M., C. Wolfheim, D. R. Marsh, and D. Hammamy. 2012. for the Lives Saved Tool (LiST).” BMC Public Health 13 “World Health Organization/United Nations Children’s (Supplement 3): S1. Fund Joint Statement on Integrated Community Case ———, C. Fischer Walker, J. Bryce, R. Bahl, S. Cousens, and Management: An Equity-Focused Strategy to Improve CHERG Review Groups on Intervention Effects. 2010. Access to Essential Treatment Services for Children.” “Standards for CHERG Reviews of Intervention Effects American Journal of Tropical Medicine and Hygiene 87 on Child Survival.” [Research Support, Non-U.S. Gov’t]. (5 Suppl): 6–10. doi:10.4269/ajtmh.2012.12-0221. Reproductive, Maternal, Newborn, and Child Health: Key Messages of This Volume 23 Chapter 2 Burden of Reproductive Ill Health Alex Ezeh, Akinrinola Bankole, John Cleland, Claudia García-Moreno, Marleen Temmerman, and Abdhalah Kasiira Ziraba INTRODUCTION surgical complications and long-term risk of poor repro- ductive outcomes, especially during delivery. This chapter presents the burden of global reproductive ill health and, where data permit, regional estimates for selected conditions. Ill health refers to morbid conditions Approach to Data Presentation and Limitations such as infections and injury and to nonmorbid measures The greatest challenge in undertaking this work is the of reproductive health that directly contribute to adverse lack of appropriate data at the global, regional, national, reproductive health outcomes, including unwanted preg- and subnational levels. Even available data are often nancies and violence against women. The chapter is not adequately disaggregated by important character- organized into six subsections: unintended pregnancies, istics. Differences in methods and designs adopted by unsafe abortions, non-sexually transmitted reproductive the various studies often limit the comparative value. tract infections (RTIs), infertility, violence against women, In many low- and middle-income countries (LMICs), and female genital mutilation (FGM). Unintended preg- sexual concerns are often not discussed with third nancies lead to unintended births and induced abortions. parties, which impedes health care seeking. Measuring Unintended births often occur among young women who and quantifying most of these conditions is logisti- are emotionally and physiologically not mature, which has cally difficult, and the reliability of responses given by effects on the health of the mother, the pregnancy, and its respondents is often poor (Allotey and Reidpath 2002). outcome. Induced abortions in countries where the prac- Because most reproductive conditions are more prev- tice is illegal are often provided in unsafe environments alent during prime ages, missed cases are likely to lead and by untrained personnel, which contribute to the high to serious underestimation of the burden of disease as maternal death from abortion complications. Sexually measured by disability-adjusted life years (DALYs) of transmitted infections (STIs) of the reproductive tract health lost (AbouZahr and Vaughan 2000). receive attention in programming and research, but little attention is focused on other infections that affect fertility and increase the risk of transmission of other infections. UNINTENDED PREGNANCIES Violence against women violates their rights, including limiting access to and use of prevention and treatment Premarital sexual abstinence, prolonged breastfeeding, services in addition to physical injury and death. FGM and abortion all influence fertility; however, contra- causes bodily disfigurement and may present immediate ceptive practice has been the most important driver of Corresponding author: Alex Ezeh, African Population and Health Research Center, Nairobi, Kenya, and School of Public Health, University of the Witwatersrand, Johannesburg, South Africa, aezeh@aphrc.org. 25 falling fertility and population growth rates in the past the lack of studies. This method has been adapted to half century. Because of its direct link to family sizes single and successive cross-sectional surveys to provide and population change, contraception has a wide range aggregate estimates of unwanted fertility (Casterline of social, economic, and environmental benefits, in and El-Zeini 2007). As with the first approach, mistimed addition to its well-documented health advantages for births are ignored. women and children. It enables women to escape the The third approach uses retrospective questions con- incessant cycle of pregnancies and infant care and rep- cerning the wantedness and preferred timing of recent resents progress toward gender equality and enhanced births. It has the advantage of incorporating mistimed opportunities for women. At the national level, a fall in as well as unwanted births, but estimates are vulnerable birth rates brings about declines in dependency ratios to post factum rationalization due to an understandable and increases potential opportunities for economic reluctance of mothers to report children as unwanted or growth. mistimed. Prospective studies in India, Malawi, Morocco, Contraception has wider social and economic ben- and Pakistan indicate that a large proportions of births efits, but its immediate purpose is to avoid unintended to women who reported at baseline a desire to have no pregnancies. The majority of these pregnancies stem more children were subsequently classified by mothers from the non-use of contraceptive methods among as wanted or mistimed (Baschieri and others 2013; Jain women wishing to avoid or postpone childbearing. and others 2014; Speizer and others 2013; Westoff and This section discusses the measurement of unintended Bankole 1998). Similarly, an appreciable fraction of pregnancies, both levels and trends, and reasons for and births that occur as the result of accidental pregnancy consequences of unintended births. while using a contraceptive method or after abandoning a method are reported as wanted. (Ali, Cleland, and Shaw 2012; Curtis, Evens, and Sambisa 2011; Trussell, Measurement Vaughan, and Stanford 1999). These inconsistencies are Measurement of unintended pregnancies is complicated usually interpreted as the consequence of rationaliza- because many are terminated, and these terminations tion, but they may reflect a genuine difference between are underreported. Because most induced abortions are a more abstract preference before childbirth and a more from unintended pregnancies, the solution is to combine emotional reaction after the event. survey data on unintended births with indirect estimates The three approaches to measurement yield very of abortion incidence available for all subregions and different results. No consensus exists on how best to many countries. obtain valid estimates of unintended births, even in the Demographic and Health Surveys (DHS) are the United States, where the topic has attracted considerable main source of data on unintended births. The measure- attention (Campbell and Mosher 2000; Santelli and ment of unintended births or current pregnancies from others 2003). This section presents results based on the this source has been approached in three ways: retrospective method because studies using this method are the sole source of global and regional estimates, but • Answers to questions on total desired family size the results are presented with the caveat that they may • Prospective questions on whether another child is be downwardly biased. Another approach that has been wanted tried, but on a limited scale, is the London Measure of • Retrospective questions on each recent birth to ascer- Unplanned Pregnancy (Morof and others 2012; Wellings tain whether the child was wanted, unwanted, or and others 2013). mistimed by two or more years. In the first approach, births that exceed total desired Prevalence and Incidence family size are defined as unwanted; if they are equal to By combining regional estimates on induced abor- or less than total desired family size, they are considered tion and retrospective survey data on mistimed and wanted. This classification can be expressed as unwanted unwanted births with allowances for miscarriages, or wanted fertility rates. No account is taken of mistimed Sedgh, Singh, and Hussain (2014) derive global and births. A more serious problem stems from the likeli- regional estimates on the incidence of unintended preg- hood that desired total family sizes are, in part, a ratio- nancies and the proportion of all pregnancies that are nalization of actual family sizes, with the consequence unintended (table 2.1). Globally, their prevalence data that unwanted births are likely to be underestimated. indicate that 40 percent of all pregnancies in 2012 were The second approach is straightforward in prospec- unintended. The prevalence of unintended pregnancies tive studies, but its application is severely limited by is higher, and such pregnancies are more likely to be 26 Reproductive, Maternal, Newborn, and Child Health Table 2.1 Indicators of Unintended Pregnancies, 2012 Pregnancy rate per 1,000 women ages 15–44 years Total number of Percent of pregnancies Region pregnancies (millions) All pregnancies Intended Unintended that are unintended Worldwide 213.4 133 80 53 40 More developed 23.4 94 50 44 47 Less developed 190.0 140 85 54 39 Africa 53.8 224 145 80 35 Eastern 19.4 246 138 108 44 Middle 7.8 279 171 108 39 Northern 7.1 144 103 41 29 Southern 1.8 124 55 69 55 Western 17.6 256 191 66 26 Asia 119.7 120 75 46 38 Eastern 36.6 99 62 37 37 South-Central 56.5 134 86 48 36 Southeastern 18.8 127 71 56 44 Western 7.8 141 79 62 44 Europe 14.1 94 52 43 45 Eastern 7.0 110 52 57 52 Northern 1.8 93 58 35 38 Southern 2.4 80 45 35 44 Western 2.8 80 52 27 34 Latin America and 17.8 122 54 68 56 the Caribbean Caribbean 1.3 133 48 84 64 Central America 5.1 125 75 50 40 South America 11.4 120 45 74 62 North America 7.1 100 49 51a 51a Oceania 0.9 116 73 43 37 Source: Sedgh, Singh, and Hussain 2014. Note: In this table, “more developed” comprises Australia, Europe, Japan, New Zealand, and North America. “Less developed” comprises all others. a. If mistimed births in North America were limited to those that occurred at least two years before they were wanted, as in Africa, Asia, and Latin America and the Caribbean, the unintended pregnancy rate would be 44 percent and the proportion of pregnancies that were unintended in North America would be 42 percent. terminated, in high-income countries (HICs) than in risk of an unintended pregnancy spans 20 years or more. LMICs. However, when expressed as annual rates per The use of effective contraception for so many years is a 1,000 women of reproductive age, unintended pregnan- daunting prospect. In societies in which the preference cies are more common in LMICs. for larger families remains high, as in much of Sub- There is little relationship between the prevalence or Saharan Africa, the risk span is shorter. Despite this incidence of unintended pregnancy and the level of con- upward pressure from increasing exposure to risk, unin- traceptive use or unmet need. The reason for this appar- tended pregnancy rates per 1,000 women of reproduc- ently counterintuitive observation is that exposure to tive age fell by an estimated 4.8 percent and 5.3 percent risk of unintended pregnancy increases as desired family in HICs and LMICs, respectively, between 2008 and size and fertility fall. In societies in which sexual activity 2012 (Sedgh, Singh, and Hussain 2014). There was a starts early and couples want two or fewer children, the 5.6 percent decline in Latin America and the Caribbean, Burden of Reproductive Ill Health 27 and a 6 percent decline in both Asia and Africa. Intended unintended pregnancies represents major savings in the pregnancy rates in LMICs did not change during the costs of maternal and neonatal health services (Singh period (85 per 1,000 women of reproductive age). and Darroch 2012). In Sub-Saharan Africa, the proportion of mistimed The reduction of mistimed and unwanted births births is about twice that of unwanted pregnancy also improves perinatal outcomes and child survival among all unplanned births. In Latin America and by lengthening interpregnancy intervals. In LMICs, the the Caribbean, mistimed births are about 37 percent risk of prematurity and low birth weight doubles when higher than unwanted pregnancy as a percentage of all conception occurs within six months of a previous birth; unplanned births (Sedgh, Singh, and Hussain 2014). An children born within two years of an older sibling are application of the standard DHS measure of unwanted 60 percent more likely to die in infancy than are those fertility, based on total desired family size, shows that born three years or more after their sibling. In early child- unwanted fertility rates are strongly related to household hood, children who experience the birth of a younger poverty. Averaged across 41 LMICs, the poorest quintile sibling within two years have twice the risk of death than recorded 1.2 unwanted births, compared with about 0.5 other children. In high-fertility countries, where most such births among the richest quintile (Gillespie and children have younger and older siblings, ensuring an others 2007). interval of at least two years between births would reduce infant mortality by 10 percent and early childhood deaths by 20 percent (Cleland and others 2012; Cohen and Reasons for Unintended Pregnancies others 2012; Hobcraft, McDonald, and Rutstein 1985; Approximately 70 percent of unintended pregnancies Kozuki and Walker 2013; Kozuki and others 2013). in LMICs are the direct result of no use or discontinued The reduction of teenage pregnancies is an inter- use of contraceptives; the balance results from acciden- national priority, both because of the excess risk to tal pregnancy while using contraception inconsistently maternal health of pregnancy and childbirth before age or incorrectly and from method failure (Bradley, Croft, 18 and because it may curtail schooling and blight aspi- and Rutstein 2011; Singh, Darroch, and Ashford 2014). rations. In most Sub-Saharan African countries, more Accordingly, the reasons for unintended pregnancy than 25 percent of women become mothers before age should be sought primarily in reasons for non-use of 18 years; equally high probabilities of early childbear- contraceptives. In-depth studies confirm survey evi- ing are recorded in Bangladesh, India, the Republic of dence that health concerns and low perceived risk Yemen, and several countries in Latin America and the of conception are genuine and common reasons for Caribbean (Dixon-Mueller 2008). However, the primary non-use but also suggest that lack of knowledge and cause is early marriage, and first births within marriage social obstacles, including fear of others’ disapproval, are unlikely to be considered unintended. are more important barriers than the survey data imply With respect to perinatal and child health and sur- (Sedgh, and Hussain 2014; Westoff 2012). vival, evidence of an adverse effect of large family sizes is weak (Desai 1995). Excess risk of death is restricted to children of birth order seven or higher, and the relation- Consequences ship between birth order and malnutrition is small and Insufficient data exist to indicate whether unintended irregular in Sub-Saharan Africa (Mahy 2003; Mukuria, pregnancies carried to term are disadvantaged in health Cushing, and Sangha 2005). or schooling, compared with intended births. Other Finally, evidence from Matlab, Bangladesh, suggests effects of unintended pregnancies on family health the long-term benefits of reduced fertility. In the exper- are easier to document. A reduction in the number of imental area in which an early decline in fertility unintended pregnancies is the greatest health benefit occurred, women had better nutritional status, more of contraception. In 2008, contraception prevented an assets, and higher earnings than in higher fertility areas. estimated 250,000 maternal deaths, and an additional Boys’ schooling and girls’ nutrition benefited from low 30 percent of maternal deaths could be avoided by fulfill- fertility (Canning and Schultz 2012). ment of the unmet need for contraception (Cleland and others 2012). By preventing high-risk pregnancies, espe- cially in women of high parities, and those that would UNSAFE ABORTION have ended in unsafe abortion, increased contraceptive The World Health Organization (WHO) defines unsafe use has also reduced the maternal mortality ratio—the abortion as the termination of an unwanted pregnancy, risk of maternal death per 100,000 live births—by either by persons lacking the necessary skills or in an 26 percent in little more than a decade. The reduction in environment lacking minimal medical standards or both. 28 Reproductive, Maternal, Newborn, and Child Health Unsafe abortion is a major cause of maternal morbid- restrictive abortion laws, its limitations include high ity and mortality, especially in LMICs. About 7 million costs, dependence on a number of assumptions, and women are treated for complications from unsafe abor- reliance on the opinions of health professionals (Juarez, tion procedures annually in LMICs (Singh and Maddow- Cabigon, and Singh 2010). Zimet 2015). Two studies, using different methodologies, indicate that at least 8 percent of maternal mortality is due to unsafe abortion, and the contribution of abortion may Incidence be as high as 18 percent of these deaths (Kassebaum and An estimated 21.6 million unsafe abortions, or 14 per others 2014; Say and others 2014). 1,000 women ages 15–44 years, were performed in 2008 (WHO 2011). These unsafe procedures constituted nearly 49 percent of all abortions, which totaled 43.8 mil- Measurement lion, or 28 per 1,000 women ages 15–44 years that year In countries in which abortion is legally restricted or (Sedgh and others 2012). Virtually all of the unsafe abor- socially stigmatized, official statistics on abortion are tions (98 percent) occurred in LMICs; the highest rates usually nonexistent; those that do exist are typically were found in Latin America and the Caribbean (31 per incomplete and unreliable (Ahman and Shah 2012). 1,000), followed by Sub-Saharan Africa (28) and Asia Approaches that directly measure unsafe abortion, such (11). The rate of unsafe abortion in HICs is only one per as sample surveys and in-depth interviews, are unreli- 1,000 (WHO 2011). able. Accordingly, efforts to better measure incidence The global incidence has remained virtually have largely used indirect methods (Ahman and Shah unchanged since 1995, at 15 per 1,000 women ages 2012), including surveys of abortion providers, compli- 15–44 years in 1995 and 14 per 1,000 in 2003 and 2008 cations statistics, anonymous third-party reports, esti- (table 2.2). In LMICs, unsafe abortion is highest among mates from experts, and regression equation approaches women ages 20–24 years and 25–29 years, with rates of 30 (Rossier 2003; Singh, Prada, and Juarez 2011). and 31, respectively, per 1,000 women in these age groups The WHO’s indirect approach involves using avail- (Ahman and Shah 2012). The rate is lowest among able information on unsafe abortion and associated women ages 40–44 years (13 per 1,000), and the rate mortality from hospital records and surveys of abortion among adolescent women is moderate (16 per 1,000). providers, women’s abortion-seeking behavior, postabor- tion care, and laws regarding abortion to obtain country estimates of unsafe abortion rates. The country-level Consequences estimates are then aggregated at the regional and global Maternal Mortality levels to ensure robust estimates that can potentially Unsafe abortion involves health, economic, and social offset underestimation or error at the level of individual sequelae (Singh and others 2006). The WHO estimates countries (Ahman and Shah 2012; WHO 2011). The that in 2008, 47,000 women died from unsafe abortion, WHO has used this methodology to produce global and translating to 30 unsafe abortion deaths per 100,000 live regional estimates of unsafe abortion for 1990, 1993, births (WHO 2011). Nearly two-thirds of the deaths 1996, 2000, 2003, and 2008. These estimates are likely to (29,000) occurred in Sub-Saharan Africa. be conservative (Ahman and Shah 2012). Worldwide, the abortion case fatality rate is 220 per Much of what is known about the magnitude of unsafe 100,000 unsafe abortions. The rate is highest in Sub- abortion at the country level is from indirect methods, Saharan Africa (460 per 100,000); it is 160 in Asia and particularly the residual method (Johnston and Westoff 80 in Latin America and the Caribbean. This wide vari- 2010), and the Abortion Incidence Complications ation across regions is not surprising, since the measure Methodology (AICM) (Singh, Prada, and Juarez 2011). is largely a function of the risks associated with prev- The AICM relies primarily on data from two surveys: a alent abortion methods and access to emergency care. nationally representative survey of health facilities likely Accordingly, while the incidence of unsafe abortion is to provide postabortion care, and a purposive sample similar for Sub-Saharan Africa and Latin America and the of health professionals knowledgeable about abortion Caribbean, the procedure is less deadly in Latin America in the country. The methodology yields estimates of and the Caribbean because of widespread use of medical the incidence of unsafe abortion and abortion-related abortion and better access to health care (WHO 2011). morbidity (table 2.3, columns 1 and 3). The rates tend In 2015, the estimated number of maternal deaths world- to be higher in Latin America and the Caribbean than in wide was 303,000 (Alkema and others 2015). According to Asia and Sub-Saharan Africa. Although AICM has been two more recent parallel studies, the proportion of these an important source of knowledge in countries with deaths that is due to unsafe abortion ranges between Burden of Reproductive Ill Health 29 Table 2.2 Trends in Rates of Unsafe Abortion and the Proportion of All Abortions That Are Unsafe: 1995–2008 2008 2003 1995 Rate of Percentage of all Rate of Percentage of all Rate of Percentage of all Region and unsafe abortions that are unsafe abortions that are unsafe abortions that are subregion abortion* unsafe abortion* unsafe abortion* unsafe World 14 49 14 47 15 44 HICs 1 6 2 7 4 9 LMICs 16 56 16 55 18 54 Africa 28 97 29 98 33 99 Asia 11 40 11 38 12 37 Europe 2 9 3 11 6 12 Latin America and 31 95 30 96 35 95 the Caribbean North America < 0.5 < 0.5 < 0.5 < 0.5 < 0.5 < 0.5 Oceania 2 15 3 16 5 22 Source: Sedgh and others 2012. Note: HICs = high-income countries; LMICs = low- and middle-income countries. *Abortions per 1,000 women ages 15–44 years. Table 2.3 Incidence of Abortion and Complications from Unsafe Abortion in Low- and Middle-Income Countries Number of women with Annual rate of Annual number Abortion complications from unsafe complications treated of women who rates per 1,000 abortion treated in health in health facilities Country, date had abortions (a) women (b) facilities (c) per 1,000 women (d) Africa Burkina Faso, 2008 (a) 87,200 25.0 22,900 6.6* Egypt, Arab Rep. 1996 (b) 324,000 23.0 216,000 15.3 Ethiopia, 2008 (c) 382,450 23.1 52,600 3.2 Kenya, 2013 (d) 464,700 48.0 119,900 12.4* Malawi, 2009 (e) 67,300 23.0 18,700 6.4* Nigeria, 1996 (f) 610,000 25.0 142,200 6.1 Rwanda, 2009 (g) 60,000 25.0 16,700 7.0 Uganda, 2002 (h) 296,700 54.0 85,000 16.4 Asia Bangladesh, 2010 (i) 647,000 18.2 231,400 6.5 Pakistan, 2002 (j) 890,000 29.0 197,000 7.0 Philippines, 2000 (k) 78,900 27.0 78,150 4.4 Latin America and the Caribbean Brazil, 1991 (f) 1,444,000 40.8 288,700 8.1 Chile, 1990 (f) 160,000 50.0 31,900 10.0 Colombia, 2008 (l) 400,400 39.0 93,300 9.0 table continues next page 30 Reproductive, Maternal, Newborn, and Child Health Table 2.3 Incidence of Abortion and Complications from Unsafe Abortion in Low- and Middle-Income Countries (continued) Number of women with Annual rate of Annual number Abortion complications from unsafe complications treated of women who rates per 1,000 abortion treated in health in health facilities Country, date had abortions (a) women (b) facilities (c) per 1,000 women (d) Dominican Republic, 1990 (f) 82,000 47.0 16,500 9.8 Guatemala, 2003 (m) 65,000 24.0 21,600 8.6 Mexico, 2009 (n) 874,700 33.0 159,000 5.9 Peru, 1989 (f) 271,000 56.1 50,000 8.6 Sources: (a) = Sedgh and others 2011; (b) = Henshaw and others 1999; (c) = Singh and others 2010; (d) = African Population and Health Research Center and Ministry of Health Kenya 2013; (e) = Levandowski and others 2013; (f) = Henshaw and others 1999; (g) = Basinga and others 2012; (h) = Singh and others 2005; (i) = Singh and others 2012; (j) = Sathar, Singh, and Fikree 2007; (k) = Juarez and others 2005; (l) = Prada, Biddlecom, and Singh 2011; (m) = Singh, Prada, and Kestler 2006; (n) = Juarez and Singh 2012. *Figures were not reported in original source; they are derived as d = [(c/a) × 100]. 8 percent and 18 percent, excluding late maternal death Table 2.4 Prevalence of Severe Symptoms from (Kassebaum and others 2014; Say and others 2014). Unsafe Abortion in Low- and Middle-Income Countries Percentage of women with severe Abortion-Related Morbidity symptoms among those presenting with Each year, 7 million women receive treatment for Country, date unsafe abortion complications complications from unsafe abortions in the develop- ing world (Singh 2006, 2010; Singh and others 2009). South Africa, 2000 (a) 10 The annual rate of treatment after unsafe abortions is Malawi, 2009 (b) 21 6.9 per 1,000 women of reproductive age, which means Ethiopia, 2008 (c) 27 4.6 million women receive needed treatment in Asia, Kenya, 2012 (d) 37 as do 1.6 million in Sub-Saharan Africa and 757,000 in Latin America and the Caribbean (Singh 2006). The Cambodia, 2005 (e) 42 incidence and severity of unsafe abortion complications Sources: (a) = Jewkes and others 2005; (b) = Kalilani-Phiri and others 2015; (c) = Gebreselassie and others 2010; (d) = African Population and Health Research are closely related to the training of the providers and Center and Ministry of Health Kenya 2013; (e) = Fetters and others 2008. the abortion methods used. A substantial proportion of the procedures are performed by untrained pro- viders, including by pregnant women. In each coun- Studies report that among women presenting with try in which the AICM has been applied to estimate unsafe abortion complications in health facilities, the abortion incidence, a substantial number of women proportion diagnosed with severe symptoms varies are admitted annually for treatment of complications widely (table 2.4). resulting from unsafe abortions. These estimates are Severe complications, if not well managed, may result approximations based on the best guesses of health care in anemia, RTIs, elevated risk of ectopic pregnancy, providers and professionals, as well as on a number of premature delivery or miscarriage in subsequent preg- assumptions. Table 2.3 shows abortion rate and abor- nancies, and infertility (WHO 2004). Almost 5 million tion complication rate. women are living with temporary or permanent dis- Health complications typically associated with abilities associated with unsafe abortion; more than unsafe abortion include hemorrhage; sepsis; perito- 3 million of these women suffer from the effects of RTIs, nitis; RTIs; and trauma to the cervix, vagina, uterus, and close to 1.7 million experience secondary infertility and abdominal organs (Grimes and others 2006; (WHO 2007). Henshaw and others 2008). Beginning with an effort sparked by a seminal WHO-led study in 1986, a Economic and Social Consequences fairly standard method has been developed and used Unsafe abortion has direct and indirect costs. Direct to measure the nature and severity of unsafe abor- costs include expenses related to the provision of med- tion complications based on nationally representative ical care to women presenting with abortion-related surveys (Benson and Crane 2005; Fetters 2010; Figa- complications, such as cost of medicine, providers’ Talamanca and others 1986). time, and hospital stays. Indirect costs are opportunity Burden of Reproductive Ill Health 31 costs due to death or disability stemming from the Vulvovaginal Candidiasis complications. VVC is characterized by excessive growth of a normal Direct costs. In 2006, the average direct per-patient vaginal flora fungus, candida, often associated with costs of treating abortion-related complications were vulval itching, abnormal vaginal discharge, vulval exco- US$130 in Latin America and the Caribbean and US$114 riation, and dyspareunia. It is common among women in Sub-Saharan Africa (Vlassoff, Walker, and others of reproductive age. VVC is relatively more common 2009). After including indirect costs, per-patient costs of among women who are pregnant, have poorly controlled treating postabortion complications in the two regions diabetes mellitus, or have compromised immunity due rose to US$227–US$320. to human immunodeficiency virus/acquired immu- Indirect costs. A study in Uganda (Sundaram and others nodeficiency syndrome (HIV/AIDS) or other causes 2013) finds that most women treated for unsafe abortion (Buchta and others 2013; de Leon and others 2002; complications experienced one or more adverse effects, Duerr and others 2003). It is also common in women including loss of productivity (73 percent); deterioration receiving antibiotic treatment and those using vagi- in household economic circumstances (34 percent); and nal douching and other forms of vaginal applications negative consequences for their children, such as inabil- (Brown and others 2013; Ekpenyong and others 2012). ity to eat well or go to school (60 percent). Unsafe abortion also has social costs, including social stigma, sanctions, divorce, and spousal and family Measurement neglect (Levandowski and others 2012; Moore, Jagwe- Measurement of prevalence and incidence of VVC in Wadda, and Bankole 2011; Rossier 2007; Shellenberg and most settings is challenging. Clinical diagnosis based on others 2011). symptoms is inadequate owing to the low sensitivity and Unintended pregnancy, unmet need for contraception, specificity of criteria used to identify clinically important and unsafe abortion. Meeting the contraceptive needs candida infections. Estimates from such studies cannot be of all 225 million women in LMICs who had unmet depended upon to generate a reliable epidemiologic profile need for modern contraception in 2014 would have pre- to act as a basis for public health planning of interventions vented an estimated 52 million unintended pregnancies (Geiger, Foxman, and Gillespie 1995; Rathod and others and averted 24 million abortions, 14 million of which 2012). In a study of women in India, the positive predic- would have been unsafe (Singh, Darroch, and Ashford tive value for candidiasis was only 19 percent, implying 2014). Similar associations have been found at the coun- a high likelihood of confusing VVC with BV, since the try level (Darroch and others 2009; Sundaram and others two are common and may occur together (Rathod and 2009; Vlassoff, Sundaram, and others 2009; Vlassoff and others 2012). However, not all positive laboratory tests for others 2011). The demand for family limitation may not candida constitute clinically important cases of VVC. In be fully satisfied by the use of contraceptives, and some response to this challenge, the Centers for Disease Control women and couples may resort to abortion. In such sit- and Prevention (CDC) has provided diagnostic criteria uations, both contraceptive use and abortion rates may that include symptoms and laboratory findings (CDC rise, while fertility declines (Marston and Cleland 2003). 2010; Ilkit and Guzel 2011). According to these criteria, a patient must have (1) one or more symptoms, such as vaginal itching or discharge; and (2) a positive wet prepa- NON-SEXUALLY TRANSMITTED ration or gram stain or positive culture (CDC 2010). INFECTIONS OF THE REPRODUCTIVE Given the challenges involved in conducting community-based studies using gynecologic specimens, SYSTEM most studies that have assessed prevalence or incidence RTIs may be classified as either transmitted sexually, as have been clinic-based among symptomatic women. with syphilis and gonorrhea, or non-sexually, for example, Only a few studies have been population based (Ahmad bacterial vaginosis (BV); others, such as yeast infections, and Khan 2009; Goto and others 2005; Oliveira and oth- may be both. The focus in this section is on non-STIs of the ers 2007). Estimates derived from clinic-based studies reproductive tract, specifically two neglected reproductive cannot be generalized. Even where community-based health morbidities: BV and vulvovaginal candidiasis (VVC). studies have been conducted, the tendency is to report These RTIs are increasingly identified as having substantial the prevalence of candida species recovered from the public health importance because of the increased risk of specimens and symptoms separately; no effort is made STI transmission, including human immunodeficiency to use the criteria that integrate laboratory findings and virus (HIV) (Cohen and others 2012; Martin and others symptoms to derive the proportion of women with clin- 1999; Myer and others 2005; Namkinga and others 2005). ically significant candida infection. 32 Reproductive, Maternal, Newborn, and Child Health Prevalence of Vulvovaginal Candidiasis presents another challenge of overtreatment and potential The prevalence of VVC varies between subpopula- drug resistance. In most settings, the diagnosis is clinical; tions along characteristics such as age, sexual activity, however, this diagnosis has a low specificity resulting in and socioeconomic status. The proportion of candida cases of BV being treated as VVC, leaving BV untreated. species–positive women among women attending clinics with symptoms is generally higher than levels observed in the general population. In some clinic-based studies, Bacterial Vaginosis results have shown prevalence as high as 40 percent to In BV, normal vaginal lactobacilli are replaced by other 60 percent (Ibrahim and others 2013; Nwadioha and bacteria, especially Gardnerella vaginalis and other anaer- others 2013; Okungbowa, Isikhuemhen, and Dede 2003). obic bacteria (Hay and Taylor-Robinson 1996). There is a Table 2.5 summarizes community-based studies of link between BV and known risk factors for STIs, includ- the prevalence of candida species from vaginal or cervical ing multiple sexual partnerships and early onset of sexual specimens and of VVC. In the few studies reporting VVC activity (Fethers and others 2008; Foxman 1990; Morris, based on clinical and laboratory findings, prevalence seems Rogers, and Kinghorn 2001; Reed and others 2003). Indeed, to be generally less than 10 percent. This result implies that the debate about whether BV is sexually transmitted or studies and estimates based on only clinical diagnoses tend enhanced remains unsettled. Other factors associated with to overdiagnose, and possibly result in overtreatment of, BV include black race (Hay and others 1994; Koumans and vaginal candidiasis. The consequences may include unnec- others 2007; Ness and others 2003; Wenman and others essary treatment costs, side effects, and development of 2004), use of intrauterine devices (Baeten and others 2001; resistance to commonly prescribed antifungal drugs. Madden and others 2012), menses (Eschenbach and others 2000), lack of male circumcision (Gray and others 2009), Consequences of Vulvovaginal Candidiasis and douching (Brotman and others 2008). Although VVC might be considered a nuisance, the inflammatory process of VVC puts women at increased Measurement risk of transmission of RTIs, including STIs and HIV Clinical diagnosis is difficult because symptoms have low (Hester and Kennedy 2003; Rathod and others 2012). predictive values, yet laboratory facilities are not always Against this background, like STIs, VVC should always available, especially in developing countries (Landers and be managed for the extra benefit of reducing the risk of others 2004; Rathod and others 2012). There has been contracting other STIs. The fact that treatment for VVC debate on the clinical presentation of BV and isolation is cheap and available over the counter in many countries of causative bacteria (Hay and Taylor-Robinson 1996). Table 2.5 Prevalence of Candida Species and Vulvovaginal Candidiasis from Community-Based Studies Prevalence Prevalence of of candida vulvovaginal Study species (%) candidiasis* (%) Epidemiologic features of vulvovaginal candidiasis among reproductive-age women in India (a) 35.0 7.1 Reproductive tract infections among young married women in Tamil Nadu, India (b) 10.0 10.0 Sexually transmitted infections, bacterial vaginosis, and candidiasis in women of reproductive age in rural Northeast 12.5 Brazil: a population-based study (c) Prevalence and risk factors for bacterial vaginosis and other vulvovaginitis in a population of sexually active 22.0 adolescents from Salvador, Bahia, Brazil (d) Sexually transmitted infections in a female population in rural Northeast Brazil: prevalence, morbidity, and risk factors (e) 5.8 Community-based study of reproductive tract infections among women of the reproductive age group in the Urban 16.1 Training Centre Area in Hubli Kamataka, India (f) Prevalence of and factors associated with reproductive tract infections among pregnant women in 10 communes in 17.0 Nghe An Province, Vietnam (g) Prevalence and risk factors for vaginal candidiasis among women seeking primary care for genital infections in Dar es 45.0 Salaam, Tanzania (h) Sources: (a) = Rathod and others 2012; (b) = Prasad and others 2005; (c) = Oliveira and others 2007; (d) = Mascarenhas, Machado, and others 2012; (e) = de Lima Soares and others 2003; (f) = Balamurugan and Bendigeri 2012; (g) = Goto and others 2005; (h) = Namkinga and others 2005. *According to Centers for Disease Control and Prevention criteria—one or more symptoms and signs and positive lab test or culture. Burden of Reproductive Ill Health 33 The commonly used clinical criteria are the Amsel cri- we only present estimates from studies that include par- teria, with reported sensitivity of more than 90 percent ticipants from the general adult female population. We and specificity of more than 75 percent as judged against exclude those that only focus on pregnant women, those gram staining (Landers and others 2004). The Nugent attending sexually transmitted diseases clinics, and those Scoring System criteria are considered the gold standard, restricted to only sexually experienced women. with better sensitivity and specificity (Mota and others 2000; Nugent, Krohn, and Hillier 1991); however, few Prevalence of Bacterial Vaginosis studies have used these criteria. Estimates presented here are from studies that use the Little systematic effort has been made to estimate Nugent Scoring System. A diagnosis of BV is defined as the global prevalence of BV. The few systematic reviews a Nugent score of 7 or higher out of 10 (Nugent, Krohn, that have been conducted reveal that the current evi- and Hillier 1991). Table 2.6 summarizes population-based dence is based on small studies (Kenyon, Colebunders, studies from regions with estimates of BV prevalence. and Crucitti 2013). Estimates from these studies are Although there are no global estimates, it is clear discussed here in the context of where the study was that BV is common and variations exist across coun- conducted rather than as global or regional estimates tries and subpopulations. The variation within regions (Kenyon, Colebunders, and Crucitti 2013). International makes interpretation of spatial distribution difficult. comparisons are difficult because of differences in the populations studied, as well as in the methods used in Consequences of Bacterial Vaginosis selecting participants. Also, because of the associations Although the etiologic mechanism of anaerobic bacteria between BV, VVC, pregnancy status, and sexual activity, found in BV-causing pelvic inflammatory disease (PID) Table 2.6 Prevalence of Bacterial Vaginosis from Population-Based Studies Prevalence of bacterial Region Country, location, year Study population vaginosis* (%) Latin America and the Caribbean Brazil, Alagoas, 1997 (a) Random sample of 341 women 15.3 Brazil, Serra Pelada, Para, 2004 (b) Random sample of 209 women 18.7 Brazil, Pacoti, Ceara, before 2007 (c) Random sample of 592 women 20.1 Peru, rural areas, 1997–98 (d) Random sample of 752 women 40.8 Peru, Lima, Trujillo, Chiclayo (e) Random sample of 779 women 26.6 North America United States, NHANES, 2001–04 (f) Random sample of 3,739 women 29.2 Western Europe Finland, Aland Islands, 1993–2008 (g) Random sample of 819 women in 1993 and 771 15.6 (1993) women in 2008 8.6 (2008) South and Southeast Asia Vietnam, Bavi District, 2006 (h) Random sample of 1,012 women, excluded 11.0 menstruating women Vietnam, Haiphong, before 2006 (i) Random sample of 284 women 27.4 Sub-Saharan Africa The Gambia, Farafenni, 1999 (j) Random sample of 1,348 women 37.0 Burkina Faso, Ouagadougou, 2003 (k) Random sample of 883 women 7.9 Sources: (a) = de Lima Soares and others 2003; (b) = Miranda and others 2009; (c) = Oliveira and others 2007; (d) = Garcia and others 2004; (e) = Jones and others 2007; (f) = Koumans and others 2007; (g) = Eriksson and others 2010; (h) = Lan and others 2008; (i) = Go and others 2006; (j) = Walraven and others 2001; (k) = Kirakoya-Samadoulougou and others 2011. Note: NHANES = National Health and Nutrition Examination Survey. *Based on the Nugent Scoring System. 34 Reproductive, Maternal, Newborn, and Child Health has not been demonstrated, studies have recovered • Exposure time: Sensitivity analysis using DHS data anaerobic bacteria from PID cases. PID is a major cause show that using a period of less than five years was of tubal factor secondary infertility, therefore identifi- likely to result in misclassification of fertile unions cation and treatment of BV is important (van Oostrum as infertile (Mascarenhas, Cheung, and others 2012). and others 2013). BV is also known to facilitate trans- Shorter periods of one year help identify individuals mission of other STIs including HIV (Kinuthia and and couples who may benefit from earlier interven- others 2015). Like VVC, clinical diagnosis of BV has low tion; epidemiological studies use two-year time frames sensitivity and a high likelihood of misdiagnosis and that allow the problem of infertility to be quantified at mistreatment; efforts to have a confirmed laboratory the population level and limit misclassification of diagnosis should always be made. BV has also been either fertile or infertile unions (WHO 2006a). associated with miscarriages, premature delivery, and • Outcome measure: The medical literature focuses postpartum infection (Nelson and others 2015). on failure to achieve or to maintain a clinical preg- nancy, which misclassifies women as fertile who have repeat early miscarriage, or endometrial insuf- INFERTILITY ficiency resulting in repeat late fetal death or still- birth. Demographers often use live birth as a more Involuntary infertility may bring about much psycho- easily measurable outcome that defines childlessness logical, economic, and social distress to affected indi- (Gurunath and others 2011). Generally, the clinical viduals, especially in societies in which childbearing is definition and its operationalization are best suited highly expected of any couple. Causes of infertility are for purposes of early diagnosis and management of many, ranging from ovulation dysfunction, tubal factor infertility, whereas the epidemiological definition is (often sequelae), implantation disorders in the uterus, best suited for population-level estimates, and demo- and male factors. Secondary infertility, the more prev- graphic definitions for trend analysis. alent type, often results from complications following • Populations studied: Some studies have examined miscarriage, delivery, untreated STI, and induced abor- women ages 15–44 years and 20–44 years, while tion in low-resource settings (Cates, Farley, and Rowe others have examined women ages 15–49 years. In 1985; Cates, Rolfs, and Aral 1990; Larsen, Masenga, countries with high levels of voluntary childlessness, and Mlay 2006). Untreated STIs such as gonorrhea, this difference needs to be accounted for because chlamydia, and PID are responsible for the majority of older women (older than age 44 years) may likely tubal factor infertility cases (Boivin and others 2007; be considered infertile although menopausal, and Bunnell and others 1999; Che and Cleland 2002; Desai, younger women (younger than age 20 years) may Kosambiya, and Thakor 2003; Heiligenberg and others likely be considered fertile, yet they may already suffer 2012; Inhorn 2003). from tubal factor infertility (Rutstein and Shah 2004; Larsen 2005; Mascarenhas, Cheung, and others 2012). Definition and Measurement The definitions of infertility used in the WHO Trend There are disciplinary variations in the definition and Analysis are as follows: operationalization of measurement of infertility, includ- ing clinical, epidemiologic, and demographic (Gurunath • Primary infertility is the absence of a live birth for and others 2011; WHO 2006a; Zegers-Hochschild and women who desire a child, have been in a union for others 2009). at least five years, and who did not use contraceptives The key issues in operationalization of the definition during that time. The prevalence of primary infertil- of infertility or childlessness that make comparison and ity is calculated as the number of women in infertile interpretation of estimates from various studies difficult union divided by the total number of fertile and include the following: infertile women. • Secondary infertility is the absence of a live birth for • Exposure to risk of pregnancy as captured by union women who desire a child, have been in a union for status, intention of getting pregnant, and contra- at least five years since their last live birth, and who ceptive use: The nature of a union has implications did not use contraceptives during that time. The for frequency and regularity of sexual intercourse, prevalence of secondary infertility is calculated as which translates into risk of pregnancy. Similarly, the number of women in a secondary infertile union variations occur in measurement of contraceptive use divided by all fertile and infertile women who have (Gurunath and others 2011). had at least one live birth. Burden of Reproductive Ill Health 35 Prevalence of Primary and Secondary Infertility region with an increase in primary infertility was Central The estimates reported here are derived from a global and Eastern Europe and Central Asia, where primary study that evaluates trends, and adjusts downward based infertility went from 1.9 percent in 1990 to 2.3 percent on the lowest ranking of the disease as part of the DALY in 2010. exercise by the Global Burden of Disease group, and reported in the World Report on Disability (WHO and World Bank 2011). The WHO, as part of the Global Consequences of Infertility Burden of Disease exercise (Mascarenhas, Flaxman, The consequences of primary and secondary involuntary and others 2012), developed an algorithm that included childlessness in LMICs, where having biological children live birth and a registered desire to have a child. More is highly valued, include stigmatization, economic depri- than 277 health surveys were analyzed to produce trend vation, denial of inheritance, divorce, and social isolation estimates of infertility at national, regional, and global (Chachamovich and others 2010; Cui 2010; Dyer and levels, for the years closest to 1990 and 2010. Patel 2012; Fisher and Hammarberg 2012; Hasanpoor- The estimates for both primary and secondary infertil- Azghdy, Simbar, and Vedadhir 2014). In many LMICs, ity are presented by seven regions (high income, Central family ties are highly valued, and having own biological and Eastern Europe and Central Asia, East Asia and children is seen as a form of insurance in old age. Women Pacific, Latin America and the Caribbean, North Africa who are unable to bear children feel insecure in their and the Middle East, Sub-Saharan Africa, and South Asia) marital unions with respect to inheritance, and they face for the two time frames, 1990 and 2010, for compara- the possibility of their husbands getting a second wife tive purposes (tables 2.7 and 2.8). Secondary fertility is and divorce. more prevalent than primary infertility at regional and Prevention and treatment of some of the major global levels. Overall, an estimated 48.5 million women causes of infertility, such as STIs, is effective and afford- worldwide were infertile (involuntarily childless) in 2010. able; treatment of infertility itself is expensive and often About 1.9 percent of women ages 20–44 years who were inaccessible. Advanced infertility treatment technol- exposed to risk of pregnancy had primary infertility, and ogies, such as in vitro fertilization, which is the only an additional 10.5 percent had secondary infertility. intervention that can overcome tubal factor infertility, Sub-Saharan Africa and South Asia showed declines are mainly available in the private sector where the costs in the prevalence of primary infertility of 0.8 percentage are high (Katz and others 2011). Because most affected points and 0.6 percentage points, respectively. Sub- individuals suffer in silence and the cost of treatment is Saharan Africa also recorded a 1.9 percentage point high, governments have not prioritized the treatment decline in secondary infertility over the period. The only of infertility; insurance either charges high premiums Table 2.7 Global and Regional Prevalence Estimates for Trend Analysis of Primary Infertility in Women Exposed to the Risk of Pregnancy Percent Age-standardized prevalence of primary infertility Estimate Lower Upper Estimate Lower Upper (percent) 95% CI 95% CI (percent) 95% CI 95% CI Region 1990 2010 Central and Eastern Europe and Central Asia 1.9 1.2 2.7 2.3 1.6 3.4 Sub-Saharan Africa 2.7 2.5 3.0 1.9 1.8 2.1 Middle East and North Africa 2.7 2.3 3.1 2.6 2.1 3.1 South Asia 2.9 2.5 3.3 2.3 1.9 2.7 East Asia and Pacific 1.5 1.3 1.7 1.6 1.3 2.0 Latin America and the Caribbean 1.6 1.4 2.0 1.5 1.2 1.8 High-income 1.9 1.6 2.3 1.9 1.3 2.6 World 2.0 1.9 2.2 1.9 1.7 2.2 Source: Mascarenhas, Flaxman, and others 2012. Note: CI = confidence interval. 36 Reproductive, Maternal, Newborn, and Child Health Table 2.8 Global and Regional Prevalence Estimates for Trend Analysis of Secondary Infertility in Women Exposed to the Risk of Pregnancy, Who Have Had a Previous Live Birth Age-standardized prevalence of secondary infertility Estimate Lower 95% Upper 95% Estimate Lower 95% Upper 95% (percent) CI CI (percent) CI CI Region 1990 2010 Central and Eastern Europe and Central Asia 16.3 12.0 21.4 18.0 13.8 24.1 Sub-Saharan Africa 13.5 12.5 14.5 11.6 10.6 12.6 Middle East and North Africa 6.7 5.8 7.8 7.2 5.9 8.6 South Asia 11.5 9.7 13.6 12.2 10.1 14.5 East Asia and Pacifica 10.1 9.0 11.4 10.9 9.1 13.0 Latin America and the Caribbean 7.3 6.2 8.4 7.5 6.1 9.0 High-income 6.8 5.5 8.4 7.2 5.0 10.2 Worlda 10.2 9.3 11.1 10.5 9.5 11.7 Source: Mascarenhas, Flaxman, and others 2012. Note: CI = confidence interval. a. Estimates exclude China. or does not cover fertility treatment. As a result, cost of The declaration describes the many forms this violence treatment of infertility is almost always borne by those can take, including the following: affected; in many cases, the available treatment is basic and ineffective (Dyer and Patel 2012). Intimate partner violence (IPV), sexual violence, including abuse of female children, dowry-related violence, killings in the name of “honor,” forced mar- VIOLENCE AGAINST WOMEN riages, FGM and other traditional practices harmful to women, violence related to exploitation, sexual harass- Violence against women is a serious health problem and ment and intimidation in workplaces, educational a violation of human rights. It has significant impacts on institutions, and elsewhere, trafficking, forced prostitu- women’s health and development, and its consequences tion, and violence perpetrated or condoned by the state. are individual as well as intergenerational and societal. Violence affects women’s health and well-being, produc- According to Heise and García-Moreno (2002), IPV tivity, and ability to bond with and care for their children. is behavior by an intimate partner or ex-partner that Although violence against women has been accepted as an causes physical, sexual, or psychological harm, includ- important public health and clinical care issue, it remains ing physical aggression, sexual coercion, psychological unaddressed in the health care policies of many countries. abuse, and controlling behaviors. This section focuses on violence against women and, Sexual violence is any sexual act, attempt to obtain a in particular, on intimate partner violence (IPV) and sexual act, or other act directed against a person’s sexu- sexual violence because these are the most common ality, using coercion, by any person, regardless of their forms of violence experienced globally, and they have relationship to the victim, in any setting. It includes rape, important sexual and reproductive health consequences. defined as the physically forced or otherwise coerced penetration of the vulva or anus with a penis, other body part, or object (Jewkes and others 2002). Definitions and Measurements There are many challenges to measuring violence against The United Nations Declaration on the Elimination women; studies are often not comparable because they of Violence against Women (1993) defines violence use different samples (all women, married women, ever- against women1 as “any act of gender-based violence partnered women, currently partnered), different measures that results in, or is likely to result in, physical, sexual, of violence, different time frames (ever, last 12 months, last or mental harm or suffering to women, including month). There are also specific ethical and safety concerns threats of such acts, coercion, or arbitrary deprivation related to asking women about partner violence. However, of liberty, whether occurring in public or in private life.” a consensus exists that the best way to measure violence Burden of Reproductive Ill Health 37 against women is by asking about behavioral acts; stan- and MRC-SA 2013). Estimates of IPV by World Health dardized methodologies are being developed, particularly Organization region are shown in map 2.1; South- for partner violence and sexual violence. Measuring vio- East Asia (37.7 percent), the Eastern Mediterranean lence against women in conflict settings is even more chal- (37.0 percent), and Africa (36.6 percent) have the highest lenging. Gaps remain in the measurement of other forms rates (WHO, LSHTM, and MRC-SA 2013). A systematic such as trafficking, honor killings, and violence in conflict. review of sexual violence among women who were refu- The methodology and ethical and safety guidelines gees and internally displaced people in complex human- developed for the Multi-country Study on Women’s itarian emergencies in 14 countries finds that 21 percent Health and Domestic Violence against Women (García- of women had experienced sexual violence (both inti- Moreno and others 2005) has contributed substantially mate partner and nonpartner) (Vu and others 2014). to a standardized methodology. They have informed the Sexual abuse during childhood affects boys and UN Statistics Division guidelines for measuring violence girls. A systematic review of population-based studies against women and the violence against women module suggests that 8.1 percent of women and 5.5 percent of of the DHS. The past 10 years have seen growing num- men experienced some form of sexual abuse before age bers of population-based prevalence surveys using either 15 years. The prevalence was higher among women than DHS or the WHO methodology. men in every region (Devries and others 2014). In 2013, slightly more than 80 countries had data on Violence among young people, including dating vio- IPV; data on nonpartner sexual violence are more lim- lence, is a common problem. The WHO multicountry ited (WHO, LSHTM, and MRC-SA 2013). study finds that the first sexual experience for many women was reported as forced, for example, 17 percent in rural areas of Tanzania, 24 percent in rural Peru, and 30 percent Magnitude of the Problem in rural Bangladesh (García-Moreno and others 2005). Worldwide, 35 percent of women have experienced Many women do not report their experiences of physical or sexual IPV or nonpartner sexual vio- IPV or sexual violence or seek help for cultural and lence; 38 percent of women who were murdered were service-related reasons, including fear of being stigma- murdered by their intimate partners (WHO, LSHTM, tized, shame, or nonexistence or lack of trust in services. Map 2.1 Rates of Intimate Partner Violence, by World Health Organization Region, 2010 IBRD 41895 | OCTOBER 2015 25.4% WHO European Region 23.2% High Income 37.0% WHO Eastern Mediterranean Region 24.6% WHO Western 29.8% 37.7% Pacific Region WHO South-East WHO Region of the Americas Asia Region 36.6% WHO African Region WHO, Global and regional estimates of violence against women: prevalence and health effects of intimate partner violence and non-partner sexual violence, 2013. Source: WHO 2013. Note: Regional prevalence rates are presented for each WHO region, including low- and middle-income countries. High-income countries are analyzed separately. 38 Reproductive, Maternal, Newborn, and Child Health Health and Other Consequences Sexual abuse during childhood is associated with The direct consequences of violence against women higher rates of sexual risk taking, substance use, and are injury, disability, or death. Indirect consequences additional victimization. Each of these behaviors include physical, mental, and sexual and reproductive increases the risks of subsequent health problems. health problems, such as stress-induced physiological There are often long-term intergenerational health changes, substance use, and lack of fertility control consequences for those who witness violence, especially and personal autonomy (WHO 2013). Women who children, with negative consequences for their health experience violence are more likely to have STIs, HIV/ and development. IPV is associated with increased mor- AIDS, unintended pregnancies, unsafe abortions, and tality in infants and children younger than age five years gynecological problems, compared with women who (Ahmed, Koenig, and Stephenson 2006; Asling-Monemi, do not experience such violence (Campbell 2002; Tabassum, and Persson 2008; Boy and Salihu 2004), and Ellsberg and others 2008; Plichta and Falik 2001). with behavioral problems among children, as well as Women who have experienced IPV are 1.5 times more low educational attainment. Health systems and health likely to have STIs and, in some regions, HIV/AIDS; care providers can play a critical role in identification, more than twice as likely to have an abortion; almost assessment, treatment, documentation, referral, and twice as likely to report depressive episodes and alco- follow-up; this role needs to be integrated into national hol use problems; and 4.5 times more likely to have health programs and policies (WHO 2013). attempted suicide, compared with women who have not been exposed to violence (WHO 2013). IPV has been associated with chronic pelvic pain and other FEMALE GENITAL MUTILATION pain syndromes, hypertension, obesity, and other non- FGM comprises all procedures that involve the partial or communicable diseases (Campbell 2002; Ellsberg and total removal of external genitalia or other injury to the others 2008; Plichta and Falik 2001). Sexual violence female genital organs for nonmedical reasons (OHCHR is also associated with higher rates of mental health and others 2008). Although FGM is internationally rec- disorders, such as depression and anxiety disorders ognized as a violation of human rights, and legislation (WHO 2013). to prohibit the procedure has been put in place in many IPV can begin or persist during pregnancy and result countries, the practice has still been documented in in serious maternal and perinatal health problems. In many African countries and several regions in Asia and the WHO multicountry study, between 1 percent and the Middle East (OHCHR and others 2008). Some forms 28 percent of ever-pregnant women reported being of FGM have also been reported in other countries, physically abused during at least one pregnancy, with including among certain ethnic groups in Central and most sites falling between 4 percent and 12 percent South America, as well as among some migrants living (García-Moreno and others 2006). Violence during in HICs (Yoder, Abderrahim, and Zhuzhini 2004). The pregnancy is associated with increased risk of miscar- importance of FGM from a public health perspective riage, premature labor, perinatal death, and low–birth arises from the fact that, in addition to medical and psy- weight babies (Campbell 2002; Fanslow and others chological complications, the practice violates human 2008; Janssen and others 2003). Women who have rights and child rights, given that it is almost always car- experienced IPV are 16 percent more likely to have ried out among minors (Yoder and Wang 2013). a low–birth weight baby (WHO 2013). IPV during pregnancy is also significantly associated with adverse health behaviors during pregnancy, including smoking, Measurement alcohol and substance abuse, and delay in prenatal Data on FGM at the population level have become care, even after controlling for other mediating factors increasingly available, mainly from population-based (Campbell 2002). surveys that include questions on the practice among Violence against women can also lead to death from women ages 15–49 years and their daughters, such as the suicide; homicide, including in the name of honor, DHSs and the UNICEF Multiple Indicator Cluster Surveys usually committed by family members for cultural rea- (MICS) (Yoder and Wang 2013; Yoder, Abderrahim, and sons; female infanticide; maternal death from unsafe Zhuzhini 2004). Before the DHSs, there were no national abortion; and deaths from HIV/AIDS. Up to 38 percent population-level data on FGM. Currently, many Sub- of murders of women are committed by their partners, Saharan African countries have national-level preva- compared with 6 percent of murders of men (Stockl and lence data, as do some in the Middle East, including the others 2013). Republic of Yemen and Iraq (Yoder and Wang 2013). Burden of Reproductive Ill Health 39 The prevalence of FGM is calculated from survey • Postprocedural complications of the skin and questions in the following areas: subcutaneous tissue, such as keloids, sebaceous cysts, scars and fibrosis, and nonhealing ulcers • Circumcision status of respondents • Disorders of the urinary system, such as acute or • Information on the event among those who were chronic urinary tract infections, meatus, urinary circumcised crystals, pyelonephritis, urinary retention and incon- • Circumcision status of one’s daughters tinence, and kidney failure • Women’s and men’s opinions of the practice. • Infections Although the phrasing and level of depth of inquiry • Hemodynamic complications, such as hemorrhage, vary by country, the key question used to estimate preva- hypovolemic or septic shock, and anemia lence is often phrased, “Have you (yourself) been circum- • Procedural and everyday life difficulties, such as cised?” The current global estimate of FGM is derived gynecological examination, cytology testing, evacu- from weighted averages of FGM prevalence among girls ation of the uterus postabortion, intrauterine device ages 0–14 years and girls and women ages 15–49 years, placement, and tampon usage using DHS, MICS, and Household Health Survey data. • Pain associated with the female genital organs or The number of girls and women who have been cut was menstrual cycle, such as hematocolpos, vulvodynia, calculated using 2011 demographic figures produced by dyspareunia, acute or chronic lower abdominal the UN Population Division (UNPD 2013). The number pain, hypersensitivity of the genital area, and clitoral of cut women ages 50 years and older is based on FGM neuroma prevalence in women ages 45–49 (UNICEF 2013). • Injury of neighboring organs and structures, such as the urethra, bladder, urinary meatus, vaginal wall, Prevalence of Female Genital Mutilation anus, and rectum • Death. An estimated 125 million girls and women concentrated in 29 countries in the Middle East and Sub-Saharan Africa have undergone FGM (UNICEF 2013). The FGM has been associated with obstetric compli- global estimate of FGM is unknown because the exact cations. Studies, including a large WHO study in number of those with FGM among migrants from African countries, show that women with FGM are countries with the practice is unknown. Although prev- significantly more at risk of cesarean section, post- alence estimates among migrants have been computed partum hemorrhage, episiotomy, extended maternal in some host countries, the overall burden is unknown hospital stay, resuscitation of infants, low–birth weight (Dorkenoo, Morison, and Macfarlane 2007; Dubourg infants, and inpatient perinatal death (Kaplan and and others 2011; Exterkate 2013). others 2013; Lovel, McGettigan, and Mohammed 2000; Table 2.9 shows the national prevalence estimates of WHO 2006b). FGM in 29 countries by age category and place of res- Several sexual and mental health complications idence. The prevalence varies across countries from as are also associated with FGM, including sexual aver- low as less than 5 percent in Cameroon, Ghana, Niger, sion and lack of sexual enjoyment or desire, vaginal Togo, and Uganda, to more than 90 percent in Djibouti, dryness, orgasmic dysfunction, nonorganic vaginis- the Arab Republic of Egypt, Guinea, and Somalia. With mus, apareunia, posttraumatic stress disorder, depres- the exception of Chad, Iraq, Mali, Nigeria, and the sion, somatization disorder, neurasthenia, anxiety Republic of Yemen, the prevalence of FGM is higher in disorders, specific phobias, psychosomatic disorders, rural areas than in urban areas. In most countries, older and eating disorders (Berg, Denison, and Rappaport age groups have higher prevalence of FGM. 2010). Although health care professionals are aware of FGM Consequences of Female Genital Mutilation and some of its health consequences, their ability to FGM is painful, traumatic, and emotionally distressful. identify and manage complications remains suboptimal Immediate and long-term health consequences include (WHO 2001). Moreover, some health care providers gynecological complications, such as the following: still consider certain forms of FGM as not harmful; some perform medical FGM (Ali 2012). The WHO has • Structural complications of the genitourinary system, condemned medicalization of FGM and recognizes that such as vaginal stenosis, urethral strictures, labial its cessation is an essential component of the human fusion, and fistulae involving the genital tract rights–based approach. 40 Reproductive, Maternal, Newborn, and Child Health Table 2.9 Prevalence of Female Genital Mutilation among Girls and Women FGM prevalence among girls and women by age and residence (%) FGM prevalence Age category Residence Country Reference among girls and (data source) year women (%) 15–19 20–24 25–29 30–34 35–39 40–44 45–49 Urban Rural Benin (DHS) 2006 13 8 10 14 14 16 17 16 9 15 Burkina Faso (DHS 2010 76 58 70 78 83 85 88 89 69 78 and MICS) Cameroon (DHS) 2004 1 0.4 3 2 1 1 2 2 1 2 Central African 2010 24 18 22 25 26 28 30 34 18 29 Republic (MICS) Chad (MICS) 2010 44 41 43 46 45 46 45 47 46 44 Côte d’Ivoire (MICS) 2006 36 28 34 38 43 44 41 40 34 39 Djibouti (MICS) 2006 93 90 94 93 96 95 93 94 93 96 Egypt, Arab Rep. (DHS) 2008 91 81 87 94 95 96 96 96 85 96 Eritrea (DHS) 2002 89 78 88 91 93 93 94 95 86 91 Ethiopia (DHS) 2005 74 62 73 78 78 81 82 81 69 76 The Gambia (MICS) 2010 76 77 77 78 75 73 75 79 75 78 Ghana (MICS) 2011 4 2 2 3 4 6 7 6 3 5 Guinea (DHS) 2005 96 89 95 97 97 99 98 100 94 96 Guinea-Bissau (MICS/RHS) 2010 50 48 49 51 50 49 54 50 41 57 Iraq (MICS) 2011 8 5 8 9 9 10 9 10 9 6 Kenya (DHS) 2008–09 27 15 21 25 30 35 40 49 17 31 Liberia (DHS) 2007 66 44 58 68 70 73 78 85 45 81 Mali (MICS) 2010 89 88 88 88 89 90 89 89 89 88 Mauritania (MICS) 2011 69 66 66 67 71 72 76 75 57 81 Niger (DHS/MICS) 2006 2 2 2 2 2 3 3 3 2 2 table continues next page Burden of Reproductive Ill Health 41 42 Table 2.9 Prevalence of Female Genital Mutilation among Girls and Women (continued) FGM prevalence among girls and women by age and residence FGM prevalence Age category Residence Country Reference among girls and (data source) year women (%) 15–19 20–24 25–29 30–34 35–39 40–44 45–49 Urban Rural Nigeria (MICS) 2011 27 19 22 26 30 32 35 38 33 24 Senegal 2010–11 26 24 24 26 25 29 27 29 23 28 (DHS/MICS) Sierra Leone (MICS) 2010 88 80 87 92 93 96 95 96 81 92 Somalia (MICS) 2006 98 97 98 98 99 99 98 99 97 98 Sudan (SHHS) 2010 88 84 87 90 88 90 90 89 84 90 Reproductive, Maternal, Newborn, and Child Health Tanzania (DHS) 2010 15 7 11 12 19 22 22 22 8 17 Togo (MICS) 2010 4 1 2 4 5 6 5 7 3 5 Uganda (DHS) 2011 1 1 1 2 2 1 2 2 1 1 Yemen, Rep. (DHS) 1997 23 19 22 21 23 24 25 25 26 22 Source: UNICEF 2013. Note: DHS = Demographic and Health Survey; FGM = female genital mutilation; MICS = Multiple Indicator Cluster Survey; RHS=Reproductive Health Survey; SHHS = Sudan Household Health Survey. CONCLUSIONS For consistency and ease of comparison, DCP3 is using the World Health Organization’s Global Health Estimates (GHE) This chapter focuses on selected reproductive health for data on diseases burden, except in cases where a relevant diseases and their predisposing factors that lead to mor- data point is not available from GHE. In those instances, an bidity and mortality but that are generally neglected in alternative data source is noted. research and public health programming. Although the data remain scant, these conditions are clearly pervasive; 1. Violence against women is also referred to as gender-based some are predisposing factors for other conditions. violence because most of the violence that women experi- ence is rooted in gender inequality. More recently, how- Part of the challenge to policy makers is in mea- ever, gender-based violence has come to be understood by surement. Variations in definitions and reference pop- some as also including violence against men and on the ulations affect the comparability of data. Unwanted basis of sexual orientation or gender identity. pregnancies, abortions, infertility, infections of the reproductive tract, and violence against women are associated with stigmatization, especially in LMICs, and are often underreported or misreported in surveys and REFERENCES health care facilities. There are few global, regional, or AbouZahr, C., and J. P. Vaughan. 2000. “Assessing the Burden of national estimates of some of these conditions. Some Sexual and Reproductive Ill health: Questions Regarding estimates are based on indirect methods, and questions the Use of Disability-Adjusted Life Years.” Bulletin of the arise about their validity. World Health Organization 78 (5): 655–66. Most of these conditions have cost-effective inter- African Population and Health Research Center and Ministry ventions. Most unwanted pregnancies can be averted of Health Kenya. 2013. Incidence and Complications of Unsafe Abortion in Kenya: Key Findings of a National Study. through the provision of proven family-planning tech- Nairobi, Kenya. nologies; safe abortion services are associated with low Ahmad, A., and A. U. Khan. 2009. “Prevalence of Candida complication rates. Treatment for RTIs is available and Species and Potential Risk Factors for Vulvovaginal affordable, yet many women never receive treatment, Candidiasis in Aligarh, India.” European Journal of Obstetrics predisposing them to the risk of other infections, and Gynecology Reproductive Biology 144 (1): 68–71. including HIV/AIDS. Violence against women is equally Ahman, E., and I. H. Shah. 2012. “Generating National prevalent; while preventive interventions pose chal- Unsafe Abortion Estimates: Challenges and Choices.” lenges, health systems can do much more for preven- In Methodologies for Estimating Abortion Incidence and tion, provision of care and services, and mitigation of Abortion-Related Morbidity: A Review, edited by S. Singh, consequences. L. Remez, and A. Tartaglione, 13–20. New York: Guttmacher The poor integration and mainstreaming of these Institute. Ahmed, S., M. A. Koenig, and R. Stephenson. 2006. “Effects cost-effective interventions in public health prevention of Domestic Violence on Perinatal and Early-Childhood and management programs exacerbates their public Mortality: Evidence from North India.” American Journal of health impacts. The counterargument might be that the Public Health 96 (8): 1423–28. burden of these conditions and their economic costs Ali, A. A. 2012. “Knowledge and Attitudes of Female Genital are vague, and no concrete evidence exists for advocacy Mutilation among Midwives in Eastern Sudan.” Reproductive within and across countries and regions. However, the Health 9: 23. evidence of the substantial burden of violence against Ali, M., J. Cleland, and I. H. Shah. 2012. Causes and women has yet to translate into significant policy and pro- Consequences of Contraceptive Discontinuation: Evidence grammatic action to address the problem in many LMICs. from 60 Demographic and Health Surveys. Geneva: World Health Organization. Alkema, L. D. Chou, D. Hogan, S. Zhang, A.-B. Moller, NOTES and others. “Global, Regional, and National Levels and Trends in Maternal Mortality between 1990 and 2015, with World Bank Income Classifications as of July 2014 are as Scenario-Based Projections to 2030: A Systematic Analysis follows, based on estimates of gross national income (GNI) by the UN Maternal Mortality Estimation Inter-Agency per capita for 2013: Group.” The Lancet. Epub November 13, 2015. doi:10.1016 /S0140-6736(15)00838-7. • Low-income countries (LICs) = US$1,045 or less Allotey, P. A., and D. D. Reidpath. 2002. “Objectivity in Priority • Middle-income countries (MICs) are subdivided: Setting Tools in Reproductive Health: Context and the a) lower-middle-income = US$1,046–US$4,125 DALY.” Reproductive Health Matters 10 (20): 38–46. b) upper-middle-income (UMICs) = US$4,126 –US$12,745 Asling-Monemi, K., N. R. Tabassum, and L. A. Persson. 2008. • High-income countries (HICs) = US$12,746 or more. “Violence against Women and the Risk of Under-Five Burden of Reproductive Ill Health 43 Mortality: Analysis of Community-Based Data from Rural Despite Moderate Risk Behaviors.” Journal of Infectious Bangladesh.” Acta Paediatrica 97 (2): 226–32. Diseases 180 (5): 1624–31. Baeten,J.M.,P.M.Nyange,B.A.Richardson,L.Lavreys,B.Chohan, Campbell, A. A., and W. D. Mosher. 2000. “A History of the and others. 2001. “Hormonal Contraception and Risk Measurement of Unintended Pregnancies and Births.” of Sexually Transmitted Disease Acquisition: Results from Maternal and Child Health 4 (3): 163–69. a Prospective Study.” American Journal of Obstetrics and Campbell, J. C. 2002. “Health Consequences of Intimate Gynecology 185 (2): 380–85. Partner Violence.” The Lancet 359 (9314): 1331–36. Balamurugan, S. S., and N. Bendigeri. 2012. “Community- Canning, D., and T. P. Schultz. 2012. “The Economic Based Study of Reproductive Tract Infections among Consequences of Reproductive and Family Planning.” The Women of the Reproductive Age Group in the Urban Lancet 380 (9837): 65–71. Health Training Centre Area in Hubli, Karnataka.” Indian Casterline, J., and L. El-Zeini. 2007. “The Estimation of Journal of Community Medicine 37 (1): 34–38. Unwanted Fertility.” Demography 44 (4): 729–45. Baschieri, A., J. Cleland, K. Machiyama, S. Floyd, A. L. N. Dube, Cates, W., Jr., T. M. Farley, and P. J. Rowe. 1985. “Worldwide and others. 2013. “Fertility Intentions, Child Growth and Patterns of Infertility: Is Africa Different?” The Lancet Nutrition in Northern Malawi.” Paper presented at IUSSP 2 (8455): 596–98. International Population Conference, Busan, August. Cates, W., Jr., R. T. Rolfs, and S. O. Aral. 1990. “Sexually Basinga, P., A. M. Moore, S. Singh, L. Remez, F. Birungi, and Transmitted Diseases, Pelvic Inflammatory Disease, and L. Nyirazinyoye. 2012. Unintended Pregnancy and Induced Infertility: An Epidemiologic Update.” Epidemiologic Abortion in Rwanda: Causes and Consequences. New York: Reviews 12: 199–220. Guttmacher Institute. CDC (Centers for Disease Control and Prevention). 2010. Benson, J., and B. Crane. 2005. “Incorporating Health Outcomes Sexually Transmitted Diseases Treatment Guidelines, 2010. into Cost Estimates of Unsafe Abortion.” Background paper Morbidity and Mortality Weekly Report 59 (RR-12). prepared for workshop on research on the economic impact Chachamovich, J. R., E. Chachamovich, E. Ezer, M. P. Fleck, of abortion-related morbidity and mortality, Guttmacher D. Knauth, and E. P. Passos. 2010. “Investigating Quality Institute, New York. of Life and Health-Related Quality of Life in Infertility: Berg, R. C., E. Denison, and F. A. Rappaport. 2010. Psychological, A Systematic Review.” Journal of Psychosomatic Obstetrics Social and Sexual Consequences of Female Genital Mutilation/ and Gynaecology 31 (2): 101–10. Cutting (FGM/C): A Systematic Review on Quantitative Che, Y., and J. Cleland. 2002. “Infertility in Shanghai: Prevalence, Studies. Report from Kunnskapssenteret nr 13-2010, Treatment Seeking and Impact.” Journal of Obstetrics and Nasjonalt kunnskapssenter for helsetjenesten, Oslo. Gynaecology 22 (6): 643–48. Boivin, J., L. Bunting, J. A. Collins, and K. G. Nygren. 2007. Cleland, J., A. Conde-Agudelo, H. Peterson, J. Ross, and A. Tsui. “International Estimates of Infertility Prevalence and 2012. “Contraception and Health.” The Lancet 380 (9837): Treatment-Seeking: Potential Need and Demand for Infertility 149–56. Medical Care.” Human Reproduction 22 (6): 1506–12. Cohen, C. R., J. R. Lingappa, J. M. Baeten, M. O. Ngayo, Boy, A., and H. M. Salihu. 2004. “Intimate Partner Violence C. A. Spiegel, and others. 2012. “Bacterial Vaginosis and Birth Outcomes: A Systematic Review.” International Associated with Increased Risk of Female-to-Male HIV-1 Journal of Fertility and Women’s Medicine 49 (4): 159–64. Transmission: A Prospective Cohort Analysis among Bradley, S. E. K., T. N. Croft, and S. O. Rutstein. 2011. The African Couples.” PLoS Medicine 9 (6): e1001251. Impact of Contraceptive Failure on Unintended Births and Cui, W. 2010. “Mother or Nothing: The Agony of Infertility.” Induced Abortions: Estimates and Strategies for Reduction. Bulletin of the World Health Organization 88 (12): DHS Analytical Studies 22, Macro International Inc., 881–82. Calverton, MD. Curtis, S., E. Evens, and W. Sambisa. 2011. “Contraceptive Brotman, R. M., M. A. Klebanoff, T. R. Nansel, W. W. Andrews, Discontinuation and Unintended Pregnancy: An Imperfect J. R. Schwebke, and others. 2008. “A Longitudinal Study of Relationship.” International Perspectives on Sexual and Vaginal Douching and Bacterial Vaginosis—A Marginal Reproductive Health 37 (2): 58–66. Structural Modeling Analysis.” American Journal of Darroch, J. E., S. Singh, H. Bal, and J. V. Cabigon. 2009. Epidemiology 168 (2): 188–96. “Meeting Women’s Contraceptive Needs in the Philippines, Brown, J. M., K. L. Hess, S. Brown, C. Murphy, A. L. Waldman, In Brief.” Guttmacher Institute, New York. and M. Hezareh. 2013. “Intravaginal Practices and Risk de Leon, E. M., S. J. Jacober, J. D. Sobel, and B. Foxman. of Bacterial Vaginosis and Candidiasis Infection among 2002. “Prevalence and Risk Factors for Vaginal Candida a Cohort of Women in the United States.” Obstetrics and Colonization in Women with Type 1 and Type 2 Diabetes.” Gynecology 121 (4): 773–80. BMC Infectious Diseases 2: 1. Buchta, V., V. Matula, J. Kestr ˇánek, M. Vejsová, L. Krˇivc ˇíková, de Lima Soares, V., A. M. de Mesquita, F. G. Cavlacante, and J. Spac ˇek. 2013. “[Is Diabetes Mellitus a Risk Factor in Z. P. Silva, V. Hora, and others. 2003. “Sexually Genital Yeast Infections?].” Ceska Gynekologie 78 (6): 537–44. Transmitted Infections in a Female Population in Rural Bunnell, R. E., L. Dahlberg, R. Rolfs, R. Ransom, K. Gershman, North-East Brazil: Prevalence, Morbidity and Risk and others. 1999. “High Prevalence and Incidence of Factors.” Tropical Medicine and International Health Sexually Transmitted Diseases in Urban Adolescent Females 8 (7): 595–603. 44 Reproductive, Maternal, Newborn, and Child Health Desai, S. 1995. “When Are Children from Large Families Fanslow, J., M. Silva, A. Whitehead, and E. Robinson. 2008. Disadvantaged? Evidence from Cross-National Surveys.” “Pregnancy Outcomes and Intimate Partner Violence in Population Studies 49 (2): 195–210. New Zealand.” Australia and New Zealand Journal of Desai, V. K., J. K. Kosambiya, and H. G. Thakor. 2003. “Prevalence Obstetrics and Gynaecology 48 (4): 391–97. of Sexually Transmitted Infections and Performance of Fethers, K. A., C. K. Fairley, J. S. Hocking, L. C. Gurrin, and STI Syndromes against Aetiological Diagnosis, in Female C. S. Bradshaw. 2008. “Sexual Risk Factors and Bacterial Sex Workers of Red Light Area in Surat, India.” Sexually Vaginosis: A Systematic Review and Meta-Analysis.” Clinical Transmitted Infections 79 (2): 111–15. Infectious Diseases 47 (11): 1426–35. Devries, K. M., J. Y. T. Mak, L. Bacchus, S. Lim, M. Petzold, Fetters, T. 2010. “Prospective Approach to Measuring and others. 2014. “Childhood Sexual Abuse and Suicidal Abortion-Related Morbidity: Individual-Level Data on Behavior: A Meta-Analysis.” Pediatrics 133 (5): e1331–e1334. Postabortion Patients.” In Methodologies for Estimating Dixon-Mueller, R. 2008. “How Young Is Too Young? Abortion Incidence and Abortion-Related Morbidity: Comparative Perspectives on Adolescent Sexual, Marital A Review, edited by S. Singh, L. Remez, and A. Tartaglione. and Reproductive Transitions.” Studies in Family Planning New York: Guttmacher Institute; Paris: International Union 39 (4): 247–62. for the Scientific Study of Population. Dorkenoo, E., L. Morison, and A. Macfarlane. 2007. Fetters, T. S. Vonthanak, C. Picardo, and T. Rathavy. 2008. A Statistical Study to Estimate the Prevalence of Female “Abortion-Related Complications in Cambodia.” BJOG: Genital Mutilation in England and Wales: Summary Report. An International Journal of Obstetrics and Gynaecology London: Foundation for Women’s Health, Research and 115 (8): 957–68; discussion 968. Development (FORWARD). Figa-Talamanca, I., T. A. Sinnathuray, K. Yusof, C. K. Fong, Dubourg, D., F. Richard, E. Leye, S. Ndame, T. Rommens, V. T. Palan, and others. 1986. “Illegal Abortion: An Attempt and others. 2011. “Estimating the Number of Women to Assess Its Cost to the Health Services and Its Incidence with Female Genital Mutilation in Belgium.” European in the Community.” International Journal of Health Services Journal of Contraceptive and Reproductive Health Care 16 16 (3): 375–89. (4): 248–57. Fisher, J. R., and K. Hammarberg. 2012. “Psychological and Duerr, A., C. M. Heilig, S. F. Meikle, S. Cu-Uvin, R. S. Klein, Social Aspects of Infertility in Men: An Overview of the and others. 2003. “Incident and Persistent Vulvovaginal Evidence and Implications for Psychologically Informed Candidiasis among Human Immunodeficiency Virus- Clinical Care and Future Research.” Asian Journal of Infected Women: Risk Factors and Severity.” Obstetrics and Andrology 14 (1): 121–29. Gynecology 101 (3): 548–56. Foxman, B. 1990. “The Epidemiology of Vulvovaginal Dyer, S. J., and M. Patel. 2012. “The Economic Impact of Candidiasis: Risk Factors.” American Journal of Public Infertility on Women in Developing Countries: A Systematic Health 80 (3): 329–31. Review.” Facts, Views and Visions, Issues in Obstetrics, Garcia, P. J., S. Chavez, B. Feringa, M. Chiappe, L. Weili, Gynaecology, and Reproductive Health 4 (2): 102–09. and others. 2004. “Reproductive Tract Infections in Rural Ekpenyong, C. E., E. C. Inyang-etoh, E. O. Ettebong, Women from the Highlands, Jungle, and Coastal Regions U. P. Akpan, J. O. Ibu, and N. E. Daniel. 2012. “Recurrent of Peru.” Bulletin of the World Health Organization 82 (7): Vulvovaginal Candidosis among Young Women in South 483–92. Eastern Nigeria: The Role of Lifestyle and Health-Care García-Moreno, C., H. A. Jansen, M. Ellsberg, L. Heise, and Practices.” International Journal of STD and AIDS 23 (10): C. Watts. 2005. WHO Multi-Country Study on Women’s 704–09. Health and Domestic Violence against Women: Initial Results Ellsberg, M., H. A. Jansen, L. Heise, C. H. Watts, on Prevalence, Health Outcomes and Women’s Responses. C. García-Moreno, and others. 2008. “Intimate Partner Geneva: World Health Organization. Violence and Women’s Physical and Mental Health in ———. 2006. “Prevalence of Intimate Partner Violence: the WHO Multi-Country Study on Women’s Health and Findings from the WHO Multi-Country Study on Women’s Domestic Violence: An Observational Study.” The Lancet Health and Domestic Violence.” The Lancet 368 (9543): 371 (9619): 1165–72. 260–69. Eriksson, K., A. Adolfsson, U. Forsum, and P. G. Larsson. Gebreselassie, H., T. Fetters, S. Singh, A. Abdella, Y. Gebrehiwot, 2010. “The Prevalence of BV in the Population on the and others. 2010. “Caring for Women with Abortion Aland Islands during a 15-Year Period.” APMIS 118 (11): Complications in Ethiopia: National Estimates and Future 903–8. Implications.” International Perspectives on Sexual and Eschenbach, D. A., S. S. Thwin, D. L. Patton, T. M. Hooton, Reproductive Health 36 (1): 6–15. A. E. Stapleton, and others. 2000. “Influence of the Geiger, A. M., B. Foxman, and B. W. Gillespie. 1995. “The Normal Menstrual Cycle on Vaginal Tissue, Discharge, Epidemiology of Vulvovaginal Candidiasis among and Microflora.” Clinical Infectious Diseases 30 (6): University Students.” American Journal of Public Health 901–07. 85 (8 Pt. 1): 1146–48. Exterkate, M. 2013. Female Genital Mutilation in the Gillespie, D., S. Ahmed, A. Tsui, and S. Radloff. 2007. “Unwanted Netherlands: Prevalence, Incidence and Determinants. Fertility among the Poor: An Inequity?” Bulletin of the Utrecht, Netherlands: Pharos. World Health Organization 85 (2): 100–7. Burden of Reproductive Ill Health 45 Go, V. F., V. M. Quan, D. D. Celentano, L. H. Moulton, and Hobcraft, J., J. McDonald, and S. O. Rutstein. 1985. J. M. Zenilman. 2006. “Prevalence and Risk Factors for “Demographic Determinants of Infant and Child Reproductive Tract Infections among Women in Rural Mortality.” Population Studies 39 (3): 363–85. Vietnam.” Southeast Asian Journal of Tropical Medicine and Ibrahim, S. M., M. Bukar, Y. Mohammed, B. M. Audu, and Public Health 37 (1): 185–89. H. M. Ibrahim. 2013. “Prevalence of Vaginal Candidiasis Goto, A., Q. V. Nguyen, N. M. Pham, K. Kato, T. P. Cao, and among Pregnant Women with Abnormal Vaginal Discharge others. 2005. “Prevalence of and Factors Associated with in Maiduguri.” Nigerian Journal of Medicine 22 (2): 138–42. Reproductive Tract Infections among Pregnant Women in Ilkit, M., and A. B. Guzel. 2011. “The Epidemiology, Ten Communes in Nghe An Province, Vietnam.” Journal of Pathogenesis, and Diagnosis of Vulvovaginal Candidosis: A Epidemiology 15 (5): 163–72. Mycological Perspective.” Critical Reviews in Microbiology Gray, R. H., G. Kigozi, D. Serwadda, F. Makumbi, F. Nalugodo, 37 (3): 250–61. and others. 2009. “The Effects of Male Circumcision on Inhorn, M. C. 2003. “Global Infertility and the Globalization of Female Partners’ Genital Tract Symptoms and Vaginal New Reproductive Technologies: Illustrations from Egypt.” Infections in a Randomized Trial in Rakai, Uganda.” Social Science and Medicine 56 (9): 1837–51. American Journal of Obstetrics and Gynecology 200 (1): Jain, A., A. Mahmood, Z. A. Sathar, and I. Masood. 2014. 42. e1–7. “Unmet Need and Unwanted Childbearing in Pakistan: Grimes, D. A., J. Benson, S. Singh, M. Romero, B. Ganatra, and Evidence from a Panel Survey.” Studies in Family Planning others. 2006. “Unsafe Abortion: The Preventable Pandemic.” 45 (2): 277–99. The Lancet 368 (9550): 1908–19. Janssen, P. A., V. L. Holt, N. K. Sugg, I. Emanuel, C. M. Critchlow, Gurunath, S., Z. Pandian, R. A. Anderson, and S. Bhattacharya. and A. D. Henderson. 2003. “Intimate Partner Violence and 2011. “Defining Infertility—A Systematic Review of Adverse Pregnancy Outcomes: A Population-Based Study.” Prevalence Studies.” Human Reproduction Update 17 (5): American Journal of Obstetrics and Gynecology 188 (5): 575–88. 1341–47. Hasanpoor-Azghdy, S. B., M. Simbar, and A. Vedadhir. 2014. Jewkes, R., H. Brown, K. Dickson-Tetteh, J. Levin, and H. Rees. “The Emotional-Psychological Consequences of Infertility 2002. “Prevalence of Morbidity Associated with Abortion among Infertile Women Seeking Treatment: Results of a before and after Legalisation in South Africa.” BMJ 324 Qualitative Study.” Iran Journal of Reproductive Medicine (7348): 1252–53. 12 (2): 131–38. Jewkes, R., H. Rees, K. Dickson, H. Brown, and J. Levin. 2005. Hay, P. E., R. F. Lamont, D. Taylor-Robinson, D. J. Morgan, “The Impact of Age on the Epidemiology of Incomplete C. Ison, and J. Pearson. 1994. “Abnormal Bacterial Abortions in South Africa after Legislative Change.” BJOG Colonisation of the Genital Tract and Subsequent 112 (3): 355–59. Preterm Delivery and Late Miscarriage.” BMJ 308 (6924): Johnston, H. B., and C. F. Westoff. 2010. “Examples of Model- 295–98. Based Approaches to Estimating Abortion.” In Methodologies Hay, P. E., and D. Taylor-Robinson. 1996. “Defining Bacterial for Estimating Abortion Incidence and Abortion-Related Vaginosis: To BV or not to BV, that Is the Question.” Morbidity: A Review, edited by S. Singh, L. Remez, and International Journal of STD and AIDS 7 (4): 233–35. A. Tartaglione. New York: Guttmacher Institute; Paris: Heiligenberg, M., B. Rijnders, M. F. Schim van der Loeff, International Union for the Scientific Study of Population. H. J. de Vries, W. I. van der Meijden, and others. 2012. Jones, F. R., G. Miller, N. Gadea, R. Meza, S. Leon, and others. “High Prevalence of Sexually Transmitted Infections in 2007. “Prevalence of Bacterial Vaginosis among Young HIV-Infected Men during Routine Outpatient Visits in Women in Low-Income Populations of Coastal Peru.” the Netherlands.” Sexually Transmitted Diseases 39 (1): International Journal of STD and AIDS 18 (3): 188–92. 8–15. Juarez, F., J. Cabigon, S. Singh, and R. Hussain. 2005. “The Heise, L., and C. García-Moreno. 2002. “Violence by Intimate Incidence of Induced Abortion in the Philippines: Current Partners.” In World Report on Violence and Health, edited Level and Recent Trends.” International Family Planning by E. G. Krug, L. L. Dahlberg, J. A. Mercy, A. B. Zwi, and Perspectives 31 (3): 140–49. R. Lozano, 87–122. Geneva: World Health Organization. Juarez, F., J. Cabigon, and S. Singh. 2010. “The Sealed Envelope Henshaw, S. K., I. Adewole, S. Singh, A. Bankole, Method of Estimating Induced Abortion: How Much of an B. Oye-Adeniran, and R. Hussain. 2008. “Severity and Cost Improvement?” In Methodologies for Estimating Abortion of Unsafe Abortion Complications Treated in Nigerian Incidence and Abortion-Related Morbidity: A Review, edited Hospitals.” International Family Planning Perspectives 34 by S. Singh, L. Remez, and A. Tartaglione. New York: (1): 40–50. Guttmacher Institute. Henshaw, S. K., S. Singh, A. Bankole, B. Oye-Adeniran, and Juarez, F., and S. Singh. 2012. “Incidence of Induced Abortion R. Hussain. 1999. “The Incidence of Abortion Worldwide.” by Age and State, Mexico, 2009: New Estimates Using International Family Planning Perspectives 25: S30–38. a Modified Methodology.” International Perspectives on Hester, R. A., and S. B. Kennedy. 2003. “Candida Infection as Sexual and Reproductive Health 38 (2): 58–67. a Risk Factor for HIV Transmission.” Journal of Women’s Kalilani-Phiri, L., H. Gebreselassie, B. A. Levandowski, Health 12 (5): 487–94. E. Kichingale, F. Kachale, and G. Kangaude. 2015.“The Severity 46 Reproductive, Maternal, Newborn, and Child Health of Abortion Complications in Malawi.” International Journal Larsen, U., G. Masenga, and J. Mlay. 2006. “Infertility in a of Gynecology and Obstetrics 128 (2): 160–64. Community and Clinic-Based Sample of Couples in Moshi, Kaplan, A., M. Forbes, I. Bonhoure, M. Utzet, M. Martin, Northern Tanzania.” East African Medical Journal 83 (1): and others. 2013. “Female Genital Mutilation/Cutting 10–17. in The Gambia: Long-Term Health Consequences and Levandowski, B. A., L. Kalilani-Phiri, F. Kachle, P. Awah, Complications during Delivery and for the Newborn.” G. Kangaude, and C. Mhango. 2012. “Investigating Social International Journal of Women’s Health 5: 323–31. Consequences of Unwanted Pregnancy and Unsafe Abortion Kassebaum, N. J., A. Bertozzi-Villa, M. S. Coggeshall, in Malawi: The Role of Stigma.” International Journal of K. A. Shackelford, C. Steiner, and others. 2014. “Global, Gynaecology and Obstetrics 118 (Suppl 2): S167–71. Regional, and National Levels and Causes of Maternal Levandowski, B. A., C. Mhango, E. Kuchingale, J. Lunguzi, Mortality during 1990–2013: A Systematic Analysis for H. Katengeza, and others. 2013. “The Incidence of Induced the Global Burden of Disease Study 2013.” The Lancet 384 Abortion in Malawi.” International Perspectives on Sexual (9947): 980–1004. and Reproductive Health 39 (2): 88–96. Katz, P., J. Showstack, J. F. Smith, R. D. Nachtigall, Lovel, H., C. McGettigan, and Z. Mohammed. 2000. S. G. Millstein, and others. 2011. “Costs of Infertility A Systematic Review of the Health Complications of Female Treatment: Results from an 18-Month Prospective Cohort Genital Mutilation Including Sequelae in Childbirth. Geneva: Study.” Fertility and Sterility 95 (3): 915–21. World Health Organization. Kenyon, C., R. Colebunders, and T. Crucitti. 2013. “The Global Madden, T., J. M. Grentzer, G. M. Secura, J. E. Allsworth, and Epidemiology of Bacterial Vaginosis: A Systematic Review.” J. F. Peipert. 2012. “Risk of Bacterial Vaginosis in Users of American Journal of Obstetrics and Gynecology 209 (6): the Intrauterine Device: A Longitudinal Study.” Sexually 505–23. Transmitted Diseases 39 (3): 217–22. Kinuthia, J., A. L. Drake, D. Matemo, B. A. Richardson, Mahy, M. 2003. Childhood Mortality in the Developing World: C. Zeh, and others. 2015. “HIV Acquisition during A Review of Evidence from the Demographic and Health Pregnancy and Postpartum Is Associated with Genital Surveys. Demographic and Health Surveys Comparative Infections and Partnership Characteristics.” AIDS 29 (15): Reports 4. Calverton, MD: ORC Macro. 2025–33. Marston, C., and J. Cleland. 2003. “Relationships between Kirakoya-Samadoulougou, F., N. Nagot, M. C. Defer, S. Yaro, Contraception and Abortion: A Review of the Evidence.” P. Fao, and others. 2011. “Epidemiology of Herpes Simplex International Family Planning Perspectives 29 (1): 6–13. Virus Type 2 Infection in Rural and Urban Burkina Faso.” Martin, H. L., B. A. Richardson, P. M. Nyange, L. Lavreys, Sexually Transmitted Diseases 38 (2): 117–23. S. L. Hillier, and others. 1999. “Vaginal Lactobacilli, Koumans, E. H., M. Sternberg, C. Bruce, G. McQuillan, Microbial Flora, and Risk of Human Immunodeficiency J. Kendrick, and others. 2007. “The Prevalence of Bacterial Virus Type 1 and Sexually Transmitted Disease Vaginosis in the United States, 2001–2004; Associations Acquisition.” Journal of Infectious Diseases 180 (6): with Symptoms, Sexual Behaviors, and Reproductive 1863–68. Health.” Sexually Transmitted Diseases 34 (11): 864–69. Mascarenhas, M. N., H. Cheung, C. D. Mathers, and G. A. Stevens. Kozuki, N., A. C. Lee, M. F. Silveira, C. G. Victora, L. Adair, 2012. “Measuring Infertility in Populations: Constructing and others. 2013. “The Associations of Birth Intervals with a Standard Definition for Use with Demographic and Small-for-Gestational-Age, Preterm, and Neonatal and Reproductive Health Surveys.” Population Health Metrics 10: 17. Infant Mortality: A Meta-Analysis.” BMC Public Health 13 Mascarenhas, M. N., S. R. Flaxman, T. Boerma, S. Vanderpoel, (Suppl 3): S3. and G. A. Stevens. 2012. “National, Regional, and Global Kozuki, N., and N. Walker. 2013. “Exploring the Association Trends in Infertility Prevalence since 1990: A Systematic between Short/Long Preceding Birth Intervals and Child Analysis of 277 Health Surveys.” PLoS Medicine 9 (12): Mortality: Using Reference Birth Interval Children of the e1001356. Same Mother as Comparison.” BMC Public Health 13 Mascarenhas, R. E. M., M. S. C. Machado, B. F. Costa e (Suppl 3): S6. Silva, R. F. Pimentel, T. T. Ferreira, and others. 2012. Lan, P. T., C. S. Lundborg, H. D. Phuc, A. Sihavong, M. Unemo, “Prevalence and Risk Factors for Bacterial Vaginosis and and others. 2008. “Reproductive Tract Infections Including other Vulvovaginitis in a Population of Sexually Active Sexually Transmitted Infections: A Population-Based Study Adolescents from Salvador, Bahia, Brazil.” Infectious Diseases of Women of Reproductive Age in a Rural District of in Obstetrics and Gynecology 2012: 378640. Vietnam.” Sexually Transmitted Infections 84 (2): 126–32. Miranda, A. E., P. R. Mercon-de-Vargas, C. E. Corbett, Landers, D. V., H. C. Wiesenfeld, R. P. Heine, M. A. Krohn, J. F. Corbett, and R. Dietze. 2009. “Perspectives on Sexual and S. L. Hillier. 2004. “Predictive Value of the Clinical and Reproductive Health among Women in an Ancient Diagnosis of Lower Genital Tract Infection in Women.” Mining Area in Brazil.” Revista Panamericana de Salud American Journal of Obstetrics and Gynecology 190 (4): Publica 25 (2): 157–61. 1004–10. Moore, A. M., G. Jagwe-Wadda, and A. Bankole. 2011. “Mens’ Larsen, U. 2005. “Research on Infertility: Which Definition Attitudes about Abortion in Uganda.” Journal of Biosocial Should We Use?” Fertility and Sterility 83 (4): 846–52. Science 43 (1): 31–45. Burden of Reproductive Ill Health 47 Morof, D., J. Steinauer, S. Haider, S. Liu, P. Darney, and Prada, E., A. Biddlecom, and S. Singh. 2011. “Induced Abortion G. Barrett. 2012. “Evaluation of the London Measure of in Colombia: New Estimates and Change between 1989 and Unplanned Pregnancy in a United States Population of 2008.” International Perspectives on Sexual and Reproductive Women.” PLoS One 7 (4): e35381. Health 37 (3): 114–24. Morris, M. C., P. A. Rogers, and G. Kinghorn. 2001. “Is Bacterial Prasad, J. H., S. Abraham, K. M. Kurz, V. George, M. K. Lalitha, Vaginosis a Sexually Transmitted Infection?” Sexually and others. 2005. “Reproductive Tract Infections among Transmitted Infections 77 (1): 63–68. Young Married Women in Tamil Nadu, India.” International Mota, A., E. Prieto, V. Carnall, and F. Exposto. 2000. “[Evaluation Family Planning Perspectives 31 (2): 73–82. of Microscopy Methods for the Diagnosis of Bacterial Rathod, S. D., J. D. Klausner, K. Krupp, A. L. Reingold, Vaginosis].” Acta Medica Portuguesa 13 (3): 77–80. and P. Madhivanan. 2012. “Epidemiologic Features of Mukuria, A., J. Cushing, and J. Sangha. 2005. Nutritional Vulvovaginal Candidiasis among Reproductive-Age Status of Children: Results from the Demographic and Women in India.” Infectious Diseases in Obstetrics and Health Surveys 1994–2001. DHS Comparative Report 10. Gynecology 859071. doi:10.1155/2012/859071. Calverton, MD: ORC Macro. Reed, B. D., P. Zazove, C. L. Pierson, D. W. Gorenflo, and Myer, L., L. Denny, R. Telerant, M. Souza, T. C. Wright Jr., and J. Horrocks. 2003. “Candida Transmission and Sexual L. Kuhn. 2005. “Bacterial Vaginosis and Susceptibility to HIV Behaviors as Risks for a Repeat Episode of Candida Infection in South African Women: A Nested Case-Control Vulvovaginitis.” Journal of Womens Health (Larchmont) 12 Study.” Journal of Infectious Diseases 192 (8): 1372–80. (10): 979–89. Namkinga, L. A., M. I. Matee, A. K. Kivaisi, and C. Moshiro. Rossier, C. 2003. “Estimating Induced Abortion Rates: 2005. “Prevalence and Risk Factors for Vaginal Candidiasis A Review.” Studies in Family Planning 34 (2): 87–102. among Women Seeking Primary Care for Genital Infections ———. 2007. “Abortion: An Open Secret? Abortion and in Dar es Salaam, Tanzania.” East African Medical Journal Social Network Involvement in Burkina Faso.” Reproductive 82 (3): 138–43. Health Matters 15 (30): 230–38. Nelson, D. B., A. L. Hanlon, B. Wu, C. Liu, and D. N. Fredricks. Rutstein, S. O., and I. H. Shah. 2004. Infecundity, Infertility, and 2015. “First Trimester Levels of BV-Associated Bacteria and Childlessness in Developing Countries. DHS Comparative Risk of Miscarriage among Women Early in Pregnancy.” Reports 9. Calverton, MD: ORC Macro and the World Maternal and Child Health Journal 19 (12): 2682–87. Health Organization. Ness, R. B., S. Hillier, H. E. Richter, D. E. Soper, C. Stamm, Santelli, J., R. Rochat, K. Hatfield-Timajchy, B. C. Gilbert, and others. 2003. “Can Known Risk Factors Explain K. Curtis, and others. 2003. “The Measurement and Racial Differences in the Occurrence of Bacterial Meaning of Unintended Pregnancy.” Perspectives on Sexual Vaginosis?” Journal of the National Medical Association and Reproductive Health 35 (2): 94–101. 95 (3): 201–12. Sathar, Z. A., S. Singh, and F. F. Fikree. 2007. “Estimating Nugent, R. P., M. A. Krohn, and S. L. Hillier. 1991. “Reliability the Incidence of Abortion in Pakistan.” Studies in Family of Diagnosing Bacterial Vaginosis Is Improved by Planning 38 (1): 11–22. a Standardized Method of Gram Stain Interpretation.” Say, L., D. Chou, A. Gemmill, O. Tunçalp, A.-B. Moller, and Journal of Clinical Microbiology 29 (2): 297–301. others. 2014. “Global Causes of Maternal Death: A WHO Nwadioha, S. I., E. O. Nwokedi, J. Egesie, and H. Enejuo. Systematic Analysis.” The Lancet Global Health 2 (6): 2013. “Vaginal Candidiasis and Its Risk Factors among e323–33. Women Attending a Nigerian Teaching Hospital.” Nigerian S edgh, G., and R. Hussain. 2014. “Reasons for Postgraduate Medical Journal 20 (1): 20–23. Contraceptive Non-Use among Women with an Unmet OHCHR, UNAIDS, UNDP, UNECA, UNESCO, and others. Need for Contraception in Developing Countries: 2008. Eliminating Female Genital Mutilation: An Interagency A Comprehensive Analysis of Levels and Trends.” Studies Statement. Geneva: World Health Organization. in Family Planning 42 (2): 151–169. Okungbowa, F. I., O. S. Isikhuemhen, and A. P. Dede. 2003. Sedgh, G., C. Rossier, I. Kaboré, A. Bankole, and M. Mikulich. “The Distribution Frequency of Candida Species in the 2011. “Estimating Abortion Incidence in Burkina Faso Genitourinary Tract among Symptomatic Individuals in Using Two Methodologies.” Studies in Family Planning 42 Nigerian Cities.” Revista Iberoamicana de Micologia 20 (2): (3): 147–54. 60–63. Sedgh, G., S. Singh, I. H. Shah, E. Ahman, S. K. Henshaw, and Oliveira, F. A., V. Pfleger, K. Lang, J. Heukelbach, I. Miralles, A. Bankole. 2012. “Induced Abortion: Incidence and Trends and others. 2007. “Sexually Transmitted Infections, Worldwide from 1995 to 2008.” The Lancet 379 (9816): Bacterial Vaginosis, and Candidiasis in Women 625–32. of Reproductive Age in Rural Northeast Brazil: A Sedgh, G., S. Singh, and R. Hussain. 2014. “Intended and Population-Based Study.” Memorias do Instituto Oswaldo Unintended Pregnancies Worldwide in 2012 and Recent Cruz 102 (6): 751–56. Trends.” Studies in Family Planning 45 (3): 301–14. Plichta, S. B., and M. Falik. 2001. “Prevalence of Violence and Shellenberg, K. M., A. M. Moore, A. Bankole, F. Juarez, Its Implications for Women’s Health.” Women’s Health A. K. Amideyi, and others. 2011. “Social Stigma and Issues 11 (3): 244–58. Disclosure about Induced Abortion: Results from an 48 Reproductive, Maternal, Newborn, and Child Health Exploratory Study.” Global Public Health 6 (Suppl 1): Partner Homicide: A Systematic Review.” The Lancet 382 S111–25. (9895): 859–65. Singh, S. 2006. “Hospital Admissions Resulting from Unsafe Sundaram, A., M. Vlassoff, A. Bankole, L. Remez, and Abortion: Estimates from 13 Developing Countries.” Y. Gebrehiwot. 2009. “Benefits of Meeting the Contraceptive The Lancet 368 (9550): 1887–92. Needs of Ethiopian Women.” In Brief, Guttmacher ———. 2010. “Global Consequences of Unsafe Abortion.” Institute, New York. Women’s Health (London, England) 6 (6): 849–60. Sundaram, A., M. Vlassoff, F. Mugisha, A. Bankole, S. Singh, Singh, S., and J. E. Darroch. 2012. Adding It Up: Costs and Benefits and others. 2013. “Documenting the Individual- and of Contraceptive Services—Estimates for 2012. New York: Household-Level Cost of Unsafe Abortion in Uganda.” Guttmacher Institute and United Nations Population Fund. Perspectives on Sexual and Reproductive Health 39 (4): ———, and L. S. Ashford. 2014. Adding It Up: The Costs and 174–84. Benefits of Investing in Sexual and Reproductive Health. New Trussell, J., B. Vaughan, and J. Stanford. 1999. “Are All York: Guttmacher Institute. Contraceptive Failures Unintended Pregnancies?” Family Singh, S., T. Fetters, H. Gebreselassie, A. Abdella, Y. Gebrehiwot, Planning Perspectives 31 (5): 246–47. and others. 2010. “The Estimated Incidence of Induced UNICEF (United Nations Children’s Fund). 2013. Female Abortion in Ethiopia, 2008.” International Perspectives on Genital Mutilation/Cutting: A Statistical Overview and Sexual and Reproductive Health 36 (1): 16–25. Exploration of the Dynamics of Change. New York: UNICEF. Singh, S., A. Hossain, I. Maddow-Zimet, H. Ullah Bhuiyan, UNPD (United Nations Population Division). 2013. “World M. Vlassoff, and R. Hussain. 2012. “The Incidence of Population Prospects: The 2012 Revision.” Department of Menstrual Regulation Procedures and Abortion in Economic and Social Affairs, Population Division, United Bangladesh, 2010.” International Perspectives on Sexual and Nations, New York. Reproductive Health 53 (3). van Oostrum, N., P. De Sutter, J. Meys, and H. Verstraelen. 2013. Singh, S., F. Juarez, J. Cabigon, H. Ball, R. Hussain, and “Risks Associated with Bacterial Vaginosis in Infertility J. Nadeau. 2006. Unintended Pregnancy and Induced Patients: A Systematic Review and Meta-Analysis.” Human Abortion in the Philippines: Causes and Consequences. New Reproduction 28 (7): 1809–15. York: Guttmacher Institute. Vlassoff, M., A. Sundaram, A. Bankole, L. Remez, and F. Mugisha. Singh, S., and I. Maddow-Zimet. 2015. “Facility-Based 2009. “Benefits of Meeting the Contraceptive Needs of Treatment for Medical Complications Resulting from Ugandan Women.” In Brief, Guttmacher Institute, New York. Unsafe Pregnancy Termination in the Developing World, Vlassoff, M., A. Sundaram, A. Bankole, L. Remez, and 2012: A Review of Evidence from 26 Countries.” BJOG. D. Yugbare. 2011. “Avantages liés à la satisfaction des beso- doi/10.1111/1471-0528.13552. ins en matière de contraception moderne au Burkina Faso.” Singh, S., E. Prada, and F. Juarez. 2011. “The Abortion Incidence In Brief, Guttmacher Institute, New York. Complications Method: A Quantitative Technique.” In Vlassoff, M., D. Walker, J. Shearer, D. Newlands, and S. Singh. Methodologies for Estimating Abortion Incidence and 2009. “Estimates of Health Care System Costs of Unsafe Abortion-Related Morbidity: A Review, edited by S. Singh, Abortion in Africa and Latin America.” International L. Remez, and A. Tartaglione. New York: Guttmacher Perspectives on Sexual and Reproductive Health 35 (3): 114–21. Institute. Vu, A., A. Adam, A. Wirtz, K. Pham, L. Rubenstein, and Singh, S., E. Prada, and E. Kestler. 2006. “Induced Abortion and others. 2014. “The Prevalence of Sexual Violence among Unintended Pregnancy in Guatemala.” International Family Female Refugees in Complex Humanitarian Emergencies: Planning Perspectives 32 (3): 136–45. A Systematic Review and Meta-Analysis.” PLoS Currents Singh, S., E. Prada, F. Mirembe, and C. Kiggundu. 2005. “The Disasters 1. Incidence of Induced Abortion in Uganda.” International Walraven, G., C. Scherf, B. West, G. Ekpo, K. Paine, and others. Family Planning Perspectives 31 (4): 183–91. 2001. “The Burden of Reproductive-Organ Disease in Singh, S., G. Sedgh, and R. Hussain. 2010. “Unintended Rural Women in The Gambia, West Africa.” The Lancet 357 Pregnancy: Worldwide Levels, Trends, and Outcomes.” (9263): 1161–67. Studies in Family Planning 41 (4): 241–50. Wellings, K., K. G. Jones, C. H. Mercer, C. Tanton, S. Clifton, Singh, S., D. Wulf, R. Hussain, A. Bankole, and G. Sedgh. and others. 2013. “The Prevalence of Unplanned Pregnancy 2009. Abortion Worldwide: A Decade of Uneven Progress. and Associated Factors in Britain: Findings from the New York: Guttmacher Institute. Third National Survey of Sexual Attitudes and Lifestyles Speizer, I. S., L. M. Calhoun, T. Hoke, and R. Sengupta. 2013. (Natsal-3).” The Lancet 382 (9907): 1807–16. “Measurement of Unmet Need for Family Planning: Wenman, W. M., M. R. Joffres, I. V. Tataryn, and the Edmonton Longitudinal Analysis of the Impact of Fertility Desires Perinatal Infections Group. 2004. “A Prospective Cohort on Subsequent Childbearing Behaviors among Urban Study of Pregnancy Risk Factors and Birth Outcomes in Women from Uttar Pradesh, India.” Contraception 88 Aboriginal Women.” CMAJ 171 (6): 585–89. (4): 553–60. Westoff, C. F. 2012. Unmet Need for Modern Contraceptive Stockl, H., K. Devries, A. Rotstein, N. Abrahams, J. Campbell, Methods. DHS Analytical Studies 28. Calverton, MD: ICF and others. 2013. “The Global Prevalence of Intimate International. Burden of Reproductive Ill Health 49 ———, and A. Bankole. 1998. “The Time Dynamics of Unmet ———. 2014. Trends in Maternal Mortality: 1990 to 2013. Need: An Example from Morocco.” International Family Estimates by WHO, UNICEF, UNFPA, The World Bank Planning Perspectives 24 (1): 12–24. and the United Nations Population Division. Geneva: WHO (World Health Organization). 2001. Management of WHO. Pregnancy, Childbirth and Postpartum Period in the Presence WHO and World Bank. 2011. World Report on Disability 2011. of Female Genital Mutilation. Geneva: WHO. Geneva: WHO. ———. 2004. Unsafe Abortion: Global and Regional Estimates WHO, LSHTM (London School of Hygiene and Tropical of the Incidence of Unsafe Abortion and Associated Mortality Medicine), and MRC-SA (South Africa Medical Research in 2000. Geneva: WHO. Council). 2013. Global and Regional Estimates of Violence ———. 2006a. Reproductive Health Indicators: Guidelines for against Women: Prevalence and Health Effects of Intimate Their Generation, Interpretation and Analysis for Global Partner Violence and Non-Partner Sexual Violence. Geneva: Monitoring. Geneva: WHO. WHO. ———. 2006b. “Female Genital Mutilation and Obstetric Yoder, P. S., N. Abderrahim, and A. Zhuzhini. 2004. Female Outcome: WHO Collaborative Prospective Study in Six Genital Cutting in the Demographic Health Surveys: A Critical African Countries.” Study Group on Female Genital and Comparative Analysis. DHS Comparative Reports 7. Mutilation and Obstetric Outcome. The Lancet 367 (9525): Calverton, MD: ORC Macro. 1835–41. Yoder, P. S., and S. Wang. 2013. Female Genital Cutting: The ———. 2007. Unsafe Abortion: Global and Regional Estimates Interpretation of Recent DHS Data. DHS Comparative of the Incidence of Unsafe Abortion and Associated Mortality Reports 33. Calverton, MD: ICF International. in 2003. Geneva: WHO. Zegers-Hochschild, F., G. D. Adamson, J. de Mouzon, ———. 2011. Unsafe Abortion: Global and Regional Estimates O. Ishihara, R. Mansour, and others. 2009. “The of the Incidence of Unsafe Abortion and Associated Mortality International Committee for Monitoring Assisted in 2008. Geneva: WHO. Reproductive Technology (ICMART) and the World ———. 2013. Responding to Intimate Partner Violence and Health Organization (WHO) Revised Glossary on Sexual Violence against Women: WHO Clinical and Policy ART Terminology, 2009.” Human Reproduction 24 (11): Guidelines. Geneva: WHO. 2683–87. 50 Reproductive, Maternal, Newborn, and Child Health Chapter 3 Levels and Causes of Maternal Mortality and Morbidity Véronique Filippi, Doris Chou, Carine Ronsmans, Wendy Graham, and Lale Say INTRODUCTION any cause related to or aggravated by the pregnancy or its management, but not from accidental or incidental In September 2000, 189 world leaders signed a declara- causes” (WHO 2010, 156). Subsequent guidance on the tion on eight Millennium Development Goals (MDGs) classification of causes includes nine groups of underly- to improve the lives of women, men, and children in their ing causes (box 3.1) (WHO 2012). respective countries (United Nations General Assembly Despite the increased global focus on maternal mor- 2000). Goal 5a calls for the reduction of maternal mor- tality as a public health issue, little detailed knowledge tality by 75 percent between 1990 and 2015. Goal 5a was is available on the levels of maternal mortality and supplemented by MDG 5b on universal access to contra- morbidity and the causes of their occurrence. A large ception. MDGs 5a and 5b have been important catalysts proportion of maternal deaths occur in settings in which for the reductions in maternal mortality levels that have vital registration is deficient and many sick women do been achieved in many settings.1 not access services. To obtain data on population levels Despite substantial progress, challenges remain. The of maternal mortality in these settings, special surveys majority of low-income countries (LICs), particularly are needed, including the following (Abouzahr 1999): in Sub-Saharan Africa and postconflict settings, have not made sufficient progress to meet MDG 5a. The • Reproductive Age Mortality Studies, which investi- post-2015 agenda on sustainable development is broader gate all reproductive age deaths than the MDG agenda, with a greater number of • Demographic and Health Surveys, which interview nonhealth goals and a strong focus on inequity reduc- women and men about their siblings’ survival in tion; the new agenda includes an absolute reduction in adulthood to identify deaths of sisters during or maternal mortality as a marker of progress.2 This new following pregnancy (the siblings are from the same indicator is expected to be framed as targets for prevent- mother) (Ahmed and others 2014) able maternal deaths (Bustreo and others 2013; Gilmore • Smaller studies, which use the indirect sisterhood and Camhe Gebreyesus 2012). method The International Classification of Diseases (ICD-10) • National investigations, which add questions to defines maternal death as “[The] death of a woman while censuses pregnant or within 42 days of the end of pregnancy, irre- • Verbal autopsy studies, which provide information spective of the duration and site of the pregnancy, from on causes and circumstances of deaths. Corresponding author: Véronique Filippi, London School of Hygiene & Tropical Medicine, Veronique.Filippi@lshtm.ac.uk. 51 nature and incidence of many indirect complications Box 3.1 that are aggravated by pregnancy. For example, reliable population-based estimates of the occurrence of asthma Underlying Causes of Maternal Deaths during pregnancy do not exist in LICs. This chapter addresses the extent and nature of mater- • Pregnancies with abortive outcome nal mortality and morbidity and serves as a backdrop to • Hypertensive disorders subsequent chapters on obstetric interventions in LICs. • Obstetric hemorrhage It introduces the determinants of maternal mortality • Pregnancy-related infection and morbidity and their strategic implications. The next • Other obstetric complications section uses the most recent estimates from the World • Unanticipated complications of management Health Organization (WHO) to show that women face • Nonobstetric complications a higher risk of maternal death in Sub-Saharan Africa. • Unknown or undetermined It discusses the recent findings of a WHO meta-analysis • Coincidental causes that show that the most important direct causes are hem- orrhage, hypertension, abortion, and sepsis; however, the Source: WHO 2012. proportion of deaths due to indirect causes is increasing in most parts of the world. The chapter then focuses on pregnancy-related complications, including nonfatal Maternal death studies require large sample sizes; illnesses such as antenatal and postpartum depression, recent national-level data are often nonexistent, and using the findings from systematic reviews conducted by maternal mortality tracking relies principally on mathe- the Child Health Epidemiology Reference Group. The matical models. This lack of data has led to a repeated call most common contributors to maternal morbidity are for countries to improve their vital registration systems probably anemia and depression at the community level, and to strengthen other mechanisms for informing inter- but prolonged and obstructed labor results in the highest vention strategies, such as the maternal death surveillance burden of disease because of fistulas (IHME 2013). The and response system proposed within the new account- chapter discusses the broader determinants of maternal ability framework (WHO 2013). Accountability remains morbidity and mortality, and then concludes by making a central part of United Nations Secretary General Ban the links with the interventions highlighted in chapter 7 Ki-Moon’s updated global strategy to accelerate progress in this volume (Gülmezoglu and others 2016). for women’s, children’s, and adolescent’s health (http:// www.everywomaneverychild.org/global-strategy-2). The accountability framework, developed under the 2010 MATERNAL MORTALITY LEVELS global strategy to accelerate women’s and children’s AND TRENDS health, included recommendations for improvements in resource tracking; international and national over- The WHO, in collaboration with the United Nations sight; and data monitoring, including maternal mortality Children’s Fund, the United Nations Population Fund, the World Bank Group, and the United Nations (Commission on Information and Accountability for Population Division, publishes global estimates of Women’s and Children’s Health 2011). maternal mortality, which are excerpted in this chapter Information on maternal morbidity is frequently col- lected in hospital studies, which are only representative (WHO 2015). A complete description of the method- of patients who seek care. Community-based studies are ology and underlying data and statistical model can be rare in LICs and suffer from methodological limitations, found in the publication and online.3 In this chapter, particularly when they rely on self-reporting of obstetric the latest estimate is for 2015. Whenever an estimate complications. Self-reporting is known not to agree suf- includes trend data between two points, updates of ficiently with medical diagnoses to estimate prevalence. those estimates typically supersede previously published In particular, studies validating retrospective interview figures. Readers are directed to the WHO’s Reproductive Health and Research web page on maternal mortality to surveys find that women without medical diagno- access the latest published data.4 ses of complications during labor frequently reported symptoms of morbidity during surveys, a phenome- non that can lead to an overestimation of prevalence Maternal Mortality Ratio Levels and Trends, 1990–2015 (Ronsmans and others 1997; Souza and others 2008). Globally, the total number of maternal deaths In addition, community-based studies have focused on decreased by 43 percent from 532,000 in 1990 to 303,000 direct obstetric complications; little is known about the in 2015. The global maternal mortality ratio (MMR) 52 Reproductive, Maternal, Newborn, and Child Health declined by 44 percent, from 385 maternal deaths per (242 per 100,000) is 14 times higher than that in 100,000 live births in 1990 to 216 in 2015—an average high-income countries (HICs, as defined by the World annual decline of 2.3 percent (WHO 2015). Bank (17 per 100,000). Most maternal deaths occur in All MDG regions experienced a decline in the MMR MDG regions Sub-Saharan Africa (201,000) and South between 1990 and 2015. The highest reduction was in Asia (66,000). Sub-Saharan Africa alone accounts for Eastern Asia (72 percent), followed by Southern Asia 66 percent of maternal deaths and has the highest MMR, (67 percent), South-Eastern Asia (66 percent), Northern at 546 maternal deaths per 100,000 live births. By MDG Africa (59 percent), Oceania (52 percent), Caucasus region, Eastern Asia has the lowest rate among developing and Central Asia (52 percent), Latin America and the regions, at 27 maternal deaths per 100,000 live births. Of Caribbean (50 percent), Sub-Saharan Africa (45 percent), the remaining developing regions, four had low MMRs: and Western Asia (43 percent). Although the Caucasus and Caucasus and Central Asia (33), Northern Africa (70), Central Asia experienced a relatively low level of decline, its Western Asia (91), and Latin America and the Caribbean already low MMR of 69 maternal deaths per 100,000 live (67). Three had moderate MMRs: South-Eastern Asia births in 1990 suggests that a different set of more finely (110), Southern Asia (176), and Oceania (187). The adult tuned strategies might be required to respond to the chal- lifetime risk of maternal mortality—the probability that lenge of achieving the same rate of decline as other regions a 15-year-old woman will die eventually from a maternal with higher 1990 MMRs, with possibly a stronger focus on cause—in Sub-Saharan Africa is the highest at 1 in 36; improved fertility control (Shelburne and Trentini 2010). this number is in contrast to 1 in 150 in Oceania; 1 in 210 Despite an initial increase in maternal mortality in in Southern Asia; 1 in 380 in South-Eastern Asia; and 1 in regions highly affected by human immunodeficiency 4,900 in developed regions. The global adult lifetime risk virus/acquired immunodeficiency syndrome (HIV/ of maternal mortality is 1 in 180. AIDS), evidence suggests that maternal mortality due to At the country level, two countries, Nigeria and HIV/AIDS peaked in 2005 and showed signs of decline India, account for more than one-third of all global in 2010 and 2015, most likely because of the increased maternal deaths in 2015, with an approximate 58,000 availability of antiretroviral medication. Of the 183 (uncertainty interval [UI] 42,000 to 84,000) maternal countries included in this exercise, 9 countries that had deaths (19 percent) and 45,000 (UI 36,000 to 56,000) high levels of maternal mortality in 1990 are categorized maternal deaths (15 percent), respectively. Ten coun- as having met the MDG goal of having reduced maternal tries account for nearly 59 percent of global maternal mortality by 75 percent. They are Maldives (90 percent deaths. In addition to Nigeria and India, they are the reduction in MMR); Bhutan (84 percent); Cambodia Democratic Republic of Congo (22,000; UI 16,000 to (84 percent); Cabo Verde (84 percent); the Islamic 33,000), Ethiopia (11,000; UI 7,900 to 18,000), Pakistan Republic of Iran (80 percent); Timor-Leste (80 percent); (9,700; UI 6,100 to 15,000), Tanzania (8,200; UI 5,800 Lao People’s Democratic Republic (78 percent); Rwanda to 12,000), Kenya (8,000; UI 5,400 to 12,000), Indonesia (78 percent); and Mongolia (76 percent). (6,400; UI 4,700 to 9,000), Uganda (5,700; UI 4,100 to An additional 39 countries are characterized as hav- 8,200), and Bangladesh (5,500; UI 3,900 to 8,800). Of the ing made a 50 percent reduction in maternal mortality; 183 countries and territories in this analysis, Sierre Leone 21 countries have made insufficient progress; and 26 and Chad have the highest adult lifetime risk of maternal made no progress. mortality, 1 in 17 and 1 in 18, respectively. These estimates should be viewed in context; accurate data on maternal mortality are lacking for the majority of countries. The range of uncertainty indicates that MEDICAL CAUSES OF MATERNAL DEATHS the true total number of maternal deaths in 2015 could Most maternal deaths do not have well-defined causes. plausibly be as low as 291,000 and as high as 349,000. Nevertheless, using the available data, nearly 73.0 percent Similarly, the global MMR plausibly ranges from 207 to of all maternal deaths between 2003 and 2009 were 249 maternal deaths per 100,000 live births. attributable to direct obstetric causes; deaths due to indirect causes accounted for 27.5 percent (95 percent confidence interval 19.7–37.5) of all deaths. The major Disproportionate Burden in Low- and Middle-Income causes of maternal mortality are as follows (Say and Countries others 2014): Low- and middle-income countries (LMICs, as defined by the World Bank) account for 99 percent (300,000) • Hemorrhage, 27.1 percent (95 percent confidence of global maternal deaths. The MMR in these regions interval 19.9–36.2); more than 72.6 percent of deaths Levels and Causes of Maternal Mortality and Morbidity 53 from hemorrhage were classified as postpartum result in intentional misclassification by providers where hemorrhage abortion is restricted. • Hypertension, 14.0 percent (95 percent confidence interval 11.1–17. 4) • Sepsis, 10.7 percent (95 percent confidence interval Deaths from Obstructed Labor 5.9–18.6) Obstructed labor is commonly considered to be or diag- • Abortive outcomes, 7.9 percent (95 percent confi- nosed as a clinical cause of maternal death. However, dence interval 4.7–13.2) as a death classification, it may be hard to capture • Embolism and other direct causes, 12.8 percent. because deaths occurring after obstructed labor and its consequences may be coded under hemorrhage or Three causes of death—unsafe abortions, obstructed sepsis. This practice is especially an issue in settings labor, and indirect causes—are of considerable program- in which verbal autopsies are used to determine cause matic interest but are particularly difficult to capture. of death, because verbal autopsy methods vary; lack The first case, unsafe abortions, is discussed further in of consistent case definitions and confusion regarding chapter 2 of this volume (Ezeh and others 2016). hierarchical assignment of causes affect the validity of the study data. In total, complications of deliv- ery accounted for 2.8 percent (95 percent confidence Deaths from Abortions interval 1.6–4.9), and obstructed labor accounted for 2.8 percent (95 percent confidence interval 1.4–5.5) Say and others (2014) estimate that 7.9 percent of all maternal deaths globally, both reported within (95 percent confidence interval 4.7–13.2) of all maternal the “other direct” category, which totals to 9.6 percent deaths were due to abortive outcomes, including spon- (95 percent confidence interval 6.5–14.3). taneous or induced abortions and ectopic pregnancies. This share is lower than in previous assessments, which estimated mortality due to unsafe abortion at 13 percent Deaths from Indirect Causes (WHO 2011b). The review found that the indirect causes of maternal death, when combined, are the most common cause of Ectopic Pregnancy maternal death. A breakdown of deaths due to indirect Although ectopic pregnancy can have very serious causes suggests that more than 70 percent are from mortality consequences, and there have been reports of preexisting medical conditions, including HIV/AIDS, increased incidence, it remains a rare event at less than 2 exacerbated by pregnancy. Information on the number per 100 deliveries (Stulberg and others 2013). This con- and proportion of maternal deaths related to HIV/AIDS dition has a high case fatality rate where urgent surgical alone is presented in box 3.2. However, these estimates care is not available. However, no systematic review of should be considered with caution, given the phenom- its global prevalence has been published since the 1980s. enon of misattribution of indirect maternal causes of death. Underestimation of 20 percent to 90 percent Induced Abortions of maternal deaths has been described in a number of In classifying maternal deaths due to abortion, and settings. In Austria, misclassification was significantly more specifically to unsafe abortion, which is defined higher for indirect deaths (81 percent, 95 percent con- as the termination of an unintended pregnancy “per- fidence interval 64–91 percent) than for direct deaths formed by persons lacking the necessary skills or in an (28 percent, 95 percent confidence interval 21 percent to environment not in conformity with minimal clinical 36 percent); in the United Kingdom, indirect deaths may standards, or both” (WHO 1993; Ganatra and others account for up to 74 percent of underreported mater- 2014, 155), there is a particular risk for misclassification nal deaths from 2003 to 2005 (Karimian-Teherani and that may lead to underreporting. ICD-10 does not have others 2002; Lewis 2007). a specific code for unsafe abortion; accordingly, deaths attributed to unsafe abortion are often documented within special studies. Even where induced abortion is Global Distribution of Maternal Deaths legal, the religious and cultural values in many countries The global distribution of maternal deaths is influenced can mean that women do not disclose abortion attempts, by the two regions, Sub-Saharan Africa and Southern and relatives or health care professionals do not report Asia, that account for the majority of all maternal these deaths as such. Underregistration of deaths may be deaths (WHO 2014b). Although estimated regional the result of the stigmatization of abortion, which may cause-of-death distributions are uncertain for many 54 Reproductive, Maternal, Newborn, and Child Health Box 3.2 Proportions of Considered AIDS-Related Indirect Maternal Deaths Assessing maternal deaths among human immuno- (18 percent), Lesotho (13 percent), and Mozambique deficiency virus (HIV)–infected women is a separate (11 percent). but related estimation process. Worldwide in 2015, AIDS-related indirect maternal deaths accounted 4,700 maternal deaths were attributed to HIV (an for 1.6 percent of global maternal deaths. indirect cause of maternal deaths because the con- Underreporting and misclassification of indirect dition usually preexists pregnancy, and this cause maternal deaths due to HIV/AIDS are a particular of death is not specific to pregnant women); 4,000 issue in death certificate coding and when coun- (85 percent) of these deaths were in Sub-Saharan tries rely on verbal autopsies to ascertain cause of Africa. The MDG region of Southern Asia was a death. This imprecision highlights the need for distant second, with 310 deaths. The proportion of review of deaths of HIV-infected women tempo- maternal deaths attributed to HIV was highest in ral to pregnancy; the women may die from HIV or Sub-Saharan Africa (2.0 percent) and Latin America with HIV while pregnant. As methods for global and the Caribbean (1.5 percent). Without HIV, the maternal death estimation evolve, the evidence MMR for Sub-Saharan Africa would be 535 mater- for the parameters needed to estimate indirect nal deaths per 100,000 live births, rather than 510. maternal HIV deaths and further clarification on The proportion of HIV-attributable maternal deaths the use of ICD-10 codes will standardize and is 10 percent or more in five countries: South Africa improve our understanding of maternal and HIV (32 percent), Swaziland (19 percent), Botswana death tallies. causes, point estimates show substantial differences confidence interval 3.2 percent to 33.4 percent) across regions. Hemorrhage accounted for 36.9 percent and 11.5 percent (95 percent confidence interval (95 percent confidence interval 24.1 percent to 1.6 percent to 40.6 percent), respectively. 51.6 percent) of deaths in northern Africa, compared The proportion of deaths due to indirect causes was with 16.3 percent (95 percent confidence interval highest in Southern Asia, 29.3 percent (95 percent confi- 11.1 percent to 24.6 percent) in developed regions. dence interval 12.2 percent to 55.1 percent), followed by Hypertensive disorders were a significant cause of death Sub-Saharan Africa, 28.6 percent (95 percent confidence in Latin American and the Caribbean, accounting for interval 19.9 percent to 40.3 percent); indirect causes 22.1 percent (95 percent confidence interval 19.9 percent also accounted for nearly 25.0 percent of the deaths in to 24.6 percent) of all maternal deaths in the region. the developed regions. The overall proportion of HIV/ Almost all sepsis deaths occurred in developing AIDS maternal deaths is highest in Sub-Saharan Africa, regions, and the percentage of deaths was high- 6.4 percent (95 percent confidence interval 4.6 percent est at 13.7 percent (95 percent confidence interval to 8.8 percent). 3.3 percent to 35.9 percent) in Southern Asia. Only a small proportion of deaths are estimated to result from abortion in Eastern Asia, 0.8 percent (95 percent confi- Trends in Maternal Death Causes dence interval 0.2 percent to 2.0 percent), where access The continued dearth of basic information in most to abortion is generally less restricted. Latin America countries of the developing region, where most of the and the Caribbean and Sub-Saharan Africa have higher deaths occur, impedes the ability to address the question proportions of deaths in this category than the global of changes in causes of maternal deaths over time. In average, 9.9 percent (95 percent confidence interval determining trends in causes of maternal deaths, it is 8.1 percent to 13.0 percent) and 9.6 percent (95 percent reasonable to conclude that the proportion of indirect confidence interval 5.1 percent to 17.2 percent), respec- deaths is increasing in all regions. The actual indirect tively. Another direct cause, embolism, accounted causes differ in that HIV/AIDS deaths are highest in for more deaths than the global average in South- Sub-Saharan Africa; other medical causes are highest in Eastern Asia and Eastern Asia, 12.1 percent (95 percent developed regions and Eastern Asia. Levels and Causes of Maternal Mortality and Morbidity 55 MEDICAL CAUSES OF MATERNAL Severity of Conditions MORBIDITY Maternal health specialists have tried since the 1990s to distinguish between women with severe and less severe Definition of Maternal Morbidity conditions in the measurement of morbidity (Stones The WHO Maternal Morbidity Working Group defines and others 1991). Maternal deaths are relatively rare maternal morbidity as “any health condition attributed events, and these specialists believe that cases at the very to and/or aggravated by pregnancy and childbirth that severe end of the maternal morbidity spectrum have has a negative impact on the woman’s wellbeing” (Firoz two useful characteristics: they are more frequent than and others 2013, 795). The working group emphasizes maternal deaths, and they share similar characteristics to the wide range of indirect conditions in the morbidity maternal deaths, including some common risk factors. that women experience during pregnancy, delivery, or Women who nearly died during pregnancy, labor, or postpregnancy by listing more than 180 diagnoses and postpregnancy, but survived, usually because of chance dividing them into 14 organ dysfunction categories, or good hospital care, are maternal “near-misses” (WHO ranging from obstetric to cardiorespiratory and rheu- 2011a). Depending on the definitions used and on the matology conditions. country and hospital settings, maternal near-misses The negative impact of pregnancy-related ill health occur for 0.05 percent to 15.0 percent of hospitalized is highlighted on the basis of subsequent disabilities, women (Tuncalp and others 2012). The WHO has devel- including how severely the woman’s functional status oped operational definitions of near-misses to facilitate is affected and for how long. The origins of maternal comparisons between settings (WHO 2011a). morbidity occur during pregnancy, but the sequelae Nevertheless, it is worth noting that the cause pat- might take several months to manifest themselves. terns of maternal mortality, near-misses, and less severe Capturing the negative impact of morbidities requires morbidity differ, depending on the case fatality of cer- a longer reference period than used for the death tain conditions and the ease of halting the progression definition. of disease (Pattinson and others 2003). Perceived Morbidity Where women are not able to access services eas- Principal Morbidity Diagnoses ily, surveys are conducted to measure their health The principal medical causes of mortality are also impor- status. Accurate diagnoses are difficult to make in tant morbidity diagnoses, but they are not the only ones survey conditions without confirmation from a clinical to consider. To this list must be added other contributing examination, laboratory reports, or medical records factors, such as depression and anemia, because of their (Ronsmans and others 1997). However, surveys provide frequency or severity. We must also add the sequelae of evidence of women’s experience of health and morbid- difficult labor, such as incontinence, fistulas, and prolapse. ity during pregnancy. Overall, many women complain A further consideration is the presence of comorbidities, about ill health in pregnancy and the puerperium. such as obstructed labor followed by infection, that com- Studies of self-reports in low-income settings typically plicate management, diagnosis, and classification. find that more than 70 percent of women report signs or Figure 3.1 illustrates a conceptual framework of the symptoms of pregnancy-related complications (Lagro ways in which different maternal conditions interact. and others 2003). In a Nepal study, women reported, on Long-term health sequelae are associated with cer- average, three to four days per week with symptoms of tain diagnoses in pregnancy. For example, neglected illness during pregnancy (Christian and others 2000). obstructed and prolonged labors are associated with The type of symptoms reported varied according to obstetric fistulas. The conceptual framework also gestational age, with nausea and vomiting more com- includes medical risk factors. One of these, obesity, has mon in early pregnancy, and swelling of the hands become a global epidemic and has been linked with and face more common toward the end of pregnancy. increasing levels of hypertension and diabetes. The Counterintuitive changes in self-reported ill health have management of pregnancy and childbirth, including been described for the postpartum period, with antic- cesarean section, is also a risk factor for future problems, ipated declines in symptoms over time sometimes for example, placenta previa. Female genital mutila- followed by increases (Filippi and others 2007; Saurel- tion, particularly in its most severe form, is associated Cubizolles and others 2000); self-perceived ill health with adverse maternal and perinatal outcomes, includ- is not simply a result of biological changes but also of ing postpartum hemorrhage and emergency cesarean social support and influences. (WHO 2006). 56 Reproductive, Maternal, Newborn, and Child Health Figure 3.1 Conceptual Framework of Maternal Health Maternal near-miss Maternal death Full recovery Main complications Obstetric Sequelae Hemorrhage Infertility Hypertension Incontinence Sepsis Prolapse Abortion Anemia Obstructed labor Risk factors Embolism Fistula Anemia Prolonged labor HIV Obesity Unsafe sex Management of delivery Female genital mutilation This section focuses on 11 groups of diagnoses that worldwide (WHO 2011b); of these, 5 million women are can lead to direct obstetric deaths or associated long- subsequently hospitalized (Singh 2006), most because of term ill health: abortion, hypertensive disease, obstetric hemorrhage (44 percent of admitted cases) or infections hemorrhage, infection, prolonged and obstructed (24 percent) (Adler and others 2012a). On average, 237 labor, anemia, postpartum depression, postpartum women experience a severe maternal morbidity associ- incontinence, fistula, postpartum prolapse, and HIV/ ated with induced abortion for every 100,000 live births AIDS. Other important indirect conditions that we in countries where abortion is unsafe (Adler and others do not consider are discussed in other DCP3 volumes, 2012b). Evidence indicates that the morbidity patterns including volume 6 on HIV/AIDS, STIs, Tuberculosis, associated with unsafe abortion are being transformed and Malaria. Figures 3.2 and 3.3 summarize the preva- by the rapid growth of the medical abortion market, lence of the considered conditions. with the incidence of severe morbidity episodes declining more rapidly than the incidence of less severe episodes Abortion (Singh, Monteiro, and Levin 2012). Morbidity with abortive outcomes comprises several diagnoses, including ectopic pregnancy, abortion, and Hypertensive Disease miscarriage, as well as other abortive conditions (WHO Women in pregnancy or the puerperium can suffer from 2013) (box 3.3). preeclampsia, eclampsia, and chronic hypertension. Induced abortion is a safe procedure, safer than Eclampsia and preeclampsia tend to occur more fre- childbirth when performed in a suitable environment quently in the second half of pregnancy; less commonly, and with the right method. Among unsafe abortions, they can occur up to six weeks after delivery. Medication the morbidity burden is large. Information on the can alleviate the symptoms and their negative effects, but incidence of unsafe abortion and subsequent outcomes the only cure is expedited delivery. The etiology of the at the population level is particularly challenging to condition remains unclear. obtain because of fear of disclosure. On the basis of One systematic review reported that the global estimates derived from hospital data (adjusted for bias), prevalence of preeclampsia is 4.6 percent (95 percent an estimated 22 million unsafe abortions occur each year confidence interval 2.7 percent to 8.2 percent), and Levels and Causes of Maternal Mortality and Morbidity 57 Figure 3.2 Prevalence of Direct Obstetric Complications are associated with perinatal deaths, placental abruption, and cardiovascular disease in later life in the mother. 20 Obstetric Hemorrhage Prevalence per 100 live births 15 Women can experience anomalous or excessive bleeding because of an early pregnancy loss, a placental implan- tation abnormality, or an abnormality in the process of 10 childbirth. The systematic review by Cresswell and others (2013) finds a global prevalence of 0.5 percent for pla- 5 centa previa (95 percent confidence interval 0.4 percent to 0.6 percent). An equivalent systematic review for placental abruption has not been published, but most 0 papers on this condition suggest an approximate preva- rrh tum via sia ia n ab d or ed tio lence of 1 percent (Ananth and others 1999). ps dl n re mp te d a ab iat Pla age mo ar ec or n lam ap tio he ostp fe oc cla nf uc ge Postpartum hemorrhage is a major cause of mater- Ec nt I sa ss str on ee ce P un y a ob rol Pr nal morbidity worldwide. A systematic review finds th dit P wi orbi a global prevalence of blood loss equal to or greater M than 500 milliliters in 10.8 percent of vaginal deliv- Sources: Based on Abalos and others 2013; Adler and Filippi, unpublished; Calvert and others eries (95 percent confidence interval 9.6 percent to 2012; Cresswell and others 2013; Dolea and Stein 2003. 12.1 percent) (Calvert and others 2012); the prevalence Figure 3.3 Prevalence of Severe Direct Obstetric Complications of severe hemorrhage (equal to or greater than 1,000 milliliters) was 2.8 percent (95 percent confidence 8 interval 2.4 percent to 3.2 percent). The review includes many study settings in which active management of the third stage of labor is practiced. The prevalence of Prevalence per 100 live births 6 postpartum hemorrhage in home deliveries is proba- bly higher. Postpartum hemorrhage is associated with anemia, which can persist for several months after birth 4 (Wagner and others 2012). The incidence of hemorrhage has increased in HICs in recent years (Mehrabadi and others 2013). This 2 trend has been linked to changes in risk factors, such as pregnancies at older ages, obesity, and previous cesar- ean delivery, as well as to better data capture systems 0 (Kamara and others 2013). These risk factors are increas- ia rrh tum e is or ab unsa ity ur ps ps ingly more common in LICs as well. ab id pt e or fe mo ar Se lam ag ith orb dl ru he ostp n te ine Ec dw m tio uc ep te iss er str Ut cia -m r ve Pregnancy-Related Infection Ob so ar Se as Ne Puerperal sepsis causes the greatest concern of all pregnancy-related infections because of its severity. No review of the prevalence of sepsis has been published Sources: Based on Abalos and others 2013; Adler and others 2012a; Adler and Filippi, unpublished; Calvert and others 2012; Hofmeyr and others 2005. since the work in the early 2000s for the Global Burden of Diseases (Dolea and Stein 2003). In this review, the prevalence of eclampsia is 1.4 percent (95 percent Dolea and Stein calculate that the incidence of sepsis confidence interval 1.0 percent to 2.0 percent) (Abalos ranged from 2.7 to 5.2 per 100 live births according to and others 2013). The review finds evidence of regional world region. A community-based study in India finds variations, with Sub-Saharan Africa having the high- that the incidence of puerperal sepsis in the first week est incidence of both conditions. Preeclampsia and postpartum was 1.2 percent after home delivery and eclampsia are more common among women in their 1.4 percent after facility-based delivery. The incidence of first pregnancy, women who are obese, women with fever was higher at 4 percent overall in the same Indian preexisting hypertension, and women with diabetes. All study (Iyengar 2012). Another study in India finds a high of these characteristics are increasingly more common incidence of puerperal infections at home (10 percent) in pregnant populations. Preeclampsia and eclampsia and of fever (12 percent), but the study uses broader 58 Reproductive, Maternal, Newborn, and Child Health Box 3.3 Definitions of Obstetric Causes of Maternal Morbidities and Deaths Abortive outcomes include abortion, miscarriage, Pregnancy-related infections include puerperal ectopic pregnancy, and other abortive conditions sepsis, infections of the genitourinary tract in (WHO 2013). Abortive outcomes take place before pregnancy, other puerperal infections, and infec- 28 weeks during pregnancy, but this time defini- tions of the breast associated with childbirth tion varies among countries, with lower cut-offs of (WHO 2013). 24 weeks also used. Prolonged labor is labor lasting more than 12 Preeclampsia is characterized by high blood pres- hours, in spite of good uterine contractions and sure and protein in the urine; women are diagnosed good cervix dilation. In obstructed labor, the with eclampsia when the preeclampsia syndrome is fetal descent is impaired by a mechanical barrier associated with convulsions. in the birth canal, despite good contractions (WHO 2008). Causes of obstructed labor include Obstetric hemorrhage refers to anomalous or exces- cephalopelvic disproportion, abnormal presenta- sive bleeding because of an early pregnancy loss, a tion, fetal abnormality, and abnormality of the placental implantation abnormality (including pla- reproductive tract. centa previa or placental abruption), or because of an abnormality in the process of childbirth. Sources: WHO 2008, 2013. definitions and followed women for only 28 days (Bang Its main symptoms include excessive fatigue; it can and others 2004). Risk factors for infections include contribute to or lead directly to a maternal death when HIV/AIDS and cesarean section. Hb concentration has reached particularly low levels. Anemia has many different causes, including blood loss; Prolonged and Obstructed Labor infection-related blood cell destruction; and deficient An unpublished systematic review by Adler and others red blood cell production because of sickle cell disease, located only 16 published population-based studies parasitic diseases such as hookworm or malaria, or of obstructed and prolonged labor worldwide since nutritional deficiency, including iron deficiency. 2000. The studies could not be combined through During pregnancy, anemia is diagnosed when Hb levels meta-analysis to obtain a global prevalence because are below the threshold of 11 grams/deciliter. Anemia of high heterogeneity, which was largely attributed to is classified as severe when the levels reach 7 grams/ differences in case definitions. However, the median deciliter. Anemia is well-documented in low-income prevalence was estimated to be 1.9 per 100 deliveries for settings thanks to the ease with which lay fieldworkers obstructed labor, and 8.7 per 100 deliveries for combined can collect hemoglobin levels in survey conditions. obstructed and prolonged labor. A systematic review of Using 257 population-based data sets for 107 coun- articles from 1997 to 2002 reporting on uterine rup- tries, Stevens and others (2013) estimate that globally ture finds extremely low prevalence in the community 38.0 percent (95 percent confidence interval 34 percent setting (median 0.053, range 0.016 to 0.30 per hundred to 43 percent) of pregnant women have anemia, and pregnant women), but it included a study with self- 0.9 percent (95 percent confidence interval 0.6 percent reporting, which tends to overestimate the prevalence of to 1.3 percent) have severe anemia. Pregnant women rare conditions (Hofmeyr, Say, and Gülmezoglu 2005). in Central and West Africa appear particularly affected (56.0 percent are anemic, and 1.8 percent are severely so). Anemia However, global prevalence trends have improved since Anemia—which occurs when the number of red cells 1995 (Stevens and others 2013). The review by Wagner or hemoglobin (Hb) concentration has reached too and others (2012) demonstrates that women who suffer low a level in the blood—is a commonly diagnosed severe blood loss during childbirth may remain anemic condition during pregnancy or the postpartum period. for several months during the postpartum period. Levels and Causes of Maternal Mortality and Morbidity 59 Postpartum Depression the risk was higher for vaginal birth (31 percent) than Mental health disorders during pregnancy and the post- for cesarean birth (15 percent), as reported in several partum period include conditions of various severity case control studies. Although the authors of this paper and etiology, ranging from baby blues to postpartum attempted to obtain information for all countries, no depression and puerperal psychosis, as well as posttrau- papers from LICs were included. matic stress disorders linked, for example, to the death of a baby. The most common of these disorders is depres- Obstetric Fistula sion, which is associated with pregnancy-related deaths Obstetric fistula results in the continuous loss of urine by suicide and with developmental delays in children. or fecal matter, occurring both day and night (Polan and Most studies detect depression through screening others 2015). It has been described as a condition worse questionnaires for psychological distress; the most than death in view of its medical manifestation, treat- widely used tool is the Edinburgh Postnatal Depression ment difficulties, and social consequences (Lewis Wall Scale, which has been translated into many languages 2006). It occurs when labor is obstructed, and contrac- and used in many different cultures. These screening tions continue with the baby’s head stuck in the pelvis questionnaires are not equivalent to clinical diagnoses or vagina; cesarean section is usually required to deliver by medical providers; rather, they indicate a high prob- the baby (Lewis Wall 2012). As a result of the severe ability of depression among those who have high scores. delay in delivery and continuous pressure of the fetal Depression is a well-studied area, with a number head on maternal tissues, blood flow is blocked, result- of systematic reviews and meta-analyses, supported by ing in necrosis. This condition leaves abnormal gaps large numbers of papers, although only a small propor- (or communications) between the vagina and bladder tion of these articles are from LMICs. Fisher and others or rectum, allowing urine or stool to pass continuously (2012) calculate that in LMICs, the prevalence of depres- through the vagina. The meta-analysis by Adler and sion and anxiety was 16 percent (95 percent confidence others (2013) of the incidence of fistula in LMICs finds a interval 15 percent to 17 percent) during pregnancy and pooled incidence of 0.09 (95 percent confidence interval 20 percent (95 percent confidence interval 19 percent to 0.01–0.25) per 1,000 recently pregnant women. Another 21 percent) during the postpartum period. Halbreich recent meta-analysis of Demographic and Health Survey and Karkun (2006), who conducted the most compre- data finds a lifetime prevalence of 3 cases per 1,000 hensive systematic review to date from a geographical women of reproductive age (95 percent credible inter- perspective, find a broader range of prevalence of vals 1.3–5.5) in Sub-Saharan Africa (Maheu-Giroux and depression (0 percent to 60 percent). They attribute this others 2015). The condition is extremely rare in HICs, wide range to cultural differences in the reporting and where there are few delays in obtaining good quality in the understanding of depression, as well as differences maternity care. in tools and other methodological approaches. They also conclude, in view of the wide ranges in the estimates, Postpartum Vaginal or Uterine Prolapse that the prevalence of depression is high and that the Pelvic organ prolapse is defined as the symptomatic widely cited prevalence of 10 percent to 15 percent is not “descent of one or more of: the anterior vaginal wall, representative of the actual global prevalence. the posterior vaginal wall, and the apex of the vagina or vault” (Haylen and others 2010, 8). In lay terms, it Incontinence is when a “descent of the pelvic organs results in the Incontinence is any involuntary loss of urine. The most protrusion of the vagina, uterus, or both” (Jelovsek, common form of urinary incontinence during and after Maher, and Barber 2007, 1027). Incidence increases with childbirth is stress urinary incontinence, which consists age, parity, and body mass index; hard physical labor is of involuntary leakages on exertion or effort. also a risk factor. Prolapse is among the Global Burden Little information is available on the incidence of of Disease’s most common sequelae, with a prevalence incontinence in the postpartum period in LMICs. of about 9.28 percent. Few population-based incidence Walker and Gunasekera (2011) find four studies of studies measure prolapse after childbirth. There is a reproductive-age women published between 1985 and lack of agreement as to what constitutes a significant 2010, in which the prevalence ranged from 5 percent prolapse; a grading system exists, but it requires clinical to 32 percent. Another systematic review calculates the interpretation. In Burkina Faso, 26 percent of women mean pooled estimates for all types of incontinence dur- with uncomplicated facility-based deliveries received a ing the first three months postpartum to be 33 percent for diagnosis of prolapse in the postpartum period (Filippi parous women and 29 percent for primiparous women and others 2007). In The Gambia, a population-based (Thom and Rortveit 2010). In addition, they find that study with physical examinations finds that 46 percent 60 Reproductive, Maternal, Newborn, and Child Health of women ages 15–54 years had prolapse, and 14 percent within the next five years than other women (Storeng had moderate or severe prolapse (Scherf and others and others 2012). Many of these deaths occur in 2002). Severe prolapse affects quality of life and is asso- subsequent pregnancies, indicating that a small number ciated with depression (Zekele and others 2013). of women, often those with chronic illnesses, accumulate pregnancy-related risks. What proportion of women suf- HIV/AIDS fer a major complication during pregnancy, taking into A positive HIV status is linked to an increased risk of account various comorbidities? Researchers at Columbia death in pregnant and nonpregnant women (Zaba University has suggested 15 percent prevalence as a bench- and others 2013). A recent systematic review suggests mark for their indicators of met need for complications that HIV-infected women had eight times the risk of (Paxton, Maine, and Hijab 2003). This number has not a pregnancy-related death, compared with uninfected been validated, except possibly by a study in India (Bang women; the excess mortality attributable to HIV/AIDS and others 2004). If all of the acute direct complications among HIV-infected pregnant and postpartum women with nonabortive outcomes mentioned in this chapter was close to 1,000 deaths per 100,000 pregnant women. (Ronsmans and others 2002) were mutually exclusive, the The excess mortality attributable to HIV in pregnant total prevalence could be as high as 31 percent. women is much smaller than in nonpregnant women, however, probably because women who become preg- nant tend to be healthier. A review that investigates BROADER DETERMINANTS OF MATERNAL the interaction between HIV/AIDS status and direct MORTALITY AND MORBIDITY obstetric complications shows that women who are HIV-positive are 3.4 times more likely to develop sepsis This section presents an overview of the broader deter- (Calvert and Ronsmans 2013). The evidence of positive minants of maternal mortality and morbidity and high- links for hypertensive diseases of pregnancy, dystocia, lights the specificities of maternal health by introducing and hemorrhage was variable. an established conceptual framework and other classi- fication approaches. Determinants include individual risk factors, such as age and parity; characteristics of the Global Burden of Diseases social, legal, and economic contexts; and the physical The prevalence of conditions, as well as the prevalence, environment, for example, water sources and geograph- severity or disability weight, and the duration of their ical accessibility. respective sequelae, are key factors in establishing the burden of various conditions in a population and in prioritizing them. Some conditions are noteworthy, for Significant Individual Risk Factors example, uterine rupture, because they are very severe Descriptive studies have demonstrated that women face and are associated with high risk of death in the mother the highest risk of pregnancy-related death and severe or the baby. A few severe conditions, for example, fistula, morbidity (Hurt and others 2008) when they are very despite being rare, can last a very long time and severely young or older (Blanc, Winfrey, and Ross 2013) when affect women’s quality of life. they are expecting their first baby or when they have The WHO Global Health Estimates and IHME had many pregnancies, when they live far away from Global Burden of Disease estimates suggest that the health facilities, or when they do not benefit from absolute number of disability-adjusted life years asso- support from their families and friends (Mbizvo and ciated with maternal conditions have decreased, owing others 1993). Table 3.1 illustrates some of the main to lower maternal mortality rates, but the number of determinants of maternal mortality and how they influ- years lived with disabilities has increased (Vos and others ence women’s chances of survival during pregnancy or 2012; WHO 2014a). The increase in disabilities is mostly childbirth. due to obstructed labor, hypertension, and indirect We consider two additional important facets of conditions (Vos and others 2012); it is also due to the maternal mortality when discussing determinants and high population growth rate, which means that the total interventions to reduce deaths. number of women of reproductive age is rising. • The risk of maternal deaths has two components: the risk of getting pregnant, which is a risk related Major Pregnancy-Related Complications to fertility and its control or lack of control; and the A longitudinal study shows that women who initially obstetric risk of developing a complication and dying survived severe complications were more likely to die while pregnant or in labor. The obstetric risk is highest Levels and Causes of Maternal Mortality and Morbidity 61 Table 3.1 Examples of Risk Factors and Pathways of Influence Individual nonmedical risk factors Age Women at the extreme ends of the reproductive age range (younger than age 20 years and older than age 35 years) have a higher risk of death for both physiological and sociocultural reasons; the largest number of deaths might be in the middle group, because this is when most births occurs. Parity Higher risks of complications and death are associated with first pregnancy and more than three to five pregnancies. Women in their first pregnancies have longer duration of labor; women with multiple pregnancies are more likely to suffer postpartum hemorrhage. Unintended Unwanted pregnancy is a risk factor for unsafe abortion, lack of social support, and domestic violence. Women who continue with pregnancies their pregnancies are less likely to plan for childbirth and more likely to commit suicide (Ahmed and others 2004). Marital status Single women who are pregnant often lack support from their partners or their families and are more likely to try to induce an abortion or to run into financial and other logistical difficulties when seeking care for labor. Women’s education Women who are educated know where to obtain effective services and are more likely to request these services. Husbands’ education The husband’s educational level is often a more important determinant of maternal mortality than the woman’s education (Evjen-Olsen and others 2008). Ethnicity and religion In high-income countries, women from black or migrant communities are more likely to die during pregnancy for cultural and medical reasons, including chronic ill health. Women from certain religious groups may seek medical advice from their religious leaders or deliver in places of worship. Poverty Money is often required to travel or to deliver safely. Emergency cesarean section is a very expensive procedure, which can lead to delays in seeking care and in catastrophic expenditures. Obesity and other Obese or anemic women are more likely to die in childbirth. Obese women face increased risk due to comorbid conditions, such as nutritional factors diabetes, hypertension, or cardiac problems; it is also technically more difficult to provide them with clinical care. Severely anemic women cannot tolerate hemorrhage to the same degree as women with higher hemoglobin levels. Past obstetric history Past stillbirths and emergency cesarean are predictors of complications and deaths. Social and economic context Women’s status Often measured using education as a proxy, women’s status indicators help to assess the extent to which women can make decisions on their own and the extent to which women and their decisions are valued. Many proxy variables have been used to measure women’s status, including age at marriage, financial decision-making power, and women’s opinions on domestic violence (Gabrysch and Campbell 2009). Legality of reproductive Where abortion laws are restrictive, women are more likely to have unsafe abortions. The current focus is on delegating certain health services procedures to midlevel providers to ensure that more women have access to safe and effective services. Conflict Extremely high levels of maternal mortality have been reported where infrastructure and communication systems have been destroyed, for example, in Afghanistan and Somalia. Physical environment and health systems characteristics Staff and facilities The number, quality, and distribution of staff members are important risk factors for mortality; it is difficult to predict which women will have complications, and women are more likely to die in home births. Skilled birth attendance is often the most significant risk factor in maternal mortality models. Women who live at a distance from facilities are much more likely to delay seeking care and to experience multiple referrals. Transportation network Patient access to transportation and problematic topography are risk factors for long duration of the second tier of delays. (See section on “Three Delays Model.”) Water and sanitation The availability and quality of water and sanitation (WATSAN) are key factors at the community level; they influence direct risks of diarrheal diseases and other water-borne infections in pregnant and parturient women, as does personal hygiene before and after delivery (Shordt, Smet, and Herschderfer 2012). WATSAN can indirectly pose risks to women’s health if they carry heavy water receptacles or are subjected to violence at public water collection points or latrines. In health care facilities, WATSAN affects the hygiene practices of providers during childbirth, such as hand washing and environmental cleaning, with attendant increased risks of maternal and newborn nosocomial infections (Hussein and others 2011). Quality of care and As more women deliver with skilled providers, the quality of care in facilities becomes increasingly important. The accountability accountability of the health sector is a new focus of interventions to improve the quality of care. The availability of blood is one of the most important determinants of the quality of care received by women who are severely ill (Graham, McCaw-Binns, and Munjanja 2013). Note: See Gabrysch and Campbell (2009) for further examples of risk factors. 62 Reproductive, Maternal, Newborn, and Child Health at the time of delivery. The determinants of these roads, as well as the performance of the referral system risks share many similarities, but also have specific between facilities. The determinants of the third delay characteristics. are related to quality of care, such as the number and • Although the overall risks of maternal death are training of staff members and the availability of blood highest among young adolescents and older women supplies and essential equipment. Although the actions of reproductive age, the highest number of deaths is and characteristics of women and families can influence in the middle group of women around age 25 years. the length of the third delay, for example, by helping to mobilize elements of the surgical kits for cesarean delivery by purchasing missing supplies in pharmacies Three Delays Model (Gohou and others 2004), most of the determinants of Conceptual models guide research and practice and help the third delay are related to service provision. in the determination of how best to reduce adverse out- The three delays model has weaknesses. It does comes, by grouping determinants and highlighting their not include the concept of primary prevention (avoid linkages with events in the pathway from health to death. pregnancy) and secondary prevention (avoid compli- The three delays model (Thaddeus and Maine 1994), cations once pregnant). It ignores family planning, attractive because of its simplicity and action-oriented noncommunicable chronic diseases, antenatal care, and presentation, is based on the following premises: postpartum care. Implicitly, it also assumes that com- plications arise at home, where women intend to give birth, whereas increasing numbers of women deliver in • Maternal complications are mostly emergencies. facilities (Filippi and others 2009). In addition, it does • Maternal complications cannot be predicted with not consider the newly identified “fourth delay,” which sufficient accuracy. arises when women are discharged unwell or chronically • Maternal deaths are largely preventable through ter- ill from facilities and die at home during the postpreg- tiary prevention (preventing deaths among women nancy period or in the next pregnancy (Pacagnella and who have been diagnosed with a complication). others 2012; Storeng and others 2012). At the 1987 launch of the Safe Motherhood Initiative, maternal health experts discussed how long a woman Rights-Based Approach would have to have a particular complication before The rights-based approach to understanding the deter- she would die, if untreated. They agreed that for the minants of maternal health is primarily concerned with most frequent complications, women with postpartum the legal, cultural, and social context of service acces- hemorrhage had less than 2 hours before death; for sibility and delivery; it has been gaining a higher profile antepartum hemorrhage, eclampsia, obstructed labor, with the introduction of MDG 5b in 2007. It began with and sepsis, the times would be 12 hours, 2 days, 3 days, the observation that most maternal deaths are avoidable, and 6 days, respectively. as illustrated by the wide divergence in lifetime risks The model has three levels of delay: of maternal death (the probability that a 15-year-old woman will die of a pregnancy related cause) between • The first delay is the elapsed time between the onset HICs (one in 3,700) and LMICs (one in 160) (WHO of a complication and the recognition of the need to 2014a), and between rich and poor women; that a con- transport the patient to a facility. siderable evidence-based literature exists with respect to • The second delay is the elapsed time between leaving effective clinical interventions; and that the reduction of the home and reaching the facility. maternal mortality is firmly embedded in women’s abil- • The third delay is the elapsed time from presenta- ity to control the occurrence and timing of pregnancy tion at the facility to the provision of appropriate (Freedman 2001). treatment. Most maternal deaths are not simply biological phe- nomena; many are in part explained by the lack of free- Each delay has a distinctive set of determinants. The dom and entitlements experienced by women and service determinants of the first delay are related to the individ- providers, as well as by the lack of accountability of ual circumstances of the women and their families, who providers, health systems, and countries toward women must first recognize that care is needed and then be able and their families (Freedman 2001; PMNCH 2013). The to access transport or money to travel to facilities. The concept of freedom refers to the right of women to con- determinants of the second delay concern the physical trol their bodies, including their reproductive options, environment, the type of transport, and the quality of the and to have access to acceptable and effective family Levels and Causes of Maternal Mortality and Morbidity 63 planning services, including safe abortions. Entitlements between the richest and the poorest women (WHO are concerned with access to good quality services, which and UNICEF 2012). Health system classifications are must be evidence based and respectful and emphasize helpful in highlighting the barriers or in facilitating equity in access for all women who need care, whether the factors that many women meet when they seek care they are rich or poor, married or single. during pregnancy, childbirth, or emergency situations. The accessibility and availability of good quality These classifications complement the three delays family planning and legal abortion services are key model because they go beyond emergency obstetric determinants of maternal mortality in many LICs. care. The WHO health system building blocks offer a Quantitative models suggest that preventing preg- starting point for classifying health system determi- nancy with contraception has a bigger role to play in nants and include the following: reducing maternal mortality than does inducing abor- tion when pregnant with an unintended pregnancy • Quality of service delivery and referral system (Singh and Darroch 2012). However, although access • Number, distribution, and training of the types to safe abortion techniques has become easier with the of providers required, including midwives and availability of medical abortion, including on the black obstetrician-gynecologists market from drug sellers or the Internet in countries • Completeness and responsiveness of the health infor- where abortion is illegal, many women still die because mation system, including the adequacy of the Maternal they cannot access safe abortion services (Ganatra and Death Surveillance and Response (WHO 2013) others 2014). The distal determinants of fertility and • Ease of access to essential medications, such as mag- unwanted pregnancy are broadly similar to the distal nesium sulfate, misoprostol, and oxytocin, and the determinants of maternal health, with their emphasis supplies necessary for blood transfusions on culture, poverty, and education, but their proximate • Leadership and financing, a particularly relevant issue determinants are somewhat different, with a focus on in several Sub-Saharan African countries that have fecundability and marriage patterns (Bongaarts 1978) ended user fees and, in the case of unwanted pregnancies, an emphasis • Governance, including the capacity of authorities at on the needs of younger and unattached women. various levels of the health system to put policies and Several studies, mostly qualitative, highlight episodes management systems in place so that women’s health of rampant disrespect and abuse of pregnant women or can improve. women in labor in some maternity units (Hassan-Bitar and Wick 2007; Silal and others 2012). Groundbreaking research is taking place with the TRAction Project in All of these building blocks are determinants of the Kenya and Tanzania to delineate the different forms coverage and quality of care that women receive across of disrespect and abuse, understand their origins, and the continuum of care. Country case studies describe the quantitatively document their frequency.5 Lack of relative importance of these building blocks or equiva- respectful care could mean that women do not seek lent groupings in understanding progress in maternal care when they need it, or do not seek it as quickly as health (McPake and Koblinsky 2009). The equitable they should, and could contribute to deaths of mothers distribution of staff and the adequacy of blood supplies and babies. appear to be issues in most settings in LICs. Coverage Finally, it is important to be aware that in HICs of one visit for antenatal care is very high; the median and LMICs, violence is sometimes one of the most coverage level is 88 percent among the Countdown frequent causes of death during pregnancy and child- Countries for which data are available (Countdown birth (Ganatra, Coyaji, and Rao 1998; Glazier and Countries comprise 75 countries where 95 percent of the others 2006). world’s maternal and child deaths occur). Progress has also been made for skilled birth attendance since 1990 (median coverage of 57 percent), emergency obstetric Health System Factors care (as measured, for example, by the cesarean section The maternal mortality level is one of the best cri- rate, and by the density of emergency obstetric care teria for assessing the relative performance of health facilities per birth or population), and postnatal care systems. One example of a coverage indicator of the for mothers (median coverage of 41 percent). However, continuum of care is skilled birth attendance, which large urban-rural and wealth inequities remain, par- is particularly inequitable. While women rely on a ticularly in countries that have made the least progress functioning health system to access and use profes- since the 1990s (Cavallaro and others 2013; WHO and sional care, this indicator has shown large differences UNICEF 2012). 64 Reproductive, Maternal, Newborn, and Child Health Intersectoral Issues CONCLUSIONS The health sector does not exist in isolation; in developing This chapter summarizes available data on the levels and and implementing effective policies, its interactions with trends of maternal mortality and morbidity and their other sectors, such as education, finance, water, and main determinants. Mathematical modeling indicates transport, must be considered. For example, the well- that maternal mortality is declining in most countries, documented decline in maternal mortality in Bangladesh that women face the highest risk of death in the MDG may be related to the availability of emergency obstetric region of Oceania and Sub-Saharan Africa, and that care interventions and fertility decline, but it is also deaths due to direct causes—such as hemorrhage and likely to be linked to the increased participation of hypertension—continue to be the main causes in Latin women in the labor force. Several ecological studies of America and the Caribbean and in Sub-Saharan Africa. maternal mortality have shown the relationship between The proportion of hemorrhage and hypertension deaths maternal mortality and skilled birth attendance, as well found globally remains high despite established interven- as to gross national product, health care expenditures, tions to prevent and treat direct causes of maternal death female literacy, population density, and access to clean (see chapter 7), such as active management of the third water (Buor and Bream 2004; Montoya, Calvert, and stage of labor. With the data available, it is not possible Filippi 2014). to determine if this high proportion is the result of a fail- Observational studies have shown inadequate lev- ure to implement policies and therefore quality of care, els of hygiene in many maternity facilities (Benova, if there is a shift toward antepartum hemorrhage, or if Cumming, and Campbell 2014), with direct health misclassifications of abortion and obstructed labor are impacts on mothers, newborns, and care providers erroneously increasing the hemorrhage category. (Mehta and others 2011). The reasons are multifac- torial and include poor infrastructure; inadequate equipment and supplies; and poor practices by care Role of Indirect Causes providers and cleaners as a result of inadequate knowl- edge, attitudes, motivation, and supervision (Campbell The data presented in this chapter also suggest that the and others 2015). Interventions to address these con- proportion of maternal deaths due to indirect causes straints go beyond the health sector, particularly for is increasing in most parts of the world. In addition, water and sanitation (Shordt, Smet, and Herschderfer although the proportion of women who have a serious 2012). Timely access to care and the difficulties in morbidity remains a hotly debated topic by epidemi- obtaining motorized transport, as well as challenging ologists, we estimate that approximately 30 percent topography and inadequate and poorly maintained of women may have a serious condition during preg- roads, are important barriers to care. Gabrysch and nancy, childbirth, or the postpartum period. The main others (2011) demonstrate that in Zambia, the odds strategies used to date to reduce maternal mortality are of women being able or choosing to deliver in a health based on the understanding that most complications facility decreased by 29 percent with every doubling of are emergencies and that most deaths occur during a distance between their home and the closest facility. very short period around childbirth. Accordingly, the They conclude that if all Zambian women lived within focus has been on reducing delays for emergency care, 5 kilometers of health facilities, 16 percent of home as well as on preventive measures, such as facilitating deliveries could be averted. access to skilled birth attendance and reproductive rights. Complementary strategies are needed to address the indirect causes of death and the broader burden of maternal morbidity, in particular, given that the sequelae A Lifecycle Perspective of maternal morbidity can last a long time. Safe motherhood programs traditionally consider each Health program managers and policy makers need to pregnancy to be a separate event. Emerging evidence continue to encourage women to deliver in health from cohort studies of near-miss patients suggests that facilities, where complications can be prevented by women who have suffered severe obstetric complica- appropriate care and where women can receive life- tions have increased mortality risks for several years saving interventions. At the same time, the gaps in and have a higher risk of complications in subsequent coverage of effective interventions for indirect causes pregnancies. It is important to be able to identify these of death according to their distribution in various set- women and offer them medical support for an extended tings have significant implications for the complexity of postpartum period and in subsequent pregnancies service delivery in light of the urgent need to accelerate (Assarag and others 2015; Storeng and others 2012). the rate of decline in maternal mortality and, ultimately, Levels and Causes of Maternal Mortality and Morbidity 65 to stop all preventable deaths. Primary health care may 1. This chapter uses World Bank regions in discussions based have a greater role in the future in improving the health on income level, and Milllennium Development Goal outcomes of pregnant and recently delivered women. (MDG) regions otherwise. See http://mdgs.un.org/unsd / mdg/Host.aspx?Content=Data/REgionalGroupings .htm for the MDG regional groupings. Quality of Health Care Services 2. See website of the Open Working Group on Sustainable Development Goals at http://sustainabledevelopment In addition, if the post-2015 agenda is to emphasize .un.org/owg.html. universal access to essential interventions, the per- 3. See http://www.who.int/reproductivehealth/publications ceived and technical quality of the health care services /monitoring/maternal-mortality-2015/en/. provided becomes even more crucial in the fight 4. This data can be found at http://www.who.int against maternal mortality and morbidity, given their /reproductivehealth/publications/monitoring /maternal consequences for both demand for and supply of ser- -mortality-2015/en/. vices. Thus, the international community emphasizes 5. http://www.urc-chs.com/news?newsItemID=324. the development and implementation of a palette of quality-of-care interventions, including clinical audits, childbirth checklists, maternal deaths surveillance REFERENCES and response, and interventions to increase awareness Abalos, E., C. Cuesta, A. L. Grosso, D. Chou, and L. Say. around respectful care. 2013. “Global and Regional Estimates of Preeclampsia and Eclampsia: A Systematic Review.” European Journal of Obstetrics and Gynecology and Reproductive Biology 170 Need for Better Data (1): 1–7. Finally, we conclude with a call for action for better data. Abouzahr, C. 1999. “Measuring Maternal Mortality: What Do Although the global attention to maternal mortality has We Need to Know?” In Safe Motherhood Initiatives: Critical engendered more studies and attempts to measure it, the Issues, edited by M. Berer and T. K. Sundari Ravindran. quality, regularity, and ability of the results to robustly London: Reproductive Health Matters. show differentials have not improved dramatically, espe- Adler, A., and V. Filippi. Unpublished. “Prevalence of Obstructed Labour: A Systematic Review.” Report, London cially routine sources of information such as vital regis- School of Hygiene & Tropical Medicine, United Kingdom. tration. We remain largely dependent on research and Adler, A. J., V. Filippi, S. L. Thomas, and C. Ronsmans. 2012a. mathematical modeling. The paucity of information “Incidence of Severe Acute Maternal Morbidity Associated on maternal morbidity is an even greater issue. At the with Abortion: A Systematic Review.” Tropical Medicine and community level, data on direct obstetric complications International Health 17 (2): 177–90. are almost nonexistent; the burden of ill health associ- ———. 2012b. “Quantifying the Global Burden of Morbidity ated with some conditions, such as sepsis and ectopic due to Unsafe Abortion: Magnitude in Hospital-Based pregnancies, has not been reviewed for many years. Studies and Methodological Issues.” International Journal of Better population-based sources for local-level decision Gynecology and Obstetrics 118 (2): S65–77. making are essential to achieving improved outcomes. Adler, A., V. Filippi, C. Calvert, and C. Ronsmans. 2013. “Estimating the Prevalence of Fistula: A Systematic Review and a Meta-Analysis.” BMC Pregnancy and Childbirth 13: 246. NOTES Ahmed, M. K., J. van Ginneken, A. Razzaque, and N. Alam. 2004. “Violent Deaths among Women of Reproductive Age World Bank Income Classifications as of July 2014 are as fol- in Rural Bangladesh.” Social Science and Medicine 59 (2): lows, based on estimates of gross national income (GNI) per 311–19. capita for 2013: Ahmed, S., L. Qingfend, C. Scrafford, and T. W. Pullum. 2014. An Assessment of DHS Maternal Mortality Data and • Low-income countries (LICs) = US$1,045 or less Estimates. DHS Methodological Report 13. Rockville, MD: • Middle-income countries (MICs) are subdivided: ICF International. a) lower-middle-income = US$1,046–US$4,125 Ananth, C. V., G. S. Berkowitz, D. A. Savitz, and R. H. Lapinski. b) upper-middle-income (UMICs) = US$4,126–US$12,745 1999. “Placental Abruption and Adverse Perinatal • High-income countries (HICs) = US$12,746 or more. Outcomes.” Journal of the American Medical Association 282 (17): 1646–51. For consistency and ease of comparison, DCP3 is using the Assarag, B., B. Dujardin, A. Essolbi, I. Cherkaoui, and World Health Organization’s Global Health Estimates (GHE) V. De Brouwere. 2015. “Consequences of Severe Obstetric for data on diseases burden, except in cases where a relevant Complications on Women’s Health in Morocco: Please, data point is not available from GHE. In those instances, an Listen to Me!” Tropical Medicine and International Health alternative data source is noted. 20 (11): 1406–14. 66 Reproductive, Maternal, Newborn, and Child Health Bang, R. A., A. T. Bang, M. H. Reddy, M. D. Deshmukh, (third edition): Volume 2, Reproductive, Maternal, Newborn, S. B. Baitule, and others. 2004. “Maternal Morbidity during and Child Health, edited by R. Black, R. Laxminarayan, Labour and the Puerperium in Rural Homes and the Need M. Temmerman, and N. Walker. Washington, DC: for Medical Attention: A Prospective Observational Study World Bank. in Gadchiroli, India.” BJOG 111 (3): 231–38. Filippi, V., R. Ganaba, R. F. Baggaley, T. Marshall, K. T. Storeng, Benova, L., O. Cumming, and O. M. R. Campbell. 2014. and others. 2007. “Health of Women after Severe Obstetric “Systematic Review and Meta-Analysis: Association between Complications in Burkina Faso: A Longitudinal Study.” Water and Sanitation Environment and Maternal Mortality.” The Lancet 370 (9595): 1329–37. Tropical Medicine and International Health 19 (4): 368–87. Filippi, V., F. Richard, I. Lange, and F. Ouattara. 2009. Blanc, A. K., W. Winfrey, and J. Ross. 2013. “New Findings for “Identifying Barriers from Home to the Appropriate Maternal Mortality Age Patterns: Aggregated Results for Hospital through Near-Miss Audits in Developing 38 Countries.” PLoS One 8 (4): e59864. Countries.” Best Practice & Research Clinical Obstetrics & Bongaarts, J. 1978. “A Framework for Analysing the Proximate Gynaecology 23 (3): 389–400. Determinants of Fertility.” Population and Development Firoz, T., D. Chou, P. von Dadelszen, P. Agrawal, R. Vanderkruik, Review 4 (1): 105–32. and others. 2013. “Measuring Maternal Health: Focusing Buor, D., and K. Bream. 2004. “An Analysis of the Determinants on Maternal Morbidity.” Bulletin of the World Health of Maternal Mortality in Sub-Saharan Africa.” Journal of Organization 91 (10): 794–96. Womens Health 13 (8): 926–38. Fisher, J., M. Cabral de Mello, V. Patel, A. Rahman, T. Tran, Bustreo, F., L. Say, M. Koblinsky, T. W. Pullum, M. Temmerman, and others. 2012. “Prevalence and Determinants of and others. 2013. “Ending Preventable Maternal Deaths: Common Perinatal Disorders in Women in Low- and The Time Is Now.” The Lancet Global Health 1 (4): E176–77. Lower-Middle-Income Countries: A Systematic Review.” Calvert, C., S. Thomas, C. Ronsmans, K. Wagner, A. Adler, and Bulletin of the World Health Organization 90: 139–49. V. Filippi. 2012. “Identifying Regional Variation in Maternal Freedman, L. P. 2001. “Using Human Rights in Maternal Haemorrhage: A Systematic Review and Meta-Analysis.” Mortality Programs: From Analysis to Strategy.” International PLoS One 7 (7). Journal of Gynecology and Obstetrics 75 (1): 51–60. Calvert, C., and C. Ronsmans. 2013. “The Contribution of HIV Gabrysch, S., and O. M. R. Campbell. 2009. “Still Too Far to to Pregnancy-Related Mortality: A Systematic Review and a Walk: Literature Review of the Determinants of Delivery Meta-Analysis.” AIDS 27 (10): 1631. Service Use.” BMC Pregnancy and Childbirth 9: 34. Campbell, O. M. R., L. Benola, G. Gon, K. Afsana, and Gabrysch, S., S. Cousens, J. Cox, and O. M. R. Campbell. 2011. O. Cumming. 2015. “Getting the Basic Rights—The “The Influence of Distance and Level of Care on Delivery Role of Water, Sanitation and Hygiene in Reproductive Care in Rural Zambia: A Study of Linked National Data Health: A Conceptual Framework.” Tropical Medicine and and Geographic Information System.” PLoS Medicine 8 (1). International Health 20 (82): 252–67. Ganatra, B. R., K. J. Coyaji, and V. N. Rao. 1998. “Too Far, Too Cavallaro, F. L., J. A. Cresswell, G. Franca, C. Victora, A. Barros, Little, Too Late: A Community-Based Case-Control Study and others. 2013. “Trends in Caesarean Delivery by Country of Maternal Mortality in Rural West Maharashtra, India.” and Wealth Quintile: Cross Sectional Surveys in Southern Bulletin of the World Health Organization 76 (6): 591–98. Asia and Sub-Saharan Africa.” Bulletin of the World Health Ganatra, B., O. Tuncalp, H. B. Johnston, B. R. Johnson, Organization 91 (12): 914–22. A. M. Gulmezoglu, and others. 2014. “From Concept to Christian, P., K. P. West, S. K. Khatry, J. Katz, S. C. Leclerq, and Measurement: Operationalizing WHO’s Definition of Unsafe others. 2000. “Vitamin A and B-Carotene Supplementation Abortion.” Bulletin of the World Health Organization 92: 155. Reduces Symptoms of Illness in Pregnant and Lactating Gilmore, K., and T. A. Camhe Gebreyesus. 2012. “What Will Nepali Women.” Journal of Nutrition 130 (11): 2675–82. It Take to Eliminate Preventable Maternal Deaths?” The Commission on Information and Accountability for Women’s Lancet 386 (9837): 87–88. and Children’s Health. 2011. Keeping Promises, Measuring Glazier, A., M. Gulmezoglu, G. P. Schmid, C. G. Moreno, and Results. Geneva: WHO. P. F. A. Van Look. 2006. “Sexual and Reproductive Health: Cresswell, J. A., C. Ronsmans, C. Calvert, and V. Filippi. A Matter of Life and Death.” The Lancet 368 (9547): 1595–607. 2013. “Prevalence of Placenta Praevia by World Region: Gohou, V., C. Ronsmans, L. Kacou, K. Yao, K. Bohousso, and A Systematic Review and Meta-Analysis.” Tropical Medicine others. 2004. “Responsiveness to Life-Threatening Obstetric and International Health 18 (6): 712–14. Emergencies in Two Hospitals in Abidjan, Côte d’Ivoire.” Dolea, C., and C. Stein. 2003. Burden of Maternal Sepsis in the Tropical Medicine and International Health 9 (3): 406–15. Year 2000. Evidence and Information for Policy. Geneva: WHO. Graham, W., S. McCaw-Binns, and S. Munjanja. 2013. Evjen-Olsen, B., S. G. Hinderaker, R. T. Lie, P. Bergsjo, “Translating Coverage Gains into Health Gains for All P. Gasheka, and G. Kvale. 2008. “Risk Factors for Maternal Women and Children: The Quality Care Opportunity.” Death in the Highlands of Rural Northern Tanzania: PLoS Medicine 10 (1). A Case-Control Study.” BMC Public Health 8: 52. Gülmezoglu, A. M., T. A. Lawrie, N. Hezelgrave, O. T. Oladoppo, Ezeh, A., A. Bankole, J. Cleland, C. Garcia-Moreno, J. P. Souza, and others. 2016. “Interventions to Reduce M. Temmerman, and A. K. Ziraba. 2016. “Burden of Maternal and Newborn Morbidity and Mortality.” Reproductive Ill Health.” In Disease Control Priorities In Disease Control Priorities (third edition): Volume 2, Levels and Causes of Maternal Mortality and Morbidity 67 Reproductive, Maternal, Newborn, and Child Health, edited of Vaginal Fistula in 19 Sub-Saharan Africa Countries: by R. Black, R. Laxminarayan, M. Temmerman, and A Meta-Analysis of National Household Survey Data.” N. Walker. Washington, DC: World Bank. The Lancet Global Health 3 (5): e271–78. Halbreich, U., and S. Karkun. 2006. “Cross-Cultural and Mbizvo, M. T., S. Fawcus, G. Lindmark, and L. Nystrom. Social Diversity of Prevalence of Postpartum Depression 1993. “Maternal Mortality in Rural and Urban and Depressive Symptoms.” Journal of Affective Disorders Zimbabwe: Social and Reproductive Factors in an 91 (2–3): 97–111. Incident Case-Referent Study.” Social Sciences and Hassan-Bitar, A., and L. Wick. 2007. “Evoking the Guardian Medicine 36 (9): 1197–205. Angel: Childbirth Care in a Palestinian Hospital.” McPake, B., and M. Koblinsky. 2009. “Improving Maternal Reproductive Health Matters 15 (30): 103–13. Survival in South Asia: What Can We Learn from Case Haylen, B. T., D. de Ritter, R. M. Freeman, S. E. Swift, B. Berghmans, Studies?” Journal of Health Population and Nutrition 27 (2): and others. 2010. “An International Urogynecological 93–107. Association (IUGA)/International Continence Society (ICS) Mehrabadi, A., J. A. Hutcheon, L. Lee, M. S. Kramer, R. M. Liston, Joint Report on the Terminology for Female Pelvic Floor and others. 2013. “Epidemiological Investigation of a Dysfunction.” Neurourology and Urodynamics 21 (1): 5–26. Temporal Increase in Atonic Postpartum Haemorrhage: Hofmeyr, G. J., L. Say, and A. Gülmezoglu. 2005. “WHO A Population-Based Retrospective Study.” BJOG 120 (7): Systematic Review of Maternal Mortality and Morbidity: 853–62. The Prevalence of Uterine Rupture.” BJOG 112 (9): 1221–28. Mehta, R., D. V. Mavalankar, K. Ramani, S. Sharma, and Hurt, L., N. Alam, G. Dieltens, N. Aktar, and C. Ronsmans. 2008. J. Hussein. 2011. “Infection Control in Delivery Care Units, “Duration and Magnitude of Mortality after Pregnancy in Gujarat, India: A Needs Assessment.” BMC Pregnancy and Rural Bangladesh.” International Journal of Epidemiology Childbirth 11: 37. 37 (2): 397–404. Montoya, A., C. Calvert, and V. Filippi. 2014. “Explaining Hussein, J., D. V. Malavankar, S. Sharma, and L. D’Ambruoso. Differences in Maternal Mortality Levels in Sub-Saharan 2011. “A Review of Health System Infection Control African Hospitals: A Systematic Review and Meta-Analysis.” Measured in Developing Countries: What Can Be Learned International Health 6 (1): 1–11. to Reduce Maternal Mortality.” Global Health 7: 14. Pacagnella, R. C., J. G. Cecatti, M. J. Osis, and J. P. Souza. IHME (Institute for Health Metrics and Evaluation). 2013. 2012. “The Role of Delays in Severe Maternal Morbidity The Global Burden of Disease: Generating Evidence, Guiding and Mortality: Expanding the Conceptual Framework.” Policy. Seattle, WA: IHME. Reproductive Health Matters 20 (39): 155–63. Iyengar, K. 2012. “Early Postpartum Maternal Morbidity Pattinson, R., E. Buchmann, G. Mantel, M. Schoon, and H. Rees. among Rural Women in Rajasthan, India: A Community 2003. “Can Enquiries into Severe Acute Maternal Morbidity Based-Study.” Journal of Health Population and Nutrition Act as a Surrogate for Maternal Death Enquiries?” BJOG 30 (2): 213–25. 110 (10): 889–93. Jelovsek, J. E., C. Maher, and J. M. Barber. 2007. “Pelvic Organ Paxton, A., D. Maine, and N. Hijab. 2003. “AMDD Workbook. Prolapse.” The Lancet 369 (9566): 1027–38. Using the UN Process Indicators of Emergency Obstetric Kamara, M., J. J Henderson, D. A. Doherty, J. E. Dickinson, Services: Questions and Answers.” Averting Death and and C. E. Pennell. 2013. “The Risk of Placenta Accreta Disability Program, Columbia University, Mailman School Following Primary Elective Caesarean Delivery: A Case- of Public Health. Control Study.” BJOG 120 (7): 879–86. PMNCH (Partnership for Maternal, Newborn and Child Karimian-Teherani, D., G. Haidinger, T. Waldhoer, A. Beck, and Health). 2013. Human Rights and Accountability. Knowledge C. Vutuc. 2002. “Under-Reporting of Direct and Indirect Summaries 23: Women’s and Children’s Health. Geneva: Obstetrical Deaths in Austria, 1980–98.” Acta Obstetricia et PMNCH. Gynecologica Scandinavica 81 (4): 323–27. Polan, M. L., A. Sleemi, M. M. Bedane, S. Lozo, and M. A. Morgan. Lagro, M., A. Liche, T. Mumba, R. Ntbeka, and J. van Roosmalen. 2015. “Obstetric Fistula.” In Disease Control Priorities 2003. “Postpartum Health among Rural Zambian Women.” (3rd edition): Volume 1, chapter 6, Essential Surgery, edited African Journal of Reproductive Health 7 (3): 41–48. by H. T. Debas, P. Donkor, A. Gawande, D. T. Jamison, Lewis, G. ed. 2007. Saving Mothers’ Lives: Reviewing Maternal M. E. Kruk, and C. N. Mock. Washington, DC: World Bank. Deaths to Make Motherhood Safer 2003–2005. The Seventh Ronsmans, C., E. Achadi, S. Cohen, and A. Zarri. 1997. “Women’s Report of the Confidential Enquiries into Maternal Deaths Recall of Obstetric Complications in South Kalimantan, in the United Kingdom. London: CEMACH. Indonesia.” Studies in Family Planning 28 (3): 204–14. Lewis Wall, L. 2006. “Obstetric Vaginal Fistula as an International Ronsmans, C., O. M. R. Campbell, J. McDermott, and Public Health Problem.” The Lancet 368 (9542): 1201–09. M. Koblinsky. 2002. “Questioning the Indicators of Need for ———. 2012. “A Framework for Analyzing the Determinants Obstetric Care.” Bulletin of the World Health Organization of Obstetric Fistula Formation.” Studies in Family Planning 80: 317–24. 43 (4): 255–72. Saurel-Cubizolles, M.-J., P. Romito, N. Lelong, and P.-Y. Ancell. Maheu-Giroux, M., V. Filippi, S. Samadoulougou, M.C. Castro, 2000. “Women’s Health after Childbirth: A Longitudinal N. Maulet, and others. 2015. “Prevalence of Symptoms Study in France and Italy.” BJOG 107 (10): 1202–09. 68 Reproductive, Maternal, Newborn, and Child Health Say, L., D. Chou, A. Gemmill, O. Tuncalpo, A.-B. Moller, and Tuncalp, O., M. Hindin, J. P. Souza, D. Chou, and L. Say. 2012. others. 2014. “Global Causes of Maternal Death: A WHO “The Prevalence of Maternal Near-Miss: A Systematic Systematic Analysis.” The Lancet Global Health 2 (6): e323–33. Review.” BJOG 119 (6): 653–61. Scherf, C., L. Morison, A. Fiander, G. Ekpo, and G. Walraven. United Nations General Assembly. 2000. “United Nations 2002. “Epidemiology of Pelvic Organ Prolapse in Rural Millennium Declaration.” United Nations General Gambia, West Africa.” BJOG 109 (4): 431–36. Assembly, New York. http://www.un.org/millennium Shelburne, R. C., and C. Trentini. 2010. “After the Financial /declaration/ares552e.htm. Crisis: Achieving the Millennium Goals in Europe, the Vos, T., A. Flaxman, M. Naghavi, R. Lozano, C. Michaud, and Caucasus and Central Asia.” Discussion Paper Series 2010.1, others. 2012. “Years Lived with a Disability (YLDs) for United Nations Economic Commission for Europe, Geneva. 1160 Sequelae of 289 Diseases and Injuries 1990–2010: A Shordt, K., E. Smet, and K. Herschderfer. 2012. Getting It Right: Systematic Analysis for the Global Burden of Disease Study Improving Maternal Health through Water, Sanitation & 2010.” The Lancet 380 (9859): 2163–96. Hygiene. Simavi: Haarlem. Wagner, K., C. Ronsmans, S. L. Thomas, C. Calvert, A. Adler, Silal, S. P., L. Penn-Kekana, B. Harris, S. Birch, and D. McIntyre. and others. 2012. “Women Who Experience Obstetric 2012. “Exploring Inequalities in Access to and Use of Haemorrhage Are at Higher Risk of Anaemia, in Both Rich Maternal Health Services in South Africa.” BMC Health and Poor Countries.” Tropical Medicine and International Services Research 12: 120. Health 17 (1): 9–22. Singh, S. 2006. “Hospital Admissions Resulting from Unsafe Walker, G. J. A., and P. Gunasekera. 2011. “Pelvic Organ Prolapse Abortions: Estimates from 13 Developing Countries.” The and Incontinence in Developing Countries: Review of Lancet 368 (9550): 1887–92. Prevalence and Risk Factors.” International Urogynecology ———, and J. E. Darroch. 2012. Adding It Up: Costs and Journal 22 (2): 127–35. Benefits of Contraceptive Services: Estimates for 2012. WHO (World Health Organization). 1993. The Prevention New York: Guttmacher Institute and UNFPA. and Management of Unsafe Abortion. Report of a Technical Singh, S., M. Monteiro, and J. Levin. 2012. “Trends in Working Group. Geneva: WHO. Hospitalization for Abortion-Related Complications in ———. 2006. “Female Genital Mutilation and Obstetric Brazil, 1992–2009: Why the Decline in Numbers and Outcome: WHO Collaborative Prospective Study in Six Severity?” International Journal of Gynaecology and African Countries.” WHO Study Group on Female Genital Obstetrics 118 (2): S99–106. Mutilation and Obstetric Outcome. The Lancet 367 (9525): Souza, J. P., M. A. Parpinelli, E. Amaral, and J. G. Cecatti. 1835–41. 2008. “Population Surveys Using Validated Questionnaires ———. 2008. Managing Prolonged and Obstructed Labor. Provided Useful Information on the Prevalence of Maternal Geneva: WHO. Morbidities.” Journal of Clinical Epidemiology 61 (2): ———. 2010. ICD-10: International Classification of Diseases 169–76. and Related Health Problems. 10th Revision, Vol. 2, Stevens, G. A., M. M. Finucane, L. M. De-Regil, C. J. Paciorek, Instruction Manual. Geneva: WHO. S. R. Flaxman, and others. 2013. “Global, Regional, and ———. 2011a. Evaluating the Quality of Care for Severe National Trends in Haemoglobin Concentration and Pregnancy Complications: The WHO Near-Miss Approach Prevalence of Total and Severe Anaemia in Children for Maternal Health. Geneva: WHO. and Pregnant and Non-Pregnant Women for 1995–2011: ———. 2011b. Unsafe Abortion: Global and Regional Estimates A Systematic Analysis of Population-Representative Data.” of Incidence of Unsafe Abortion and Associated Mortality in The Lancet Global Health 1 (1): E16–25. 2008. Sixth edition. Geneva: WHO. Stones, W., W. Lim, F. Al-Azzawi, and M. Kelly. 1991. “An ———. 2012. The WHO Application of ICD-10 to Deaths Investigation of Maternal Morbidity with Identification during Pregnancy, Childbirth and the Puerperium: ICD-MM. of Life-Threatening ‘Near-Miss’ Episodes.” Health Trends Geneva: WHO. 23 (1): 13–15. ———. 2013. Maternal Death Surveillance and Response Storeng, K. T., S. Drabo, R. Ganaba, J. Sundby, C. Calvert, and Technical Guidance: Information for Action to Prevent others. 2012. “Mortality after Near-Miss Complications in Maternal Death. Geneva: WHO. Burkina Faso: Medical, Social and Health-Care Factors.” ———. 2014a. “Global Health Estimates for Deaths by Cause, Bulletin of the World Health Organization 90 (6): 418–25. Age, and Sex for Years 2000–2012.” WHO, Geneva. http:// Stulberg, D. B., L. R. Cain, I. Dahlquist, and D. S. Lauderdale. www.who.int/healthinfo/global_burden_disease/en/. 2013. “Ectopic Pregnancy Rates in the Medicaid Population.” ———. 2014b. Trends in Maternal Mortality: 1990 to 2013. American Journal of Obstetrics and Gynecology 208 (4): 274. Estimates by WHO, UNICEF, UNFPA, the World Bank and Thaddeus, S., and D. Maine. 1994. “Too Far to Walk: Maternal the United Nations Population Division. Geneva: WHO. Mortality in Context.” Social Sciences and Medicine 38 (8): ———. 2015. Trends in Maternal Mortality: 1990 to 2015. 1091–110. Estimates by WHO, UNICEF, UNFPA, the World Bank and Thom, D. H., and G. Rortveit. 2010. “Prevalence of Postpartum the United Nations Population Division. Geneva: WHO. Urinary Incontinence: A Systematic Review.” Acta Obstetricia WHO and UNICEF (United Nations Children’s Fund). 2012. et Gynecologica Scandinavica 89 (12): 1511–22. Countdown to 2015, Maternal, Newborn, and Child Survival. Levels and Causes of Maternal Mortality and Morbidity 69 Building a Future for Women and Children: The 2012 Report. Analysing Longitudinal Population-Based HIV/AIDS Data Geneva: WHO and UNICEF. on Africa (ALPHA).” The Lancet 381 (9879): 1763–71. Zaba, B., C. Calvert, M. Marston, R. Isingo, J. Nakiyingi-Miiro, and Zekele, B. M., T. A. Ayele, M. A. Woldetsadik, T. A. Bisetegn, others. 2013. “Effect of HIV Infection on Pregnancy-Related and A. A. Adane. 2013. “Depression among Women with Mortality in Sub-Saharan Africa: Secondary Analyses of Obstetric Fistula, and Pelvic Organ Prolapse in Northwest Pooled Community-Based Data from the Network for Ethiopia.” BMC Psychiatry 13: 236. 70 Reproductive, Maternal, Newborn, and Child Health Chapter 4 Levels and Causes of Mortality under Age Five Years Li Liu, Kenneth Hill, Shefali Oza, Dan Hogan, Yue Chu, Simon Cousens, Colin Mathers, Cynthia Stanton, Joy Lawn, and Robert E. Black INTRODUCTION LEVELS AND TRENDS OF MORTALITY This chapter reviews recent estimates of levels and UNDER AGE FIVE YEARS, 2000–15 distributions by cause of death of children under age Mortality rates among young children are the best single five years, including stillbirths. We focus on 2000–15 indicator of child health in low- and middle-income and present results by World Bank region. We introduce countries (LMICs), and they are often also used as indi- an innovation by including information on stillbirths, cators of general social and economic development. The defined as deaths from the 28th week of gestation. The most widely used measure of child mortality in recent standard convention has been to use live birth as the years has been the under-five mortality rate (U5MR), starting point of risk measurement, as in Millennium defined as the probability of dying between live birth and Development Goal 4 (MDG 4) to reduce mortality age five years; this measure was adopted as the primary under age five years by two-thirds from 1990 to 2015 target for MDG 4 (UN 2013). However, like all summary (UN 2000). However, substantial proportions of still- measures, the U5MR conceals age detail and patterns of births are preventable given adequate obstetric care, mortality—and mortality change—in the first month and would, if prevented, increase the number of live and year of life that are of epidemiological and pro- births. We argue that including stillbirths in summary grammatic interest. In this chapter, we include stillbirths measures of child mortality provides a more inclusive as part of the risk of dying under age five years, and assessment of health service provision than the standard the pregnancies at risk as all those that reach 28 weeks convention. gestation (described as “viable fetuses”). We introduce Data on levels and trends of mortality before age a new measure, the total under-five mortality rate, or five years are taken from the 2015 report by the United TU5MR, defined as the probability of dying between the Nations Inter-Agency Group on Mortality Estimation 28th week of pregnancy and the fifth birthday. (IGME) (You and others 2015). Data on levels and We present estimates both as probabilities of dying trends of causes of mortality under age five years are and in the form of numbers of deaths and for age ranges taken from the latest estimates produced by the World 28 weeks to live birth, live birth to 27 days, 28 days to Health Organization (WHO) and UNICEF’s (United one year, and one year to five years. The probabilities Nations Children’s Fund) Child Health Epidemiology of dying for these age ranges correspond to the con- Reference Group (Liu and others, forthcoming). ventional stillbirth, neonatal, postneonatal, and child Corresponding author: Li Liu, The Institute for International Programs, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; lliu26@jhu.edu. 71 mortality rates. We also present estimates of the broadest only by possible differences in stillbirth rates, which are measure of child mortality risk, the TU5MR. likely to be minor, given the close overlap of the regions. As a result of using this new conceptualization, we have to combine information from two sources, one for stillbirths and the other for mortality following a Results live birth, and make some approximations along the Table 4.1 shows probabilities of dying for the four way. However, the approximations are relatively minor age ranges and for the TU5MR. Globally, the TU5MR and do not affect the overall picture of recent levels and declined from 95.4 per 1,000 viable fetuses in 2000 to trends in TU5MR. 59.1 in 2015, an annual average rate of reduction (ARR) of 3.2 percent (table 4.2). For LMICs, the TU5MR declined from 105.9 in 2000 to 65.2 in 2015, and the Sources decline for high-income countries (HICs) was from The estimates presented in this section are based on sepa- 14.3 to 9.7. The ARR was somewhat faster in the LMICs rate estimation exercises, one for the stillbirth rate and one (3.2 percent) than in the HICs (2.6 percent), so the risk for mortality of live-born children to age five years. For ratio for LMICs to HICs declined from 7.4 to 6.7 over mortality of live-born children, we use the estimates by the period; the absolute difference narrowed much more the IGME (You and others 2015); the methodology used sharply, from 92 to 56 per 1,000 viable fetuses. In both by the IGME to arrive at estimates is described elsewhere years, there is large variation across regions. HICs had (Alkema and others 2014). We present the probabilities of the lowest risks, about one-third that of the next best dying from live birth and the ratio of numbers of deaths region, Latin America and the Caribbean. Sub-Saharan to live births for World Bank regions for 2000 and 2015. Africa had the highest risk, with the TU5MR remaining The derivation of stillbirth rates and numbers of still- substantially greater than 100 per 1,000 in both years, births is less direct. The most recent systematic analysis more than 10 times the risk in HICs. The region with of stillbirth rates provides estimates for MDG regions the second-highest risk in both years was South Asia, for 1995 and 2009 (Cousens and others 2011). We use although its TU5MR fell to less than 100 in 2015; its the rate of change in the stillbirth rate between 1995 disadvantage relative to HICs declined only slightly, and 2009 for each MDG region to interpolate to 2000 however, from 8.3 to 7.9. The remaining regions had and extrapolate to 2015. We then assume that these rates rather similar TU5MRs, between 44 and 59 per 1,000 in for MDG regions, suitably aggregated, closely approx- 2000 and between 26 and 36 in 2015, slightly narrowing imate those for World Bank regions for those years. their disadvantage relative to HICs. Specifically, to approximate the World Bank region of At the global level, the neonatal period has the highest East Asia and Pacific, we combine the MDG regions of age-specific risk in both 2000 and 2015. This is also the East Asia, South-East Asia, and Oceania; for the World case for LMICs as a group and for all regions individ- Bank region of Middle East and North Africa, we com- ually, except Sub-Saharan Africa in 2000 and East Asia bine the MDG regions of Western Asia and North Africa; and Pacific in 2015. For all LMICs, and particularly for and for the World Bank region of Europe and Central Sub-Saharan Africa, the age range of lowest risk shifts Asia, we combine the Commonwealth of Independent from stillbirths in 2000 to ages one to five years in 2015. States (CIS) Europe and CIS Asia. South Asia’s lowest risk is in the postneonatal group in To estimate numbers of stillbirths, we use the rela- 2000; for all other regions, the lowest risk in both years tionship between rates and numbers of events. The neo- is from ages one to five years. The absolute difference natal mortality rate (NMR) is calculated as the number between the highest and lowest risk among age ranges of neonatal deaths (ND) divided by the number of live decreased by more than 90 percent from 2000 to 2015. births, so given the number of ND and the NMR, we can The mortality rate estimate for Sub-Saharan Africa is calculate the number of live births. The stillbirth mortal- 2.4 times that of the next highest region (South Asia), ity rate (SBR) is calculated as the number of stillbirths for both postneonatal and ages one to five years, despite divided by the sum of the number of stillbirths and live similar neonatal and stillbirth rates. births. We can estimate the number of stillbirths from Table 4.2 shows the ARR in probabilities of dying the NMR, ND, and SBR as follows: between 2000 and 2015 for the age ranges and regions shown in table 4.1. As noted, the ARR for TU5MR SB = ND × SBR/[NMR × (1 − SBR)]. globally was 3.2 percent, somewhat less than the rate needed (4.4 percent) to achieve the MDG 4 target These numbers are not affected by differences in num- for the conventional U5MR. If we apply the MDG 4 bers of live births between MDG and World Bank regions, target for U5MR to the TU5MR, the only region to 72 Reproductive, Maternal, Newborn, and Child Health Table 4.1 Probabilities of Dying per 1,000 Pregnancy Completions from the 28th Week of Pregnancy to Age Five Years, 2000 and 2015 2000 2015 28 weeks 28 weeks gestation Birth to 28 days 1–5 gestation Birth to 28 days 1–5 World Bank region to birth 27 days to 1 year years TU5MR to birth 27 days to 1 year years TU5MR Low- and middle-income 22.8 33.0 25.0 25.1 105.9 19.1 20.7 13.7 11.7 65.2 countries East Asia and Pacific 15.2 21.0 12.2 9.1 57.5 9.2 8.9 5.9 3.0 27.0 Europe and Central Asia 10.0 19.7 14.9 7.6 52.2 8.1 10.6 7.1 2.6 28.4 Latin America and the 10.8 15.1 12.8 5.7 44.4 7.6 9.6 6.2 2.9 26.2 Caribbean Middle East and North 14.8 22.2 13.4 9.1 59.4 11.4 13.8 6.7 3.6 35.7 Africa South Asia 28.9 44.9 21.3 23.9 119.0 25.3 29.2 11.4 10.6 76.5 Sub-Saharan Africa 30.0 39.6 51.5 56.3 177.4 27.2 27.8 26.8 25.2 107.0 High-income countries 3.6 5.7 3.2 1.7 14.3 2.8 3.7 2.1 1.0 9.7 World 20.6 29.9 22.5 22.4 95.4 17.3 18.9 12.4 10.5 59.1 Sources: Based on Cousens and others 2011; and 2015 UN Inter-Agency Group for Child Mortality Estimation (IGME). Note: TU5MR = total under-5 mortality rate. Table 4.2 Annual Rates of Reduction in Probabilities of Dying per 1,000 Pregnancy Completions from the 28th Week of Pregnancy to Age Five Years, between 2000 and 2015 2000–15 World Bank region 28 weeks gestation to birth Birth to 27 days 28 days to 1 year 1–5 years TU5MR Low- and middle-income countries 1.18 3.11 4.01 5.09 3.23 East Asia and Pacific 3.35 5.72 4.84 7.40 5.04 Europe and Central Asia 1.40 4.13 4.94 7.15 4.06 Latin America and the Caribbean 2.34 3.02 4.83 4.51 3.52 Middle East and North Africa 1.74 3.17 4.62 6.18 3.39 South Asia 0.89 2.87 4.17 5.42 2.95 Sub-Saharan Africa 0.65 2.36 4.35 5.36 3.37 High-income countries 1.68 2.88 2.81 3.54 2.59 World 1.16 3.06 3.97 5.05 3.19 Sources: Based on Cousens and others 2011; and 2015 UN Inter-Agency Group for Child Mortality Estimation (IGME). Note: TU5MR = total under-5 mortality rate. exceed the MDG 4 target ARR was East Asia and Pacific for postneonatal mortality exceeded the TU5MR, on (5.0 percent), although LMIC countries of Europe and average, in most regions. It is interesting to note how Central Asia (4.1 percent) came fairly close. All other similar the rates of decline are for postneonatal mortality regions, with ARRs ranging between 2.6 percent and risks and risks between ages one and five years on the 3.5 percent, performed well below the MDG target. one hand, and how different stillbirth rates of decline are Globally and in all regions, declines were slowest for from declines of risk after birth, on the other hand. The stillbirths, averaging only about 1 percent per year in the ARR of mortality risk after the neonatal period was very aggregate, and highest for child mortality rates except close to or greater than the rate of reduction required to for Latin America and the Caribbean; rates of decline achieve the primary MDG 4 target in all LMICs; failure Levels and Causes of Mortality under Age Five Years 73 Table 4.3 Numbers of Deaths from the 28th Week of Pregnancy to Age Five Years, 2000 and 2015 (thousands) 2000 2015 28 weeks 28 weeks 28 days gestation Birth to 28 days 1–5 gestation Birth to to 1 1–5 World Bank region to birth 27 days to 1 year years TU5MR to birth 27 days year years TU5MR Low- and middle- income countries 2,639 3,826 2,891 2,906 12,262 2,420 2,625 1,735 1,478 8,256 East Asia and Pacific 420 581 337 252 1,591 279 270 178 89 816 Europe and Central Asia 39 78 59 30 206 36 47 31 12 126 Latin America and the Caribbean 111 156 132 59 458 71 90 58 27 246 Middle East and North Africa 102 154 93 63 412 105 128 62 34 328 South Asia 1,130 1,755 834 932 4,651 925 1,065 416 389 2,795 Sub-Saharan Africa 836 1,103 1,437 1,569 4,945 1,003 1,025 990 928 3,946 High-income countries 54 86 49 25 213 44 58 33 16 152 World 2,693 3,912 2,940 2,931 12,476 2,464 2,682 1,768 1,494 8,408 Sources: Based on Cousens and others 2011; and 2015 UN Inter-Agency Group for Child Mortality Estimation (IGME). Note: TU5MR = total under-5 mortality rate. Table 4.4 Annual Rates of Reduction in Numbers of Deaths from the 28th Week of Pregnancy to Age Five Years, 2000 and 2015 2000–15 World Bank region 28 weeks gestation to birth Birth to 27 days 28 days to 1 year 1–5 years TU5MR Low- and middle-income countries 0.58 2.51 3.41 4.51 2.64 East Asia and Pacific 2.73 5.12 4.26 6.94 4.45 Europe and Central Asia 0.63 3.37 4.19 6.30 3.28 Latin America and the Caribbean 2.99 3.66 5.47 5.29 4.15 Middle East and North Africa −0.19 1.24 2.72 4.18 1.51 South Asia 1.33 3.33 4.64 5.83 3.40 Sub-Saharan Africa −1.21 0.49 2.49 3.50 1.50 High-income countries 1.31 2.64 2.51 2.85 2.27 World 0.59 2.52 3.39 4.49 2.63 Sources: Based on Cousens and others 2011; and 2015 UN Inter-Agency Group for Child Mortality Estimation (IGME). Note: TU5MR = total under-5 mortality rate. to achieve the target rate of decline overall was the result postneonatal period in 2000 but by stillbirths in 2015. of relatively slower declines for stillbirths (especially) The numbers of deaths declined for all regions and for and neonatal mortality. all age ranges, except for stillbirths in Sub-Saharan Africa The numbers of deaths by age range are a product of and the Middle East and North Africa, which increased risk (probability of dying) and numbers at risk (whether at 1.21 percent and 0.19 percent per year, respectively, population, births, or viable fetuses). Table 4.3 shows reflecting slowly increasing risks, especially in Sub- estimated numbers of deaths by age range, region, and Saharan Africa. The numbers of deaths under age five year. The number of deaths between 28 weeks of ges- years declined fastest in Latin America and the Caribbean tation and age five declined from 12.5 million in 2000 and in East Asia and Pacific; the slowest rate of decline, to 8.4 million in 2015, a decline of 2.6 percent per year by a substantial margin, was in Sub-Saharan Africa and (table 4.4). Globally, the numbers of deaths are highest the Middle East and North Africa (1.5 percent in both in the neonatal period in both years, followed by the regions); the third-slowest were HICs (2.2 percent). 74 Reproductive, Maternal, Newborn, and Child Health During this period, there was a marked concentration mortality rates (annual rates of decline of 1.2 percent1 of global deaths before the fifth birthday in Sub-Saharan and 3.1 percent, respectively, at the global level) and a Africa, with the proportion increasing from 40 percent shift in at-risk populations away from lower mortality to 47 percent; the proportion of child deaths between the to higher mortality regions, particularly in Sub-Saharan ages of one and five years increased from 54 percent to Africa. Population estimates (UN 2015) indicate that 62 percent. Approximately 98 percent of deaths occurred the proportion of global births in Sub-Saharan Africa in LMICs in all age groups in both 2000 and 2015. In increased from 20.1 percent in 2000 to 25.3 percent in East Asia and Pacific and South Asia, which are the 2015, and this trend is expected to continue. Another two regions with shares of global deaths under age five characteristic of under-five mortality in Sub-Saharan years of more than 10 percent, the proportion declined, Africa is the high child mortality rate (ages one to five from 13 percent to 10 percent and from 37 percent to years) relative to other age ranges. 33 percent, respectively. Further reductions in child mortality accordingly face Estimates of stillbirth rates have not been developed several challenges: by gender of the fetus, but estimates are available of the conventional U5MR by gender. For LMICs overall in • First, faster reductions in stillbirth rates and neonatal 2013, the ratio of boys to girls U5MR was about 1.08, mortality rates are needed. In both cases, progress will but this average conceals substantial regional variation. require greater contact with effective health systems For Europe and Central Asia, Latin America and the around childbirth, with higher proportions of deliv- Caribbean, East Asia and Pacific, and HICs, the ratio eries taking place in well-equipped facilities with high ranged from 1.19 to 1.26; for Sub-Saharan Africa and quality of care; the development of such facilities will the Middle East and North Africa, the ratio was about be expensive. 1.15, but was less than 1.0 in South Asia, indicating a • Second, faster declines must be achieved at all ages disadvantage for girls (results not shown). The numbers under five years in Sub-Saharan Africa; given a con- of deaths by gender of child reflect both differences in tinuing trend toward higher proportions of births risk by gender and differences in gender ratios at birth, in the region, declines in risk must reach at least such that the overall ratio for LMICs of deaths of boys the LMIC average so as not to be a brake on global to deaths of girls under age five years is 1.17; this rate progress; some preliminary evidence (You and others varies from 1.08 in South Asia to about 1.30 in East Asia 2015) suggests that rates of decline are accelerating in and Pacific (elevated by the very high sex ratio at birth some countries in the region. in China), Europe and Central Asia, Latin America and • Finally, the high mortality risk of children between the Caribbean, and HICs. As a general rule (Hill and their first and fifth birthdays is a concern, particularly Upchurch 1995), the ratio of boys to girls U5MR tends in Sub-Saharan Africa. Progress has been substantial to rise as overall U5MR declines until it reaches values of in this age range, but risks remain high; in some less than about 25 per 1,000 live births, so the ratio for regions, injury risks are actually increasing (Liu and LMICs is likely to increase in coming decades. others, forthcoming). Child mortality reduction benefits from some tail- Discussion and Policy Implications winds however. An increasing proportion of births will A major advance in the discussion of child mortality occur in urban areas, with lower mortality risks (Fink change in this chapter is the inclusion of stillbirths in and Hill 2013). The numbers of births are likely to stop overall mortality before age five years; this change adds increasing in regions other than Sub-Saharan Africa; in 2.5 million deaths before age five, many of them pre- some regions, the numbers are already falling, which ventable given existing interventions, to the global total will affect the numbers of child deaths, although not in 2015. We see this as important because some overlap the rates. Falling fertility will also somewhat reduce the exists between the infrastructure and interventions to risk profile of births, with smaller proportions of high prevent stillbirths and those to reduce neonatal deaths. parity births and births to older mothers; falling fertility Our analysis shows that both mortality risks and does, however, increase the proportion of one high risk numbers of deaths under age five years declined sub- group, first births, and it appears to have limited impact stantially from 2000 to 2015, and that all four age ranges on birth intervals (Hill and Liu 2013). One of the most benefited in all regions. However, the global pace of widely recognized factors associated with child mortality decline was still slower than that required to achieve the decline is maternal education (Hill and Liu 2013), and MDG 4 target. This disappointing rate of decline was the educational profile of women in LMICs is improving due to slow progress in reducing stillbirth and neonatal rapidly; cohorts with high proportions of women with Levels and Causes of Mortality under Age Five Years 75 secondary or higher education, the levels with the stron- and factors associated with stillbirth, two aspects of the gest associations with reduced child mortality, are now International Classification of Diseases that are particu- approaching the peak years of reproduction. larly weak. A final positive factor is likely to be continued eco- With respect to deaths in childhood, the Child nomic growth, which, according to some forecasts, Health Epidemiology Reference Group has published may differentially favor Sub-Saharan Africa; much may a series of estimates of the distribution of causes of depend, however, on how the gains in income growth are child death since 2005, during which time estimation distributed among populations. methods and the quality and quantity of input data have improved (Black and others 2010; Bryce and others 2005; Johnson and others 2010; Lawn, Wilczynska- LEVELS AND TRENDS OF CAUSES OF Ketnede, and Cousens 2006; Liu and others 2012; Liu and others 2015; Liu and others, forthcoming; Morris, MORTALITY UNDER AGE FIVE YEARS, 2000–15 Black, and Tomaskovic 2003). We report here estimates Both probabilities of dying and numbers of deaths of the distribution of child deaths by cause among live under age five years declined substantially from 2000 births in 2015 and time trends of child deaths by cause to 2015. At the global level, however, the declines failed since 2000 (Liu and others 2015). to reach the MDG 4 targets, and acceleration is needed at the global, regional, and national levels beyond 2015. Progress can be accelerated by using reliable information Data and Methods about the distribution of deaths by cause and by scaling In LMICs, data on stillbirths by cause are sparse and up cause-specific interventions (Bhutta and others 2008; generally based on classification systems that rely on Darmstadt and others 2005; Jones and others 2003; Lawn maternal history and health and intrapartum events, and others 2011). To guide global and national programs and less frequently, on placental histopathology and and research efforts, information about the distribution other tests. Such classification systems have been of causes of child deaths should be routinely updated. judged to be suboptimal and are not recommended To assess the lasting effects of child health interventions (Flenady and others 2009). Given that approximately and assist the development of long-term child survival 40 percent of births in LMICs are managed at home and strategies, time trends of child deaths by cause that are that limited stillbirth data are recorded even at health derived using consistent methods are needed. facilities, the WHO and collaborators have developed a This chapter focuses on major child deaths from the stillbirth verbal autopsy, validated in Ghana (Edmond 28th week of pregnancy to age five years, so we discuss and others 2008), India (Aggarwal, Jain, and Kumar causes of both stillbirths and deaths from live birth to 2011), and Pakistan (Nausheen and others 2013), with age five years. Because there is only moderate overlap the goal of establishing population-based cause-of- between the causes of death in late pregnancy and in the stillbirth data. Other endeavors to expand the available neonatal period, we will first discuss cause structures of data on the causes of stillbirth include a probabilistic stillbirths, and then the causes of death after a live birth. model to predict likely causes of stillbirth based on National data on causes of stillbirth are not available verbal autopsy questions (Vergnano and others 2011) for either HICs or LMICs. As of 2011, more than 35 and the use of birth attendants as respondents for stillbirth classification systems had been published in the stillbirth verbal autopsy (Engmann and others 2012). literature, the majority of them developed to describe Accordingly, given the current state of cause-of- the 2 percent of stillbirths occurring in HICs. These stillbirth data, for the purposes of this chapter, global classification systems generally require fetal surveil- estimates of the percent of stillbirths occurring after the lance, advanced diagnostics, and post mortem examina- onset of labor are presented. Where cause data are weak, tion, making their use in resource-constrained settings categorizing stillbirths by time of death (antepartum impractical (Lawn and others 2011). Even if data exist, versus intrapartum) is helpful in that many intrapartum unexplained stillbirths have been shown to account for deaths are term fetuses who should survive if born alive; 15 percent to 71 percent of stillbirths, limiting the use- these deaths are often associated with poor quality care fulness of the data, especially for comparative purposes. (Lawn and others 2011). In addition, selected data are Flenady and others (2009, 10) state that restricting presented to illustrate common causes of stillbirth from reporting to the underlying cause of stillbirth is “chal- HICs and LMICs. lenging, (and often inappropriate), due to the complex- A detailed description of the input data and esti- ity of the clinical situation in which the fetus dies.” For mation methods for the cause-of-death distribution this reason, data are also needed on contributing causes among live-born children has been published elsewhere 76 Reproductive, Maternal, Newborn, and Child Health (Liu and others 2012; Liu and others 2015; Liu and the results of a systematic review of the literature (Lawn others, forthcoming). and others 2011). Globally, 45 percent of stillbirths occur during labor, ranging from 14 percent in HICs, to 16 percent in the Middle East and North Africa, and Results 23–56 percent in LMICs (Lawn and others 2011). Table 4.5 shows the percentage of stillbirths occurring Table 4.6 summarizes the distribution of single causes during the intrapartum period by world region based on of stillbirth and contributing conditions from areas within six HICs using the Cause of Death and Associated Conditions classification system that was judged favor- Table 4.5 Estimates of the Percentage of Stillbirths ably for retention of stillbirth information in an eval- during the Intrapartum Period, by Region, 2008 uation of stillbirth classification systems (Flenady Estimated intrapartum and others 2009). The six countries include Australia, World region stillbirths (%) Canada, the Netherlands, Norway, the United Kingdom, Low- and middle-income countries 44.3 and the United States. Stillbirth is defined in table 4.6 as a fetal death at a gestational age of 22 weeks or more, or East Asia and Pacific 24.0 500 or more grams birth weight. The leading causes of Europe and Central Asia 20.0 death are “unknown” (30 percent), followed by placental Latin America and the Caribbean 23.1 pathology (29 percent) and infection (12 percent). Fewer Middle East and North Africa 16.4 than 10 percent of stillbirths were attributed to any one of the remaining five causes. However, although only South Asia 56.6 7 percent of stillbirths were attributed to maternal condi- Sub-Saharan Africa 46.5 tions as the single cause, maternal causes contributed to High-income countries 13.7 24 percent of stillbirths, and placental pathologies con- World 43.7 tributed to more than 50 percent of all stillbirths. Using Source: Adapted from Lawn and others (2011) to reflect regions consistent with those this data-intensive classification system, intrapartum used elsewhere in this chapter. conditions, defined narrowly as extreme prematurity Table 4.6 Distribution of Single Causes of Stillbirth and Percentage of Contributing Causes in Six High-Income Countries Using the Cause of Death and Associated Conditions Classification System Percent Single cause of stillbirth Contributing causes of death Unknown 30 Lacking or despite documentation and autopsy results 30 Placental pathologies 29 Infection or inflammation, abruption or retroplacental hematoma, infarction 59 and thrombi, circulatory disorders, transfusion or feto-maternal hemorrhage, small-for-gestation placenta, villous or vascular maldevelopment Infection 12 Unspecified, Group B streptococci 14 Cord 9 Knots, loops, abnormal insertion, focal anomaly, generalized anomaly, 17 infection or inflammation Maternal 7 Unspecified, hypertensive disorder, cervix insufficiency, hematology, diabetes, 24 autoimmune disease Congenital abnormalities 6 Unspecified, cardiovascular or lymphatic, triploidies 11 Fetal 4 Unspecified 7 Intrapartum 3 Extreme prematurity, asphyxia of unknown cause 5 Associated perinatal n.a. Small for gestational age, oligohydramnios, preterm premature rupture of the 26 membranes, multiples, antepartum hemorrhage, suboptimal care Associated maternal n.a. Smoking, maternal body mass index ≥ 30 kg/m2, obstetric history 10 Total 100 Source: Flenady and others 2009. Note: kg/m2 = kilograms per square meter; n.a. = not applicable. High-income countries for this table comprise Australia, Canada, the Netherlands, Norway, the United Kingdom, and the United States. Levels and Causes of Mortality under Age Five Years 77 Table 4.7 Distribution of Causes of Stillbirth during Table 4.8 Distribution of Causes of Stillbirth in a the Antepartum and Intrapartum Periods in Kintampo, Hospital in Chandigarh, India, 2006–08 Ghana, 2003–04 Percent Causes of stillbirth determined via clinical assessment Percent Antepartum Intrapartum Congenital malformations 12.0 period period Underlying maternal illness 12.9 Congenital abnormalities 1.7 0.8 Pregnancy-induced hypertension 30.7 Maternal disease 14.0 0.0 Antepartum hemorrhage 15.6 Obstetric complications 0.0 59.3 Obstetric complications 8.4 Maternal hemorrhage 4.1 4.8 Multiple pregnancy 2.2 Other 22.8 3.6 Asphyxia not explained by any maternal condition 1.8 Unexplained 57.4 31.5 Other specific fetal problem 4.0 Total (N) 100 (413) 100 (248) Unexplained stillbirth 10.2 Source: Edmond and others 2008. Unexplained small size for gestational date 0.0 Unexplained preterm birth (< 37 weeks) 2.2 and asphyxia from unknown cause, were responsible for Total (N) 100 (225) only 3 percent of stillbirths in these HICs. Nine percent Source: Aggarwal, Jain, and Kumar 2011. of stillbirths occurred during the intrapartum period (data not shown), although the cause of most of them stemmed from the antepartum period. (0.922 million, 15.5 percent), and intrapartum-related Table 4.7 presents the percentage distribution of events or birth asphyxia (0.689 million, 11.6 percent) causes of stillbirth occurring during the antepartum (table 4.9). Other important causes include diarrhea and intrapartum periods in rural Ghana (Edmond and (0.526 million, 8.9 percent), congenital malforma- others 2008). Data were collected via verbal autopsy tion (0.505 million, 8.5 percent), sepsis or meningitis among women who delivered at home and at health (0.525 million, 8.8 percent), and injury (0.331 million, facilities, with stillbirth defined as fetal death at 28 or 5.6 percent). more weeks of gestation. More than 37.5 percent of still- The burden of mortality by cause in live-born chil- births occurred during the intrapartum period. More dren younger than age five years varied widely across the than half of antepartum stillbirths were unexplained regions in 2015 (figure 4.1). Nearly half (49.5 percent, (57.4 percent), making interpretation of the remain- 2.943 million) of deaths in children younger than age ing categories difficult. Among intrapartum stillbirths, five years were in Sub-Saharan Africa, which included 31.5 percent were unexplained and 59.3 percent were 96.4 percent (0.294 million) of global child deaths due to attributed to obstetric complications. malaria and 90.6 percent (0.077 million) of global child Table 4.8 presents hospital-based cause-of-stillbirth deaths due to HIV/AIDS. South Asia had the highest data from Chandigarh, India, based on clinical and lab- number of any region of neonatal deaths in live-born oratory information and following standard obstetric children (1.065 million deaths, 57.0 percent). Preterm guidelines. Stillbirth is defined here as a birth for which no birth complications were the leading cause in this region, fetal heart sounds were heard during labor and the neo- responsible for 24.8 percent, or 0.465 million deaths natologist perceived no signs of life upon physical exami- under age five years. nation after birth. Findings indicate that 30.6 percent The Democratic Republic of Congo, Ethiopia, of stillbirths occurred during the intrapartum period; India, Nigeria, and Pakistan collectively accounted for 80.0 percent were attributed to the five major causes of about half the total number of global under age five stillbirth, with pregnancy-induced hypertension the lead- years deaths (48.3 percent, 2.871 million) and neo- ing cause (30.7 percent). Only 10.2 percent were classified natal deaths (50.8 percent, 1.362 million) in 2015. In as “unexplained” (Aggarwal, Jain, and Kumar 2011). India, 1.2 million children younger than age five years Among the 5.9 million deaths of live-born children died in 2015; more than half of them (57.9 percent, who died in the first five years of life in 2015, 45.1 percent 0.696 million) died in the first 28 days of life. Major (2.7 million) occurred in the neonatal period (table 4.3). causes of death included preterm birth compli- The three leading causes of deaths are preterm birth cations (0.321 million, 26.7 percent), pneumonia complications (1.056 million, 17.8 percent), pneumonia (0.180 million, 15.0 percent), and intrapartum-related 78 Reproductive, Maternal, Newborn, and Child Health complications (0.142 million, 11.9 percent). Angola, Table 4.9 Estimated Numbers of Deaths by Cause among the Democratic Republic of Congo, India, Nigeria, Live-Born Children Younger than Age Five Years, 2015 and Pakistan were the top five countries with the most Estimated Cause-specific pneumonia deaths and the most diarrhea deaths. For number mortality rate (per intrapartum-related complications, Ethiopia replaced Causes (millions) 1,000 live births) Angola on the list. For preterm birth complications, China replaced Angola. Burkina Faso, the Democratic Neonates ages 0–27 days Republic of Congo, Co ˆ te d’Ivoire, Mali, and Nigeria Preterm birth complicationsa 0.946 6.770 had the most malaria deaths. Intrapartum-related events b 0.635 4.547 Compared with 2000, approximately 4 million fewer c Sepsis or meningitis 0.410 2.937 deaths under age five years occurred in 2015. Deaths from pneumonia, diarrhea, and malaria decreased the Congenital abnormalitiesd 0.299 2.139 e most in absolute terms, by 680,000, 663,000 million, Other conditions 0.177 1.268 and 419,000 million, respectively. Collectively, the three Pneumonia f 0.162 1.159 causes were responsible for 43.9 percent of the absolute Tetanus 0.035 0.247 reduction in under age five years deaths in 2000–15. g Diarrhea 0.017 0.125 In 2000–15, child mortality rates of all the causes decreased, albeit at differing rates. In neonates, the Children ages 1–59 months burden of preterm birth complications decreased from Pneumoniaf 0.760 5.443 1.242 million in 2000 to 0.946 million in 2015, with e the associated mortality rate falling by 2.4 percent per Other conditions 0.655 4.691 year. Intrapartum-related deaths decreased from 1.040 Diarrhea g 0.509 3.643 to 0.635 million, with the mortality rate declining at an Injury 0.331 2.367 average ARR of 3.9 percent. Neonatal sepsis or meningi- Malaria 0.306 2.193 tis decreased from 0.529 million in 2000 to 0.410 million d in 2015, a rate of 2.3 percent per year. Neonatal teta- Congenital abnormalities 0.206 1.471 nus decreased from 0.164 million to 0.034 million at Meningitisc 0.115 0.826 10.9 percent per year. For children who died between Preterm birth complications a 0.110 0.790 the ages of 1 and 59 months, trends in numbers and AIDS 0.086 0.614 rates of death by cause were highly variable from 2000 to 2015. Pneumonia deaths in this age group Measles 0.074 0.531 b decreased from 1.44 million to 0.76 million, with the Intrapartum-related events 0.054 0.388 pneumonia-specific mortality rate dropping an average Pertussis 0.054 0.387 of 4.8 percent per year. Diarrhea deaths decreased from Source: Liu and others, forthcoming. 1.172 million to 0.509 million, a 6.1 percent decrease Note: Other conditions among children ages 1–59 months include congenital malformation, causes in the mortality rate per year during this period. originating during the perinatal period, cancer, pertussis, severe malnutrition, and other specified causes. Intrapartum-related events were formerly referred to as “birth asphyxia.” AIDS = acquired Malaria deaths declined from 0.725 million in 2000 to immunodeficiency syndrome. 0.306 million in 2015, with the malaria-specific mor- a. Estimated number of preterm deaths in children younger than age five years overall including the tality rate dropping 6.3 percent per year. Measles mor- neonatal period is 1.056 million. b. Estimated number of intrapartum-related events deaths in children younger than age five years tality fluctuated, in part due to outbreaks, but overall it overall including the neonatal period is 0.689 million. decreased from 0.481 million to 0.074 million, a rate of c. Estimated number of sepsis or meningitis deaths in children younger than age five years overall 13.1 percent per year. including the neonatal period is 0.526 million. d. Estimated number of congenital abnormalities deaths in children younger than age five years overall In 2000–15, the U5MR decreased at varying rates across including the neonatal period is 0.504 million. regions. HICs and South Asia had the slowest reduc- e. Estimated number of other conditions deaths in children younger than age five years overall including tions, at an average ARR of 3.0 percent and 3.8 percent, the neonatal period is 0.832 million. f. Estimated number of pneumonia deaths in children younger than age five years overall including the respectively. In Sub-Saharan Africa, the pneumonia- neonatal period is 0.922 million. specific mortality rate among children ages 1–59 months g. Estimated number of diarrhea deaths in children younger than age five years overall including the decreased at an annual rate of 4.2 percent. The ARR neonatal period is 0.526 million. for preterm birth complications was only 1.3 percent among children ages 1–59 months (0.3 percent among Asia, the mortality rates for pneumonia and diarrhea children under age five). The malaria-specific mortality among children ages 1–59 months decreased on average rate decreased 7.6 percent annually. Measles had the by 5.6 percent and 6.1 percent per year, respectively. highest ARR at an average of 16.5 percent. In South However, the mortality rate attributable to neonatal Levels and Causes of Mortality under Age Five Years 79 Figure 4.1 Causes of Childhood Deaths among Live-Born Children Younger than Age Five Years, by World Bank Region, 2015 Pneumonia Pneumonia Low and middle High income income 2.8% Other 1.0% Preterm 14.2% 4.4% Preterm 13.0% 22.4% 15.8% Other 11.0% Congenital 12.4% Congenital 3.3% Neonatal death Intrapartum- 45.0% Intrapartum- related events Neonatal death Intrapartum- 0.7% 53.7% Intrapartum- related events related events 10.8% Preterm related events 0.9% 5.9% Preterm 2.6% 1.8% Sepsis or Pertussis meningitis Sepsis or Pertussis 0.4% meningitis 0.9% 7.0% Other Meningitis 3.7% Meningitis 1.0% Other 2.0% 2.9% AIDS AIDS 6.3% Congenital 0.3% 1.5% Malaria 8.7% 0.3% 4.9% 5.2% Injury Tetanus Malaria 0.3% Injury Measles Congenital 5.5% Measles Diarrhea 0.6% 1.3% 8.2% 0.2% Diarrhea 14.5% 1.5% Europe and East Asia and Pneumonia Central Asia Pneumonia Pacific 3.1% 2.5% 11.9% 9.9% Other Preterm Preterm 11.3% 17.4% 19.2% Other Congenital 13.9% 5.2% Intrapartum- Congenital related events Neonatal death Neonatal death 53.7% 8.4% Intrapartum- 0.8% Intrapartum- 52.2% Intrapartum- related events Preterm related events related events 9.6% 1.3% 11.9% 1.6% Pertussis Preterm 1.1% Sepsis or Sepsis or meningitis 1.9% meningitis Meningitis 4.7% Pertussis 5.7% 1.5% 0.4% AIDS Other Other 4.2% Meningitis 0.5% 1.1% 4.2% Congenital AIDS Injury 4.5% 0.1% Malaria Injury 5.1% 0.2% Tetanus 8.6% Congenital 0.8% 9.1% 0.2% 0.2% 5.8% Tetanus 10.8% Measles Diarrhea 0.1% 1.2% Diarrhea Latin American and Pneumonia Middle East and Pneumonia the Caribbean North Africa 2.1% 10.3% 3.2% Other 10.1% Other Preterm 10.6% 12.9% 17.2% Preterm Congenital 19.9% Congenital 5.6% 9.4% Intrapartum- related events Intrapartum- 0.8% related events Neonatal death Neonatal death 51.5% Intrapartum- Preterm 0.9% related events 57.2% 2.4% Preterm 8.4% 1.8% Pertussis Intrapartum- 0.9% related events Pertussis Meningitis 11.8% 0.7% Sepsis or meningitis 0.8% Meningitis AIDS 1.4% 7.3% Sepsis or 0.1% meningitis AIDS Other Malaria 0.4% 5.8% 5.4% 6.6% 0.1% 0.2% Other Malaria Injury 0.1% 6.5% 4.4% 0.1% Tetanus Congenital Injury Measles 4.5% 10.5% 5.7% 0.2% Diarrhea Tetanus Congenital Diarrhea 0.1% 0.5% 10.5% South Asia Pneumonia Sub-Saharan Africa Pneumonia Preterm 3.1% 2.5% 10.4% Other 12.0% 14.2% 8.7% Congenital Preterm 2.3% 23.0% Other 12.2% Intrapartum- Intrapartum- related events related events 0.7% 10.2% Congenital Neonatal death Preterm 2.9% Sepsis or 1.8% Neonatal death 34.8% 57.0% meningitis Pertussis Intrapartum- 6.1% 0.6% related events Other Intrapartum- 1.1% Meningitis related events 2.0% 1.7% 11.6% Preterm Congenital AIDS 1.9% 2.8% 0.2% Pertussis 0.2% Tetanus Malaria 9.0% Sepsis or 1.1% 0.6% 0.4% Injury 0.5% meningitis 9.8% 4.1% Measles Other 9.0% Meningitis Diarrhea 1.6% Diarrhea 2.4% AIDS Tetanus Congenital 3.5% 2.6% Malaria Injury Measles 0.7% 5.6% 10.0% 5.7% 1.3% Source: Liu and others, forthcoming. Note: AIDS = acquired immunodeficiency syndrome. 80 Reproductive, Maternal, Newborn, and Child Health preterm births fell little, on average only 1.3 percent. care, is a key strategy in reducing neonatal deaths due At the country level, varying trends in cause-specific to intrapartum-related complications and preterm death rates were seen in 2000–15 (data are not shown). birth complications (Bhutta and others 2014). Scaling up new vaccines, such as Haemophilus influenza type B, pneumococcus, and rotavirus vaccines has the poten- Discussion and Policy Implications tial to further reduce pneumonia and diarrhea (Bhutta Our estimate of 2.5 million stillbirths based on an and others 2013; Walker and others 2013). Additional extrapolation of previous estimates is very similar to implementation research is urgently needed to under- a new estimate for 2015 of 2.6 million (Blencowe and stand how to better scale up coverage and quality of others, forthcoming). The numbers have been declin- these interventions (Requejo and others 2015). Social ing by 0.6 percent annually since 2000 and showing the interventions to improve child survival are as impor- lowest rate of decline of the four age groups constituting tant as cause-specific interventions. Examples include TU5MR. Although cause-of-stillbirth data are sparse improving family planning programs to help couples and lack comparability, it is clear that the percentage achieve their desired family size by minimizing unin- of intrapartum stillbirths is two to four times higher in tended pregnancies and increasing women’s education LMICs than HICs and that continued improvements (Cleland and others 2012; Gakidou and others 2010). in the implementation of evidence-based obstetric care Causes of 3.5 percent of deaths under age five years require policy prioritization to prevent the majority of among live-born children were directly derived based these deaths. Equally important is the need for consen- on vital registration data and 6.4 percent from a model sus on a cause-of-stillbirth classification system that using vital registration data; causes for 90.1 percent can be used in high- and low-resource settings to mon- were derived using verbal autopsy data (Liu and others, itor trends and assess program effectiveness. Although forthcoming). Verbal autopsy as a distinct scientific area probabilities of stillbirth are eight or more times has been improving substantially yet remains subject higher in South Asia and Sub-Saharan Africa than in to inherent limitations (Anker 1997; Fottrell and Byass HICs, many stillbirths in HICs are considered poten- 2010; Murray and others 2011). Estimates produced by tially preventable, particularly among disadvantaged sophisticated modeling cannot and should not replace women, requiring greater outreach for antenatal care any existing and future data collection efforts to generate and improved living standards. Research to address context-specific information, given that the strengths antepartum stillbirths and stillbirths associated with and limitations of the local data collection process extreme prematurity and infection are priorities in are fully accessible and well understood. Furthermore, high-income settings (Flenady and others 2009). national civil registration and vital statistics systems Among the 5.9 million live-born children who died need to be further strengthened and invested in more before reaching their fifth birthday in 2015, 45.1 percent heavily to deliver on the promise of improved and reli- died in the neonatal period. Preterm birth complications able health statistics. Ultimately, evidence-based policy and pneumonia remained the top killers in this age group. making and program planning can only be optimized Intrapartum-related events became the third leading if full openness and transparency can be achieved in the cause of child deaths globally. Other important leading evidence-generating process (Sutherland 2013). causes of child deaths include diarrhea, congenital malfor- mation, neonatal sepsis or meningitis, injury, and malaria. From 2000 to 2015, substantial reductions in deaths CONCLUSION under age five years were seen at the global level. However, the pace of reduction varied by cause. Pneumonia, diar- We present in this chapter a new concept of TU5MR, rhea, and malaria collectively contributed nearly half of which is a composite measure of mortality occurring the total reduction. Other major causes, such as preterm between 28 weeks gestation and age five years. Within birth complications, declined at a much slower rate this age group, child survival efforts should focus on globally and nearly stalled in South Asia. stillbirth and neonatal mortality, as well as preterm birth Scale-up of proven interventions to prevent and complications, pneumonia, and intrapartum-related treat childhood infectious diseases and leading neona- complications. More information is needed to better tal conditions is urgently needed to maintain and accel- understand levels and causes of stillbirth. To end pre- erate the pace of improving child survival worldwide ventable child deaths in a generation and attain the (Liu and others 2015). Improving quality care at birth, ambitious Sustainable Development Goals, child sur- such as better implementation of neonatal resuscita- vival needs to remain front and center on the global tion, antenatal corticosteroids, and kangaroo mother development agenda. Levels and Causes of Mortality under Age Five Years 81 NOTES Cousens, S., H. Blencowe, C. Stanton, D. Chou, S. Ahmed, and others. 2011. “National, Regional, and Worldwide World Bank Income Classifications as of July 2014 are as Estimates of Stillbirth Rates in 2009 with Trends since 1995: unnumbered note 1 as follows, based on estimates of gross A Systematic Analysis.” The Lancet 377 (9774): 1319–30. national income (GNI) per capita for 2013: Darmstadt, G. L., Z. A. Bhutta, S. Cousens, T. Adam, N. Walker, and others. 2005. “Evidence-Based, Cost-Effective • Low-income countries (LICs) = US$1,045 or less Interventions: How Many Newborn Babies Can We Save?” • Middle-income countries (MICs) are subdivided: The Lancet 365 (9463): 977–88. a) lower-middle-income = US$1,046 to US$4,125 Edmond, K. M., M. A. Quigley, C. Zandoh, S. Danso, b) upper-middle-income (UMICs) = US$4,126 to US$12,745 C. Hurt, and others. 2008. “Aetiology of Stillbirths and • High-income countries (HICs) = US$12,746 or more. Neonatal Deaths in Rural Ghana: Implications for Health Programming in Developing Countries.” Paediatric and 1. A constant annual rate of decline was assumed when Perinatal Epidemiology 22 (5): 430–37. interpolating and extrapolating to derive stillbirth rates for Engmann, C., A. Garces, I. Jehan, J. Ditekemena, M. Phiri, 2000 and 2015 from 1995 and 2009 estimates, respectively. and others. 2012. “Birth Attendants as Perinatal Verbal However, if the reduction of stillbirth rates has been accel- Autopsy Respondents in Low- and Middle-Income erating in this period, we could have underestimated the Countries: A Viable Alternative?” Bulletin of the World annual rate of decline of stillbirth rates. Health Organization 90 (3): 200–08. Fink, G., and K. Hill. 2013. “Urbanization and Child Mortality—Evidence from Demographic and Health Surveys.” Background paper prepared for Commission REFERENCES on Investing in Health. Harvard School of Public Health, Aggarwal, A. K., V. Jain, and R. Kumar. 2011. “Validity of Verbal Cambridge, MA. Autopsy for Ascertaining the Causes of Stillbirth.” Bulletin Flenady, V., J. F. Frøen, H. Pinar, R. Torabi, E. Saastad, and of the World Health Organization 89 (1): 31–40. others. 2009. “An Evaluation of Classification Systems for Alkema, L., J. R. New, J. Pedersen, and D. You. 2014. “Child Stillbirth.” BMC Pregnancy and Childbirth 9 (1): 24. Mortality Estimation 2013: An Overview of Updates Fottrell, E., and P. Byass. 2010. “Verbal Autopsy: Methods in in Estimation Methods by the United Nations Inter- Transition.” Epidemiologic Reviews 32 (1): 38–55. Agency Group for Child Mortality Estimation.” PLoS One Gakidou, E., K. Cowling, R. Lozano, and C. J. Murray. 2010. 9 (7): e101112. doi: http://dx.doi.org/10.1371/journal “Increased Educational Attainment and Its Effect on .pone.0101112. Child Mortality in 175 Countries between 1970 and 2009: Anker, M. 1997.“The Effect of Misclassification Error on Reported A Systematic Analysis.” The Lancet 376 (9745): 959–74. Cause-Specific Mortality Fractions from Verbal Autopsy.” Hill, K., and L. Liu. 2013. “Challenges and Opportunities International Journal of Epidemiology 26 (5): 1090–96. for Further Reductions in Infant and Child Mortality.” Bhutta, Z. A., T. Ahmed, R. E. Black, S. Cousens, K. Dewey, and Expert Paper 2013/11, United Nations Population Division, others. 2008. “What Works? Interventions for Maternal and New York. Child Undernutrition and Survival.” The Lancet 371 (9610): Hill, K., and D. M. Upchurch. 1995. “Gender Differences 417–40. in Child Health: Evidence from the Demographic and Bhutta, Z. A., J. K. Das, R. Bahl, J. E. Lawn, R. A. Salam, and Health Surveys.” Population and Development Review others. 2014. “Can Available Interventions End Preventable 21 (1): 127–51. Deaths in Mothers, Newborn Babies, and Stillbirths, and at Johnson, H. L., L. Liu, C. Fischer-Walker, and R. E. Black. 2010. What Cost?” The Lancet 384 (9940): 347–70. “Estimating the Distribution of Causes of Death among Bhutta, Z. A., J. K. Das, N. Walker, A. Rizvi, H. Campbell, Children Age 1–59 Months in High-Mortality Countries and others. 2013. “Interventions to Address Deaths from with Incomplete Death Certification.” International Journal Childhood Pneumonia and Diarrhoea Equitably: What of Epidemiology 39 (4): 1103–14. Works and at What Cost?” The Lancet 381 (9875): 1417–29. Jones, G., R. W. Steketee, R. E. Black, Z. A. Bhutta, S. S. Morris, Black, R. E., S. Cousens, H. L. Johnson, J. E. Lawn, I. Rudan, and others. 2003. “How Many Child Deaths Can We and others. 2010. “Global, Regional, and National Causes of Prevent This Year?” The Lancet 362 (9377): 65–71. Child Mortality in 2008: A Systematic Analysis.” The Lancet Lawn, J. E., H. Blencowe, R. Pattinson, S. Cousens, R. Kumar, 375 (9730): 1969–87. and others. 2011. “Stillbirths: Where? When? Why? How to Bryce, J., C. Boschi-Pinto, K. Shibuya, R. E. Black, and WHO Make the Data Count?” The Lancet 377 (9775): 1448–63. Child Health Epidemiology Reference Group. 2005. “WHO Lawn, J. E., K. Wilczynska-Ketende, and S. N. Cousens. 2006. Estimates of the Causes of Death in Children.” The Lancet “Estimating the Causes of 4 Million Neonatal Deaths 365 (9465): 1147–52. in the Year 2000.” International Journal of Epidemiology Cleland, J., A. Conde-Agudelo, H. Peterson, J. Ross, and A. Tsui. 35 (3): 706–18. 2012. “Contraception and Health.” The Lancet 380 (9837): Liu, L., H. L. Johnson, S. Cousens, J. Perin, S. Scott, and 149–56. others. 2012. “Global, Regional, and National Causes 82 Reproductive, Maternal, Newborn, and Child Health of Child Mortality: An Updated Systematic Analysis the Health Agenda for Women and Children.” The Lancet for 2010 with Time Trends since 2000.” The Lancet 379 385 (9966): 466–76. (9832): 2151–61. Sutherland, W. J. 2013. “Review by Quality Not Quantity for Liu, L., S. Oza, D. Hogan, J. Perin, I. Rudan, and others. Better Policy.” Nature 503 (7475): 167. 2015. “Global, Regional, and National Causes of Child UN (United Nations). 2000. United Nations Millennium Mortality in 2000–13, with Projections to Inform Post-2015 Declaration: Resolution Adopted by the General Assembly. Priorities: An Updated Systematic Analysis.” The Lancet 55/2. New York: United Nations. 385 (9966): 430–40. ———. 2013. The Millennium Development Goals Report 2013. Liu, L., S. Oza, D. Hogan, Y. Chu, J. Perin, and others. New York: United Nations. Forthcoming. National, Regional and Global Causes of ———. 2015. World Population Prospects: The 2015 Child Mortality in 2000–2015: Reflecting on the MDG 4 and Revision . New York: DoEaSA, Population Division, Embarking on the SDG 3.2. UN. DVD. Morris, S. S., R. E. Black, and L. Tomaskovic. 2003. “Predicting Vergnano, S., E. Fottrell, D. Osrin, P. N. Kazembe, the Distribution of Under-Five Deaths by Cause in C. Mwansambo, and others 2011. “Adaptation of a Countries without Adequate Vital Registration Systems.” Probabilistic Method (InterVA) of Verbal Autopsy to International Journal of Epidemiology 32 (6): 1041–51. Improve the Interpretation of Cause of Stillbirth and Murray, C. J., A. D. Lopez, R. Black, R. Ahuja, S. M. Ali, Neonatal Death in Malawi, Nepal, and Zimbabwe.” and others. 2011. “Population Health Metrics Research Population Health Metrics 9: 48. Consortium Gold Standard Verbal Autopsy Validation Walker, C. L. F., I. Rudan, L. Liu, H. Nair, E. Theodoratou, and Study: Design, Implementation, and Development of others. 2013. “Global Burden of Childhood Pneumonia and Analysis Datasets.” Population Health Metrics 9 (1): 27. Diarrhoea.” The Lancet 381 (9875): 1405–16. Nausheen, S., S. B. Soofi, K. Sadiq, K. A. Habib, A. Turab, You, D., L. Hug, S. Ejdemyr, and J. Beise. 2015. Levels and others. 2013. “Validation of Verbal Autopsy Tool for and Trends in Child Mortality. Report 2015. Estimates Ascertaining the Causes of Stillbirth.” PLoS One 9 (8): 10. Developed by the UN Inter-Agency Group for Child Requejo, J. H., J. Bryce, A. J. Barros, P. Berman, Z. Bhutta, and Mortality Estimation. New York: United Nations others. 2015. “Countdown to 2015 and Beyond: Fulfilling Children’s Fund. Levels and Causes of Mortality under Age Five Years 83 Chapter 5 Levels and Trends in Low Height-for-Age Gretchen A. Stevens, Mariel M. Finucane, and Christopher J. Paciorek INTRODUCTION the complete distributions of child height-for-age by country, including stunting prevalence. Paciorek and Children’s nutritional status influences their survival, others (2013) extend this body of work to separately cognitive development, and lifelong health (Adair estimate children’s height-for-age distribution in urban and others 2013; Black and others 2013; Grantham- and rural areas, by country and year. Separate estimates McGregor and others 2007; Olofin and others 2013). for urban and rural areas allow strategies that target Inadequate nutrition, together with infections, results in children in each setting to be prioritized. restricted linear growth. Stunting, or low height-for-age, is an indicator of overall nutritional status (Black and others 2013; WHO 2013) and an important cause of METHODS morbidity and mortality in infants and children (Black and others 2013; Olofin and others 2013). We present published estimates of the height-for-age Stunting caused an estimated 14 percent to 17 percent distribution from the NIMS study (Paciorek and of mortality in children under age five years in 2011, others 2013; Stevens and others 2012). We accessed accounting for 1.0 million to 1.2 million deaths (Black population-representative data on the height of children and others 2013). The World Health Assembly endorsed under age five years from nationally or regionally rep- the target of reducing the number of children with resentative household surveys, including Demographic stunting by 40 percent by 2025, compared with the 2010 and Health Surveys and Multiple Indicator Cluster baseline (World Health Assembly 2012). According to Surveys, as follows: the World Health Organization (WHO), rates of stunt- ing reduction need to be accelerated to meet this target • We obtained these data as anonymized individual (World Health Assembly 2012). anthropometric measurements, if accessible, or as Country-level information on trends in child height- summary statistics from the WHO’s Global Database for-age is needed for priority setting, planning, and on Child Growth and Malnutrition (de Onis and program evaluation. Stunting estimates are made at the Blossner 2003), or from preliminary reports not yet regional level for all world regions by UNICEF, WHO, included in the WHO’s database. and World Bank (2012, 2014). This chapter presents a • For data obtained as individual observations, we set of country-level estimates by the Nutrition Impact extracted information on urban or rural place of Model Study (NIMS) for 1985–2011 (Stevens and oth- residence for each observation. We calculated height- ers 2012). The NIMS collaboration estimates trends in for-age z-scores (HAZ) using the 2006 WHO child Corresponding author: Gretchen A. Stevens, Department of Health Statistics and Information Systems, World Health Organization, Geneva; stevensg@who.int. 85 growth standards for each individual measurement of 0–59 months may have more variation relative to (WHO 2006). the true levels than nationally representative data and • For data obtained as summary statistics, we extracted data that covered the full range of ages. Estimates by the summary statistic for the entire population cov- sex were not made because little difference was found ered by each data source, usually at the national level, between male and female stunting prevalence (Stevens and, where possible, separately for urban and rural and others 2012). areas. For the second analysis, the statistical model was • In cases for which only summarized statistics were extended to make separate estimates for urban and rural calculated using the 1977 National Center for children. The urban-rural difference in HAZ distribu- Health Statistics reference, regression equations were tion was allowed to vary by country and year. Both anal- developed to convert these estimates to the 2006 yses were also carried out for children’s weight-for-age WHO child growth standards (Stevens and others distribution, not reported here. 2012). Our final data set included measured heights Public health professionals usually report the preva- of more than 7.7 million children under age five years. lence of stunting (as defined by the WHO as HAZ below −2), rather than other metrics, such as mean HAZ or Despite the extensive data search, there were gaps the prevalence of severe stunting (HAZ below −3). In in data availability; an average of 4.5 data sources this chapter, we report mean HAZ, prevalence of stunt- were available for each country over the 26 years in ing (HAZ below −2), and prevalence of severe stunting the study period. We therefore developed Bayesian (HAZ below −3). hierarchical mixture models to estimate the complete distribution of childhood HAZ for each country and year, from which we calculated summary statistics GLOBAL AND REGIONAL TRENDS such as mean HAZ and the prevalence of stunting. The inputs for our model were individual-level records Global Trends and summary statistics. Two statistical analyses were In LMICs the prevalence of stunting has declined conducted: and mean HAZ has improved since 1985. In 1985, 47.2 percent (95 percent uncertainty interval 44.0–50.3) • An analysis of HAZ distribution in 141 low- and of children under age five years were moderately or middle-income countries (LMICs) for each year from severely stunted; this rate improved to 29.9 percent 1985 to 2011 (27.1–32.9) in 2011 (figure 5.1). Mean HAZ increased • An analysis of HAZ distribution in urban and rural during the same period, from −1.86 (−2.01 to −1.72) to areas in the same 141 LMICs for each year from 1985 −1.16 (−1.29 to −1.04). to 2011. Despite large improvements, many children remain stunted. In 2011, 314 million (95 percent uncertainty In the first model, estimates for each country-year interval 296 million to 331 million) children had HAZ were informed by data from that country-year itself, below −1, a moderate improvement from 367 million if available, and by data from other years in the same (352 million to 379 million) in 1985. Of the children with country and in other countries, especially those in the HAZ below −1 in 2011, 46 percent had HAZ between −1 same region with data in similar periods. This hier- and −2, 31 percent had HAZ between −2 and −3, and archical model shares information to a greater degree 23 percent had HAZ below −3. where data are nonexistent or weakly informative (for example, because they have a small sample size), and to a lesser degree in data-rich countries and regions. Regional Trends We modeled trends over time both as a linear trend Although child height improved in LMICs as a whole, and as a smooth nonlinear trend. The estimates were progress was less consistent at the regional level informed by time-varying covariates that help predict (figure 5.1). East Asia and Pacific and South Asia show HAZ, including maternal education, national income the largest improvements in mean HAZ, increasing by (natural logarithm of per capita gross domestic product about 0.4 per decade. Mean HAZ also increased to a [GDP] in inflation-adjusted U.S. dollars), proportion lesser extent in Europe and Central Asia, the Middle East of the population in urban areas, and an aggregate and North Africa, and Latin America and the Caribbean metric of access to basic health care. Finally, the model (increases of 0.20–0.23 per decade). However, children’s accounted for the fact that data did not cover the entire height in Sub-Saharan Africa showed inconsistent prog- country; data that did not cover the complete age range ress. In Sub-Saharan Africa, stunting prevalence may 86 Reproductive, Maternal, Newborn, and Child Health Figure 5.1 Trends in Mean Height-for-Age Z-Score and Stunting Prevalence, by Region, 1985–2011 a. Mean HAZ b. Stunting (HAZ<-2) c. Severe Stunting (HAZ<-3) 60 –1.0 40 Z-score Percent Percent 40 –2.0 20 20 –3.0 0 0 1985 1995 2005 1985 1995 2005 1985 1995 2005 South Asia East Asia and Pacific All low- and middle- Sub-Saharan Africa Europe and Central Asia income countries Middle East and North Africa Latin America and the Caribbean Source: Stevens and others 2012. Note: Shaded areas show the 95 percent uncertainty interval. HAZ = height-for-age z-scores. have increased from 41.4 percent (95 percent uncer- Improvement in mean HAZ at the national level can tainty interval 37.3–45.6) in 1985 to more than 45 from be divided into three components: 1995 to 1999; it subsequently decreased to 37.7 percent (35.3–40.2) by 2011. • Improvement in mean HAZ in rural children In 1985, mean HAZ was higher and the prevalence • Improvement in mean HAZ in urban children of stunting was lower in urban areas than in rural • Increases in the proportion of children in urban areas. areas in all regions (figure 5.2). Urban and rural mean HAZ and prevalence of stunting largely improved at Figure 5.3 shows each component’s contribution in the same pace; the urban-rural gaps in mean HAZ each region. In East Asia and Pacific and in South Asia, and prevalence of stunting were, in most cases, both predominantly rural regions in 1985 (less than maintained during the period. Nevertheless, some 30 percent urban) and in 2011 (less than 50 percent urban), improvements were observed. In Europe and Central improvements in rural HAZ contributed 68 percent or Asia and the Middle East and North Africa, both the more of the overall improvement in HAZ. In contrast, in absolute and relative gaps in the prevalence of stunt- Latin America and the Caribbean, a predominantly urban ing decreased. In Europe and Central Asia, the gap region (66 percent urban in 1985, increasing to 78 percent between urban and rural prevalence of stunting fell urban by 2011), urban improvements contributed more from 15 percent in 1985 to 7 percent, the narrowest than 70 percent of the overall improvement. gap observed, in 2011. The most impressive improvement in children’s height occurred in China, followed by Vietnam, Bangladesh, Height-for-Age in 2011 India, Bhutan, Brazil, Nepal, and Tunisia; in these coun- Despite large improvements in HAZ in most regions, tries, mean HAZ increased by 0.35–0.51 per decade. In only a few countries have mean HAZ and stunting prev- most of these high-performing countries, the urban- alence that approach the ideal of a mean HAZ of at least rural gap in mean HAZ also declined; the exceptions zero and stunting prevalence of 2.3 percent (maps 5.1, are China, Vietnam, and with large uncertainty, Jamaica. 5.2, 5.3). Chile, Jamaica, and Kuwait have mean HAZ HAZ may have deteriorated in 17 countries between greater than 0 and a prevalence of stunting of less than 1985 and 2011, nearly all in Sub-Saharan Africa and the 5 percent, as do urban areas of China. Oceania region of East Asia and Pacific; most had large The majority of stunted children still live in rural uncertainties, with the exception of estimated declines in areas. These stunted children live mainly in South Asia Côte d’Ivoire and Niger. Overall, the rate of improvement (52 million [uncertainty interval 42 million to in mean HAZ was positively correlated with a reduction 62 million]) and Sub-Saharan Africa (37 million in urban-rural inequality in mean HAZ. [35 million to 40 million]). In rural areas in Afghanistan, Levels and Trends in Low Height-for-Age 87 Figure 5.2 Trends in Urban and Rural Prevalence of Stunting, by Region, 1985–2011 a. All low- and middle-income b. East Asia and Pacific c. Europe and Central Asia countries Percentage stunted Percentage stunted Percentage stunted 60 60 60 40 40 40 20 20 20 0 0 0 1985 1995 2005 1985 1995 2005 1985 1995 2005 Year Year Year d. Latin America and e. Middle East f. South Asia the Caribbean and North Africa Percentage stunted Percentage stunted Percentage stunted 60 60 60 40 40 40 20 20 20 0 0 0 1985 1995 2005 1985 1995 2005 1985 1995 2005 Year Year Year g. Sub-Saharan Africa Percentage stunted 60 40 20 0 1985 1995 2005 Year Rural Urban Source: Paciorek and others 2013. Note: Shaded areas show the 95 percent uncertainty interval of the trend. Burundi, Guatemala, Niger, Timor-Leste, and the and 15 million (14 million to 16 million) in urban Republic of Yemen, more than 50 percent of the children Sub-Saharan Africa. under age five years were stunted in 2011. Nevertheless, as urbanization increases, a rising per- centage of stunted children live in urban areas—from IMPLICATIONS FOR PRIORITY SETTING 23 percent in 1985 to 31 percent in 2011 (figure 5.4). Stunting has received increased attention as a primary In 2011, 18 million (uncertainty interval 14 million to indicator of children’s nutritional status. It has been 22 million) stunted children lived in urban South Asia included as one of three health status indicators by the 88 Reproductive, Maternal, Newborn, and Child Health Commission on Information and Accountability for Stunting prevalence and mean HAZ have improved Women’s and Children’s Health, together with mater- globally and in most regions, although progress has nal mortality ratios and mortality in children under been uneven in Sub-Saharan Africa. Improvements age five years (WHO 2013). The Scaling-Up Nutrition in HAZ at the national level have generally not been initiative provides a catalyst for implementing effective accompanied by reductions in the gap between urban nutrition interventions at the population level, and the and rural stunting or between stunting in poorer and WHO’s target to reduce the number of stunted children wealthier populations (Restrepo-Méndez and others provides a goal (World Health Assembly 2012). Other 2014). South Asia and Sub-Saharan Africa, the regions anthropometric indicators, such as wasting and severe with the highest rates of stunting and severe stunting, wasting, provide complementary information on acute also have the highest rates of child mortality (UNICEF nutritional situations (box 5.1). 2014; WHO 2013). Because children’s nutrition, as measured by linear growth, is protective (Olofin and Figure 5.3 Contributions of Urban Improvement, Urbanization, others 2013), it is important to prioritize programs and Rural Improvement to Overall Improvements in Mean that target these areas. HAZ, 1985–2011 Children’s linear growth is restricted when they do All low- and middle-income not receive sufficient nutrition (through nonexclusive countries breastfeeding or inappropriate complementary feed- East Asia and Pacific ing) or when they lose nutrients during sickness. Both South Asia situations have a range of contributing factors. Food Europe and Central Asia insufficiency, poor water and sanitation, and limited access to high-quality primary care are all associated Middle East and North Africa with household and community poverty; all may lead to Latin America and the poor growth outcomes (WHO 2014a). However, inter- Caribbean Sub-Saharan Africa ventions such as nutrition education and diarrhea case management can mitigate low height-for-age (Bhutta 0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 and others 2008; Bhutta and others 2013). Gain in mean HAZ, 1985–2011 We previously found that reductions in stunting Urban improvement Urbanization Rural improvement were consistent with a shift of the entire distribution of Source: Paciorek and others 2013. HAZ (Stevens and others 2012). This finding implies Note: HAZ = height-for-age z-scores. that, for the past two and a half decades, the primary Map 5.1 Prevalence of Stunting by Country, 2011 IBRD 41896 | OCTOBER 2015 Prevalence of Stunting by Country, 2011 Greater than 50 40–49 30–39 20–29 10–19 0–9 No estimate made Source: Pacionek and others, 2013. Source: Stevens and others 2012. Levels and Trends in Low Height-for-Age 89 Map 5.2 Prevalence of Stunting by Country: Urban Areas, 2011 IBRD 41897 | OCTOBER 2015 Prevalence of Stunting in Urban Areas, 2011 Greater than 40 30–39 20–29 10–19 0–9 No estimate made Source: Pacionek and others, 2013. Source: Paciorek and others 2013. Map 5.3 Prevalence of Stunting by Country: Rural Areas, 2011 IBRD 41897 | OCTOBER 2015 Prevalence of Stunting in Rural Areas, 2011 Greater than 50 40–49 30–39 20–29 10–19 0–9 No estimate made Source: Pacionek and others, 2013. Source: Paciorek and others 2013. mechanism for improvement has been population Although the relative importance of various popu- improvements rather than targeted interventions. These lation forces is uncertain, several lessons have emerged population improvements include enhanced health from the research: promotion, such as breastfeeding and complemen- tary feeding; improved environmental and sanitary • Growth in national income seems to have a pos- conditions; increased availability and affordability of itive effect on child nutrition but may be insuffi- nutritious foods; and improved income and education cient, perhaps because improving nutritional status levels. Because the burden of stunting is still largely in requires more equitable income distribution and rural areas, evaluating potential interventions’ expected increased investments in health care and nutrition benefits for rural children is appropriate. programs (Anand and Ravallion 1993; Haddad and 90 Reproductive, Maternal, Newborn, and Child Health Figure 5.4 Number of Stunted Children, by Region and Urban or Rural Residence, 1985–2011 a. Number of stunted children in rural areas b. Number of stunted children in urban areas 200 200 180 180 160 160 140 140 120 120 Millions Millions 100 100 80 80 60 60 40 40 20 20 0 0 11 91 93 95 97 99 01 03 05 07 09 97 99 01 85 87 89 85 87 89 91 93 95 03 05 07 09 11 20 20 20 20 20 19 19 19 19 19 19 19 19 20 19 19 20 19 19 19 19 19 19 20 20 20 20 20 Sub-Saharan Africa Middle East and North Africa Europe and Central Asia South Asia Latin America and the Caribbean East Asia and Pacific Source: Paciorek and others 2013. Box 5.1 Global Patterns in Wasting or Low Weight-for-Height Child wasting may be caused by acute illness, inap- North Africa, with estimated regional prevalence of propriate feeding, or insufficient feeding. The World wasting ranging between 15 percent and 7 percent. Health Assembly endorsed a target goal of reducing Of the 102 countries for which data on severe and maintaining childhood wasting to less than wasting from 2006 to 2012 were available, 51 had at 5 percent by 2025 (World Health Assembly 2012). least one survey with a severe wasting prevalence of The global prevalence of wasting in 2013 was 7.7 per- 2 percent or higher. Of the 110 countries reporting cent (uncertainty interval 6.6 percent to 8.9 percent), data on wasting in the same period, 64 reported and the global prevalence of severe wasting was prevalence of wasting greater than 5 percent in at 2.6 percent (uncertainty interval 2.1 percent to least one survey. In nine countries—Bangladesh, 3.2 percent) (UNICEF, WHO, and World Bank Benin, Chad, Djibouti, India, Niger, Papua New 2014). According to these estimates, the prevalence Guinea, South Sudan, and Timor-Leste—the most of wasting and severe wasting were highest in the recent survey data (excluding data before 2006) indi- World Bank regions (in decreasing order) of South cate a prevalence of wasting greater than 15 percent Asia, Sub-Saharan Africa, and the Middle East and (WHO 2014b). others 2003; Ravallion 1990; Smith and Haddad 2002; Pongou, Salomon, and Ezzati 2006). The adverse Subramanyam and others 2011). effects on nutrition were greatest in poorer house- • Macroeconomic shocks, structural adjustment, and holds, especially in rural areas, transmitted through trade policy reforms have been implicated in the lower household earnings and assets, reduced food worsening nutritional status in Sub-Saharan Africa in subsidies, and reduced health care use (Cooper Weil the 1980s and 1990s (Cooper Weil and others 1990; and others 1990; Pongou, Salomon, and Ezzati 2006). Levels and Trends in Low Height-for-Age 91 In contrast, programs that improve income, nutrition, REFERENCES and health care among the poor generally also Adair, L. S., C. H. Fall, C. Osmond, A. D. Stein, R. Martorell, and improve growth outcomes, especially in children of others. 2013. “Associations of Linear Growth and Relative lower socioeconomic status (Bhutta and others 2013; Weight Gain during Early Life with Adult Health and Fernald, Gertler, and Neufeld 2008; Lagarde, Haines, Human Capital in Countries of Low and Middle Income: and Palmer 2007; Rivera and others 2004). Findings from Five Birth Cohort Studies.” The Lancet P382 (9891): 525–34. These findings indicate that child nutrition is best Anand, S., and M. Ravallion. 1993. “Human Development in improved through equitable economic growth, pro- Poor Countries: On the Role of Private Incomes and Public poor primary care, and nutrition programs that support Services.” Journal of Economic Perspectives 7 (1): 133–50. breastfeeding and appropriate complementary feeding. Bassett, L. 2008. “Can Conditional Cash Transfer Programs Conditional cash transfer programs, especially those Play a Greater Role in Reducing Child Undernutrition?” linked to nutrition education and primary health care, Social Protection Discussion Paper 0835, World Bank, Washington, DC. offer the potential to help target and deliver these inter- Bhutta, Z. A., T. Ahmed, R. E. Black, S. Cousens, K. Dewey, and ventions (Bassett 2008). others. 2008. “What Works? Interventions for Maternal and Child Undernutrition and Survival.” The Lancet 371 (9610): 417–40. CONCLUSIONS Bhutta, Z. A., J. K. Das, A. Rizvi, M. F. Gaffey, N. Walker, Prioritizing improvements in HAZ in rural areas of and others. 2013. “Evidence-Based Interventions for high-burden countries is an essential component of ini- Improvement of Maternal and Child Nutrition: What Can Be Done and at What Cost?” The Lancet 382 (9890): tiatives to improve child health and nutrition. Achieving 452–77. this goal may occur through policies that improve house- Black, R. E., C. G. Victora, S. P. Walker, Z. A. Bhutta, P. Christian, holds’ economic status and food security; provide more and others. 2013. “Maternal and Child Undernutrition equitable access to interventions and services, such as and Overweight in Low-Income and Middle-Income clean water and sanitation; encourage breastfeeding and Countries.” The Lancet 382 (9890): 427–51. complementary feeding using local foods; and offer case Cooper Weil, D., A. Alicbusan, J. Wilson, M. Reich, and management of diarrhea and other infectious diseases D. Bradley. 1990. The Impact of Development Policies on (Bhutta and others 2013; Sanchez and Swaminathan Health: A Review of the Literature. Geneva: World Health 2005; WHO 2014a). Organization. A second essential component of improvement ini- de Onis, M., and M. Blossner. 2003. “The World Health tiatives is the development and implementation of com- Organization Global Database on Child Growth and Malnutrition: Methodology and Applications.” International plementary policies and programs for children in urban Journal of Epidemiology 32 (4): 518–26. settings. An increasing share of undernourished children Fernald, L. C., P. J. Gertler, and L. M. Neufeld. 2008. “Role of live in cities; these children are susceptible to economic Cash in Conditional Cash Transfer Programmes for Child shocks that affect food prices and may face different bar- Health, Growth, and Development: An Analysis of Mexico’s riers to accessing adequate nutrition than rural children. Oportunidades.” The Lancet 371 (9615): 828–37. Grantham-McGregor, S., Y. B. Cheung, S. Cueto, P. Glewwe, L. Richter, and others. 2007. “Developmental Potential in NOTES the First 5 Years for Children in Developing Countries.” The Lancet 369 (9555): 60–70. World Bank Income Classifications as of July 2014 are as Haddad, L., H. Alderman, S. Appleton, L. Song, and follows, based on estimates of gross national income (GNI) Y. Yohannes. 2003. “Reducing Child Malnutrition: How per capita for 2013: Far Does Income Growth Take Us?” World Bank Economic Review 17 (1): 107–31. • Low-income countries (LICs) = US$1,045 or less Lagarde, M., A. Haines, and N. Palmer. 2007. “Conditional Cash • Middle-income countries (MICs) are subdivided: Transfers for Improving Uptake of Health Interventions in a) lower-middle-income = US$1,046 to US$4,125 Low- and Middle-Income Countries: A Systematic Review.” b) upper-middle-income (UMICs) = US$4,126 to US$12,745 Journal of the American Medical Association 298 (16): • High-income countries (HICs) = US$12,746 or more. 1900–10. Olofin, I., C. M. McDonald, M. Ezzati, S. Flaxman, R. E. Black, The authors alone are responsible for the views expressed and others. 2013. “Associations of Suboptimal Growth with in this chapter and they do not necessarily represent the views, All-Cause and Cause-Specific Mortality in Children under decisions, or policies of the institutions with which they are Five Years: A Pooled Analysis of Ten Prospective Studies.” affiliated. PLoS One 8 (5): e6636. 92 Reproductive, Maternal, Newborn, and Child Health Paciorek, C. J., G. A. Stevens, M. L. Finucane, and M. Ezzati. Stevens, G. A., M. M. Finucane, C. J. Paciorek, S. R. Flaxman, 2013. “Children’s Height and Weight in Rural and Urban R. A. White, and others. 2012. “Trends in Mild, Moderate, Populations in Low-Income and Middle-Income Countries: and Severe Stunting and Underweight, and Progress A Systematic Review.” The Lancet Global Health 1 (5): towards MDG 1 in 141 Developing Countries: A Systematic e300–e309. Analysis of Population Representative Data.” The Lancet Pongou, R., J. A. Salomon, and M. Ezzati. 2006. “Health Impacts 380 (9844): 824–34. of Macroeconomic Crises and Policies: Determinants of Subramanyam, M. A., I. Kawachi, L. F. Berkman, and Variation in Childhood Malnutrition Trends in Cameroon.” S. V. Subramanian. 2011. “Is Economic Growth Associated International Journal of Epidemiology 35 (3): 648–56. with Reduction in Child Undernutrition in India?” PLoS Ravallion, M. 1990. “Income Effects on Undernutrition.” Medicine 8 (3): e1000424. Economic Development and Cultural Change 38 (3): 489–515. UNICEF (United Nations Children’s Fund). 2014. Levels and Restrepo-Méndez, M. C., A. J. D. Barros, R. E. Black, and Trends in Child Mortality. New York: UNICEF. C. G. Victora. 2014. “Time Trends in Socio-Economic UNICEF, WHO, and World Bank. 2012. UNICEF-WHO-World Inequalities in Stunting Prevalence: Analyses of Repeated Bank Joint Child Malnutrition Estimates. Geneva: WHO. National Surveys.” Public Health Nutrition 18 (12) 2097–104. ———. 2014. UNICEF-WHO-The World Bank: 2013 Joint Child doi:10.1017/S1368980014002924. Malnutrition Estimates: Levels and Trends. Geneva: WHO. Rivera, J. A., D. Sotres-Alvarez, J. P. Habicht, T. Shamah, and http://www.who.int/nutgrowthdb/estimates2013/en/. S. Villalpando. 2004. “Impact of the Mexican Program WHO (World Health Organization). 2006. WHO Child for Education, Health, and Nutrition (Progresa) on Rates Growth Standards Length/Height-for-Age, Weight-for-Age, of Growth and Anemia in Infants and Young Children: Weight-for-Length, Weight-for-Height and Body Mass A Randomized Effectiveness Study.” Journal of the American Index-for-Age: Methods and Development. Geneva: WHO. Medical Association 291 (21): 2563–70. ———. 2013. Global Health Observatory: Health Equity Sanchez, P. A., and M. S. Swaminathan. 2005. “Hunger in Monitor. Geneva: WHO. Africa: The Link between Unhealthy People and Unhealthy ———. 2014a. “Global Nutrition Targets 2025: Stunting Policy Soils.” The Lancet 365 (9457): 442–44. Brief.” WHO/NMH/NHD/14.3, WHO, Geneva. Smith, L. C., and L. Haddad. 2002. “How Potent Is Economic ———. 2014b. World Health Statistics 2014. Geneva: WHO. Growth in Reducing Undernutrition? What Are the World Health Assembly. 2012. “Comprehensive Implementation Pathways of Impact? New Cross-Country Evidence.” Plan on Maternal, Infant and Young Child Nutrition.” Economic Development and Cultural Change 51 (1): 55–76. World Health Organization, Geneva. Levels and Trends in Low Height-for-Age 93 Chapter 6 Interventions to Improve Reproductive Health John Stover, Karen Hardee, Bella Ganatra, Claudia García Moreno, and Susan Horton INTRODUCTION 1990s. Family planning offers a range of potential ben- efits that encompass economic development, maternal Health systems and individuals can take a number of and child health, education, and women’s empowerment actions to safeguard reproductive health. These actions (Bongaarts and others 2012). Furthermore, family plan- differ from many other health interventions in that the ning is cost-effective. The United Nations (UN) estimates motivation for their use is not necessarily limited to that for every US$1 spent on family planning, from US$2 better health and involves cultural and societal norms. to US$6 can be saved from the reduced numbers of peo- Irrespective of these additional considerations, these ple needing other public services, such as immunizations, interventions have important health implications. This health care, education, and sanitation (UN Population chapter describes four areas of intervention: Division 2009). Support for voluntary family planning has been • Family planning based on several rationales, including the following • Adolescent sexual and reproductive health (Habumuremyi and Zenawi 2012): • Unsafe abortion • Violence against women. • Population and development, the so-called demo- graphic rationale Each of these areas involves the delivery of specific • Maternal and child health health services to prevent or alleviate health risks; each • Human rights and equity also involves the complex social and cultural issues that • Environment and sustainable development. affect the widespread implementation and use of the services. Demographic Rationale The population and development rationale for family FAMILY PLANNING planning emerged in the 1960s amid a concern that rates of rapid population growth would hinder economic Rationales for Family Planning Programs growth in low- and middle-income countries (LMICs) Family planning has been a major development success and affect the ability of these countries to improve the over the past half century, with global fertility rates fall- well-being of their citizens. This rationale has been ing from more than six children per woman during her in and out of favor (Birdsall, Kelly, and Sinding 2001; lifetime in the 1960s to less than three children in the Bongaarts and others 2012; NAS 1986). Recent evidence Corresponding author: John Stover, Vice President and founder of Avenir Health, Glastonbury, Connecticut, United States, JStover@avenirhealth.org. 95 shows positive links between slower population growth population conferences in 1974, 1984, and 1994 reaf- and economic development—at least in the initial phase firmed this right (Singh 2009). of the demographic transition, when countries enjoy a The human rights rationale has focused on sexual demographic dividend, if other economic and human reproductive health and rights, with family planning capital policies are in place. The demographic dividend implicitly included. Efforts are underway to more explic- allows countries to take advantage of a beneficial depen- itly define a rights-based approach to implementing dency ratio between the working-age population and voluntary family planning programming (Hardee and the groups who need support, that is, children and the others 2014). Ensuring equity is a fundamental principal elderly (Bloom, Canning, and Sevilla 2003). It is impor- of human rights–based programming. Wealth quintiles tant to have supportive economic policies and labor analysis has shown that wealthier women have lower regulations in place to reap the potential benefits of the fertility rates and better access to family planning than demographic dividend; many countries in Sub-Saharan poorer women. Gillespie and others (2007), in a study Africa need to coordinate development of their eco- of 41 countries, find that although variations were nomic and reproductive health policies to fully realize observed among countries, the number of unwanted this effect. births in the poorest quintile was more than twice that in the wealthiest quintile, at 1.2 and 0.5, respectively. Maternal and Child Health Rationale The improved health of mothers and children has Environment and Sustainable Development Rationale long been a rationale for the provision of family A resurgence of interest in global population dynam- planning (Seltzer 2002). In the 2009 round of the ics is linked to growing attention to environmental Family Planning Effort Index, measured periodically issues, climate change, and concerns about food security since 1972, women’s health was the dominant justi- (Engelman 1997; Jiang and Hardee 2011; Martine and fication for family planning programs, followed by Schensul 2013; Moreland and Smith 2012; Royal Society reducing unwanted fertility (Ross and Smith 2011). 2012). Although global population growth is slowing, These reasons ranked higher than fertility reduction, the momentum built into past population trends means economic development, and reduction of childbearing that the world’s population will continue to grow. The among unmarried youth. Contraception can serve as world’s population surpassed 7 billion in 2012; the 2013 an effective primary prevention strategy in LMICs to UN Population Division projection estimates that it reduce maternal mortality (Ahmed and others 2012). could grow to 9.6 billion by the middle of the century By one estimate, increases in contraceptive use from and level off at about 10.9 billion by the end of the 1990 to 2008 contributed to 1.7 million fewer maternal century under their low scenario, or it could grow to deaths (Ross and Blanc 2012). Reductions in fertility more than 16 billion by the end of the century under rates accounted for 53 percent of the decline in mater- their high scenario. According to the United Nations nal deaths; lower maternal mortality rates per birth Population Fund (UNFPA), “Whether future demo- accounted for 47 percent of the decline (Ross and graphic trends work for or against sustainable develop- Blanc 2012). ment will depend on policies that are put in place today” Family planning can have significant effects on the (UNFPA 2013, 5). If the unmet need for family planning health of children. Analysis of data from Demographic services were satisfied in all countries, world population and Health Surveys (DHS) from 52 countries showed growth would fall between the UN’s low and medium that children born within two years of a previous projections (Moreland, Smith, and Sharma 2010). birth have a 60 percent increased risk of infant death, and those within two to three years have a 10 percent increased risk of infant death, compared with children Health Consequences of High Fertility born after an interval of three or more years from the High fertility affects the health of mothers and chil- last sibling (Rutstein and others 2008). These analyses dren in several ways. Unwanted pregnancies may lead have confirmed the usefulness of program initiatives to to unsafe abortions, which are associated with elevated promote healthy timing and spacing of births. risks of maternal mortality. All births carry some risk of maternal mortality, so women with a large number Human Rights and Equity Rationale of births have higher lifetime risk of dying from mater- The right of couples and individuals to decide freely and nal causes. The World Health Organization’s (WHO’s) responsibly on the number and spacing of their children Global Health Estimates reports that there were 303,000 was articulated at the 1968 International Conference on maternal deaths in 2015; 300,000 of these deaths occurred Human Rights (UN 1968). Subsequent international in LMICs (WHO 2015). The maternal mortality ratio 96 Reproductive, Maternal, Newborn, and Child Health (MMR) in LMICs averages about 242 maternal deaths children; long-acting reversible contraceptives (such as per 100,000 live births. At that rate, a woman with seven intrauterine devices [IUDs], implants, and injections) births has a 2 percent chance of dying from maternal for couples who do not want more children in the near causes, compared with 0.5 percent for a woman with two term but may want more later; temporary methods births. In Sub-Saharan Africa, where the MMR is 546, the (such as oral contraceptives and condoms) that provide risk of death increases to almost 5 percent for a women short-term protection; and nonmedical methods (such with seven births (WHO 2014a, 2014b, 2015). as fertility awareness methods, lactational amenorrhea, The risk of maternal mortality is particularly high for and withdrawal) for couples who do not want to use a older women; it is typically two to three times higher for contraceptive agent or device or who do not have access women over age 40 years who give birth than for those to them. ages 35–39 years (Blanc, Winfrey, and Ross 2013). High- Women and men report a number of factors that parity births (fourth and higher births) may also carry are important to them in choosing methods (WHO an increased risk. Family planning can reduce maternal 1997). Among the key factors that allow potential users mortality by reducing the number of times a woman is to match contraceptive methods to their needs are exposed to the risk and by helping women avoid high- effectiveness, duration of effectiveness, and reversibility. risk births. From 1990 to 2005, family planning may Other major considerations include side effects, ease of have averted more than 1.5 million maternal deaths use, ability to hide use from a partner, and familiarity through lower fertility rates and reductions in the MMR with the method. Some women are also concerned about due to fewer high-parity births to older women (Stover whether the method regulates menstruation or causes and Ross 2009). amenorrhea. Family planning also influences child survival rates. Although the number of approved methods is quite Child mortality rates are generally higher for high-risk large, in practice couples in most countries have limited births, typically defined as births of order four (a wom- options. Ross and Stover (2013) analyze data from the an’s fourth birth) and above, births occurring less than Family Planning Effort Index scores to show the num- 24 months after a previous birth, and births to mothers ber of methods available over time in 80 countries. The who are less than age 18 years or more than age 35 years. Family Planning Effort Index measures, among other Short birth intervals, young age of mother at birth, and things, the percentage of the population that has ready parity greater than three are associated with greater and easy access to contraceptive methods (Ross and chances of births that are preterm, low birth weight, and Smith 2011). If a method is considered to be available small for gestational age (Kozuki, Lee, Silveira, Sania, and when more than 50 percent of the population has access, others 2013; Kozuki, Lee, Silveira, Victora, and others then potential users had access to 3.5 methods in 2009, 2013). DHS data show the risk of child mortality by birth up from 2 methods in 1982. characteristic. Mortality rates are about 50 percent higher Globally, female sterilization is used by the largest for closely spaced births and births to mothers under age share of couples (figure 6.2) and dominates the method 18 years. The largest effects occur when multiple risk fac- mix in Asia, Latin America and the Caribbean, and tors are combined. Mortality increases by 150 percent to North America. The second most popular method is the 300 percent for births with short intervals to very young IUD, which has the largest share of users in Asia. Oral mothers and those with high parity and short birth inter- contraceptives have a significant share of users in most vals. Family planning affects the distribution of births regions, except Asia. The highest share for injectables by risk factor. On average, the percentage of births with is in Latin America and the Caribbean and in Sub- any one of these avoidable risk factors drops from about Saharan Africa. 73 percent when the national total fertility rate is greater Although cost and demand play roles in determin- than seven to 25 percent at a total fertility rate of less than ing method availability, the most important factors two. As figure 6.1 shows, the greatest change from a high affecting availability in many settings are religious to a low total fertility rate is in the proportion of births and cultural factors and program factors. Figure 6.3 that are high parity and have multiple risk factors. shows the wide variation in method mix across a selec- tion of countries with total contraceptive prevalence between 45 percent and 75 percent. In Bangladesh, Contraceptive Methods Morocco, and Zimbabwe, oral contraceptives account for A wide variety of contraceptive methods are available 50 percent or more of all contraceptive use; in Brazil and to women and men (table 6.1). These include perma- India, sterilization is the preferred option. In the Arab nent methods, that is, female and male sterilization, Republic of Egypt and other Muslim countries, the IUD for couples who know that they do not want any more is the most popular form of long-acting contraceptive. Interventions to Improve Reproductive Health 97 Figure 6.1 Distribution of Births by Risk Factor by Total Fertility Rate 100 90 80 70 60 Percentage of births 50 40 30 20 10 0 <2 (N = 6) 2–3 (N = 28) 3–4 (N = 32) 4–5 (N = 38) 5–6 (N = 38) 6–7 (N = 32) 7+ (N = 6) Total fertility rate (number of surveys) Bl < 24 and BO > 3 Age > 34 and BI < 24 and BO > 3 Age > 34 and BO > 3 Age > 34 and BI < 24 Age < 18 and BI < 24 BO > 3 BI < 24 Age > 34 Age < 18 First birth No risk factor Source: Demographic and Health Surveys from 1980 to 2012. Note: Age = mother’s age at time of birth; BI = birth interval; BO = birth order. The method mix in Kenya has evolved, and injectables are the population, resulting in greater reliance on methods now the most popular form of contraception. In Turkey appropriate for those delivery channels, such as oral con- and Ukraine, for example, withdrawal and condoms are traceptives, injectables, and condoms. In countries with used most often; high rates of abortion compensate for higher access to medical providers, physician-supplied the lower effectiveness of these methods (UN Population methods, such as IUDs, may be preferred. Division 2013b). In countries with limited access to More than 180 new contraceptive methods are health clinics, community-based distribution (CBD) in various stages of research and development and social marketing are used to reach a large portion of (http://pipeline.ctiexchange.org/products/table). 98 Reproductive, Maternal, Newborn, and Child Health Table 6.1 Contraceptive Methods Effectivenessa Method Types Duration (percent) CYP factor Sterilization Female sterilization Permanent 99 10–13 per sterilization Male sterilization Permanent 99 10–13 per sterilization Implants Implanon 3 years 99 2.5 per implant Sino-Implant 4 years 99 3.2 per implant Jadelle 5 years 99 3.8 per implant Intrauterine devices Copper-T-380A 10 years 99 4.6 per insertion Levonorgestrel-releasing 5 years 99 3.3 per insertion intrauterine device Injectables Depo-Provera 3 months 93 4 injections per CYP Noristerat 2 months 93 6 injections per CYP Cyclofem 1 month 93 13 injections per CYP Oral contraceptives Many brands One month per cycle 90 15 cycles per CYP Condoms Male One sex act 79 120 units per CYP Female One sex act 75 120 units per CYP Spermicides Vaginal foaming tablets One sex act 67 120 tablets per CYP Emergency contraception One unprotected sex act 75 20 doses per CYP Monthly vaginal ring or One month 90 15 units per CYP patch Diaphragm One sex act 88 — Lactational amenorrhea 6 months 99 4 active users per CYP Fertility-awareness methods Standard days, Two Day One sex act 72 1.5 CYP per trained adopter Ovulation, Symptothermal Withdrawal One sex act 75 — Source: USAID: http://www.usaid.gov/what-we-do/global-health/family-planning/couple-years-protection-cyp. Note: — = not available; CYP = couple-years of protection. a. Effectiveness estimates are drawn from Trussel (2011). Although many will never reach the market, some to programs that rely on community workers to reach have the potential to address current barriers to use large numbers of users. In the longer term, it may even for some users. Several new methods that may address be labeled for self-injection. some limitations in current methods are becoming available. Sino-implant (II), a subdermal contra- ceptive implant consisting of two silicone rods with Organization of Family Planning Programs 75 milligrams of levonorgestrel, provides four years of Global Initiatives protection. Although similar to other implants already Family planning programming has been guided by on the market, Sino-implant (II) is considerably less global initiatives for decades, including through decen- expensive and could potentially expand the avail- nial population conferences in 1974 in Bucharest, ability of implants. It is registered for use in about 1984 in Mexico City, and 1994 in Cairo, as well as 20 countries. Sayana Press, an injectable contraceptive global frameworks, including the 2000 Millennium (Depo-Provera) with a duration of three month, is Development Goals (MDGs). The twentieth anniversary packaged in a Uniject system that allows subcutane- of the 1994 International Conference on Population and ous injection. The main advantage of this system is Development (ICPD) has passed, and the UN recently that field workers can easily administer it without the adopted the post-2015 development agenda. The ICPD need for users to visit clinics. It is expected to appeal positioned family planning within a broad context of Interventions to Improve Reproductive Health 99 Figure 6.2 Global Distribution of Contraceptive Methods, 2012 reproductive health and human rights. Both the ICPD and the SDGs now include targets and indicators related Other to universal access to reproductive health. Attention to modern 2% shortages of contraceptives led to the 2001 Istanbul con- Traditional ference, “Meeting the Reproductive Health Challenge: 10% Securing Contraceptives, and Condoms for HIV/AIDS Prevention,” which resulted in the establishment of the Female sterilization Reproductive Health Supplies Coalition (http://www Condom 30% 12% .rhsupplies.com). In 2010 the UN Secretary General launched Every Woman Every Child, a global effort to provide catalytic support to achieve MDGs 4, 5, and 6 by 2015 (http://www IUD Male .everywomaneverychild.org/about). The Ouagadougou 23% Oral sterilization Declaration, to which eight West African countries agreed contraceptives 3% in 2011, called for countries to accelerate the implemen- 14% tation of national strategies for reproductive health and family planning and to address the unmet needs of pop- ulations (FP Ouagadougou Partnership 2014). The 2012 Injectable London Summit on Family Planning resulted in pledges 6% of resources to reach an additional 120 million new users Source: Biddlecom and Kantorova 2013. with voluntary family planning services by 2020 (Bill & Note: IUD = intrauterine device. Melinda Gates Foundation and DFID 2012). Figure 6.3 Share of Contraceptive Users by Method, Selected Countries 100 90 80 70 60 Percent 50 40 30 20 10 0 Bangladesh Brazil Egypt, India Kenya Morocco Turkey Ukraine Zimbabwe Arab Rep. Sterilization IUD Implant Oral contraceptives Injection Condom Other modern Traditional Source: Demographic and Health Surveys, latest available survey for each country. Note: IUD = intrauterine device. 100 Reproductive, Maternal, Newborn, and Child Health Services Delivery of clinics to serve clients who were unable to travel to Family planning is delivered through a variety of pro- clinics or who did not know about clinic services for grams and services. In 2011, 91 percent of governments family planning. CBD programs focused on rural areas in LMICs surveyed by the UN reported that they provide and trained community members to provide family plan- direct support for family planning, an increase from ning information and selected resupply methods. Under 64 percent in 1976 (UN 2011). Currently, a focus on total various names, including community-based distributor, market approaches includes all service modalities— community health worker, and health extension worker, this public, private, and nongovernmental organizations— cadre of staff has delivered information and selected ser- to expand the reach of family planning services and vices to families’ doorsteps, providing access for women meet the needs of the diverse clientele across countries with limited mobility and those at a distance from clinical (Barnes, Vail, and Crosby 2012). Initiatives to identify services. These workers, for example, the Accredited Social the ingredients of successful family planning programs Health Activists in India, at times accompany clients to (Richey and Salem 2008) and high-impact practices health facilities for clinical methods of contraception. in family planning (www.fphighimpactpractices.org/), A review of the evidence shows that CBD has increased and approaches to scaling up services and ensuring access to and use of contraception in Sub-Saharan Africa equitable access (Amadou and others 2013; Simmons (Phillips, Greene, and Jackson 1999). Bongaarts and and Shiffman 2007), are shaping service delivery pro- others (2012) report that CBD resulted in increases gramming. Scaling-up approaches include task-shifting in contraceptive acceptance and use on the order of (Janowitz, Stanback, and Boyer 2012) and innovative 15 percent to 25 percent. In Bangladesh, the Matlab pro- financing schemes. gram achieved a 25 percent reduction in fertility during an eight-year period among women who were visited Public, nongovernmental, and commercial providers. every two weeks by trained community health workers Funding for public family planning programs comes (Koenig and others 1987). A study in Madagascar finds from a variety of sources. Many middle-income countries that individuals who had direct communication with fund contraceptive services, along with all other health community health workers were 10 times more likely services, out of tax revenues. Low-income countries to use contraceptives than individuals who did not often rely on donor funding for commodities, training, (Stoebenau and Valente 2003). Community-based health research, policy reform, evaluation, and service delivery workers have successfully reached underserved popula- outside the health facility. Donors that have supported tions, including unmarried women, those with less sup- family planning programs include bilateral donors portive husbands, and indigenous women (Malarcher such as the United States Agency for International and others 2011; Prata and others 2005). Development and the U.K. Department for International Community-based programming is considered to Development; multilateral donors such as the United be a high-impact practice in family planning (HIP Nations Population Fund; and foundations such as 2012), and interest is growing. To rapidly scale up access the Bill & Melinda Gates Foundation. This support to a range of public health services, including family usually takes the form of commodities and funding planning, Ethiopia in 2003 began to deploy more than of nongovernmental organizations to provide specific 30,000 health extension workers at the community services. Many LMICs have provided line items in their level. Ethiopia’s health extension workers are partially budgets for family planning commodities. Even in low- credited with achieving that country’s rapid increase in income countries, national governments provide most of its contraceptive prevalence rate, from 13.9 percent in the funds for infrastructure and personnel. 2005 to 27.3 percent in 2011 (USAID/Africa Bureau and others 2013). Integration with other sectors. Family planning services are usually integrated with other health services. Social marketing. Social marketing has been part of Activities for outreach, advocacy, the building of polit- family planning programming since the 1960s, when ical commitment, and resource mobilization are often it was first used to link social good with marketing integrated with other development priorities, such as approaches to raise awareness and promote condom HIV prevention and treatment, child immunization, and use (Chandy and others 1965). Social marketing com- environmental protection. bines the “4Ps” of marketing—product, price, place, and promotion—to increase use by population groups. Social Community-based programming. Community-based marketing in family planning programs makes con- programming has been part of family planning programs traceptive products accessible and affordable through since the 1970s. CBD was designed to extend the reach private-sector outlets, most notably, pharmacies and shops, Interventions to Improve Reproductive Health 101 while using commercial marketing techniques to achieve and more than 33 percent of voluntary male sterilization behavioral change goals (HIP 2012). procedures (Ministry of Health and Population [Nepal], Using a variety of models, family planning social mar- New ERA, and Macro International Inc. 2012). For keting has been used most widely to promote condoms mobile services to provide optimal care, it is important and oral contraceptives, with strong evidence of impact that adequate follow-up care be available. (Chapman and Astatke 2003; Madhavan and Bishai 2010; Sweat and others 2012). It has also been used to mHealth. Family planning programming has made use promote injectables, emergency contraception, and the of a range of media, including radio and television, Standard Days Method (CycleBeads®). In 1990, social to raise awareness and spread messages about services marketing contributed an estimated 7.4 million couple- (Bertrand and others 2006). These conventional uses of year protection (CYP), growing to 23.4 million in 2000 information and communication technologies are being and 53.4 million in 2010 (DKT International 2011), more supplemented by use of wireless technology, most notably than a sevenfold increase during the 20-year time span. cell phones. mHealth is reaching clients with information and financing mechanisms and measures to strengthen Social franchising. Social franchising has been used to services, including providing training and support to increase the share of the private commercial sector in health workers, addressing commodity logistics, and family planning. From the first social franchises for fam- monitoring and evaluation. These mHealth initiatives are ily planning that Sangini started in Nepal in 1994 and building on the rapidly growing use of wireless technol- Greenstar in Pakistan in 1995, the use of this approach ogy. A 2012 review of information and communication has grown globally and includes PROSALUD in Bolivia technologies for family planning and reproductive health and Blue Star in Ghana. An extension of social market- noted that such initiatives “range from using SMS [short ing, social franchises use the same techniques as com- message service] and text messages to give information mercial franchises—standardized, high-quality services, on family planning methods to women mobile users; to offered by trained providers under a franchise name. wireless solutions that update and connect rural health Social franchising for family planning supports fee- workers to web-based distance learning programs; to based provision of a range of clinical contraceptive mobile phones and PC [personal computer] solutions methods and broader reproductive health services. Fees that help to manage health data, drug supplies, patient can be paid with cash, vouchers, or other mechanisms. medical records, and the health workforce” (AIDSTAR- An analysis of the effect of social franchising on contra- Two 2012, 32). mHealth initiatives are relatively new, and ceptive use in four countries finds that “franchising has few have been well evaluated; most are in pilot phases, a positive association with both general and family plan- with little current evidence of scale up. ning client volumes, and the number of family planning brands available,” with client satisfaction varying across Results-based financing. Use of results-based financ- settings (Stephenson and others 2004, 2053). A 2010 ing, known by many names, including performance-based assessment of evaluations of social franchising concludes financing and performance-based incentives, is a rising that the studies demonstrate strong evidence that social trend in health programming. Given the history of mis- franchising increases the uptake of family planning use of incentive payments in family planning (Norman services, and moderate evidence that it increases use by 2013), careful consideration of which aspects of perfor- poor populations (Madhavan and Bishai 2010). mance are to be rewarded is critical. Performance pay- ments that focus on improving access to family planning Mobile services. Mobile services have been used to services and reducing financial and other barriers are extend access to long-acting and permanent contraceptive appropriate. For example, reasonable reimbursement methods to remote populations using trained providers to compensate for the costs of obtaining a voluntary (Bakamjian 2008). A 2010 evaluation of mobile out- sterilization are allowable. However, paying clients to reach services operated by Marie Stopes International in accept contraception or to accept certain methods are Ethiopia, Myanmar, Pakistan, Sierra Leone, and Vietnam not. Similarly, offering incentives to providers to achieve to provide IUDs and implants finds that women were target numbers of users or specific methods is not con- generally satisfied with the services, would use the mobile doned (Eichler and others 2010). services again, and would recommend the services to others (Eva and Ngo 2010). In Nepal, mobile services are Vouchers. Performance-based financing for family plan- a key component of the government’s program to reach ning has included vouchers for services and conditional remote areas. Government-run mobile clinics provide cash transfers. Vouchers can increase access for poor 20 percent of voluntary female sterilization procedures and marginalized populations to specific reproductive 102 Reproductive, Maternal, Newborn, and Child Health services and products at qualified outlets at subsidized vasectomy compared with older methods reduced the prices (Bongaarts and others 2012). A systematic review cost per CYP in three countries, provided that clinics do of the evidence on vouchers in LMICs finds 13 programs a large enough volume of procedures to maintain qual- that fit the systematic review criteria; of these, all evalua- ity. Abbas, Khan, and Khan (2013); Nakhaee and others tions reported positive findings, indicating that voucher (2002); and Onwujekwe and others (2013) examine the programs increased the use of reproductive health ser- expansion of modern contraceptive use in countries with vices, improved quality of care, and improved population limited access. Abbas, Khan, and Khan (2013) conclude health outcomes (Bellows, Bellows, and Warren 2011). that the public services in Pakistan are high cost per CYP However, most voucher programs are small, and addi- compared with other countries; Nakhaee and others tional research is needed to evaluate their impact. (2002) rank the cost-effectiveness of various methods for the Islamic Republic of Iran; and Onwujekwe and others Conditional cash transfers. Conditional cash transfer (2013) conclude that willingness to pay exceeds costs for (CCT) programs can include family planning, although methods other than female condoms in Nigeria. such programs should not make contraceptive use a condition for acceptance into the program. CCTs are rel- atively new and require more research on their effects on ADOLESCENT SEXUAL AND REPRODUCTIVE family planning decision making. For example, Brazil’s HEALTH Bolsa Família CCT, which reaches 12 million families with payments going through women, resulted in sig- The public health outcomes of adolescent pregnancy are nificantly increased women’s decision-making power profound. Adolescents ages 15–19 years are twice as likely related to contraception but only in urban areas (De to die during pregnancy and childbirth than women Brauw and others 2013). In Mexico’s Oportunidades older than age 20 years; those under age 15 years are five program, contraceptive use increased more among the times more likely to die during pregnancy or childbirth beneficiaries in communities with the CCT program, (WHO 2011). Complications of pregnancy and child- compared with women in communities in which the birth are the leading cause of death for adolescent girls program had not been initiated (Feldman and others ages 15–19 years in LMICs. Adolescents undergo an esti- 2009). Nicaragua’s CCT, Red de Proteccíon Social, is mated 3.2 million unsafe abortions every year (UNFPA credited with increasing birth spacing among beneficia- 2013). The social outcomes of adolescent pregnancy are ries (Todd, Winters, and Stecklov 2010). also profound, with girls’ potential remaining unfulfilled and their basic human rights denied (Hindon and Fatusi 2009; UNFPA 2013; WHO 2011). Cost-Effectiveness of Family Planning A systematic literature search identified seven stud- ies on cost-effectiveness of contraceptives published Programming for Adolescents since 2000; one additional study was obtained from Providing adolescents with the means to attain high a supplemental search adding the term “couple-year standards of health, in ways that ensure equality, protection” as an economic term. The literature on nondiscrimination, privacy, and confidentiality, is an cost-effectiveness of family planning is well established, integral part of respecting and protecting globally given that lending and aid for family planning has been accepted human rights (Ringheim 2007; UNFPA 2012). available since at least the 1970s. Recent studies focus Ensuring that adolescents have access to sexual and on the cost-effectiveness of extending benefits to under- reproductive health services requires extending the served countries and on newer family planning methods. availability, accessibility, acceptability, and quality of Four studies use cost per life-year saved, examining the information and the services (Hardee and others primarily the benefits to the mother’s health from preg- 2013). Helping adolescents make a healthy transition nancies averted; the other four use cost per CYP. The to adulthood involves programs to protect them from four studies focusing on mother’s health (Afghanistan, unintended pregnancy, sexually transmitted infections India, and two from Nigeria; see Horton, Wu, and (STIs), and poor reproductive health outcomes. These Brouwer 2015) conclude that modern contraceptives are programs can enable young people to delay sexual very cost-effective in that cost per life-year saved was less activity, to protect themselves from pregnancy and STIs than per capita gross domestic product (GDP). once they do initiate sexual activity, and to ensure that The four studies using CYP as an outcome examined sex is not coerced. somewhat disparate policies. Seamans and Harner-Jay The range of interventions suggested include (2007) conclude that using more modern methods of strengthening the enabling environment, and providing Interventions to Improve Reproductive Health 103 information and services and support programs to As the late Doug Kirby stated, young people around build resilience and assets. the world are seeking access to reliable information on reproductive health and answers for their questions Enabling Environment and concerns about sexuality. “They need information Provide legal protection. Although the need for strong not only about physiology and a better understanding legal protection for adolescents is clear, few interven- of the norms that society has set for sexual behavior, tions have been documented or evaluated. Still, laws but they also need to acquire the skills necessary to protecting against child marriage and against rape and develop healthy relationships and engage in respon- other forms of gender-based violence clearly need to sible decision-making about sex, especially during be developed and implemented (Lee-Rife and others adolescence when their emotional development accel- 2012; WHO 2011). Laws requiring parental consent for erates” (Kirby 2011). adolescents to access HIV testing discourage adolescents Evidence shows that comprehensive sex education from knowing their HIV status and accessing treatment with specific characteristics regarding content and ped- in a timely fashion. agogy, taught by trained teachers, can affect behavior, including delaying sexual debut, decreasing number Reduce gender-inequitable norms and violence. Norms of sexual partners, and increasing the use of condoms about acceptable behavior for males and females strongly or other contraceptives (Grunseit and others 1997; influence the socialization of children and adolescents; Mavedzenge, Doyle, and Ross 2011; UNESCO 2009). It is gender disparities become more evident as children near important to include a discussion of gender norms that adolescence (UNICEF 2011). Gender norms tend to dic- can put both male and female adolescents at risk (Barker tate that girls should be sexually submissive, while boys and others 2010; Pulerwitz and others 2006). should be sexually adventurous; these norms promote the acceptance of gender-based violence, place girls at Use mass media. Multiple mass media approaches have risk of unintended pregnancy, and put both girls and been used to inform adolescents about sexual and boys at risk for HIV (Gay and others 2011). Gender reproductive health issues, particularly AIDS and HIV norms that accept gender-based violence are harmful to (UNFPA 2013). Evaluated media approaches include the lives and reproductive health of adolescents. entertainment-education, social marketing, and media channels (television, radio, magazines, and the Internet) Keep girls and boys in school. Staying in school pro- (Gurman and Underwood 2008). Newer social media vides a protective effect. Girls who stay in school are approaches are promising, but their effects have yet to less likely to become pregnant, less likely to marry at a be evaluated. young age (Lloyd and Young 2009; UNFPA 2013), and A systematic review of the effectiveness of 24 mass more likely to use contraception. Staying in school also media interventions on HIV-related knowledge, atti- provides a protective effect against HIV acquisition tudes, and behaviors finds that such programs generally (Bradley and others 2007; Hargreaves and others 2008). produced small to moderate changes (Bertrand and Interventions to abolish school fees have enabled ado- others 2006). Outcomes included increased knowledge lescents to attend or to stay in school (Burns, Mingat, and behavioral changes, such as reduction in high-risk and Rakotomalala 2003; Deininger 2003; UNICEF 2005; behavior, increased communication, and increased con- World Bank and UNICEF 2009). dom use. A similar review by Gurman and Underwood CCTs show the potential to enable girls to stay in (2008), which focuses specifically on media interven- school (Baird and others 2012), but context is impor- tions for adolescents, finds similar outcomes, although tant. Recent studies in South Africa show an effect of the review highlights the paucity of results in the liter- cash transfers on herpes simplex virus type 2 (HSV-2) ature pertaining to gender-specific and youth-focused but no effect on HIV incidence (Karim and others 2015; interventions. Pettifor and others 2015). Community-based program- Gurman and Underwood (2008) offer four lessons ming (CBP) to encourage girls to stay in school can also from their review: be effective (Erulkar and Muthengi 2009). • Ensure that the intervention is appropriate for the Information and Services intended audience. Offer age-appropriate comprehensive sex educa- • Design interventions that go beyond the individual tion. Ensuring that young people have the appropriate level to include contextual factors, such as improving information to plan to protect themselves—before communication with caring adults, changing gender their first sexual experience—is vitally important. norms, and linking to services. 104 Reproductive, Maternal, Newborn, and Child Health • Include a range of media, as well as interpersonal prevention, as well as for prevention of HIV and other communication. STIs, could increase condom use for safe sex among • Plan for the evaluation at the beginning of the young people (Agha 2003). An analysis of survey data program. from 18 Sub-Saharan African countries finds that use of condoms for pregnancy prevention rose significantly in Provide adolescent-friendly contraceptive services. 13 of 18 countries between 1993 and 2001. Condom use The importance of providing adolescents and youth with among young Sub-Saharan African women increased by services that are tailored to their special needs has long an average annual rate of 1.4 percent, with 58.5 percent of been recognized (Senderwitz 1999). Rather than stand- the users reporting that they were motivated by a desire to alone youth-friendly services or separate spaces within prevent pregnancy (Cleland, Ali, and Shah 2006). services for adolescents, current programming is focusing Evidence suggests that if condom use is established on mainstreaming adolescent-friendly contraceptive ser- during adolescence, it is more likely to be sustained vices with existing family planning services. Four com- in the long term (Schutt-Aine and Maddaleno 2003). ponents of adolescent-friendly contraceptive services are A study of sexually active youth in Ethiopia, 75 percent important to reducing the common barriers adolescents of whom were female, finds that once young people face in accessing services (box 6.1). started to use condoms, they were more likely to con- Interventions in China, Ghana, India, Kenya, tinue to use them (Molla, Astrøm, and Berhane 2007). Nicaragua, Tanzania, Uganda, and Zimbabwe have shown Still, a review of 28 studies of HIV prevention in Sub- that providing one or more of the components of ado- Saharan Africa finds that the effect of interventions on lescent-friendly contraceptive services can increase use of condom use at last sexual activity were generally greater contraceptives or condoms (Decker and Montagu 2007; in males than in females, suggesting that “women still Kanesathasan and others 2008; Karim and others 2009; experience marked difficulties in negotiating condom Kim and others 2001; Lou and others 2004; Meuwissen, use or assuming full control over their sexual activity” Gorter, and Knottnerus 2006; Williams and others 2007). (Michielsen and others 2010, 1201). Youth centers, however, have not been found to be an A gender-transformative approach could be to ensure effective and efficient programming strategy for reach- that all adolescent girls receive fertility awareness training, ing youth (Zuurmond, Geary, and Ross 2012). for example, using CycleSmar™ or using CycleBeads® as they begin menstruation as a teaching tool to empower Expand access to and promotion of the use of condoms them to know and understand their reproductive cycles and other contraceptives. Ensuring access to and regular and to understand when they can get pregnant (IRH, use of condoms and other contraceptives is an essential n.d.a). A new study is underway to study the effects of element in programs to protect youth from unintended fertility awareness on contraceptive use (IRH, n.d.b). pregnancies and STIs. The use of condoms to guard against STIs can provide the added benefit of safeguarding Implement programs for out-of-school and married fertility (Brady 2003). Promoting condoms for pregnancy adolescents. Most programming for adolescents is school- or health facility–based, yet millions of children and adolescents are not in school. UNESCO estimates Box 6.1 that 57 million children of primary school age and 69 million children of lower-secondary school age do Components of Adolescent-Friendly not attend school (UNESCO 2013; UNFPA 2013). Mass media approaches and CBP show promise in reaching Contraceptive Services: out-of-school adolescents, although programming for • Train providers to provide nonjudgmen- this group is challenging (Bhuiya and others 2004). tal services that promote gender-equitable norms and encourage healthy decision mak- Building Resilience and Assets ing by adolescents. Programs to improve life skills and build resilience to • Enforce confidentiality and ensure audio and risk factors among adolescents have shown promising visual privacy. results (Askew and others 2004; Erulkar and others • Offer a wide range of contraceptive methods. 2004; Kanesathasan and others 2008; Kim and others • Provide no-cost or subsidized services. 2001; Mathur, Mehta, and Malhotra 2004; Meekers, Stallworthy, and Harris 1997). These programs, which Source: HIP, forthcoming. focus on building protective factors to promote success rather than eliminating factors associated with failure, Interventions to Improve Reproductive Health 105 have included a mix of community awareness and benefit if it is not used by providers and is not accessible engagement of community leaders; assistance to link to women. Therein lies the challenge. Legal restrictions adolescents with significant adults in their lives, most on the circumstances under which abortions are permit- notably parents; provision of safe spaces for adoles- ted or who can provide them; critical health workforce cents; and provision of information, services, and the shortages, particularly in South Asia and Sub-Saharan building of skills. Cuidate, a sexual-risk-reduction pro- Africa; lack of training opportunities for providers; gram in Mexico, provides a six-hour training program conscientious objection to care provision on the part for parents and adolescents. After four years, the adoles- of some providers; and the social, cultural, and political cent program participants were more likely to be older stigma around abortion all make it difficult to ensure at first sexual activity and to use a condom or other access to safe abortion care. Despite the availability of contraceptive at first sexual activity, compared with the vacuum aspiration for more than 40 years, the use of control group (Villarruel and others 2010). sharp curettage (dilation and curettage) is still common in many countries. The WHO no longer recommends dilation and curettage because it has more complica- UNSAFE ABORTION tions, often needs general anesthesia, and has higher Interventions to Reduce Unsafe Abortion costs for women and health facilities (WHO 2012). Similarly, although both mifepristone and misoprostol Although the need for abortion can be reduced if the are included in the WHO’s model list of essential med- need for contraceptive options is better addressed, the icines, mifepristone is not registered or available across need for safe abortion care will remain. Contraceptive most of Latin America and the Caribbean and Sub- methods do fail; women often become pregnant in cir- Saharan Africa (Gynuity 2013). cumstances in which the use of contraception may not be possible or where sex is nonconsensual. Medical or other circumstances for the woman could change even Promising Approaches after she becomes pregnant. Services to the full extent of the law. Although laws Abortion in early pregnancy (less than nine weeks) vary, all but six countries allow legal abortion in some performed with appropriate techniques by trained per- circumstances, most often to save the life of the woman sonnel is one of the safest medical procedures, with a case and often when pregnancy is the result of rape or incest fatality rate of 0.6 per 100,000 procedures (Raymond (UN Population Division 2013a). Whatever the legal and Grimes 2012); this rate is 14 times lower than the context, the treatment of women with complications risk of death associated with childbirth. Complications is legal, and evacuation in case of incomplete abortion increase with increasing gestation, but the termination is a signal function of basic emergency obstetric care. of pregnancy remains a safe procedure. Interpreting and implementing laws to their full extent and keeping the health of women center stage can make Safe and Simple Technologies safer care more accessible. The WHO recognizes vacuum aspiration (manual and electric) up to 12–14 weeks of gestation, and dilation and Expanding the pool of providers. A systematic review evacuation beyond that stage, as safe and appropriate of the evidence shows that both vacuum aspiration surgical procedures. Medical abortion using the sequen- and medical abortion can be safely provided by non- tial combination of mifepristone, followed by misopros- physician providers (Renner, Brahmi, and Kapp 2013). tol, is recommended as a safe and effective method that Many countries allow clinical associates, midwives, or can be used at any stage of pregnancy, although doses and nurses to treat incomplete abortion using manual vac- specific protocols change as gestation advances. Vacuum uum aspiration; several, including Vietnam, allow them aspiration can be provided on an outpatient basis at the to provide induced abortion as well. Bangladesh has primary care level; medical abortion up to nine weeks is had a mature program with auxiliary workers providing a process rather than a procedure and can be managed menstrual regulation for more than 40 years (Johnston as an outpatient primary care service, with some of the and others 2011). Because medical abortion is a rela- medications taken by women at home (WHO 2012). tively newer technology, fewer countries have yet moved to decentralize care; it is well-suited to a wider provider base since it does not need surgical skills. Ethiopia Access to Technologies and Ghana both allow midwives to provide medical Although simple, safe, and effective medical interven- abortions, and Nepal has incrementally progressed to tions already exist, appropriate technology is of little allowing midwives, then nurses, and more recently, 106 Reproductive, Maternal, Newborn, and Child Health auxiliary nurses working at lower-level facilities to pro- and others 2013; Bingham and others 2011). Telephone vide medical abortions, demonstrating the feasibility help lines can provide confidential sources of informa- even in low-resource settings. tion and support. Social networking and Internet-based In many contexts, a pharmacy is the first and sometimes information are becoming increasingly important in only health care contact for a woman with an unintended providing accurate information; however, empowering pregnancy. Although results have not always been suc- women to be able to detect misinformation and avoid cessful, interventions to provide pharmacy workers with dangers, like the sale of spurious medical abortion accurate information, minimize harm, or develop referral agents, is also needed. linkages with other authorized providers have potential Addressing the stigma and taboos around sexuality, and need to be further explored (Sneeringer and others unintended pregnancies, and abortion is important, 2012). Similarly, community health workers can play a role as is providing women with the information and skills in assessing eligibility, making appropriate referrals, and to negotiate traditional gender roles and inequities. helping women determine the need for follow-up care. Providers need medically accurate information and the skills to be able to clarify internal values and provide care Where mifepristone is not available. If mifepristone to women in a nonjudgmental way. is not available, misoprostol, an inexpensive anti-ulcer medicine with other obstetric and gynecological uses, Postabortion contraception. Although the evidence on is usually more readily accessible and can be used alone its overall impact on maternal mortality has not been to terminate a pregnancy. The failure rate is higher than well studied, ensuring effective and seamless linkages when used in combination with mifepristone, but it is among abortion care, contraceptive information, volun- still safe and effective, and is a WHO-recommended tary counseling, and onsite availability of contraception option (WHO 2012). Important gains in reducing is an important strategy for increasing the use of post- the morbidity and mortality from unsafe abortions abortion contraception and helping women prevent have been made, especially in Latin America and the subsequent unintended pregnancies (Tripney, Kwan, Caribbean, with the use of this strategy. and Bird 2013). However, ensuring that contraceptive acceptance does not become coercive or a precondition Innovations. The use of telemedicine to provide med- to getting abortion care is also needed. ical abortions can help bring needed care to women A multifaceted approach is needed. An excellent who do not have physical access (Gomperts and others example is seen in Nepal, where legal reform followed 2012; Grindlay, Lane, and Grossman 2013; Grossman by proactive efforts to scale up services has yielded rich and others 2011). Decreasing the need for clinic visits dividends and already shows some evidence of a decline through approaches that allow telephone follow-up in serious morbidity from unsafe abortion (Henderson or self-assessment of the abortion process using semi- and others 2013; Samandari and others 2012). quantitative pregnancy tests (Lynd and others 2013) is another promising innovation. mHealth approaches Conclusion. A combination of approaches that include with text messaging can help support women through sexuality education and women’s contraceptive needs the abortion process, providing information and remind- to reduce the need for abortion, the provision of safe ers about medications, side effects, and postabortion abortion services, and the availability of treatment for contraception. The risk-reduction model pioneered in complications to attenuate morbidity and reduce the Uruguay combines provision of information and post- mortality from unsafe abortions—grounded in a frame- abortion care; this approach can be legally implemented work of human rights—can collectively minimize the even in countries with restrictive legal environments burden of the consequences of unsafe abortion. Safe (Fiol and others 2012). abortion has been shown to be cost-effective (see DCP3, volume 1, Essential Surgery, chapter 18 [Prinja and Information and attitudes. Even where abortion is others 2015]). legal, women are often unaware of how and where to access it (Adinma and others 2011; Banerjee and others VIOLENCE AGAINST WOMEN 2013; Thapa, Sharma, and Khatiwada 2014). Approaches to empowering women with knowledge using inter- What Can the Health Sector Do? personal communication, drama, theater, radio, wall Primary prevention of violence is critically important, signage, and mass media communication have all had but it is also necessary to provide care and support for some success; understanding the local context and the many women who already face violence. Early iden- appropriately tailoring the approach is critical (Banerjee tification and response can play an important role in Interventions to Improve Reproductive Health 107 secondary prevention by mitigating the consequences of recognize the signs and respond appropriately and safely. violence and reducing the risk of further violent episodes. Women exposed to violence require comprehensive, Early identification and response can also contribute gender-sensitive health care services that address the to primary prevention by identifying and supporting physical and mental health consequences of their experi- the children of women who suffer domestic violence. ence and aid their recovery. Women may also require cri- Evidence suggests that early intervention is likely to sis intervention services to prevent further harm. Treating have a positive impact on later risk behaviors and health cases of rape includes providing emergency contraception problems among children and adolescents. It can also and prophylaxis for HIV and other STIs; psychologi- contribute to reducing the social and economic costs of cal first-line support; and access to safe abortion and such violence. (Bott, Morrison, and Ellsberg 2005; García longer-term mental health care support, if needed. In Moreno and others 2014). (See DCP3 volume 7, Injury addition to providing immediate medical services, the Prevention and Environmental Health, Mercy and others, health sector is a potentially crucial gateway to providing forthcoming, for further discussion of interpersonal assistance through referral to specific services for violence violence) against women—or other aid that women may require at Although violence against women has been accepted a later date, such as social welfare and legal aid. In all cir- as a critical public health and clinical care issue, the cumstances, all health care providers should be trained to health care policies of many countries still do not provide a minimum first-line supportive response (WHO address it. The critical role that the health system and 2013, 2014b). health care providers can play in identification, assess- The WHO recommendations are addressed to health ment, treatment, crisis intervention, documentation, care providers because they are in a unique position to referral, and follow-up is poorly understood or poorly address the health and psychosocial needs of women accepted within national health programs and policies who live with or who have experienced violence. They (WHO 2013; WHO 2014c). Women who have been also seek to inform health policy makers or program subjected to violence often seek health care for their managers in charge of planning and implementing injuries, even if they may not disclose the associated health care services and those designing curricula. abuse or violence, and a health care provider is likely to The health sector can also play an advocacy role by be the first professional contact for survivors of intimate supporting research to document the impact and extent partner violence or sexual assault. Women also identify of the problem, raise awareness, and establish links in health care providers as the professionals they would the multisectoral response that is needed to address this most trust with the disclosure of abuse (Feder and serious health risk for women. others 2006). Reproductive health care providers are particularly well positioned given that most women will at some point consult them for contraception, antenatal CONCLUSIONS care, and delivery. Significant progress in improving reproductive health has been made in some areas. Family planning has expanded worldwide through new approaches and new Responding to Intimate Partner Violence and Sexual methods. A renewed commitment to family planning Violence among donors and national governments has stimu- The WHO clinical and policy guidelines (WHO 2013) lated wider coverage of services accompanied by greater summarize the evidence for clinical interventions for emphasis on quality and human rights. A new focus on intimate partner violence and for sexual violence against adolescent sexual health has spurred interest in better women. They also review the evidence for service deliv- ways to reach adolescents with effective messages and ery and training on these issues for health care providers services. New approaches to reducing gender-based and make evidence-based recommendations to improve violence have been tested and the lessons learned have the response of the health sector to violence against been distilled in clinical and policy guidelines. women. However, much remains to be done. In spite of the Health professionals can provide assistance to women advances in family planning, in 35 countries fewer than suffering from violence by facilitating disclosure, offer- 30 percent of women of reproductive age use modern ing support and referral, gathering forensic evidence— contraception. Choice of methods is still limited in particularly in cases of sexual violence—and providing many countries, even some with high levels of con- the appropriate medical services and follow-up care. traceptive prevalence, because of lack of access, pro- Health care providers who come into contact with women vider biases, and other program factors. Although good facing intimate partner violence need to be able to options for safe abortion exist, these services remain 108 Reproductive, Maternal, Newborn, and Child Health unavailable in many countries because of legal barriers, Bakamjian, L. 2008. “Linking Communities to Family Planning lack of training, and stigma. We have more information and LAPM via Mobile Services.” Presentation at the Flexible about how to reach adolescents with effective services Fund Partner’s Meeting, Washington, DC. EngenderHealth, and how to reduce gender-based violence. The major New York. Banerjee, S. K., K. L. Andersen, J. Warvadekar, and E. Pearson. challenge is how to more widely implement those pro- 2013. “Effectiveness of a Behavior Change Communication grams that have been proven to be safe, effective, and Intervention to Improve Knowledge and Perceptions about affordable. Abortion in Bihar and Jharkhand, India.” International Perspectives on Sexual and Reproductive Health 39 (3): 142–51. NOTE Barker, G., C. Ricardo, M. Nascimento, A. Olukoya, and C. Santos. 2010. “Questioning Gender Norms with Men World Bank Income Classifications as of July 2014 are as fol- to Improve Health Outcomes: Evidence of Impact.” Global lows, based on estimates of gross national income (GNI) per Public Health 5 (5): 539–53. capita for 2013: Barnes, J., J. Vail, and D. Crosby. 2012. “Total Market Initiatives for Reproductive Health. Strengthening Health Outcomes • Low-income countries (LICs) = US$1,045 or less through the Private Sector Project.” Abt Associates, • Middle-income countries (MICs) are subdivided: Bethesda, MD. a) lower-middle-income = US$1,046 to US$4,125 Bellows, N. M., B. W. Bellows, and C. Warren. 2011. “The b) upper-middle-income (UMICs) = US$4,126 to US$ 12,745 Use of Vouchers for Reproductive Health Services in • High-income countries (HICs) = US$12,746 or more. Developing Countries: A Systematic Review.” Tropical Medicine and International Health 16 (1): 84–96. Bertrand, J., K. O’Reilly, J. Denison, R. Anhang, and M. Sweat. 2006. “Systematic Review of the Effectiveness of Mass REFERENCES Communication Programs to Change HIV/AIDS-Related Abbas, K., A. A. Khan, and A. Khan. 2013. “Costs and Utilization Behaviors in Developing Countries.” Health Education of Public Sector Family Planning Services in Pakistan.” Research 21 (4): 567–97. Journal of the Pakistan Medical Association 63 (4 Suppl 3): Bhuiya, I., U. Rob, A. H. Chowdhury, L. Rahman, N. Haque, S33–9. and others. 2004. “Improving Adolescent Reproductive Adinma, E. D., J. I. Adinma, J. Ugboaja, C. Iwuoha, A. Akiode, Health in Bangladesh.” FRONTIERS, Population Council, and others. 2011. “Knowledge and Perception of the Washington, DC. Nigerian Abortion Law by Abortion Seekers in South- Biddlecom, A., and V. Kantorova. 2013. “Global Trends in Eastern Nigeria.” Journal of Obstetrics and Gynaecology Contraceptive Method Mix and Implications for Meeting 31 (8): 763–76. Demand for Family Planning.” Presented in Session 81 Agha, S. 2003. “The Impact of a Mass Media Campaign on at the meeting of the Population Association of America, Personal Risk Perception, Perceived Self-Efficacy and on New Orleans, April 11–13. Other Behavioral Predictors.” AIDS Care 15 (6): 749–62. Bill & Melinda Gates Foundation and DFID (UK Department Ahmed, S., Q. Li, L. Liu, and A. Tsui. 2012. “Maternal for International Development). 2012. “Landmark Summit Deaths Averted by Contraceptive Use: An Analysis of Puts Women at Heart of Global Health Agenda.” Press 172 Countries.” The Lancet 380 (9837): 111–25. Release. http://www.londonfamilyplanningsummit.co.uk AIDSTAR-Two. 2012. The Use of Information and /1530%20FINAL%20press%20release.pdf. Communication Technology in Family Planning, Bingham, A., J. K. Drake, L. Goodyear, C. Y. Gopinath, Reproductive Health and Other Health Programs: A Review A. Kaufman, and others. 2011. “The Role of Interpersonal of Trends and Evidence. Cambridge, MA: Management Communication in Preventing Unsafe Abortion in Sciences for Health. Communities: The Dialogues for Life Project in Nepal.” Amadou, B., J. Curran, L. Wilson, N. A. Dagadu, V. Jennings, Journal of Health Communication 16 (3): 245–63. and others. 2013. “Guide for Monitoring Scale up of Health Birdsall, N., A. C. Kelly, and S. W. Sinding, eds. 2001. Practices and Innovations.” Manual. MEASURE Evaluation Population in the Developing World Matters: Demography, PRH, Chapel Hill, NC. Economic Growth and Poverty. Oxford: Oxford University Askew, I., J. Chege, C. Njue, and S. Radeny. 2004. “A Multi- Press. Sectoral Approach to Providing Reproductive Health Blanc, A. K., W. Winfrey, and J. Ross. 2013. “New Findings for Information and Services to Young People in Western Maternal Mortality Age Patterns: Aggregated Results for Kenya: Kenya Adolescent Reproductive Health Project.” 38 Countries.” PLoS One 8 (4): e59864. doi:10.1371/journal FRONTIERS Project, Population Council, Washington, DC. .pone.0059864. Baird, S. J., R. S. Garfein, C. T. McIntosh, and B. Ozler. 2012. Bloom, D. E., D. Canning, and J. Sevilla. 2003. The Demographic “Effect of a Cash Transfer Programme for Schooling on Dividend: A New Perspective on the Economic Consequences Prevalence of HIV and Herpes Simplex Type 2 in Malawi: of Population Change. Santa Monica, CA: Population A Cluster Randomised Trial.” The Lancet 379 (9823): 1320–29. Matters, RAND. Interventions to Improve Reproductive Health 109 Bongaarts, J., J. Cleland, J. Townsend, J. Bertrand, and M. Das Ethiopia.” International Perspectives on Sexual and Gupta. 2012. Family Planning in the 21st Century: Rationale Reproductive Health 35 (1): 6–14. and Design. New York, NY: Population Council. Eva, G., and T. D. Ngo. 2010. MSI Mobile Outreach Services: Bott, S., A. Morrison, and M. Ellsberg. 2005. “Preventing Retrospective Evaluations from Ethiopia, Myanmar, and Responding to Gender-Based Violence in Middle- and Pakistan, Sierra Leone and Vietnam. London: Marie Stopes Low-Income Countries: A Global Review and Analysis.” International. World Bank, Washington, DC. Feder, G. S., M. Hutson, J. Ramsay, and A. R. Taket. 2006. Bradley, H., A. Bedada, H. Brahmbhatt, A. Kidanu, D. Gillespie, “Women Exposed to Intimate Partner Violence: and others. 2007. “Educational Attainment and HIV Status Expectations and Experiences When They Encounter among Ethiopian Voluntary Counseling and Testing Health Care Professionals: A Meta-Analysis of Qualitative Clients.” AIDS and Behavior 11 (5): 736–42. Studies.” Archives of Internal Medicine 166 (1): 22–37. Brady, M. 2003. “Preventing Sexually Transmitted Infections Feldman, B. S., A. M. Zaslavsky, M. Ezzati, K. E. Peterson, and and Unintended Pregnancy, and Safeguarding Fertility: M. Mitchell. 2009. “Contraceptive Use, Birth Spacing, and Triple Protection Needs of Young Women.” Reproductive Autonomy: An Analysis of the Oportunidades Program in Health Matters 11 (22): 134–41. Rural Mexico.” Studies in Family Planning 40 (1): 51–62. Burns, B., A. Mingat, and R. Rakotomalala. 2003. Achieving Fiol, V., L. Briozzo, A. Labandera, V. Recchi, and M. Piñeyro. Universal Primary Education by 2015: A Chance for Every 2012. “Improving Care of Women at Risk of Unsafe Child. Washington, DC: World Bank. Abortion: Implementing a Risk-Reduction Model at the Chandy, K. T., T. R. Balakrishman, J. M. Kantawalla, K. Mohan, Uruguayan-Brazilian Border.” International Journal of N. P. Sen, and others. 1965. “Proposals for Family Planning Gynaecology and Obstetrics 118 (Suppl 1): S21–27. Promotion: A Marketing Plan.” Studies in Family Planning FP Ouagadougou Partnership. 2014. Family Planning: 1 (6): 7–12. Francophone West Africa on the Move—A Call to Action. Chapman, S., and H. Astatke. 2003. “Review of DFID Approach Family Planning Ouagadougou Partnership. http://www to Social Marketing. Annex 5: Effectiveness, Efficiency, and .prb.org/pdf12/ouagadougou-partnership_en.pdf. Equity in Social Marketing, and Appendix to Annex 5: The García Moreno, C., C. Zimmerman, A. Morris-Gehring, Social Marketing Evidence Base.” DFID Health Systems L. Heise, A. Amin, and others. 2014. “Addressing Violence Resource Centre, London. against Women: A Call to Action.” The Lancet 385 (9978): Cleland, J., M. Ali, and I. Shah. 2006. “Trends in Protective 1685–95. doi:10.1026/S0140-6736(14)61830-4 Behavior among Single vs. Married Young Women in Gay, J., K. Hardee, M. Croce-Galis, and C. Hall. 2011. “What Sub-Saharan Africa: The Big Picture.” Reproductive Health Works to Meet the Sexual and Reproductive Health Needs of Matters 14 (28): 17–22. Women Living with HIV/AIDS?” Journal of the International De Brauw, A., D. O. Gilligan, J. Hoddinott, and S. Roy. 2013. AIDS Society 14 (56). doi: 10.1186/1758-2652-14-56. “The Impact of Bolsa Família on Women’s Decision- Gillespie, D., S. Ahmed, A. Tsui, and S. Radloff. 2007. Making Power.” World Development 59: 487–504. “Unwanted Fertility among the Poor: An Inequity?” Decker, M., and D. Montagu. 2007. “Reaching Youth through Bulletin of the World Health Organization 85 (2): 100–7. Franchise Clinics: Assessment of Kenyan Private Sector Gomperts, R., S. Petwo, K. Jelinksa, L. Steen, K. Gemzell- Involvement in Youth Services.” Journal of Adolescent Health Danielsson, and others. 2012. “Regional Differences in 40: 280–82. Surgical Intervention Following Medical Termination of Deininger, K. 2003. “Does Cost of Schooling Affect Enrollment Pregnancy Provided by Telemedicine.” Acta Obstetricia by the Poor? Universal Primary Education in Uganda.” Gynecologica Scandinavica 91 (2): 226–31. Economics of Education Review 22 (3): 291–305. Grindlay, K., K. Lane, and D. Grossman. 2013. “Women DHS (Demographic and Health Surveys. Data from multiple and Health Providers’ Experiences with Medical Abortion surveys and years. http://www.statcompiler.com. Provided through Telemedicine: A Qualitative Study.” DKT International. 2011. “1990–2010 Contraceptive Social Women’s Health Issues 23 (2): e117–22. Marketing Statistics.” DKT International, Washington, DC. Grossman, D., K. Grindlay, T. Buchacker, K. Lane, and Eichler, R., B. Seligman, A. Beith, and J. Wright. 2010. K. Blanchard. 2011. “Effectiveness and Acceptability Performance-Based Incentives: Ensuring Voluntarism in of Medical Abortion Provided through Telemedicine.” Family Planning Initiatives. Bethesda, MD: Health Systems Obstetrics and Gynecology 118 (2 pt 1): 296–303. 20/20 Project, Abt Associates Inc. Grunseit, A., S. Kippax, P. Aggleton, M. Baldo, and G. Slutkin. Engelman, R. 1997. Why Population Matters: International 1997. “Sexuality Education and Young People’s Sexual Edition. Washington, DC: Population Action International. Behavior: A Review of Studies.” Journal of Adolescent Erulkar, A. S., L. Ettyang, C. Onoka, F. K. Nyagah, and Research 12 (4): 421–53. A. Muyonga. 2004. “Behavior Change Evaluation of a Gurman, T. A., and C. Underwood. 2008. “Using Media to Culturally Consistent Reproductive Health Program for Address Adolescent Sexual Health: Lessons Learned Abroad.” Young Kenyans.” International Family Planning Perspectives In Managing the Media Monster. The Influence of Media (from 30 (2): 58–67. Television to Text Messages) on Teen Sexual Behavior and Erulkar, A. S., and E. Muthengi. 2009. “Evaluation of Berhane Attitude, edited by J. D. Brown. Washington, DC: National Hewan: A Program to Delay Child Marriage in Rural Campaign to End Teen and Unplanned Pregnancy. 110 Reproductive, Maternal, Newborn, and Child Health Gynuity. 2013. “Map of Mefepristone Approvals.” http:// Kanesathasan, A., L. J. Cardinal, E. Pearson, S. Gupta, gynuity.org/downloads/mapmife__en.pdf. S. Mukherjee, and A. Malhotra. 2008. “Catalyzing Change: Habumuremyi, P. D., and M. Zenawi. 2012. “Making Family Improving Youth Sexual and Reproductive Health through Planning a National Development Priority.” The Lancet 380 DISHA, an Integrated Program in India.” International (9837): 78–80. Centre for Research on Women, Washington, DC. Hardee, K., J. Kumar, K. Newman, L. Bakamjian, S. Harris, Karim, Q. A., K. Leasek, A. Kharsany, H. Humphries and others. 2014. “Voluntary, Human Rights-Based Family F. Ntombela, and others. 2015. “Impact of Conditional Cash Planning: A Conceptual Framework.” Studies in Family Incentives of HSV-2 and HIV Prevention in Rural South Planning 45 (1): 1–18. African High School Students: Results of the CAPRISA 007 Hardee, K., K. Newman, L. Bakamjian, J. Kumar, S. Harris, and Cluster Randomized Controlled Trial.” International AIDS others. 2013. “Voluntary Family Planning Programs that Conference, Vancouver, July 19–22. Respect, Protect, and Fulfill Human Rights: A Conceptual Karim, A., T. Williams, L. Patkykewish, D. Ali, C. Colvin, Framework.” Futures Group, Washington, DC. and others. 2009. “The Impact of African Youth Alliance Hargreaves, J. R., L. A. Morison, J. C. Kim, C. P. Bonell, Program on the Sexual Behavior of Young People in J. D. H. Porter, and others. 2008. “The Association between Uganda.” Studies in Family Planning 40 (4): 289–306. School Attendance, HIV Infection and Sexual Behaviour Kim, Y. M., A. Kols, R. Nyakauru, C. Marangwanda, and among Young People in Rural South Africa.” Journal of P. Chibatamoto. 2001. “Promoting Sexual Responsibility Epidemiology and Community Health 62 (2): 113–19. among Young People in Zimbabwe.” International Family Henderson, J., M. Puri, M. Blum, C. C. Harper, A. Rana, and Planning Perspectives 27 (1): 11–19. others. 2013. “Effects of Abortion Legalization in Nepal, Kirby, D. 2011. “Sex Education: Access and Impact on Sexual 2001–2010.” PLoS One 8 (5): e64755. Behaviour of Young People.” UN/POP/EGM-AYD/2011/07, Hindon, M., and A. O. Fatusi. 2009. “Adolescent Sexual and United Nations Population Division, New York. Reproductive Health in Developing Countries: An Overview Koenig, M. A., J. F. Phillips, R. S. Simmons, and M. A. Khan. of Trends and Interventions.” International Perspectives on 1987. “Trends in Family Size Preferences and Contraceptive Sexual and Reproductive Health 35 (2): 58–62. Use in Matlab, Bangladesh.” Studies in Family Planning HIP (High Impact Practices for Family Planning). 2012. 18 (3): 117–27. “Community Health Workers: Bringing Family Planning Kozuki, N., A. C. Lee, M. F. Silveira, A. Sania, J. P. Vogel, and Services to Where People Live.” USAID, Washington, others. 2013. “The Associations of Parity and Maternal DC. http://www.fphighimpactpractices.org/resources Age with Small-for-Gestational-Age, Preterm, and /community-health-workers-bringing-family-planning Neonatal and Infant Mortality: A Meta-Analysis.” BMC -services-where-people-live-and-work. Public Health 13 (Suppl 3): S2. http://www.biomedcentral ———. Forthcoming. “Making Existing Contraceptive Services .com/1471-2458/13/S3/S2. Adolescent Friendly.” USAID, Washington, DC. http://www Kozuki, N., A. C. Lee, M. F. Silveira, C. G. Victora, L. Adair, .fphighimpactpractices.org. and others. 2013. “The Associations of Birth Intervals Horton, S., D. C. N. Wu, and E. Brouwer. 2015. “Methodology with Small-for-Gestational Age, Preterm and Neonatal, and Results for Systematic Search, Cost and Cost- and Infant Mortality: A Meta-Analysis.” BMC Public Effectiveness Analysis.” Working Paper, Disease Control Health 13 (Suppl 3): S3. http://www.biomedcentral Priorities, 3rd edition, Volume 2. http://www.dcp-3.org .com/1471-2458/13/S3/S3. /resources/working-papers. Lee-Rife, S., A. Malhotra, A. Warner, and A. M. Glinski. 2012. IRH (Institute for Reproductive Health). n.d.a. “CycleSmartTM “What Works to Prevent Child Marriage: A Review of the CycleBeads.” Brochure. Georgetown University, Evidence.” Studies in Family Planning 43 (4): 287–303. Washington, DC. http://irh.org/resource-library/cyclesmart Lloyd, C., and J. Young. 2009. New Lessons: The Power of -cyclebeads-brochure/. Educating Adolescent Girls. New York: Population Council. ———. n.d.b. “IRH Awarded Fertility Awareness ‘Fact Project’ Lou, C., B. Wang, Y. Shen, and E. Gao. 2004. “Effects of a by USAID.” Institute for Reproductive Health, Georgetown Community-Based Sex Education and Reproductive Health University, Washington, DC. http://irh.org/blog/irh-awarded Service Program on Contraceptive Use of Unmarried Youths -fertility-awareness-fact-project-by-usaid/. in Shanghai.” Journal of Adolescent Health 33: 433–40. Janowitz, B., J. Stanback, and B. Boyer. 2012. “Task Sharing in Lynd, K., J. Blum, N. Ngoc, T. Shochet, P. D. Blumenthal, and Family Planning.” Studies in Family Planning 43 (1): 47–62. others. 2013. “Simplified Medical Abortion Using a Semi- Jiang, L., and K. Hardee. 2011. “How Do Recent Population Quantitative Pregnancy Test for Home Based Follow Up.” Trends Matter to Climate Change?” Population Research International Journal of Gynecology and Obstetrics 121 (2): and Policy Review 30: 287–312. 144–48. Johnston, H. B., A. Schurmann, E. Oliveras, and H. H. Akhter. Madhavan, S., and D. Bishai. 2010. “Private Sector Engagement 2011.“Scaled Up and Marginalized: A Review of Bangladesh’s in Sexual and Reproductive Health and Maternal and Menstrual Regulation Programme and Its Impact.” In Social Neonatal Health: A Review of the Evidence.” Human Determinants Approaches to Public Health: From Concept to Development Resource Center, DFID, London. Practice, edited by E. Blas, J. Sommerfeld, and A. S. Kurup, Malarcher, S., O. Meirik, E. Lebetkin, I. Shah, J. Spieler, and 9–24. Geneva: World Health Organization. others. 2011. “Provision of DMPA by Community Health Interventions to Improve Reproductive Health 111 Workers: What the Evidence Shows.” Contraception 83 (6): Norman, C. 2013. “Utilizing Incentives for Global Family 495–503. Planning and Reproductive Health Services Update: Martine, G., and D. Schensul, eds. 2013. The Demography of Altruistic or Euphemism for Population Control?” Master’s Adaptation to Climate Change. New York, London, and Thesis, Global Studies Program, Brandeis University, Mexico City: UNFPA, IIED, and El Colegio de Mexico. Waltham, MA. Mathur, S., M. Mehta, and A. Malhotra. 2004.“Youth Reproductive Onwujekwe, O., C. Ogbonna, O. Ibe, and B. Ozochukwu. Health in Nepal: Is Participation the Answer?” International 2013. “Willingness-to-Pay and Benefit-Cost of Modern Center for Research on Women, Washington, DC. Contraceptives in Nigeria.” International Journal of Mavedzenge, S. N., A. Doyle, and D. Ross. 2011. “HIV Prevention Gynecology and Obstetrics 122: 94–98. in Young People in Sub-Saharan Africa: A Systematic Review.” Pettifor, A., C. MacPhail, A. Selon, X. Gomez-Olive, J. Hughes, Journal of Adolescent Health 49 (6): 568–86. and others. 2015 “HPTN 068 Conditional Cash Transfer to Meekers, D., G. Stallworthy, and J. Harris. 1997. “Changing Prevent Infection among Young Women in South Africa: Adolescents’ Beliefs about Protective Sexual Behavior: Results of a Randomized Controlled Trial.” International The Botswana Tsa Banana Program.” Working Paper 3, AIDS Conference, Vancouver, July 19–22. Population Services International, Research Division, Phillips, J. F., W. L. Greene, and E. F. Jackson. 1999. “Lessons Washington, DC. from Community-Based Distribution of Family Planning in Mercy, J., S. Hilis, A. Butchart, M. Bellis, C. Ward, and Africa.” Working Paper 121, Population Council, New York. others. “Interpersonal Violence: Global Impact and the http://www.popcouncil.org/pdfs/wp/121.pdf. Paths to Prevention.” Forthcoming. In Disease Control Prata, N., F. Vahidnia, M. Potts, and I. Dries-Daffner. 2005. Priorities (third edition): Volume 7, Intentional Injury and “Revisiting Community-Based Distribution Programs: Are Environmental Health, edited by C. N. Mock, R. Nugent, They Still Needed?” Contraception 72 (6): 402–7. and O. Kobusingye. Washington, DC: World Bank. Prinja, S., A. Nandi, S. Horton, X. Levin, and R. Laxminarayan. Meuwissen, L. E., A. C. Gorter, and A. J. Knottnerus. 2006. 2015. “Costs, Effectiveness, and Cost-Effectiveness of “Impact of Accessible Sexual and Reproductive Health Selected Surgical Procedures and Platforms.” In Disease Care on Poor and Underserved Adolescents in Managua, Control Priorities (third edition): Volume 1, Essential Nicaragua: A Quasi-Experimental Intervention Study.” Surgery, edited by H. T. Debas, P. Donkor, A. Gawande, Journal of Adolescent Health 38 (1): 56. D. T. Jamison, M. E. Kruk, and C. N. Mock. Washington, Michielsen, K., M. Chersich, S. Luchters, P. De Koker, R. Van DC: World Bank. Rossem, and others. 2010. “Effectiveness of HIV Prevention Pulerwitz, J., G. Barker, M. Segundo, and M. Nascimento. for Youth in Sub-Saharan Africa: Systematic Review and 2006. Promoting More Gender-Equitable Norms and Meta-Analysis of Randomized and Non-Randomized Behaviors among Young Men as an HIV/AIDS Prevention Trials.” AIDS 24 (8): 1193–202. Strategy. Washington, DC: Horizons Program, Population Ministry of Health and Population [Nepal], New ERA, and Council. Macro International Inc. 2012. Demographic and Health Raymond, E. G., and D. A. Grimes. 2012. “The Comparative Survey 2011. Kathmandu, Nepal: Ministry of Health and Safety of Legal Induced Abortion and Childbirth in the Population, New ERA, and ICF International, Calverton, United States.” Obstetrics and Gynecology 119 (2 Pt 1): Maryland. 215–19. Molla, M., A. Astrøm, and Y. Berhane. 2007. “Applicability Renner, R., D. Brahmi, and N. Kapp. 2013. “Who Can Provide of the Theory of Planned Behavior to Intended and Self- Effective and Safe Termination of Pregnancy Care? A Reported Condom Use in a Rural Ethiopian Population.” Systematic Review.” BJOG 120 (1): 23–31. AIDS Care 19 (3): 425–31. Richey, M., and R. M. Salem. 2008. Elements of Success in Moreland, S., and E. Smith. 2012. “Modeling Climate Change, Family Planning. Population Reports Series J (57), INFO Food Security, and Population Change. Pilot-Testing the Project, Johns Hopkins Bloomberg School of Public Health, Model in Ethiopia.” USAID, MEASURE Evaluation PRH, Baltimore. and the David and Lucile Packard Foundation, Chapel Ringheim, K. 2007. “Ethical and Human Rights Perspectives Hill, NC. on Providers’ Obligation to Ensure Adolescents’ Rights to Moreland, S., E. Smith, and S. Sharma. 2010. “World Population Privacy.” Studies in Family Planning 38 (4): 245–52. Prospects and Unmet Need for Family Planning.” Futures Ross, J., and A. K. Blanc. 2012. “Why Aren’t There More Group, Washington, DC. Maternal Deaths? A Decomposition Analysis.” Maternal Nakhaee, N., A. R. Mirahmadizadeh, H. A. Gorji, and Child Health Journal 16 (2): 456–63. doi:10.1007 M. Mohammadi. 2002. “Assessing the Cost-Effectiveness of /s10995-011-0777-x. Contraceptive Methods in Shiraz, Islamic Republic of Iran.” Ross, J., and E. Smith. 2011. “Trends in National Family Eastern Mediterranean Health Journal 8: 55–63. Planning Programs, 1999, 2004 and 2009.” International NAS (National Academy of Sciences). 1986. Population Growth Perspectives on Sexual and Reproductive Health 37 (3): and Economic Development: Policy Questions. Committee on 125–33. Population, National Research Council. Washington, DC: Ross, J., and J. Stover. 2013. “Use of Modern Contraception National Academy Press. Increases When More Methods Become Available: Analysis 112 Reproductive, Maternal, Newborn, and Child Health of Evidence from 1982–2009.” Global Health: Science and Thapa, S., S. Sharma, and N. Khatiwada. 2014. “Women’s Practice 1 (2): 203–12. doi:10.9745/GHSP-D-13-00010. Knowledge of Abortion Law and Availability of Services in Royal Society. 2012. People and the Planet. London: The Royal Nepal.” Journal of Biosocial Science 46 (2): 266–77. Society. Todd, J. E., P. Winters, and G. Stecklov. 2010. “Evaluating Rutstein, S. O., K. Johnson, A. Conde-Agudelo, and A. Rosas- the Impact of Conditional Cash Transfer Programs on Bermudez. 2008. “Further Analysis of the Effects of Birth Fertility: The Care of the Red de Proteccíon Social in Spacing on Infant and Child Mortality: A Systematic Review Nicaragua.” Journal of Population Economics 25 (1): 267–90. and Meta-Analysis.” Technical Consultation and Scientific doi:10.1007/s00148-010-0337-5. Review of Birth Spacing, World Health Organization, Tripney, J., I. Kwan, and K. Bird. 2013. “Postabortion Family Geneva, June 13–15. Planning Counseling and Services for Women in Low- Samandari, G., M. Wolf, I. Basnett, A. Hyman, and Income Countries: A Systematic Review.” Contraception K. Andersen. 2012. “Implementation of Legal Abortion in 87: 17–25. Nepal: A Model for Rapid Scale-Up of High-Quality Care.” Trussel, J. 2011. “Contraceptive Efficacy.” In Contraceptive Reproductive Health 9: 7. Technology, Twentieth Revised Edition, edited by Schutt-Aine, J., and M. Maddaleno. 2003. Sexual Health and R. A. Hatcher, J. Trussel, A. L. Nelson, W. Cates, D. Kowal, Development of Adolescents and Youth in the Americas: and M. Policar. New York: Ardent Media. Program and Policy Implications. Washington, DC: Pan UN (United Nations). 1968. “Final Act of the International American Health Organization. Conference on Human Rights, Teheran, April 22–May 13.” Seamans, Y., and C. M. Harner-Jay. 2007. “Modelling Cost- UN, New York. Effectiveness of Different Vasectomy Methods in India, Kenya, ———. 2011. World Population Prospects 2011. New York: and Mexico.” Cost Effectiveness and Resource Allocation 5: 8. Department of Economic and Social Affairs, Population Senderwitz, J. 1999. “Making Reproductive Health Services Division, UN. Youth Friendly.” Research, Program and Policy Series. UN Population Division. 2009. “What Would It Take to Pathfinder International, FOCUS on Young Adults, Accelerate Fertility Decline in the Least Developed Washington, DC. Countries?” Policy Brief 2009/1, United Nations, New York. Seltzer, J. 2002. The Origins and Evolution of Family Planning ———. 2013a. World Abortion Policies 2013. New York. Programs in Developing Countries. Santa Monica, CA: http://www.un.org/en/development/desa/population RAND. /publications/policy/world-abortion-policies-2013.shtml. Simmons, R., and J. Shiffman. 2007. “Scaling-up Reproductive ———. 2013b. World Contraceptive Patterns 2013. New York: Health Service Innovations: A Framework for Action.” In Department of Economic and Social Affairs, United Nations. Scaling Up Health Service Delivery: From Pilot Innovations UNESCO (United Nations Educational, Scientific and Cultural to Policies and Programmes, edited by Ruth Simmons, Peter Organization). 2009. UNESCO’s Short Guide to Essential Fajans, and Laura Ghiron, 1–30. Geneva: World Health Characteristics of Effective HIV Prevention. Paris: UNESCO. Organization. www.unesco.org/aids Singh, J. S. 2009. Creating a New Consensus on Population: The ———. 2013. “Schooling for millions of Children Jeopardized Politics of Reproductive Health, Reproductive Rights and by Reductions in Aid.” Institute for Statistics Database, Women’s Empowerment. London: Earthscan. No. 25, UNESCO. Sneeringer, R. K., D. L. Billings, B. Ganatra, and T. L. Baird. UNFPA (United Nations Population Fund). 2012. By Choice, 2012. “Roles of Pharmacists in Expanding Access to Safe Not by Chance. State of World Population 2012. New York: and Effective Medical Abortion in Developing Countries: UNFPA. A Review of the Literature.” Journal of Public Health Policy ———. 2013. Motherhood in Childhood. Facing the Challenge 33 (2): 218–29. of Adolescent Pregnancy. 2013 State of the World Population Stephenson, R., A. O. Tsui, S. Sulzbach, P. Bardsley, G. Bekele, Report. New York: UNFPA. and others. 2004. “Franchising Reproductive Health UNICEF (United Nations Children’s Fund). 2005. “Progress Services.” Health Services Research 39 (6 Pt 2): 2053–80. for Children: A Report Card on Gender Parity and Primary Stoebenau, K., and T. W. Valente. 2003. “Using Network Education.” No. 2. UNICEF, New York. Analysis to Understand Community-Based Programs: A ———. 2011. The State of the World’s Children 2011. New York: Case Study from Highland Madagascar.” International UNICEF. Family Planning Perspectives 29 (4): 167–73. USAID/Africa Bureau, USAID/Population and Reproductive Stover, J., and J. Ross. 2009. “How Increased Contraceptive Health, Ethiopia Federal Ministry of Health, Malawi Use Has Reduced Maternal Mortality.” Maternal and Child Ministry of Health, and Rwanda Ministry of Health. Health 14 (5): 687–95. doi:10.1007/s10995-009-0505-y. 2013. Three Successful Sub-Saharan Africa Family Planning Sweat, M. D., J. Denison, C. Kennedy, V. Tedrow, and K. O’Reilly. Programs: Lessons for Meeting the MDGs. Washington, DC: 2012. “Effects of Condom Social Marketing on Condom USAID. Use in Developing Countries: A Systematic Review and Villarruel, A. M., Y. Zhou, E. C. Gallegos, and D. L. Meta-Analysis, 1990–2010.” Bulletin of the World Health Ronis. 2010. “Examining Long-Term Effects of Organization 90 (8): 613–22A. doi:10.2471/BLT.11.094268. Cuidate—A Sexual Risk Reduction Program in Mexican Interventions to Improve Reproductive Health 113 Youth.” Revista Panamericana de Salud Publica 27 (5): ———. 2014b. Trends in Maternal Mortality: 1990 to 2013. 345–51. Estimates by WHO, UNFPA, World Bank, and the United World Bank and UNICEF. 2009. Abolishing School Fees in Nations Population Division. Geneva: WHO. Africa: Lessons from Ethiopia, Ghana, Kenya, Malawi, and ———. 2014c. Health Care for Women Subjected to Intimate Mozambique. Washington, DC: World Bank. Partner Violence or Sexual Violence. A Clinical Handbook. WHO (World Health Organization). 1997. “Beyond Geneva: WHO Acceptability: Users’ Perspectives on Contraception, ———. 2015. Trends in Maternal Mortality: 1990 to 2015. Reproductive Health Matters.” WHO, Geneva. Estimates by WHO, UNFPA, World Bank, and the United ———. 2011. Unsafe Abortion: Global and Regional Estimates Nations Population Division. Geneva: WHO. of the Incidence of Unsafe Abortion and Associated Mortality Williams, T., S. Mullen, A. Karim, and J. Posner. 2007. Evaluation in 2008, 6th ed. Geneva: WHO. of the Africa Youth Alliance Program in Ghana, Tanzania ———. 2012. Safe Abortion: Technical and Policy Guidance for and Uganda: Impact on Sexual and Reproductive Health Health Systems. Geneva: WHO. Behavior among Young People. Arlington, VA: JSI Research ———. 2013. Responding to Intimate Partner Violence and and Training Institute. Sexual Violence against Women: WHO Clinical and Policy Zuurmond, M. A., R. S. Geary, and D. A. Ross. 2012. Guidelines. Geneva: WHO. “The Effectiveness of Youth Centers in Increasing ———. 2014a. Global Health Estimates for Deaths by Cause, Use of Sexual and Reproductive Health Services: Age, and Sex for Years 2000–2012. Geneva: WHO. http:// A Systematic Review.” Studies in Family Planning www.who.int/healthinfo/global_burden_disease/en/. 43 (4): 239–54. 114 Reproductive, Maternal, Newborn, and Child Health Chapter 7 Interventions to Reduce Maternal and Newborn Morbidity and Mortality A. Metin Gülmezoglu, Theresa A. Lawrie, Natasha Hezelgrave, Olufemi T. Oladapo, João Paulo Souza, Marijke Gielen, Joy E. Lawn, Rajiv Bahl, Fernando Althabe, Daniela Colaci, and G. Justus Hofmeyr INTRODUCTION seems low. Respiratory infections, diarrhea, and malaria remain important causes of under-five mortality after In 2015, an estimated 303,000 women died as a result the first month of life (Liu and others 2016). Neonates of pregnancy and childbirth-related complications account for 45 percent of all deaths under age five years (WHO 2015a). Most of these deaths occurred in low- (Liu and others 2016); this share exceeds 50 percent in and middle-income countries (LMICs). Sub-Saharan several regions (Lawn and others 2014). Of all newborn Africa had the highest maternal mortality ratio (MMR) deaths, preterm birth and intrapartum-related compli- in 2015, an estimated 546 maternal deaths per 100,000 cations account for 59 percent (Liu and others 2016), live births; the MMR for high-income countries (HICs) and preterm birth is now the leading direct cause of was an estimated 17 maternal deaths per 100,000 live all deaths under age five years (Lawn and others 2014). births (map 7.1) (WHO 2015a). Although significant The tracking of progress does not include stillbirths. In progress has been made since 1990 in achieving the 2009, an estimated 2.6 million stillbirths occurred in the Millennium Development Goals (MDGs), with a reduc- last trimester of pregnancy, with more than 45 percent in tion in the global MMR from 385 to 216 maternal deaths the intrapartum period (Lawn and others 2011; Lawn and per 100,000 live births, this reduction falls short of the others 2016). The majority of these stillbirths (98 percent) 2015 MDG 5 target of a 75 percent reduction. occur in LMICs (Lawn and others 2014). Similarly, mortality for children under age five years Significant proportions of these maternal, fetal, and (MDG 4) declined by 49 percent, from 12.4 million in newborn deaths are preventable. A crucial focus of 1990 to 5.9 million in 2015, but still substantially short recent initiatives, such as Ending Preventable Maternal of the 2015 target of a reduction by two-thirds, and Mortality, is quality of care (WHO 2015b). This chapter the decline is much slower for neonatal deaths (Liu discusses biomedical interventions for major causes of and others 2016). Within countries, when the popu- morbidity and mortality in pregnancy and childbirth lation is disaggregated by income, education, or place in the context of people’s right to access good quality, of residence, wide disparities in child mortality can be respectful, and timely care—wherever they may live. shown, even in those areas where the overall mortality Corresponding author: A. Metin Gülmezoglu, Department of Reproductive Health and Research, World Health Organization, Geneva, gulmezoglum@who.int. 115 Map 7.1 Maternal Mortality Ratio per 100,000 Live Births, 2015 IBRD 42032 | DECEMBER 2015 1–19 20–99 100–299 300–499 500–999 ≥ 1,000 Data not available or not applicable Source: Based on WHO 2015a; map re-created based on WHO 2015a. INTERVENTIONS TO REDUCE MATERNAL Integrated Management in Pregnancy and Childcare MORTALITY AND MORBIDITY (IMPAC) package (WHO 2010a). Interventions to reduce indirect causes of maternal mortality and morbidity are Major obstetric causes of maternal mortality include not addressed in this chapter. hemorrhage (postpartum hemorrhage [PPH], and hem- Table 7.1 provides an overview of selected medical orrhage due to placental abruption, placenta previa, interventions to reduce poor maternal outcomes for ruptured uterus, and other causes), hypertensive diseases which there is moderate to high-quality evidence. of pregnancy (mainly preeclampsia/eclampsia), and maternal sepsis. In a study conducted across 29 countries in Asia, Latin America and the Caribbean, the Middle Postpartum Hemorrhage East and North Africa, and Sub-Saharan Africa, PPH and Most of the evidence for PPH comes from reviews of stud- preeclampsia/eclampsia each accounted for more than ies in both high-income countries (HICs) and LMICs. 25 percent of maternal deaths and near-misses; maternal sepsis accounted for approximately 8 percent (Souza and Preventing Postpartum Hemorrhage others 2013). The burden of disease due to obstructed The most effective intervention for preventing PPH is labor is difficult to estimate because these data may be the use of uterotonics—drugs that contract the uterus— coded under sepsis or hemorrhage. However, ruptured during the third stage of labor before the placenta is uterus, a possible consequence of obstructed labor, delivered. An injectable uterotonic is the drug of choice; accounted for 4.3 percent of maternal deaths and near- however, oral or sublingual misoprostol may be used miss events in the multicountry study. when injectable uterotonics are not available (table 7.2). Data on indirect causes of maternal deaths—those Oxytocin and ergot alkaloids. A Cochrane review associated with conditions, such as heart disease, malaria, assessed the effect of prophylactic oxytocin given during tuberculosis, and HIV, exacerbated by pregnancy—are the third stage of labor on PPH (blood loss greater than also difficult to capture. However, the contribution of 500 milliliters) (Westhoff, Cotter, and Tolosa 2013). The indirect causes of maternal deaths is estimated to be about review included 20 randomized controlled trials (RCTs) 28 percent and seems to be increasing, particularly in Sub- conducted in LMICs and HICs involving 10,806 women. Saharan Africa (Say and others 2014). In 2015, 2.0 percent Prophylactic oxytocin, compared with placebo, halved of indirect maternal deaths in Sub-Saharan Africa were the risk of PPH; when compared with ergot alkaloids, related to HIV, with the proportion reaching 10 percent it reduced the risk of PPH by 25 percent. There was no or more in five countries (WHO 2015a). This highlights significant difference in the risk of PPH with the combi- the importance of integrating service delivery during nation of oxytocin and ergometrine versus ergot alkaloids pregnancy and childbirth as recommended by the WHO alone. Oxytocin was better tolerated than ergot alkaloids. 116 Reproductive, Maternal, Newborn, and Child Health Table 7.1 Evidence-Based Interventions that Reduce Maternal Morbidity and Mortality Type of intervention Main effects Quality of evidencea Source of evidence Postpartum hemorrhage (PPH) Oxytocin • Halves PPH risk when used routinely for Moderate Westhoff, Cotter, and Tolosa 2013; prevention WHO 2012 • Recommended for prevention and treatment Misoprostol • Reduces PPH risk and the need for blood Moderate Tunçalp, Hofmeyr, and Gülmezoglu transfusion 2012; WHO 2012 • Recommended for PPH prevention if oxytocin unavailable Preeclampsia and eclampsia Calcium supplementation • Halves preeclampsia risk in all women Moderate Hofmeyr and others 2014; • Risk reduction is greatest in high-risk women WHO 2013 and those with low dietary calcium intake Aspirin supplementation • Reduces the risk of preeclampsia in high-risk Moderate Duley and others 2007; women WHO 2011b Magnesium sulphate • Reduces the risk of first seizure in women High Altman and others 2002; Duley, with preeclampsia and recurrent seizures in Gülmezoglu, and others 2010; eclampsia, with a trend to reduced maternal WHO 2011b mortality Sepsis Prophylactic antibiotics at • Reduces risk of wound infection, endometritis, Moderate Smaill and Grivell 2014 cesarean section and serious maternal infectious morbidity Note: This list is not comprehensive. PPH = postpartum hemorrhage. a. Based on GRADE Working Group grades of evidence (Atkins and others 2004). The GRADE approach considers evidence from randomized trials to be high quality in the first instance, and downgrades the evidence to moderate, low, or very low if there are limitations in trial quality suggesting bias, inconsistency, imprecise or sparse data, uncertainty about directness, or high probability of publication bias. Evidence from observational studies is graded low quality in the first instance and upgraded to moderate (or high) if large effects are yielded in the absence of obvious bias. Table 7.2 Interventions to Prevent Postpartum Hemorrhage Evidence-based effective interventions for postpartum hemorrhage prevention • Uterotonics used during the third stage of labor: Oxytocin (10 IU IM or IV) is the drug of choice (Westhoff, Cotter, and Tolosa 2013). • In settings where oxytocin is unavailable, other injectable uterotonics—ergot alkaloids if appropriate, or the fixed drug combination of oxytocin and ergometrine), or oral misoprostol (600 micrograms)—are recommended (WHO 2012). Note: IM = intramuscular; IU = international unit; IV = intravenous; µg = microgram. Misoprostol. A Cochrane review assessed the effect severe PPH (blood loss greater than 1,000 milliliters). of prophylactic misoprostol compared with uteroton- However, misoprostol was significantly more effective ics or no uterotonic given during the third stage of than placebo in reducing PPH and blood transfusions. labor to women at risk of PPH (Tunçalp, Hofmeyr, Misoprostol is associated with an increased risk of and Gülmezoglu 2012). The review included 72 tri- shivering and fever (temperature of 38°C or higher) als conducted in LMICs and HICs involving 52,678 compared with oxytocin and placebo. It does not appear women. In comparison with oxytocin, oral or sublingual to increase or decrease severe maternal morbidity or misoprostol was associated with an increased risk of mortality (Hofmeyr and others 2013). Interventions to Reduce Maternal and Newborn Morbidity and Mortality 117 Misoprostol does not require refrigeration and is Treating Postpartum Hemorrhage inexpensive and easy to administer. In settings in which Evidence for the most common interventions for treat- skilled birth attendants are not present and oxytocin ing PPH due to atony is based on data extrapolated from is unavailable, the World Health Organization (WHO) studies of PPH prevention. recommends that misoprostol (600 micrograms orally) Primary interventions. Emptying the bladder and be given to women in the third stage of labor by uterine massage to stimulate contractions are the community health care workers and lay health workers first steps for the treatment of PPH. Although no to prevent PPH (WHO 2012). Continued vigilance for high-quality evidence supports these interventions, they adverse effects is essential. Additional research is needed allow easier assessment of the uterus and its contractil- to further determine the relative effectiveness and the ity. Uterine massage is strongly recommended for PPH risks of various dosages of misoprostol and to identify treatment (WHO 2012). Fluid replacement is a key the lowest effective dose. element in the resuscitation of women with PPH. No RCTs have assessed fluid replacement in this particu- Other Interventions lar condition; the evidence in favor of crystalline fluid Uterine massage. Evidence on the efficacy of uterine replacement is extrapolated from a Cochrane review of massage for the prevention of PPH is limited and fluid replacement in critically ill patients (Perel, Roberts, inconclusive. A Cochrane review evaluated data from and Ker 2013). two RCTs of 1,491 women that investigated the effects Drug interventions. The injectable uterotonic drugs of uterine massage before, after, or both before and oxytocin and ergometrine are both extremely effective after delivery of the placenta (Hofmeyr, Abdel-Aleem, in causing uterine contraction. Oxytocin is preferred and Abdel-Aleem 2013). No significant difference was initially, especially in women with a history of hyperten- observed in uterine blood loss, irrespective of when sion, because ergometrine can cause hypertension. The the massage was initiated, between the intervention intravenous route is recommended for administration of and control groups. The WHO does not recommend oxytocin. Evidence suggests that administering misopros- sustained uterine massage as an intervention to prevent tol and injectable uterotonics together for PPH treatment PPH in women who have received prophylactic oxyto- does not confer additional benefits (Mousa and others cin. However, early postpartum identification of uterine 2014). However, if injectable uterotonics are not available atony—failure of the uterus to contract sufficiently—is or have been ineffective, misoprostol can be adminis- recommended for all women. tered. Tranexamic acid may also be given (WHO 2012). Early versus late cord clamping. A Cochrane review Uterine tamponade. Uterine tamponade, involving assessed the effects of early cord clamping (less than a mechanical device to exert pressure from within the one minute after birth), compared with late cord uterus, has a reported success rate of between 60 percent clamping after birth, on maternal and neonatal out- and 100 percent (Diemert and others 2012; Georgiou comes (McDonald and others 2013). The review 2009; Majumdar and others 2010; Porreco and Stettler included 15 trials conducted in LMICs and HICs 2010; Sheikh and others 2011; Thapa and others 2010; involving 3,911 women and infant pairs. There was Yoong and others 2012). This evidence is indirect and no significant difference between early versus late cord comes mainly from case series. The types of devices clamping groups with respect to PPH and severe PPH used for uterine tamponade include urinary catheters in the mothers. However, late cord clamping increased (Sengstaken-Blakemore or Foley’s), balloon catheters early hemoglobin concentrations and iron stores in (Bakri and Rusch), and condoms. Although the quality infants, compared with early cord clamping, and the of the evidence is low, the WHO considers the benefits WHO recommends late cord clamping to improve to outweigh the disadvantages and weakly recommends infant outcomes (WHO 2012). this intervention (WHO 2012). Controlled cord traction. Two large trials of controlled Artery embolization. Artery embolization is used to cord traction (CCT) have been conducted, one of 23,861 treat PPH in facilities with appropriate equipment and women in eight LMICs (Gülmezoglu, Lumbiganon, and expertise. There are no RCTs evaluating this procedure; others 2012) and the other of 4,013 women in France the evidence from case series and case reports indicates (Deneux-Tharaux and others 2013). The results of that the success rate ranges between 82 percent and these trials suggest that CCT performed as part of the 100 percent (Ganguli and others 2011; Kirby and others management of the third stage of labor has no clinically 2009; Lee and Shepherd 2010; Touboul and others 2008; important effect on the incidence of PPH. The WHO Wang and others 2009; Zwart, Djik, and van Roosmalen weakly recommends CCT by skilled birth attendants 2010). The WHO weakly recommends this intervention (WHO 2012). (WHO 2012), depending on available resources. 118 Reproductive, Maternal, Newborn, and Child Health Surgical interventions. Surgical interventions are gen- 34 weeks). Generalized seizures (eclampsia) occur in erally used when other treatments have failed. Surgical up to 8 percent of women with preeclampsia in LMICs interventions include compression sutures (for example, (Steegers and others 2010), a rate that is 10 times to the B-Lynch technique); ligation of the uterine, ovarian, 30 times more common than in HICs (Duley 2009). or iliac artery; and total or subtotal hysterectomy. The evidence supporting these procedures is limited because Preventing Preeclampsia they are emergency, life-saving procedures. The B-Lynch The only interventions that have shown clear benefit technique has some advantages in that it is relatively in reducing preeclampsia risk in selected populations simple to perform, preserves fertility, and has good suc- are low-dose aspirin (Duley and others 2007) and cess rates (89 percent to 100 percent) (Price and Lynch dietary supplementation with calcium (Hofmeyr and 2005). The WHO strongly recommends these life-saving others 2014). procedures when indicated (WHO 2012). Calcium supplementation. A WHO synthesis of evi- Nonpneumatic antishock garment. A nonpneumatic dence from two Cochrane reviews (Buppasiri and others antishock garment is a simple low-technology, first-aid 2011; Hofmeyr and others 2014) involving 15 RCTs con- device that may help stabilize women with hypovolemic ducted in LMICs and HICs and 16,490 women found shock, particularly during transport to facilities; how- that calcium supplementation more than halves the ever, high-quality research on the garment is lack- incidence of preeclampsia in all women, compared with ing. The WHO weakly recommends this intervention, placebo, with greater reductions in high-risk women and depending on available resources (WHO 2012). populations with low dietary calcium intake. Calcium supplementation was associated with a 20 percent reduc- Interventions in the Pipeline tion in the risk of the composite outcome of maternal Several lines of active research are underway in PPH pre- death or serious morbidity. The WHO strongly recom- vention and treatment: A large RCT with a sample size of mends that in areas with low dietary calcium intake, 20,000 is evaluating tranexamic acid compared with pla- calcium supplementation commence in early pregnancy, cebo in women with PPH (http://www.thewomantrial particularly for women at high risk of preeclampsia, .lshtm.ac.uk/). An inhaled oxytocin development project including those with multiple pregnancies, previous has been awarded seed funding and is undergoing initial preeclampsia, preexisting hypertension, diabetes, renal development research in Australia (http://www.monash or autoimmune disease, or obesity (WHO 2011a, 2013). .edu.au/pharm/research/iop/). The WHO is evaluating a Low-dose aspirin. In a Cochrane review of 18 trials room-temperature-stable synthetic oxytocin analogue, conducted in LMICs and HICs of prophylactic aspirin carbetocin. In addition, various forms of occlusive gels in 4,121 pregnant women, low-dose aspirin in women and foams are in development. at high risk of preeclampsia was associated with a 25 percent risk reduction (Duley and others 2007). In addition, an 18 percent reduction in the risk of fetal or Preeclampsia and Eclampsia neonatal death was observed for a subgroup of trials Hypertensive disorders in pregnancy, particularly preec- that commenced treatment before 20 weeks’ gestation. lampsia, complicate 2 percent to 8 percent of all pregnan- The WHO recommends low-dose aspirin (75 milligrams cies, accounting for the majority of the estimated 76,000 a day) to be prescribed and initiated before 20 weeks annual maternal deaths occurring in LMICs (Duley gestation to those women at high risk of developing 2009). A WHO multicountry survey on maternal and preeclampsia (WHO 2011b). newborn health estimates that preeclampsia is associated Screening for preeclampsia. Early detection is vital with more than 25 percent of severe maternal outcomes for timely intervention and prevention of progression and is the direct cause of 20 percent of reported mater- to severe disease. Monitoring blood pressure and per- nal deaths (Souza and others 2013). It is associated with forming urinalysis are the cornerstones of antenatal 20 percent of infants born prematurely and 25 percent screening, as are asking about symptoms that may sug- of stillbirths and neonatal deaths (Ngoc and others 2006). gest preeclampsia and noting if a fetus is smaller than The etiology of preeclampsia is unknown. It is expected. Detection of preeclampsia should prompt thought to arise from the placenta and is associated referral for specialist care. with malfunction of the lining of blood vessels. The clinical spectrum of disease in preeclampsia varies, Treating Preeclampsia and Eclampsia ranging from mild, asymptomatic disease, often occur- The only definitive cure for preeclampsia is delivery of the ring close to term, to severe, uncontrolled hyperten- baby, by induction of labor or by prelabor cesarean sec- sion typically developing remote from term (less than tion (CS), to prevent progression of disease and related Interventions to Reduce Maternal and Newborn Morbidity and Mortality 119 morbidity and mortality. The mainstays of treatment are versus expectant management depends on the severity antihypertensive drugs for blood pressure control and of disease and is influenced by the setting. A Cochrane magnesium sulphate (MgSO4) for eclampsia. review finds insufficient evidence for intervention versus Antihypertensive therapy. Antihypertensive ther- expectant management for women with severe preec- apy in preeclampsia aims to reduce the risk of severe lampsia between 24 and 34 weeks gestation (Churchill hypertension and stroke, with a steady reduction in and others 2013); however, the expectant approach is blood pressure to safe levels, avoiding sudden drops that probably associated with less neonatal morbidity. No may compromise blood supply to the fetus. No evidence systematic reviews address the optimal timing of delivery is available on the comparative efficacy of commonly for preeclampsia between 34 and 36 weeks gestation, and used antihypertensive medications, such as labetolol, significant variation in practice exists. In the absence calcium channel blockers (nifedipine), hydralazine, and of robust evidence, the WHO recommends a policy of methyldopa, for mild to moderate or severe hyperten- expectant management for women with severe preec- sion. All of the agents listed have been used extensively, lampsia, both before 34 weeks gestation and between 34 and the WHO guidelines recognize that they are all rea- and 36 weeks gestation with a viable fetus, provided that sonable choices for controlling hypertension. The choice the pregnancy can be monitored for increasing hyper- of drug should be based on the prescribing clinician’s tension, maternal organ dysfunction, and fetal distress experience with that particular drug, its cost, and local (WHO 2011b). Clearly, this management requires equi- availability (WHO 2011b). table access to facilities for safe delivery (including CS), Anticonvulsant prophylaxis and treatment. Substantial skilled attendance at delivery, access to appropriate drugs, evidence exists to demonstrate that MgSO4, a low-cost and maternal and fetal monitoring. intramuscular or intravenous treatment, is effective in preventing and controlling eclampsia. The Magpie Technologies and Interventions in the Pipeline study, a multicountry prospective RCT involving 33 Prevention and treatment. Early calcium supplementa- centers and 10,141 women (two-thirds of the partici- tion during preconception and early pregnancy, possibly pating centers were in LMICs), compared MgSO4 with by means of food fortification, is being evaluated by the placebo in women with preeclampsia. A reduction of WHO/PRE-EMPT Calcium in Pre-eclampsia (CAP) more than 50 percent in preeclamptic seizures occurred study. Funded by the Bill & Melinda Gates Foundation, in the treatment arm, with the number needed to treat of the trial is being conducted in centers in Argentina, 100 women to prevent 1 case of eclampsia (Altman and South Africa, and Zimbabwe in populations with known others 2002); the number needed to treat fell to 63 for calcium dietary deficiencies. Work is ongoing to assess women with severe preeclampsia. whether pregnancy and pre-pregnancy supplementa- A Cochrane review and meta-analysis of six trials tion with selenium, which is reduced in preeclampsia including Magpie confirmed a clinically significant reduc- (Mistry and others 2008), will affect outcomes from tion in risk of eclampsia of 59 percent, regardless of the preeclampsia. route of administration of MgSO4 (Duley, Gülmezoglu, The use of statins to treat early-onset preeclampsia and others 2010 ), with the risk of dying nonsignificantly has shown initial promise and is under investigation reduced by 46 percent. Strong evidence indicates that (Ahmed 2011). MgSO4 is also substantially more effective than pheny- Screening. Interest has increased in the development toin for the treatment of eclampsia (Duley, Henderson- of a blood pressure monitor suitable for settings without Smart, and Chou 2010). The evidence regarding the medically trained health workers. Such monitors should effectiveness and safety of a low-dose MgSO4 regimen is be automated, validated for accuracy in pregnancy, insufficient (Duley, Gülmezoglu, and others 2010); the affordable, and hardwearing, and should have a reliable WHO recommends the administration of the full intra- power supply, for example, solar power or mobile phone venous or intramuscular regimen involving a loading charging technology. dose followed by at least 24 hours of maintenance dosing. Recent evidence from a diagnostic test accuracy study Timing of delivery. For mild, moderate, and severe suggests that low plasma levels of placental growth fac- preeclampsia diagnosed at term, the WHO recommends tor can accurately predict delivery within two weeks in a policy of early delivery by induction of labor, or cesar- women with suspected preeclampsia before 35 weeks’ ean section if induction is not appropriate (WHO 2011b). gestation (Chappell and others 2013). In this study, However, limited evidence suggests that induction at normal levels of placental growth factor accurately more than 36 weeks of gestation reduces poor maternal predicted which women did not need delivery for preec- outcomes in mild preeclampsia (Koopmans and others lampsia within two weeks. This test, which is potentially 2009). For earlier gestations, the decision for delivery available as a rapid bedside diagnostic tool, shows 120 Reproductive, Maternal, Newborn, and Child Health promise as an adjunct to clinical assessment of women on reducing maternal deaths and stillbirths. However, with preeclampsia, particularly for its apparent ability to there was insufficient evidence for robust conclusions distinguish women who require intensive surveillance to be drawn (van Lonkhuijzen, Stekelenburg, and van and delivery from those who can be managed expec- Roosmalen 2012). tantly as outpatients. External cephalic version. External cephalic version (ECV) is a method of manually encouraging a breech fetus into a cephalic presentation, through the maternal Obstructed Labor abdomen. Very low quality evidence from a Cochrane Labor is considered obstructed when the presenting review of eight trials conducted in LMICs and HICs part of the fetus cannot progress through the birth canal involving 1,308 women shows that attempting ECV from despite strong uterine contractions. Obstruction usually 36 weeks gestation may reduce the risk of not achieving occurs at the pelvic brim, but may occur in the cavity a normal vaginal (cephalic) delivery by half, and may or outlet. Causes include cephalopelvic disproportion, reduce the risk of CS by approximately 43 percent shoulder dystocia (fetal shoulders trapped in the pelvis (Hofmeyr, Kulier, and West 2015). The WHO currently during delivery), and fetal malposition and malpre- supports ECV in women with uncomplicated singleton sentation. Obstructed labor accounts for an estimated breech presentations at or beyond 36 weeks, but more 4 percent of maternal deaths (Lozano and others 2012), research is needed. which are caused by ruptured uterus, hemorrhage and puerperal sepsis. Other outcomes, such as obstetric fistu- Treating Obstructed Labor las, lead to considerable long-term maternal morbidity. Cesarean section. CS forms the backbone of the man- In LMICs, women with obstructed labor are more likely agement of obstructed labor and saves many lives. to have stillbirths, neonatal deaths, and neonatal infec- Because of the availability of operative delivery in tions (Harrison and others 2015). Obstructed labor can HICs, maternal deaths there due to obstructed labor only be alleviated by means of a CS or other instrumen- are rare; however, CS rates are often disproportionately tal delivery (forceps, vacuum, symphysiotomy); there- high in these settings. Overuse of CS has important fore, referral and appropriate action during labor play a negative implications for health equity within and crucial role in reducing the burden of disease. across countries (Gibbons and others 2010). A sys- tematic review of ecologic studies finds that maternal, Preventing Obstructed Labor neonatal, and infant mortality decreased with increas- A substantial proportion of maternal deaths in LMICs ing CS rates up to a threshold between 9 percent and due to obstructed labor occur in community settings, 16 percent (Betran and others 2015). Above this thresh- where women are unable to access assisted delivery at old, CS rates were not associated with reductions in health facilities, either because they are disempowered to mortality. Therefore, increasing the availability of CS challenge existing social norms (for example, delivering in countries that show underuse could substantially alone or with traditional birth attendants), or because reduce maternal deaths. infrastructure is lacking (for example, roads, transpor- Vacuum and forceps delivery. Operative vaginal deliv- tation, and health facilities). In addition, women may ery may be used to assist women with obstructed labor prefer to deliver in the community without skilled at the pelvic outlet or low or mid-cavity. Operative assistance because they are afraid of financial costs, low vaginal delivery occurs at rates of about 10 percent in quality of care in health facilities, and disrespectful treat- HICs, in contrast with the rate of 1.6 percent reported ment (Stenberg and others 2013). The first priority for in a large, prospective, population-based study con- preventing poor outcomes related to obstructed labor is ducted in six LMICs (Harrison and others 2015). to create the demand for skilled birth assistance and to Vacuum and forceps procedures are associated with ensure that this demand can be met. different benefits and risks: forceps are more likely Maternity waiting homes. A maternity waiting home than vacuum to achieve a vaginal delivery but are is a facility that is within easy reach of a hospital or associated with more vaginal trauma and newborn health center that provides antenatal care and emergency facial injuries (O’Mahony, Hofmeyr, and Menon 2010). obstetric care (van Lonkhuijzen, Stekelenburg, and van Metal cups may be more effective than soft cups for Roosmalen 2012). Women with high-risk pregnancies vacuum delivery, but may be associated with more or those who live remotely are encouraged to stay at cephalhematomas in newborns (O’Mahony, Hofmeyr, these facilities, if they exist, toward the end of their and Menon 2010). The lack of appropriate and func- pregnancies. A Cochrane review conducted in 2012 tional equipment, as well as the lack of knowledge, sought to evaluate the role of maternity waiting homes experience, and skills to perform these procedures, Interventions to Reduce Maternal and Newborn Morbidity and Mortality 121 contributes to the low operative vaginal delivery rates Maternal Sepsis in many LMICs. Operator training is vital in all facility Sepsis associated with pregnancy and childbirth is settings to maximize benefits and reduce morbidity among the leading direct causes of maternal mortality with vacuum and forceps deliveries. worldwide, accounting for approximately 10 percent of Symphysiotomy. Symphysiotomy is an operation the global burden of maternal deaths (Khan and others in which the fibers of the pubic symphysis are par- 2006). Most of these deaths occur in LMICs; in a pro- tially divided to allow separation of the joint and thus spective study conducted in seven LMICs, 11.6 percent enlargement of the pelvic dimensions during childbirth of maternal deaths were due to sepsis (Saleem and oth- (Hofmeyr and Shweni 2012). The procedure is per- ers 2014). Although the reported incidence in HICs is formed with local analgesia and does not require an relatively low (between 0.1 and 0.6 per 1,000 deliveries), operating theater or advanced surgical skills; it may be a sepsis was reported as the leading direct cause of mater- lifesaving procedure for the mother, the baby, or both in nal death in the United Kingdom’s Confidential Enquiry clinical situations in which CS is unavailable and there is into Maternal Death (2006–08 triennium). failure to progress in labor, or in obstructed birth of the Maternal infections occurring before or during the aftercoming head of a breech baby. birth of the baby have considerable impact on new- A Cochrane review found no RCTs evaluating sym- born mortality, and an estimated 1 million newborn physiotomy for fetopelvic disproportion (Hofmeyr and deaths associated with maternal infection are recorded Shweni 2012). Criticism of the procedure because of each year. Efforts to reduce maternal sepsis have largely potential subsequent pelvic instability and because it focused on avoiding the risk factors, with an emphasis is considered a second-best option has resulted in its on reducing the frequency of unsafe abortion, intrapar- decline or disappearance from use in many countries. tum vaginal examination, and prolonged or obstructed Proponents argue that many maternal and neonatal labor; providing antibiotic cover for operative delivery; deaths from obstructed labor could be prevented in and using appropriate hospital infection control. parts of the world without CS facilities if symphysiot- omy was used. Research is needed to provide robust Preventing Maternal Sepsis evidence of the relative effectiveness and safety of sym- The most effective intervention for preventing maternal physiotomy compared with no symphysiotomy, or com- sepsis is the use of stringent infection control measures parisons of alternative symphysiotomy techniques in to limit the spread of microorganisms, particularly clinical situations in which CS is not available (Hofmeyr within hospital environments. General measures, such and Shweni 2012). as handwashing with soap or other cleansing agents, Maneuvers for shoulder dystocia. A Cochrane review are widely acceptable practices for preventing hospital evaluated evidence for maneuvers to relieve shoul- transmissible infections. der dystocia by manipulating the fetal shoulders (for Antibiotic prophylaxis in operative vaginal delivery. example, through suprapubic pressure or the corkscrew There is a general assumption that the use of vacuum maneuver), and increasing the functional size of the and forceps–assisted vaginal deliveries increases the inci- maternal pelvis by utilizing an exaggerated knee-chest dence of postpartum infections compared with spon- position (Athukorala, Middleton, and Crowther 2006). taneous vaginal delivery. The evidence from available The evidence from this review of two small trials was Cochrane reviews is insufficient to determine whether insufficient to support or refute any benefits of these prophylactic antibiotics given with operative delivery or maneuvers. following third- or fourth-degree perineal tears reduces infectious postpartum morbidities (Buppasiri and others Technologies and Interventions in the Pipeline 2010; Liabsuetrakul and others 2004). However, the use The Odon device has been developed to assist vaginal of antibiotics among women with a third- or fourth- delivery. This technological innovation has the potential degree perineal tear is recommended by the WHO for to facilitate assisted delivery for prolonged second stage prevention of wound complications (WHO 2014c). of labor. It consists of a film-like polyethylene sleeve that Antibiotic prophylaxis at cesarean delivery. CS is is applied to the fetal head with the help of an inserter. the single most important risk factor for postpartum Because the device is designed to minimize trauma to maternal infection, and routine antibiotic prophy- the mother and baby, it is potentially a safer alternative laxis has considerable clinical benefits. In a Cochrane to forceps and vacuum delivery. A feasibility and safety review that includes 95 trials from LMICs and HICs study is in progress and a comparative trial is planned involving more than 15,000 women (Smaill and Grivell if it is shown to be safe (WHO Odon Device Research 2014), the use of prophylactic antibiotics compared Group 2013). with placebo after CS was associated with substantially 122 Reproductive, Maternal, Newborn, and Child Health lower risks of endometritis (infection of the lining of of an aminoglycoside (mostly gentamicin) and clin- the womb) (62 percent reduction), wound infection damycin compared with other regimens. (60 percent), and serious maternal infectious complica- tions (69 percent reduction). This evidence was consid- ered to be moderate quality. INTERVENTIONS TO REDUCE STILLBIRTHS Preterm and term prelabor rupture of membranes. AND NEWBORN MORTALITY AND Rupture of the fetal membranes remote from term car- MORBIDITY ries substantial risk of chorioamnionitis (infection of the fetal membranes) and severe maternal sepsis. Evidence Addressing stillbirths and neonatal mortality requires on the benefits of prophylactic antibiotics with preterm interventions across the continuum of care (preconcep- rupture of membranes is demonstrated in a Cochrane tion, antenatal, intrapartum, immediate postnatal period, review of 22 RCTs conducted in LMICs and HICs that and after) and interventions across the health system involved 6,872 women (Kenyon, Boulvain, and Neilson (family and community level, outreach, and clinical care 2013). Findings reveal that the use of prophylactic or facility level). Most of these interventions are included antibiotics was associated with a significant reduction in the Lives Saved Tool, developed to model the impact of in chorioamnionitis (moderate-quality evidence) and the interventions at different coverage levels (Walker, Tam, markers of neonatal morbidity. and Friberg 2013), and are part of existing sets of recom- There is no convincing evidence to support the use mended intervention packages for addressing maternal of prophylactic for prelabor rupture of membranes at and neonatal outcomes. The Lancet Every Newborn Series term, and this practice should be avoided in its absence presents Lives Saved Tool modeling with estimates of lives (Wojcieszek, Stock, and Flenady 2014). saved for maternal and neonatal deaths and stillbirths, Vaginal application of antiseptics for vaginal delivery. showing high gains and triple return on investment, with A Cochrane systematic review of three RCTs involving the potential to avert 3 million deaths per year, especially 3,012 participants assesses the effectiveness and side with facility-based care around birth and care of small effects of chlorhexidine vaginal douching during labor and sick newborns (Bhutta and others 2014). (Lumbiganon and others 2004). The review shows no RCTs for several well-established interventions that difference in the incidence of chorioamnionitis and form the cornerstones of newborn care, for exam- postpartum endometritis between women who received ple, neonatal resuscitation and thermal care for term chlorhexidine and placebo. No benefits to neonatal newborns, would be impossible for ethical reasons. infection were observed. Important interventions initiated in the antenatal or Vaginal application of antiseptics for cesarean delivery. neonatal period with evidence of health benefits later A Cochrane review compares the effect of vaginal cleans- in childhood, like newborn vaccination or antiretroviral ing with any antiseptic agent before cesarean delivery therapy (ART) in babies born to HIV-positive mothers, to placebo on the risk of maternal infectious morbid- are not included in this chapter. In addition, we have not ities (Haas, Morgan, and Contreras 2013). The review covered preconception or adolescent care interventions, includes five trials involving 1,946 women. The risk of such as family planning, for which there is good evidence postoperative endometritis was reduced by 61 percent, of a positive impact on perinatal health (Stenberg and but no clear difference was detected in postoperative others 2013). fever or any wound complications. Subgroup analysis suggests that beneficial effects might be greater for women with ruptured membranes. Antenatal Interventions Routine Antenatal Care Visits Treating Maternal Sepsis A Cochrane review of antenatal care programs reveals Chorioamnionitis and postpartum endometritis. The that reduced antenatal visits may be associated with an mainstay of treating maternal sepsis is antibiotics. increase in perinatal mortality, compared with standard Although evidence from Cochrane reviews is limited, care (Dowswell and others 2010) (table 7.3). Indirect intrapartum treatment with potent antibiotics is clini- evidence of the effectiveness of antenatal care in reduc- cally reasonable (Hopkins and Smaill 2002). A Cochrane ing stillbirths is available from further analysis of data review of 39 RCTs involving 4,221 women evaluates the from the WHO antenatal care trial, which showed that comparative efficacy and side effects of different antibi- stillbirth was reduced in the standard care group for par- otic regimens for postpartum endometritis (French and ticipants who received more frequent routine antenatal Smaill 2004). Wound infection was significantly reduced visits (Vogel and others 2013). This finding is consistent and treatment was less likely to fail with a combination with those of other trials (Hofmeyr and Hodnett 2013). Interventions to Reduce Maternal and Newborn Morbidity and Mortality 123 Table 7.3 Evidence-Based Antenatal Interventions that Reduce Perinatal Morbidity and Mortality Type of intervention Main effects Quality of evidencea Source of evidence Nutritional Folic acid • Reduces the risk of neural tube High De-Regil, Fernandez-Gaxiola, defects when given periconceptually and others 2010 Infection prevention and treatment Syphilis detection and treatment • Reduces stillbirths, neonatal deaths, High Blencowe and others 2011 and preterm birth IPT (malaria-endemic areas) • Reduces neonatal mortality and low High Radeva-Petrova and others birthweight 2014 • Reduces maternal anemia Insecticide-treated bednets (malaria) • Reduces fetal loss and low High Gamble, Ekwaru, and ter Kuile birthweight 2006 Antitetanus vaccine • Reduces neonatal mortality from Moderate Blencowe, Lawn, and others tetanus 2010 Intrauterine growth restriction interventions Antithrombotic agents in • Reduces perinatal mortality, preterm High Dodd and others 2013 pregnancies identified as high risk birth, and low birthweight Doppler velocimetry in high-risk • Reduces perinatal mortality Moderate Alfirevic, Stampalija, and Gyte pregnancies 2013 Other interventions Labor induction at 41+ weeks for • Reduces perinatal deaths and High Gülmezoglu, Crowther, and postterm pregnancy meconium aspiration others 2012 Intensive management of • Reduces macrosomia, perinatal Moderate Alwan, Tuffnell, and West gestational diabetes with optimal morbidity, and mortality 2009; glucose control Syed and others 2011 Note: This list is not comprehensive. IPT = intermittent preventive treatment. a. Based on GRADE Working Group grades of evidence (Atkins and others 2004). The GRADE approach considers evidence from randomized trials to be high quality in the first instance, and downgrades the evidence to moderate, low, or very low if there are limitations in trial quality suggesting bias, inconsistency, imprecise or sparse data, uncertainty about directness, or high probability of publication bias. Evidence from observational studies is graded low quality in the first instance and upgraded to moderate (or high) if large effects are yielded in the absence of obvious bias. Nutritional Interventions that includes 15 trials involving 7,410 pregnant women Folic acid. Several nutritional interventions may be imple- (Ota and others 2012), the risk of stillbirth and small- mented before and during pregnancy. Supplementation for-gestational-age babies was reduced by 38 percent of diets with folic acid and fortification of staple com- for women receiving BES advice, and mean birthweight modities periconceptually reduces the risk of neural tube was increased. Further research on the effectiveness and defects that account for a small proportion of stillbirths implementation of BES is necessary. or neonatal deaths (Blencowe, Cousens, and others 2010; Maternal calcium supplementation. The WHO synthe- De-Regil and others 2010). sized evidence from two systematic reviews on maternal Dietary advice and balanced energy supplementation. calcium supplementation (Buppasiri and others 2011; Balanced energy and protein supplementation (BES), Hofmeyr and others 2014) and found moderate-quality defined as a diet that provides up to 25 percent of total evidence that calcium supplementation has no effect energy in the form of protein, is an important interven- on preterm birth overall (WHO 2013). The WHO rec- tion for the prevention of adverse perinatal outcomes ommends maternal calcium supplementation from 20 in populations with high rates of food insecurity and weeks’ gestation in populations in which calcium intake maternal undernutrition (Imdad and Bhutta 2012). is low to reduce the risk of hypertensive disorders in In a Cochrane review of dietary advice interventions pregnancy (WHO 2013). 124 Reproductive, Maternal, Newborn, and Child Health Maternal zinc supplementation. Some evidence recommend that all pregnant women who are eligible for suggests that zinc supplementation may reduce the risk ART (CD4 ≤ 350 cells per cubic millimeter or advanced of preterm birth. A Cochrane review of the intervention clinical disease) should receive it (WHO 2010b). For includes 20 RCTs involving more than 15,000 women ineligible women, combination ART should be provided and infants (Mori and others 2012). Zinc supplemen- during pregnancy beginning in the second trimester and tation resulted in a small but significant reduction in should be linked with postpartum prophylaxis (WHO preterm birth of 14 percent, without any other signifi- 2010b). Findings from the Kesho-Bora trial, in which early cant benefits compared with controls. The reviewers weaning was associated with higher HIV-related infant conclude that studies of strategies to improve the overall mortality even with maternal ART prophylaxis during nutrition of populations in impoverished areas, rather breastfeeding, highlight the importance of breastfeeding than studies of micronutrient supplementation in isola- in low-resource settings (Cournil and others 2015). ART tion, should be a priority. prophylaxis in these settings should be provided to either the mother or infant for the duration of breastfeeding. Antenatal Treatment of Maternal Infections Other infections. There is currently no conclusive Maternal infections frequently have adverse effects on evidence of the effects on perinatal outcomes of using perinatal outcomes, and striking mortality reductions viral influenza, pneumococcal, and Haemophilus can be obtained by antenatal interventions related to influenzae type b vaccines during pregnancy malaria, HIV, syphilis, and tetanus. (Chaithongwongwatthana and others 2012; Salam, Das, Tetanus. A review of tetanus toxoid immunization and Bhutta 2012). concludes that there is clear evidence of the high impact of two or more doses of tetanus vaccine in pregnancy on Treatment of Diabetes Mellitus and Gestational reducing neonatal tetanus mortality (Blencowe, Lawn, Diabetes and others 2010). Immunizing pregnant women or Complications of diabetes range from variations in women of childbearing age with at least two doses of birthweight to fetal malformations and potentially an tetanus toxoid was estimated to reduce mortality from excess of perinatal mortality. Any specific treatment for neonatal tetanus by 94 percent. gestational diabetes versus routine antenatal care is asso- Syphilis. Pregnant women with untreated syphilis ciated with a reduction in perinatal mortality (Alwan, have a 21 percent increased risk of stillbirths (Gomez Tuffnell, and West 2009). Intensified management and others 2013). Evidence of the effect of antenatal including dietary advice, monitoring, or pharmacother- syphilis detection combined with treatment with peni- apy for women with gestational diabetes mellitus, when cillin suggests a significant reduction in stillbirths, pre- compared with conventional management, resulted in term births, congenital syphilis, and neonatal mortality a 54 percent reduction of macrosomic (> 4,000 grams) (Blencowe and others 2011). babies. It was also associated with statistically nonsig- Malaria. Effective prevention strategies for malaria nificant reductions in other outcomes, including peri- include prophylactic antimalarial drugs through intermit- natal death, stillbirths, neonatal hypoglycemia, shoulder tent preventive treatment (IPT) and insecticide-treated dystocia, CS, and birthweight (Lassi and Bhutta 2013). bednets (ITNs). IPT has been shown to improve mean Optimal blood glucose control in pregnancy com- birthweight and reduce the incidence of low birthwei- pared with suboptimal control was associated with a ght and neonatal mortality (Radeva-Petrova and others 60 percent reduction in the risk of perinatal mortality 2014). ITNs have been shown to reduce fetal loss by but a statistically insignificant impact on stillbirths (Syed 33 percent (Gamble, Ekwaru, and ter Kuile 2006). The and others 2011). WHO recommends the use of long-lasting ITN and IPT with sulfadoxine-pyramethamine to prevent infection Intrauterine Growth Restriction during pregnancy in malaria-endemic areas in Africa Risk factors for stillbirths and intrauterine growth (WHO 2014b). restriction (IUGR) largely overlap, and growth-restricted HIV. Most children with HIV acquire it from their fetuses are at increased risk of mortality and serious mothers, and ART is vital in preventing vertical (mother- morbidity. Improved detection and management of to-child) transmission. Triple drug regimens commenced IUGR using maternal body mass index, symphysial- antenatally are most effective; however, short ART courses fundal height measurements, and targeted ultrasound commencing before labor, with treatment extended to could be effective in reducing IUGR-related stillbirths by newborns during the first week of life, have been shown 20 percent (Imdad and others 2011). to significantly reduce mother-to-child HIV transmis- Doppler velocimetry. A Cochrane review of RCTs sion (Siegfried and others 2011). The WHO guidelines in HICs shows that the use of Doppler ultrasound of Interventions to Reduce Maternal and Newborn Morbidity and Mortality 125 umbilical and fetal arteries in high-risk pregnancies labor, assisted vaginal delivery and CS are vital to reduce was associated with a 29 percent reduction in perinatal perinatal morbidity and mortality. mortality; however, the specific effect on stillbirths was Worldwide, an estimated 40 million births occur at not significant (Alfirevic, Stampalija, and Gyte 2013). home, most in LMICs and usually in the absence of Antithrombotic agents. Treatment with heparin for skilled birth attendants. Limited evidence from two pregnant women considered to be at high risk of com- before-and-after studies of community-based skilled plications secondary to placental insufficiency leads to a birth attendance shows a 23 percent significant reduc- significant reduction in the risk of perinatal mortality, tion in the risk of stillbirth (Yakoob and others 2011). preterm birth, and infant birthweight below the 10th Although there has been an increase in the use of centile for gestational age when compared with no treat- skilled birth attendants globally, much remains to be ment (Dodd and others 2013). done for the organization and provision of services; Fetal movement counting. The lack of trials has however, this issue is beyond the scope of this chapter. resulted in insufficient evidence of any benefits of rou- An overview of selected intrapartum interventions can tine fetal movement counting (Mangesi, Hofmeyr, and be found in table 7.4. Smith 2007). However, a reduction in fetal movements may be indicative of fetal compromise; when identified General Interventions by the mother, awareness could trigger prompt care Hygiene. Poor hygienic conditions and poor delivery seeking and further assessment. practices contribute to the burden of neonatal mortality. Pooled data from 19,754 home births at three sites in Postterm Pregnancy South Asia indicate that the use of clean delivery kits or Elective induction of labor in low-risk pregnancies at clean delivery practices almost halves the risk of neonatal or beyond 41 weeks gestation (late term) is recom- mortality (Seward and others 2012). The use of a plastic mended in settings with adequate gestational age dat- sheet during delivery, a boiled blade to cut the cord, a ing and appropriate facility care. In a Cochrane review boiled thread to tie the cord, and antiseptic to clean the of 22 RCTs involving 9,383 women of late-term labor umbilicus were each significantly associated with reduc- induction, compared with expectant management, the tions in mortality, independent of kit use. newborns of women who were induced were 69 percent The partograph. A partograph is usually a preprinted less likely to die perinatally and 50 percent less likely form that provides a pictorial overview of labor progress to aspirate meconium (Gülmezoglu, Crowther, and that can alert health professionals to any problems with others 2012); there was no significant reduction in the mother or baby (Lavender, Hart, and Smyth 2013). stillbirths. Although the partograph is widely used and accepted to detect abnormal labor, strong evidence to recommend its general use is lacking (Lavender, Hart, and Smyth Intrapartum Interventions 2013). Until stronger evidence is available, the WHO Labor surveillance is needed for early detection, clinical supports the use of a partograph with a four-hour action management, and referral of women for complications. line for monitoring the progress of labor (WHO 2014a). Basic emergency obstetric care should be available at Fetal monitoring in labor. There is no evidence that first-level facilities providing childbirth care. This basic the use of electronic fetal heart rate monitoring during emergency care includes the following: labor reduces perinatal mortality. A Cochrane review of 13 RCTs involving more than 37,000 women of con- • The capacity to perform assisted vaginal delivery tinuous cardiotocography compared with intermittent (including vacuum or forceps assistance for delivery, auscultation shows no reduction in perinatal mortality episiotomy, advanced skills for manual delivery of (Alfirevic, Devane, and Gyte 2013). Continuous cardi- the infant with shoulder dystocia, and skilled vaginal otocography halved the risk of neonatal seizures without delivery of the breech infant) significant reductions in cerebral palsy, infant mortality, • Availability of parenteral antibiotics, parenteral oxy- or other standard measures of neonatal well-being and tocin, and parenteral anticonvulsants for preeclamp- was associated with an increased risk of assisted and sia or eclampsia operative delivery. • Skills for manual removal of the placenta and removal Active management of labor. Active management refers of retained products. to a package of care that includes strict diagnosis of labor, routine amniotomy, oxytocin for slow progress, and one- Because stillbirths and intrapartum-related neonatal to-one support (Brown and others 2013). A Cochrane deaths are often associated with difficult and obstructed review of seven RCTs involving 5,390 women finds 126 Reproductive, Maternal, Newborn, and Child Health Table 7.4 Evidence-Based Intrapartum and Neonatal Interventions that Reduce Perinatal Morbidity and Mortality Type of intervention Main effects Quality of evidencea Source of evidence General Clean delivery kits • Reduces neonatal mortality Moderate Seward and others 2012 Preterm birth and PPROM Antenatal Corticosteroids • Reduces neonatal mortality Moderate Roberts and Dalziel 2006 • Reduces the risk of RDS and other neonatal morbidities Magnesium sulphate • Reduces the risk of cerebral palsy in Moderate Doyle and others 2009 preterm infants Antibiotics (PPROM only) • Reduces neonatal infection High Kenyon, Boulvain, and Neilson 2013 Surfactant • Reduces RDS-related mortality Moderate Seger and Soll 2009; Soll and Özek 2010 Neonatal care Kangaroo mother care • Reduces mortality in low-birthweight High Conde-Agudelo, Belizán, and infants Diaz-Rossello 2014 Cord cleansing • Reduces neonatal mortality and Low-Moderate Imdad and others 2013; WHO 2014c (chlorhexidine) omphalitis in community settings Hypoxic ischemic encephalopathy Induced hypothermia • Reduces mortality High Jacobs and others 2013 Neonatal sepsis Community-administered • Reduces all-cause neonatal mortality Moderate Zaidi and others 2011 antibiotics and pneumonia-specific mortality Note: This list is not comprehensive. PPROM = preterm premature rupture of membranes; RDS = respiratory distress syndrome. a. Based on GRADE Working Group grades of evidence (Atkins and others 2004). The GRADE approach considers evidence from randomized trials to be high quality in the first instance, and downgrades the evidence to moderate, low, or very low if there are limitations in trial quality suggesting bias, inconsistency, imprecise or sparse data, uncertainty about directness, or high probability of publication bias. Evidence from observational studies is graded low quality in the first instance and upgraded to moderate (or high) if large effects are yielded in the absence of obvious bias. no significant difference in poor neonatal outcomes; (Roberts and Dalziel 2006). However, a large cluster however, CS rates were nonsignificantly reduced in the randomized trial (Antenatal Corticosteroids Trial) active management group (Brown and others 2013). conducted in LMICs to test provision of antenatal corticosteroids at lower levels of the health system with Preterm Labor and Preterm Prelabor Rupture of mainly unskilled workers and limited assessment of Membranes gestational age finds no difference in neonatal mortal- Antenatal corticosteroids. The administration of ante- ity with the administration of antenatal corticosteroids natal corticosteroids to women in preterm labor, or (Althabe and others 2015). Neonatal mortality in the in whom preterm delivery is anticipated (for example, intervention clusters overall was increased, which may in severe preeclampsia), for the prevention of neo- have been due to overtreatment, as were maternal natal respiratory distress syndrome (RDS) has been infections. This trial has important implications for shown to be very effective in preventing poor neona- the setting, implementation, and scale up of this inter- tal outcomes in well-resourced settings. A Cochrane vention, notably that antenatal corticosteroids should review of 21 RCTs involving 4,269 neonates finds be used in the context of more accurate assessment of that a single course of steroids administered between gestational age and assessment for maternal infection; 26 weeks and 35 weeks gestation reduced the risk of ensuring that maternal and newborn care can be pro- neonatal death by 31 percent and reduced neonatal vided should also be a part of this intervention. In the morbidity including cerebroventricular hemorrhage, Antenatal Corticosteroids Trial, half of the births were necrotizing enterocolitis, RDS, and systemic infections at home (Althabe and others 2015). Interventions to Reduce Maternal and Newborn Morbidity and Mortality 127 Antibiotics. The evidence does not support the routine Neonatal Interventions administration of antibiotics to women in preterm labor The immediate cause of many of the world’s 2.8 million with intact membranes in the absence of overt signs of annual neonatal deaths is an illness presenting as an infection (Flenady and others 2013). However, antibi- emergency, either soon after birth (such as complica- otics for preterm premature rupture of membranes are tions of preterm birth and intrapartum hypoxia) or effective in reducing the risk of a number of early mor- later (due to neonatal tetanus or community-acquired bidities, including RDS and postnatal infection, with- infections). Other important but less prevalent condi- out having a significant impact on mortality (Kenyon, tions include jaundice and hemorrhagic disease of the Boulvain, and Neilson 2013). newborn. These conditions all have high fatality rates, Magnesium sulphate. A Cochrane review of five particularly tetanus and encephalopathy (Lawn and RCTs involving 6,145 babies found that MgSO4 given others 2014). to women considered to be at risk of preterm birth Preventive measures needed to adequately reduce this reduced the risk of cerebral palsy by 32 percent and burden of disease include much of what has already been improved long-term outcomes into childhood (Doyle discussed. Other interventions include routine vitamin and others 2009). However, evidence is insufficient to K administration in newborns for the prevention of determine the existence of neuroprotective benefits vitamin K deficiency bleeding and early phototherapy for infants of women with high-risk pregnancies at for jaundice. Early phototherapy reduces both mortality term (Nguyen and others 2013), and more research and chronic disability subsequent to kernicterus and is is needed. feasible in facilities (Djik and Hulzebos 2012; Maisels and others 2012). Newborn Resuscitation Training of birth attendants. Newborn resuscitation is Postnatal Care not available for the majority of newborns in LMICs. Kangaroo mother care. Kangaroo mother care, which is Limited evidence suggests that training of birth atten- part of the extra newborn care package for small and dants improves initial resuscitation practices and low-birthweight infants and includes continuous skin- reduces inappropriate and harmful practices (Carlo to-skin contact between mothers and newborns, frequent and others 2010; Opiyo and English 2010) but may and exclusive breastfeeding, and early discharge from not have a significant impact on perinatal mortality. hospital, has been evaluated in comparison with con- This finding may be because advanced resuscitation, ventional care in a Cochrane review. The review includes including intubation and drugs, is appropriate only 18 RCTs involving 2,751 infants (Conde-Agudelo, in institutions that provide ventilation. A large cluster Belizán, and Diaz-Rossello 2014). In low-birthweight RCT of a combined community- and facility-based infants, kangaroo mother care reduced neonatal mor- approach with a package of interventions including tality by 40 percent, hypothermia by 66 percent, and community birth attendant training, hospital trans- nosocomial infection by 55 percent. port, and facility staff training finds the intervention Exclusive breastfeeding. The WHO recommends package to have no detectable impact on perinatal exclusive breastfeeding of infants until age six months mortality (Pasha and others 2013). This finding sug- (WHO 2014c). Infants who are exclusively breastfed for gests that substantially more infrastructure may be six months experience less gastrointestinal morbidity necessary, in addition to provider training and com- (Kramer and Kakuma 2012), less respiratory morbidity, munity mobilization, to have a meaningful effect on and less infection-related neonatal mortality than par- neonatal outcomes. tially breastfed neonates (WHO 2014c). A meta-analysis shows that breastfeeding education or support (or a Essential Newborn Care combination of education and support) increased exclu- The WHO defines essential newborn care as including sive breastfeeding rates (Haroon and others 2013). For cleaning, drying, and warming the infant; initiating small or preterm babies, extra feeding support is needed exclusive breastfeeding; and cord care (WHO 2011a). (WHO 2011a). Ideally, this care should be provided by a skilled atten- Cord cleansing. Pooled data from three commu- dant; however, most of these tasks can be carried out at nity trials involving 54,624 newborns of cord care home by alternative attendants. with chlorhexidine versus dry care show a reduc- High-quality evidence shows that home visits by tion in omphalitis of 27 percent to 56 percent and community health workers in the first week after birth in neonatal mortality of 23 percent (Imdad and significantly reduces neonatal mortality and are strongly others 2013). Chlorhexidine cord cleansing did not recommended by the WHO (WHO 2014c). have these effects when used in hospital settings 128 Reproductive, Maternal, Newborn, and Child Health (Sinha and others 2015). The WHO recommends prophylaxis (IAP) for mothers colonized with GBS daily chlorhexidine application to the umbilical cord (three trials and 500 women) finds low-quality evidence stump during the first week of life for newborns who that early neonatal GBS infection was reduced with are born at home in settings with high neonatal mor- IAP compared with no prophylaxis (Ohlsson and Shah tality (WHO 2014c). 2014). European consensus recommends IAP based on a universal intrapartum GBS screening strategy (Di Management of Neonatal Encephalopathy Renzo and others 2014); however, data on GBS prev- Seizures are common following perinatal hypoxic alence are not routinely available to inform policies ischemia. Induced hypothermia (cooling) in newborn in most LMICs. In the absence of GBS screening and infants who are encephalopathic because of intrapartum strong evidence to guide clinical practice regarding hypoxia reduces neonatal mortality, major neurodevel- routine prescription of antibiotics (Ungerer and others opmental disability, and cerebral palsy. This evidence is 2004), the use of presumptive antibiotic therapy for derived from a Cochrane review of 11 RCTs involving newborns at risk of GBS and other bacterial infections 1,505 term and late preterm infants with moderate is recommended (WHO 2011a). or severe hypoxic ischemic encephalopathy (Jacobs and others 2013). Cooling reduced neonatal mortality Interventions in the Pipeline by 25 percent and the authors conclude that induced Household air pollution is recognized as a risk factor hypothermia should be performed in term and late pre- for several health outcomes, including stillbirth, preterm term infants with moderate or severe hypoxic ischemic birth, and low birthweight, but rigorous evidence for encephalopathy if identified before age six hours (Jacobs the impact of reducing household air pollution on these and others 2013). However, most of these studies were birth outcomes is lacking (Bruce and others 2013). conducted in HICs and more trials in LMICs are needed Interventions to reduce household air pollution may before implementing this intervention in these settings. reduce poor perinatal outcomes. Routine anticonvulsant prophylaxis with barbiturates A habitual supine sleeping position has been asso- for the neuroprotection of term infants with perina- ciated with an increase in stillbirth (Owusu and others tal asphyxia is not recommended (Evans, Levene, and 2013). Whether sleeping position can be changed Tsakmakis 2007). by advice or other interventions, and whether such a change would affect stillbirth rates, remains to be Management of Respiratory Distress Syndrome established. RDS is the most important cause of mortality in pre- term infants. Administration of surfactant in preterm infants significantly decreases the risk of poor neonatal COST-EFFECTIVENESS OF INTERVENTIONS outcomes, but cost is a major factor for LMICs (Seger and Soll 2009; Soll and Özek 2010). Institution of Increasing the coverage of interventions demon- continuous positive airway pressure may bring down strated to be effective and cost-effective is essential, the requirement and cost of surfactant therapy (Rojas- but reliable data remain limited (Mangham-Jefferies Reyes, Morley, and Soll 2012). and others 2014). Chapter 17 of this volume (Horton and Levin 2016) summarizes the findings of a sys- Management of Neonatal Sepsis tematic search of the cost-effectiveness literature of Antibiotics for treatment. Over 1 million neonatal deaths reproductive, maternal, newborn, and child health annually in LMICs are attributable to infectious causes, interventions and discusses the difficulties, including including neonatal sepsis, meningitis, and pneumonia methodological gaps, multiple platforms, and out- (Liu and others 2016). Feasible and low-cost inter- come measures. ventions to prevent these deaths exist. Oral antibiotics For the 75 high-burden Countdown countries, administered in the community reduce all-cause mor- Bhutta and others (2014) estimate that the additional tality by 25 percent and pneumonia-specific mortality funding required to scale up effective interventions to by 42 percent (Zaida and others 2011). reduce preventable maternal and newborn deaths and Presumptive antibiotics for group B streptococcus. still births is US$5.65 billion annually, which they equate The risk of serious infection in term newborn infants to US$1.15 per person, excluding the initial investment is increased if group B streptococcus (GBS) is present in new facilities. They further estimate that increased in the birth canal, if rupture of membranes is pro- coverage and quality of care would reduce maternal longed, and if maternal temperature is raised during and newborn deaths and prevent stillbirths at a cost of labor. A Cochrane review of intrapartum antibiotic US$1,928 per life saved (or US$60 per disability adjusted Interventions to Reduce Maternal and Newborn Morbidity and Mortality 129 life-year [DALY] averted); 82 percent of this effect would NOTE be from facility-based care. For consistency and ease of comparison, DCP3 is using the Costs per DALY averted have been estimated for World Health Organization’s Global Health Estimates (GHE) training initiatives (for example, LeFevre and others for data on diseases burden, except in cases where a relevant 2013), participatory women’s groups (for example, data point is not available from GHE. In those instances, an Fottrell and others 2013), and safe motherhood initia- alternative data source is noted. tives (for example, Erim, Resch, and Goldie 2012), and World Bank Income Classifications as of July 2014 are as range from US$150 to US$1,000. Cost estimates for follows, based on estimates of gross national income (GNI) CS for obstructed labor have a wider range (US$200 per capita for 2013: to US$4,000 per DALY averted, depending on the country), with a median of slightly more than US$400 • Low-income countries (LICs) = US$1,045 or less (Alkire and others 2012). Other innovations with • Middle-income countries (MICs) are subdivided: lower costs per DALY averted, in the range of US$20– a) lower-middle-income = US$1,046 to US$4,125 US$100—for example, clean delivery kits for home b) upper-middle-income (UMICs) = US$4,126 to births (Sabin and others 2012)—have a modest impact US$12,745 on DALYs averted. • High-income countries (HICs) = US$12,746 or more. CONCLUSIONS REFERENCES Although evidence of effectiveness is not available Ahmed, A. 2011. “New Insights into the Etiology of for several vital interventions, these interventions Preeclampsia: Identification of Key Elusive Factors for the save the lives of thousands of mothers and newborns Vascular Complications.” Thrombosis Research 127 (Suppl. 3): every day. For other simple interventions, research S72–75. doi:10.1016/S0049-3848(11)70020-2. has demonstrated convincingly that, if provided in Alfirevic, Z., D. Devane, and G. M. L. Gyte. 2013. “Continuous the appropriate time and with the appropriate proto- Cardiotocography (CTG) as a Form of Electronic Fetal Monitoring (EFM) for Fetal Assessment during Labour.” col, many more lives can be saved. However, effective Cochrane Database of Systematic Reviews (5): CD006066. interventions are not consistently used or available doi:10.1002/14651858. CD006066.pub2. in LMICs, and accelerated investments are needed Alfirevic, Z., T. Stampalija, and G. M. L. Gyte. 2013. “Fetal and in health system infrastructure, intervention imple- Umbilical Doppler Ultrasound in High-Risk Pregnancies.” mentation, health worker training, and patient edu- Cochrane Database of Systematic Reviews (11): CD007529. cation to improve health outcomes for mothers and doi:10.1002/14651858.CD007529.pub3. newborns. Alkire, B. C., J. R. Vincent, C. T. Burns, I. S. Metzler, P. E. Farmer, Even in the poorest settings simple approaches at and others. 2012. “Obstructed Labor and Caesarean the family and community levels and through out- Delivery: The Cost and Benefit of Surgical Intervention.” reach services can save many lives now. Well-known PLoS One 7 (4): e34595. interventions, such as neonatal resuscitation and case Althabe, F., J. M. Belizan, E. M. McClure, J. Hemingway-Foday, M. Berrueta, and others. 2015. “A Population-Based, management of infections, can be added to existing pro- Multifaceted Strategy to Implement Antenatal grams, particularly Safe Motherhood and Integrated Corticosteroid Treatment versus Standard Care for the Management of Childhood Illness programs, at low Reduction of Neonatal Mortality Due to Preterm Birth marginal cost. Although community-based options are in Low-Income and Middle-Income Countries: The ACT often most feasible, if the commitment to strengthen Cluster-Randomised Trial.” The Lancet 385 (9968): 629–39. clinical care systems is lacking, the potential improve- Altman, D., G. Carroli, L. Duley, B. Farrell, J. Moodley, ments in health outcomes from these options is and others. 2002. “Magpie Trial Collaboration Group. limited. Do Women with Pre-Eclampsia, and Their Babies, Scaling-up of skilled care for pregnancy and child- Benefit from Magnesium Sulphate? The Magpie Trial: birth is still required to reach the MDGs in LMICs. A Randomised Placebo-Controlled Trial.” The Lancet 359 However, as increasing numbers of women and babies (9321): 1877–90. Alwan, N., D. J. Tuffnell, and J. West. 2009. “Treatments for reach first-level facilities and hospitals, the quality of Gestational Diabetes.” Cochrane Database of Systematic Reviews care challenges in these facilities need to be addressed. (3): CD003395. doi:10.1002/14651858.CD003395.pub2. A shift in focus to quality of care has the potential to Athukorala, C., P. Middleton, and C. A. Crowther. 2006. unlock significant returns for every mother and every “Intrapartum Interventions for Preventing Shoulder newborn beyond 2015 to end preventable maternal and Dystocia.” Cochrane Database of Systematic Reviews (4): newborn deaths and stillbirths by 2030. CD005543. doi:10.1002/14651858.CD005543.pub2. 130 Reproductive, Maternal, Newborn, and Child Health Atkins, D., D. Best, P. A. Briss, M. Eccles, Y. Falck-Ytter, Chappell, L. C., S. Duckworth, P. T. Seed, M. Griffin, J. Myers, and others. 2004. “Grading Quality of Evidence and and others. 2013. “Diagnostic Accuracy of Placental Strength of Recommendations.” British Medical Journal Growth Factor in Women with Suspected Preeclampsia: 328 (7454): 1490. A Prospective Multicenter Study.” Circulation 128: 2121–31. Betran, A. P., M. R. Torloni, J. Zhang, J. Ye, R. Mikolajczyk, doi:10.1161/CIRCULATIONAHA.113.003215. and others. 2015. “What Is the Optimal Rate of Caesarean Churchill, D., L. Duley, J. G. Thornton, and L. Jones. 2013. Section at Population Level? A Systematic Review of “Interventionist versus Expectant Care for Severe Pre- Ecologic Studies.” Reproductive Health 12: 57. doi:10.1186 Eclampsia between 24 and 34 Weeks’ Gestation.” /s12978-015-0043-6. Cochrane Database of Systematic Reviews (7): CD003106. Bhutta, Z. A., J. K. Das, R. Bahl, J. E. Lawn, R. A. Salam, and doi:10.1002/14651858.CD003106.pub2. others. 2014. “Can Available Interventions End Preventable Conde-Agudelo, A., J. M. Belizán, and J. Diaz-Rossello. Deaths in Mothers, Newborn Babies, and Stillbirths, and at 2014. “Kangaroo Mother Care to Reduce Morbidity and What Cost?” The Lancet 384 (9940): 347–70. Mortality in Low Birthweight Infants.” Cochrane Database Blencowe, H., S. Cousens, B. Modell, and J. Lawn. 2010. of Systematic Reviews (4): CD002771. doi:10.1002/14651858 “Folic Acid to Reduce Neonatal Mortality from Neural .CD002771.pub3. Tube Disorders.” International Journal of Epidemiology 39 Cournil, A., P. Van de Perre, C. Cames, I. de Vincenzi, J. S. Read, (Suppl. 1): i110–21. doi:10.1093/ije/dyq028. and others. 2015. “Early Infant Feeding Patterns and HIV- Blencowe, H., J. Lawn, J. Vandelaer, M. Roper, and S. Cousens. Free Survival: Findings from the Kesho-Bora Trial (Burkina 2010. “Tetanus Toxoid Immunization to Reduce Mortality Faso, Kenya, South Africa).” Pediatric Infectious Disease from Neonatal Tetanus.” International Journal of Journal 34 (2): 168–74. Epidemiology 39 (Suppl. 1): i102–9. doi:10.1093/ije/dyq027. Deneux-Tharaux, C., L. Sentilhes, F. Maillard, E. Closset, Blencowe, H., S. Cousens, M. Kamb, S. Berman, and J. E. Lawn. D. Vardon, and others. 2013. “Effect of Routine Controlled 2011. “Lives Saved Tool Supplement Detection and Cord Traction as Part of the Active Management of the Treatment of Syphilis in Pregnancy to Reduce Syphilis Third Stage of Labour on Postpartum Haemorrhage: Related Stillbirths and Neonatal Mortality.” BMC Public Multicentre Randomised Controlled Trial (TRACOR).” Health 11 (Suppl 3): S9. doi:10.1186/1471-2458-11-S3-S9. British Medical Journal 346: f1541. doi:10.1136/bmj.f1541. Brown, H. C., S. Paranjothy, T. Dowswell, and J. Thomas. 2013. De-Regil, L. M., A. C. Fernández-Gaxiola, T. Dowswell, and “Package of Care for Active Management in Labour for J. P. Peña-Rosas. 2010. “Effects and Safety of Periconceptional Reducing Caesarean Section Rates in Low-Risk Women.” Folate Supplementation for Preventing Birth Defects.” Cochrane Database of Systematic Reviews (9): CD004907. Cochrane Database of Systematic Reviews (10): CD007950. doi:10.1002/14651858.CD004907.pub3.29. doi: 10.1002/14651858.CD007950.pub2. Bruce, N. G., M. K. Dherani, J. K. Das, K. Balakrishnan, H. Diemert, A., G. Ortmeyer, B. Hollwitz, M. Lotz, T. Somville, and Adair-Rohani, and others. 2013. “Control of Household others. 2012. “The Combination of Intrauterine Balloon Air Pollution for Child Survival: Estimates for Intervention Tamponade and the B-Lynch Procedure for the Treatment Impacts.” BMC Public Health 13 (Suppl. 3): S8. of Severe Postpartum Hemorrhage.” American Journal of doi:10.1186/1471-2458-13-S3-S8. Obstetrics and Gynecology 206 (1): 65.e1–4. doi:10.1016/j Buppasiri, P., P. Lumbiganon, J. Thinkhamrop, and .ajog.2011.07.041. B. Thinkhamrop. 2010. “Antibiotic Prophylaxis for Third- Dijk, P. H., and C. V. Hulzebos. 2012. “An Evidence-Based View and Fourth-Degree Perineal Tear during Vaginal Birth.” on Hyperbilirubinaemia.” Acta Paediatrica Supplement 101 Cochrane Database of Systematic Reviews (11): Cd005125. (464): 3–10. doi:10.1111/j.1651-2227.2011.02544.x. doi:10.1002/14651858.CD005125.pub3 Di Renzo, G. C., P. Melin, A. Berardi, M. Blennow, X. Carbonell- Buppasiri, P., P. Lumbiganon, J. Thinkhamrop, C. Ngamjarus, Estrany, and others. 2014. “Intrapartum GBS Screening and and M. Laopaiboon. 2011. “Calcium Supplementation Antibiotic Prophylaxis: A European Consensus Conference.” (Other than for Preventing or Treating Hypertension) Journal of Maternal, Fetal and Neonatal Medicine 28 (7): for Improving Pregnancy and Infant Outcomes.” 766–82. Cochrane Database of Systematic Reviews (10): CD007079. Dodd, J. M., A. McLeod, R. C. Windrim, and J. Kingdom. 2013. doi:10.1002/14651858.CD007079.pub2. “Antithrombotic Therapy for Improving Maternal or Infant Carlo, W. A., S. S. Goudar, I. Jehan, E. Chomba, A. Tshefu, Health Outcomes in Women Considered at Risk of Placental and others. 2010. “Newborn-Care Training and Perinatal Dysfunction.” Cochrane Database of Systematic Reviews (6): Mortality in Developing Countries.” New England CD006780. doi: 10.1002/14651858.CD006780.pub3. Journal of Medicine 362 (7): 614–23. doi:10.1056/ Dowswell, T., G. Carroli, L. Duley, S. Gates, A.M. Gülmezoglu, NEJMsa0806033. and others. 2010. “Alternative versus Standard Packages of Chaithongwongwatthana, S., W. Yamasmit, S. Limpongsanurak, Antenatal Care for Low-Risk Pregnancy.” Cochrane Database P. Lumbiganon, J. A. DeSimone, and others. 2012. of Systematic Reviews 10: CD000934. doi:10.1002/14651858 “Pneumococcal Vaccination during Pregnancy for .CD000934.pub2. Preventing Infant Infection.” Cochrane Database of Doyle, L. W., C. A. Crowther, P. Middleton, S. Marret, and Systematic Reviews (7): CD004903. doi:10.1002/14651858. D. Rouse. 2009. “Magnesium Sulphate for Women at CD004903.pub3. Risk of Preterm Birth for Neuroprotection of the Fetus.” Interventions to Reduce Maternal and Newborn Morbidity and Mortality 131 Cochrane Database of Systematic Reviews (1): CD004661. Gibbons, L., J. M. Belizán, J. A. Lauer, A. P. Betrán, M. Merialdi, doi:10.1002/14651858. CD004661.pub3. and others. 2010. “The Global Numbers and Costs of Duley, L. 2009. “The Global Impact of Pre-Eclampsia and Additionally Needed and Unnecessary Caesarean Sections Eclampsia.” Seminars in Perinatology 33: 130–37. Performed per Year: Overuse as a Barrier to Universal doi:10.1053/j.semperi.2009.02.010. Coverage.” World Health Report (2010), Background paper ———, A. M. Gülmezoglu, D. J. Henderson-Smart, and 30. http://www.who.int/healthsystems/topics/financing D. Chou. 2010. “Magnesium Sulphate and other /healthreport/30C-sectioncosts.pdf. Anticonvulsants for Women with Pre-Eclampsia.” Gomez, G. B., M. L. Kamb, L. M. Newman, J. Mark, N. Broutet, Cochrane Database of Systematic Reviews 11: CD000025. and S. J. Hawkes. 2013. “Untreated Maternal Syphilis and doi:10.1002/14651858.CD000025.pub2. Adverse Outcomes of Pregnancy: A Systematic Review and Duley, L., D. J. Henderson-Smart, D. Chou. 2010. Meta-Analysis.” Bulletin of the World Health Organization “Magnesium Sulphate versus Phenytoin for Eclampsia.” 91 (3): 217–26. doi:10.2471/BLT.12.107623. Cochrane Database of Systematic Reviews 10: CD000128. Gülmezoglu, A. M., C. A. Crowther, P. Middleton, and doi:10.1002/14651858.CD000128.pub2. E. Heatley. 2012. “Induction of Labour for Improving Duley, L., D. J. Henderson-Smart, S. Meher, and J. F. King. 2007. Birth Outcomes for Women at or Beyond Term.” Cochrane “Antiplatelet Agents for Preventing Preeclampsia and Its Database of Systematic Reviews (6): CD004945. doi:10.1002 Complications.” Cochrane Database of Systematic Reviews /14651858.CD004945.pub3. (2): CD004659. doi:10.1002/14651858.CD004659.pub2. Gülmezoglu, A. M., P. Lumbiganon, S. Landoulsi, M. Widmer, Duley, L., H. E. Matar, M. Q. Almerie, and D. R. Hall. 2010. H. Abdel-Aleem, and others. 2012. “Active Management of “Alternative Magnesium Sulphate Regimens for Women the Third Stage of Labour with and without Controlled with Pre-Eclampsia and Eclampsia.” Cochrane Database of Cord Traction: A Randomised, Controlled, Non-Inferiority Systematic Reviews (8): CD007388. doi:10.1002/14651858. Trial.” The Lancet 379 (9827): 1721–27. doi:10.1016 CD007388.pub2. /S0140-6736(12)60206-2. Erim, D. O., S. C. Resch, and S. J. Goldie. 2012. “Assessing Haas, D. M., S. Morgan, and K. Contreras. 2013. “Vaginal Health and Economic Outcomes of Interventions to Preparation with Antiseptic Solution before Cesarean Reduce Pregnancy-Related Mortality in Nigeria.” BMC Section for Preventing Postoperative Infections.” Public Health 12: 786. doi:10.1186/1471-2458-12-786. Cochrane Database of Systematic Reviews (1): CD007892. Evans, D. J., M. Levene, and M. Tsakmakis. 2007. doi:10.1002/14651858.CD007892.pub3. “Anticonvulsants for Preventing Mortality and Morbidity Haroon, S., J. K. Das, R. A. Salam, A. Imdad, and Z. A. Bhutta. in Full Term Newborns with Perinatal Asphyxia.” 2013. “Breastfeeding Promotion Interventions and Cochrane Database of Systematic Reviews (3): CD001240. Breastfeeding Practices: A Systematic Review.” BMC Public doi:10.1002/14651858.CD001240.pub2. Health 13 (3): 1–18. doi:10.1186/1471-2458-13-S3-S20. Flenady, V., G. Hawley, O. M. Stock, S. Kenyon, and N. Badawi. Harrison, M. S., A. Ali, O. Pasha, S. Saleem, F. Althabe, and 2013. “Prophylactic Antibiotics for Inhibiting Preterm others. 2015. “A Prospective Population-Based Study of Labour with Intact Membranes.” Cochrane Database of Maternal, Fetal, and Neonatal Outcomes in the Setting of Systematic Reviews 12: CD000246. doi:10.1002/14651858. Prolonged Labor, Obstructed Labor and Failure to Progress CD000246.pub2. in Low- and Middle-income Countries.” Reproductive Fottrell, E., K. Azad, A. Kuddus, L. Younes, S. Shaha, and others. Health 12 (suppl 2): S9. 2013. “The Effect of Increased Coverage of Participatory Hofmeyr, G. J., H. Abdel-Aleem, and M. A. Abdel-Aleem. Women’s Groups on Neonatal Mortality in Bangladesh: A 2013. “Uterine Massage for Preventing Postpartum Cluster Randomized Trial.” JAMA Pediatrics 167 (9): 816–25. Haemorrhage.” Cochrane Database of Systematic Reviews French, L., and F. M. Smaill. 2004. “Antibiotic Regimens (7): CD006431. doi:10.1002/14651858.CD006431.pub3. for Endometritis after Delivery.” Cochrane Database of Hofmeyr, G. J., A. M. Gülmezoglu, N. Novikova, and Systematic Reviews (4): CD001067. doi:10.1002/14651858. T. A. Lawrie. 2013. “Postpartum Misoprostol for Preventing CD001067.pub2. Maternal Mortality and Morbidity.” Cochrane Database of Gamble, C. L., J. P. Ekwaru, and F. O. ter Kuile. 2006. Systematic Reviews (7): CD008982. doi:10.1002/14651858. “Insecticide-Treated Nets for Preventing Malaria in CD008982.pub2. Pregnancy.” Cochrane Database of Systematic Reviews (2): Hofmeyr, G. J., and E. D. Hodnett. 2013. “Antenatal Care CD003755. doi:10.1002/14651858.CD003755.pub2. Packages with Reduced Visits and Perinatal Mortality: Ganguli, S., M. S. Stecker, D. Pyne, R. A. Baum, and C. M. Fan. A Secondary Analysis of the WHO Antenatal Care Trial— 2011. “Uterine Artery Embolization in the Treatment of Commentary: Routine Antenatal Visits for Healthy Postpartum Uterine Hemorrhage.” Journal of Vascular Pregnant Women Do Make a Difference.” Reproductive and Interventional Radiology 22 (2): 169–76. doi:10.1016/j Health 10: 20. .jvir.2010.09.031. Hofmeyr, G. J., R. Kulier, and H. M. West. 2015. “External Georgiou, C. 2009. “Balloon Tamponade in the Management Cephalic Version for Breech Presentation at Term.” Cochrane of Postpartum Haemorrhage: A Review.” British Database of Systematic Reviews (4): CD000083. Journal of Obstetrics and Gynaecology 116 (6): 748–57. Hofmeyr, G. J., T. A. Lawrie, Á. N. Atallah, L. Duley, doi:10.1111/j.1471-0528.2009.02113.x. and M. R. Torloni. 2014. “Calcium Supplementation 132 Reproductive, Maternal, Newborn, and Child Health during Pregnancy for Preventing Hypertensive Disorders Kramer, M. S., and R. Kakuma. 2012. “Optimal Duration of and Related Problems.” Cochrane Database of Systematic Exclusive Breastfeeding.” Cochrane Database of Systematic Reviews (8): CD001059. doi:10.1002/14651858. Reviews (8): CD003517. doi:10.1002/14651858. CD003517. CD001059.pub3. pub2. Hofmeyr, G. J., and P. M. Shweni. 2012. “Symphysiotomy Lassi, Z. S., and Z. A. Bhutta. 2013. “Risk Factors and for Feto-Pelvic Disproportion.” Cochrane Database of Interventions Related to Maternal and Pre-Pregnancy Systematic Reviews (10): CD005299. doi:10.1002/14651858. Obesity, Pre-Diabetes and Diabetes for Maternal, Fetal and CD005299.pub3. Neonatal Outcomes: A Systematic Review.” Expert Review of Hopkins, L., and F. M. Smaill. 2002. “Antibiotic Regimens Obstetrics and Gynecology 8 (6): 639–60. for Management of Intraamniotic Infection.” Cochrane Lavender, T., A. Hart, and R. M. D. Smyth. 2013. “Effect of Database of Systematic Reviews (3): CD003254. Partogram Use on Outcomes for Women in Spontaneous doi:10.1002/14651858.CD003254. Labour at Term.” Cochrane Database of Systematic Reviews Horton, S., and C. Levin. 2016. “Cost-Effectiveness of (7): CD005461. doi:10.1002/14651858.CD005461.pub4. Interventions for Reproductive, Maternal, Neonatal, Lawn, J. E., H. Blencowe, S. Oza, D. You, A. C. Lee, and others. and Child Health.” In Disease Control Priorities (third 2014. “Every Newborn: Progress, Priorities, and Potential edition): Volume 2, Reproductive, Maternal, Newborn, beyond Survival.” The Lancet 384 (9938): 189–205. and Child Health, edited by R. Black, R. Laxminarayan, Lawn, J. E., H. Blencowe, R. Pattinson, S. Cousens, R. Kumar, M. Temmerman, and N. Walker. Washington, DC: and others. 2011. “Stillbirths: Where? When? Why? How to World Bank. Make the Data Count?” The Lancet 377 (9775): 1448–63. Imdad, A., R. M. M. Bautista, K. A. A. Senen, M. E. V. Uy, Lawn, J., H. Blencowe, P. Waiswa, A. Amouzou, C. Mathers, J. B. Mantaring III, and others. 2013. “Umbilical Cord and others. 2016. “Stillbirths: Rate, Risk Factors, and Antiseptics for Preventing Sepsis and Death among Acceleration towards 2030.” The Lancet 387: 587–603. Newborns.” Cochrane Database of Systematic Reviews (5): Lee, J. S., and S. M. Shepherd. 2010. “Endovascular Treatment of CD008635. doi:10.1002/14651858. CD008635.pub2. Postpartum Hemorrhage.” Clinical Obstetrics and Gynecology Imdad, A., and Z. A. Bhutta. 2012. “Maternal Nutrition 53 (1): 209–18. doi:10.1097/GRF.0b013e3181ce09f5. and Birth Outcomes: Effect of Balanced Protein-Energy LeFevre, A. E., S. D. Shillcutt, H. R. Waters, S. Haider, Supplementation.” Paediatric and Perinatal Epidemiology 26 S. El Arifeen, and others. 2013. “Economic Evaluation (Suppl. 1): 178–90. doi:10.1111/j.1365-3016.2012.01308.x. of Neonatal Care Packages in a Cluster-Randomized Imdad, A., M. Y. Yakoob, S. Siddiqui, and Z. A. Bhutta. 2011. Controlled Trial in Sylhet, Bangladesh.” Bulletin of the “Screening and Triage of Intrauterine Growth Restriction World Health Organization 91 (10): 736–45. (IUGR) in General Population and High Risk Pregnancies: Liabsuetrakul, T., T. Choobun, K. Peeyananjarassri, and A Systematic Review with a Focus on Reduction of IUGR Q. M. Islam. 2004. “Antibiotic Prophylaxis for Operative Related Stillbirths.” BMC Public Health 11 (Suppl. 3): S1. Vaginal Delivery.” Cochrane Database of Systematic Reviews doi:10.1186/1471-2458-11-S3-S1. (3): CD004455. doi:10.1002/14651858.CD004455.pub2. Jacobs, S. E., M. Berg, R. Hunt, W. O. Tarnow-Mordi, Liu, L., K. Hill, S. Oza, D. Hogan, Y. Chu, and others. 2016. T. E. Inder, and others. 2013. “Cooling for Newborns with “Levels and Causes of Mortality under Age Five Years.” Hypoxic Ischaemic Encephalopathy.” Cochrane Database of In Disease Control Priorities (third edition): Volume 2, Systematic Reviews (1): CD003311. doi:10.1002/14651858. Reproductive, Maternal, Newborn, and Child Health, CD003311.pub3. edited by R. Black, R. Laxminarayan, M. Temmerman, and Kenyon, S., M. Boulvain, and J. P. Neilson. 2013. “Antibiotics N. Walker. Washington, DC: World Bank. for Preterm Rupture of Membranes.” Cochrane Database of Lozano, R., M. Naghavi, K. Foreman, S. Lim, K. Shibuya, and Systematic Reviews (12): CD001058. doi:10.1002/14651858. others. 2012. “Global and Regional Mortality from 235 CD001058.pub3. Causes of Death for 20 Age Groups in 1990 and 2010: Khan, K. S., D. Wojdyla, L. Say, A. M. Gülmezoglu, and P. F. Van A Systematic Analysis for the Global Burden of Disease Look. 2006. “WHO Analysis of Causes of Maternal Death: Study 2010.” The Lancet 380 (9859): 2095–128. A Systematic Review.” The Lancet 367 (9516): 1066–74. Lumbiganon, P., J. Thinkhamrop, B. Thinkhamrop, and Kirby, J. M., J. R. Kachura, D. K. Rajan, K. W. Sniderman, J. E. Tolosa. 2004. “Vaginal Chlorhexidine during Labour for M. E. Simons, and others. 2009. “Arterial Embolization for Preventing Maternal and Neonatal Infections (Excluding Primary Postpartum Hemorrhage.” Journal of Vascular and Group B Streptococcal and HIV).” Cochrane Database of Interventional Radiology 20 (8): 1036–45. doi:10.1016/j.jvir Systematic Reviews (4): CD004070. doi:10.1002/14651858. .2009.04.070. CD004070.pub2. Koopmans, C. M., D. Bijlenga, H. Groen, S. M. Vijgen, Maisels, M. J., J. F. Watchko, V. K. Bhutani, and D. K. Stevenson. J. G. Aarnoudse, and others. 2009. “Induction of Labour 2012. “An Approach to the Management of versus Expectant Monitoring for Gestational Hypertension Hyperbilirubinaemia in the Preterm Infant Less than 35 or Mild Pre-Eclampsia after 36 Weeks’ Gestation Weeks Gestation.” Journal of Perinatology 32 (9): 660–64. (HYPITAT): A Multicentre, Open-Label Randomised doi:10.1038/jp.2012.71. Controlled Trial.” The Lancet 374 (9694): 979–88. Majumdar, A., S. Saleh, M. Davis, I. Hassan, and P. J. Thompson. doi:10.1016/S0140-6736(09)60736-4. 2010. “Use of Balloon Catheter Tamponade for Massive Interventions to Reduce Maternal and Newborn Morbidity and Mortality 133 Postpartum Haemorrhage.” Journal of Obstetrics and Systematic Reviews (9): CD000032. doi:10.1002/14651858. Gynaecology 30 (6): 586–93. doi:10.3109/01443615.2010. CD000032.pub2. 494202. Owusu, J. T., F. J. Anderson, J. Coleman, S. Oppong, J. D. Seffah, Mangesi, L., G. J. Hofmeyr, and V. Smith. 2007. “Fetal and others. 2013. “Association of Maternal Sleep Practices Movement Counting for Assessment of Fetal Wellbeing.” with Pre-Eclampsia, Low Birth Weight, and Stillbirth Cochrane Database of Systematic Reviews (1): CD004909. among Ghanaian Women.” International Journal of doi:10.1002/14651858.CD004909.pub2. Gynecology and Obstetrics 121 (3): 261–65. doi:10.1016/j. Mangham-Jefferies, L., C. Pitt, S. Cousens, A. Mills, and ijgo.2013.01.013. J. Schellenberg. 2014. “Cost-Effectiveness of Strategies to Pasha, O., E. M. McClure, L. L. Wright, S. Saleem, S. S. Goudar, Improve the Utilization and Provision of Maternal and and others. 2013. “A Combined Community- and Facility- Newborn Health Care in Low-Income and Lower-Middle- Based Approach to Improve Pregnancy Outcomes in Low- Income Countries: A Systematic Review.” BMC Pregnancy Resource Settings: A Global Network Cluster Randomized Childbirth 14: 243. doi:10.1186/1471-2393-14-243. Trial.” BMC Medicine 11: 215. McDonald, S. J., P. Middleton, T. Dowswell, and Perel, P., I. Roberts, and K. Ker. 2013. “Colloids versus P. S. Morris. 2013. “Effect of Timing of Umbilical Cord Crystalloids for Fluid Resuscitation in Critically Ill Patients.” Clamping of Term Infants on Maternal and Neonatal Cochrane Database of Systematic Reviews (2): CD000567. Outcomes.” Cochrane Database of Systematic Reviews (7): doi:10.1002/14651858.CD000567.pub6. CD004074. doi:10.1002/14651858.CD004074.pub3. Porreco, R. P., and R. W. Stettler. 2010. “Surgical Remedies for Mistry, H. D., V. Wilson, M. M. Ramsay, M. E. Symonds, Postpartum Hemorrhage.” Clinical Obstetrics and Gynecology and F. Broughton Pipkin. 2008. “Reduced Selenium 53 (1): 182–95. doi:10.1097/GRF.0b013e3181cc4139. Concentrations and Glutathione Peroxidase Activity in Price, N., and C. B. Lynch. 2005. “Technical Description of the Pre-Eclamptic Pregnancies.” Hypertension 52 (5): 881–88. B-Lynch Brace Suture for Treatment of Massive Postpartum doi:10.1161/HYPERTENSIONAHA.108.116103. Hemorrhage and Review of Published Cases.” International Mori, R., E. Ota, P. Middleton, R. Tobe-Gai, K. Mahomed, Journal of Fertility and Women’s Medicine 50 (4): 148–63. and others. 2012. “Zinc Supplementation for Improving Radeva-Petrova, D., K. Kayentao, F. O. ter Kuile, D. Sinclair, and Pregnancy and Infant Outcome.” Cochrane Database of P. Garner. 2014. “Drugs for Preventing Malaria in Pregnant Systematic Reviews (7): CD000230. doi:10.1002/14651858 Women in Endemic Areas: Any Drug Regimen versus .CD000230.pub4. Placebo or No Treatment.” Cochrane Database of Systematic Mousa, H. A., J. Blum, G. Abou El Senoun, H. Shakur, and Reviews (10): CD000169. Z. Alfirevic. 2014. “Treatment for Primary Postpartum Roberts, D., and S. R. Dalziel. 2006. “Antenatal Corticosteroids Haemorrhage.” Cochrane Database of Systematic Reviews for Accelerating Fetal Lung Maturation for Women at Risk (2): CD003249. doi:10.1002/14651858.CD003249.pub3. of Preterm Birth.” Cochrane Database of Systematic Reviews Ngoc, N. T., M. Merialdi, H. Abdel-Aleem, G. Carroli, (3): CD004454. doi:10.1002/14651858.CD004454.pub2. M. Purwar, and others. 2006. “Causes of Stillbirths and Rojas-Reyes, M. X., C. J. Morley, and R. Soll. 2012. “Prophylactic Early Neonatal Deaths: Data from 7993 Pregnancies in versus Selective Use of Surfactant in Preventing Morbidity Six Developing Countries.” Bulletin of the World Health and Mortality in Preterm Infants.” Cochrane Database of Organization 84: 699–705. Systematic Reviews (3): CD000510. doi:10.1002/14651858. Nguyen, T. M. N., C. A. Crowther, D. Wilkinson, and E. Bain. CD000510.pub2. 2013. “Magnesium Sulphate for Women at Term for Sabin, L. L., A. B. Knapp, W. B. MacLeod, G. Phiri-Mazala, Neuroprotection of the Fetus.” Cochrane Database of J. Kasimba, and others. 2012. “Costs and Cost-Effectiveness Systematic Reviews (2): CD009395. doi:10.1002/14651858. of Training Traditional Birth Attendants to Reduce CD009395.pub2. Neonatal Mortality in the Lufwanyama Neonatal Survival Ohlsson, A., and V. S. Shah. 2014. “Intrapartum Antibiotics Study (LUNESP).” PLoS One 7 (4): e35560. for Known Maternal Group B Streptococcal Colonization.” Salam, R. A., J. K. Das, and Z. A. Bhutta. 2012. “Impact of Cochrane Database of Systematic Reviews (6): CD007467. Haemophilus Influenza Type B (Hib) and Viral Influenza doi:10.1002/14651858.CD007467.pub4. Vaccinations in Pregnancy for Improving Maternal, O’Mahony, F., G. J. Hofmeyr, and V. Menon. 2010. “Choice Neonatal and Infant Health Outcomes.” Cochrane Database of Instruments for Assisted Vaginal Delivery.” Cochrane of Systematic Reviews (7): CD009982. doi:10.1002/14651858 Database of Systematic Reviews (11): CD005455. .CD009982. doi:10.1002/14651858.CD005455.pub2. Saleem, S., E. M. McClure, S. S. Goudar, A. Patel, F. Esamai, Opiyo, N., and M. English. 2010. “In-Service Training for and others. 2014. “A Prospective Study of Maternal, Health Professionals to Improve Care of the Seriously Ill Fetal and Neonatal Deaths in Low- and Middle-Income Newborn or Child in Low and Middle-Income Countries Countries.” Bulletin of the World Health Organization 92 (Review).” Cochrane Database of Systematic Reviews (4): (8): 605–12. CD007071. doi:10.1002/14651858.CD007071.pub2. Say, L., D. Chou, A. Gemmill, Ö. Tunçalp, A. B. Moller, and Ota, E., R. Tobe-Gai, R. Mori, and D. Farrar. 2012. “Antenatal others. 2014. “Global Causes of Maternal Death: A WHO Dietary Advice and Supplementation to Increase Systematic Analysis.” The Lancet 6: e323–33. doi:10.1016 Energy and Protein Intake.” Cochrane Database of /S2214-109X(14)70227-X. Epub May 5. 134 Reproductive, Maternal, Newborn, and Child Health Seger, N., and R. Soll. 2009. “Animal Derived Surfactant Tunçalp, Ö., G. J. Hofmeyr, and A. M. Gülmezoglu. 2012. Extract for Treatment of Respiratory Distress Syndrome.” “Prostaglandins for Preventing Postpartum Haemorrhage.” Cochrane Database of Systematic Reviews (2): CD007836. Cochrane Database of Systematic Reviews (8): CD000494. doi:10.1002/14651858.CD007836. doi:10.1002/14651858.CD000494.pub4. Seward, N., D. Osrin, L. Li, A. Costello, A. M. Pulkki-Brännström, Ungerer, R. L. S., O. Lincetto, W. McGuire, H. H. Saloojee, and and others. 2012. “Association between Clean Delivery Kit A. M. Gülmezoglu. 2004. “Prophylactic versus Selective Use, Clean Delivery Practices, and Neonatal Survival: Pooled Antibiotics for Term Newborn Infants of Mothers with Analysis of Data from Three Sites in South Asia.” PLoS Risk Factors for Neonatal Infection.” Cochrane Database of Medicine 9 (2): e1001180. doi:10.1371/journal.pmed.1001180. Systematic Reviews (4): CD003957. doi:10.1002/14651858 Sheikh, L., N. Najmi, U. Khalid, and T. Saleem. 2011. “Evaluation .CD003957.pub2. of Compliance and Outcomes of a Management Protocol UNICEF and WHO. 2014. “Countdown to 2015. for Massive Postpartum Hemorrhage at a Tertiary Care Maternal, Newborn and Child Survival.” http://www Hospital in Pakistan.” BMC Pregnancy and Childbirth 11: .countdown2015mnch.org/countdown-highlights. 28. doi:10.1186/1471-2393-11-28. van Lonkhuijzen, L., J. Stekelenburg, and J. van Roosmalen. Siegfried, N., L. van der Merwe, P. Brocklehurst, and 2012. “Maternity Waiting Facilities for Improving Maternal T. T. Sint. 2011. “Antiretrovirals for Reducing the Risk of and Neonatal Outcome in Low-Resource Countries.” Mother-to-Child Transmission of HIV Infection.” Cochrane Cochrane Database of Systematic Reviews (10): CD006759. Database of Systematic Reviews (7): CD003510. doi:10.1002/14651858.CD006759.pub3. Sinha, A., S. Sazawal, A. Pradhan, S. Ramji, and N. Opiyo. Vogel, J. P., H. A. Ndema, J. P. Souza, M. A. Gülmezoglu, 2015. “Chlorhexidine Skin or Cord Care for Prevention of T. Dowswell, and others. 2013. “Antenatal Care Packages Mortality and Infections in Neonates.” Cochrane Database with Reduced Visits and Perinatal Mortality: A Secondary of Systematic Reviews (3): CD007835. Analysis of the WHO Antenatal Care Trial.” Reproductive Smaill, F. M., and R. M. Grivell. 2014. “Antibiotic Prophylaxis Health 10 (1): 19. versus no Prophylaxis for Preventing Infection after Walker, N., Y. Tam, and I. K. Friberg. 2013. “Overview of the Cesarean Section.” Cochrane Database of Systematic Reviews Lives Saved Tool (LiST).” BMC Public Health 13 (Suppl 3): (10): CD007482. doi:10.1002/14651858.CD007482.pub3. S1. doi:10.1186/1471-2458-13-S3-S1. Soll, R., and E. Özek. 2010. “Prophylactic Protein Free Synthetic Wang, M. Q., F. Y. Liu, F. Duan, Z. J. Wang, P. Song, and Surfactant for Preventing Morbidity and Mortality in others. 2009. “Ovarian Artery Embolization Supplementing Preterm Infants.” Cochrane Database of Systematic Reviews Hypogastric-Uterine Artery Embolization for Control of (1): CD001079. doi:10.1002/14651858.CD001079.pub2. Severe Postpartum Hemorrhage: Report of Eight Cases.” Souza, J. P., A. M. Gülmezoglu, J. Vogel, G. Carroli, Journal of Vascular and Interventional Radiology 20 (7): 971–76. P. Lumbiganon, and others. 2013. “Moving beyond Essential Westhoff, G., A. M. Cotter, and J. E. Tolosa. 2013. “Prophylactic Interventions for Reduction of Maternal Mortality (the Oxytocin for the Third Stage of Labour to Prevent WHO Multi-Country Survey on Maternal and Newborn Postpartum Haemorrhage.” Cochrane Database of Health): A Cross-Sectional Study.” The Lancet 381 (9879): Systematic Reviews (10): CD001808. 1747–55. doi:10.1016/S0140-6736(13)60686-8. WHO 2010a. “Integrated Management of Pregnancy and Steegers, E. A., P. von Dadelszen, J. J. Duvekot, and Childbirth (IMPAC).” WHO, Geneva. http://www.who.int R. Pijnenborg. 2010 “Preeclampsia.” The Lancet 376 (9741): /maternal_child_adolescent/topics/maternal/impac/en/. 631–44. doi:10.1016/S0140-6736(10)60279-6. ———. 2010b. “PMTCT Strategic Vision 2010–2015.” WHO, Stenberg, K., H. Axelson, P. Sheehan, I. Anderson, Geneva. http://whqlibdoc.who.int/publications/2010/9789 A. M. Gülmezoglu, and others. 2013. “Advancing Social 241599030_eng.pdf?ua=1. and Economic Development by Investing in Women’s ———. 2011a. “Essential Interventions, Commodities and and Children’s Health: A New Global Investment Guidelines for Reproductive Maternal, Newborn, and Child Framework.” The Lancet 383 (9925): 1333–54. doi:10.1016 Health.” WHO, Geneva. http://www.who.int/pmnch/topics /S0140-6736(13)62231-X. /part_publications/essential_interventions_18_01_2012 Syed, M., H. Javed, M. Y. Yakoob, and Z. A. Bhutta. 2011. .pdf. “Effect of Screening and Management of Diabetes during ———. 2011b. Recommendations for Prevention and Treatment Pregnancy on Stillbirths.” BMC Public Health 11 (Suppl. 3): of Pre-Eclampsia and Eclampsia. Geneva: WHO. S2. doi:10.1186/1471-2458-11-S3-S2. ———. 2012. “WHO Recommendations for the Prevention Thapa, K., B. Malla, S. Pandey, and S. Amatya. 2010. and Treatment of Postpartum Haemorrhage.” WHO, Geneva. “Intrauterine Condom Tamponade in Management http://www.who.int/reproductivehealth/ publications of Postpartum Haemorrhage.” Journal of Nepal Health /maternal_perinatal_health/9789241548502/en/. Research Council 8 (1): 19–22. ———. 2013. Guideline: Calcium Supplementation in Pregnant Touboul, C., W. Badiou, J. Saada, J. P. Pelage, D. Payen, and Women. Geneva: WHO. others. 2008. “Efficacy of Selective Arterial Embolisation ———. 2014a.“Effect of Partogram Use on Outcomes for Women for the Treatment of Life-Threatening Post-Partum in Spontaneous Labour at Term.” The WHO Reproductive Haemorrhage in a Large Population.” PLoS One 3 (11): Health Library. http://apps.who.int/rhl/pregnancy_childbirth e3819. doi:10.1371/journal.pone.0003819. /childbirth/routine_care/cd005461/en/. Interventions to Reduce Maternal and Newborn Morbidity and Mortality 135 ———. 2014b. “WHO Policy Brief for the Implementation of Attendance and Emergency Obstetric Care in Preventing Intermittent Preventive Treatment of Malaria in Pregnancy Stillbirths.” BMC Public Health 11 (Suppl. 3): S7. Using Sulfadoxine-Pyrimethamine (IPTp-SP).” WHO, doi:10.1186/1471-2458-11-S3-S7. Geneva. Yoong, W., A. Ridout, M. Memtsa, A. Stavroulis, M. Aref- ———. 2014c. WHO Recommendations on Postnatal Care of Adib, and others. 2012. “Application of Uterine the Mother and Newborn. Geneva: WHO. Compression Suture in Association with Intrauterine ———. 2015a. Trends in Maternal Mortality: 1990 to 2015: Balloon Tamponade (‘Uterine Sandwich’) for Postpartum Estimates by WHO, UNICEF, UNFPA, World Bank, and the Hemorrhage.”Acta Obstetricia et Gynecologica Scandinavica United Nations Population Division. Geneva: WHO. 91 (1): 147–51. doi:10.1111/j.1600-0412.2011.01153.x. ———. 2015b. “Strategies toward Ending Preventable Maternal Zaidi, A. K., H. A. Ganatra, S. Syed, S. Cousens, A. C. Lee, Mortality (EPMM).” Geneva, WHO. and others. 2011. “Effect of Case Management on WHO Odon Device Research Group. 2013. “Feasibility and Neonatal Mortality Due to Sepsis and Pneumonia.” BMC Safety Study of a New Device (Odon device) for Assisted Public Health 11 (Suppl. 3): S13. doi:10.1186/1471-2458 Vaginal Deliveries: Study Protocol.” Reproductive Health 10: -11-S3-S13. 33. doi:10.1186/1742-4755-10-33. Zwart, J. J., P. D. Dijk, and J. van Roosmalen. 2010. Wojcieszek, A. M., O. M. Stock, and V. Flenady. 2014. “Antibiotics “Peripartum Hysterectomy and Arterial Embolization for Prelabour Rupture of Membranes at or Near Term.” for Major Obstetric Hemorrhage: A 2-Year Nationwide Cochrane Database of Systematic Reviews (10): CD001807. Cohort Study in the Netherlands.” American Journal of Yakoob, M. Y., M. A. Ali, M. U. Ali, A. Imdad, J. E. Lawn, Obstetrics and Gynecology 202 (2): 150. e1–7. doi:10.1016/j and others. 2011. “The Effect of Providing Skilled Birth .ajog.2009.09.003. 136 Reproductive, Maternal, Newborn, and Child Health Chapter 8 Diagnosis and Treatment of the Febrile Child Julie M. Herlihy, Valérie D’Acremont, Deborah C. Hay Burgess, and Davidson H. Hamer INTRODUCTION Multiple studies summarized in table 8.1 highlight the most common presenting symptoms at the facility and Fever is one of the most common presenting symptoms community levels. of pediatric illnesses. Fever in children under age five Before the availability of affordable and accurate years signifies systemic inflammation, typically in malaria rapid diagnostic tests (RDTs), most health care response to a viral, bacterial, parasitic, or less commonly, providers in malaria-endemic countries presumed that a noninfectious etiology. Patients’ ages and geographic malaria was the cause of fever; the proportion of fevers settings can help direct the appropriate diagnostic due to malaria was very high in the early 1990s, and the approach and treatment, if local epidemiology is well priority was to reduce malaria mortality by any means. understood. The 1997 World Health Organization’s (WHO’s) ini- The combined proportion of deaths due to AIDS, tial Integrated Management of Childhood Illness (IMCI) diarrheal diseases, pertussis, tetanus, measles, meningitis/ guidelines recommended the use of injectable antima- encephalitis, malaria, pneumonia and sepsis was larials and antibiotics in children in malaria-endemic 58.5 percent for children ages 1–59 months in 2015; areas who were suspected of having severe disease with it was 23.4 percent for neonates (Liu and others 2016, the presence of danger signs (Gove 1997; Communicable chapter 4 of this volume). Evidence regarding fever Disease Surveillance and Response Vaccines and incidence is variable, with country-specific reports from Biologicals 1997). Until 2010, the first edition of the cross-sectional surveys or weekly active case detection WHO guidelines for the treatment of malaria recom- ranging from two to nine febrile episodes per child mended empiric, oral, antimalarial therapy for fever under age five years per year, a mean of 5.88 fever epi- without other source in children under age five years liv- sodes per child under age five years per year (Gething ing in malaria-endemic areas (WHO 2006). The decline and others 2010). National survey data from 42 Sub- of malaria incidence; rise of antimicrobial resistance; and Saharan African countries (excluding Botswana, Cabo availability of accurate, low-cost, point-of-care diagnos- Verde, Eritrea, and South Africa) were collected and tics have challenged the effectiveness of the presumptive analyzed for an estimated 655.6 million under-five fever treatment of febrile illnesses and reopened the discus- episodes in 2007; 32 percent of these episodes occurred sion of the most accurate and cost-effective approaches in 11 outpatient units in the Democratic Republic of for fever diagnosis and treatment. There are settings with Congo, Ethiopia, and Nigeria (Gething and others 2010). very high malaria transmission and limited availability At the health facility and community levels, fever is by of diagnostic test where presumptive treatment would far the most common pediatric presenting symptom. Corresponding author: Julie M. Herlihy, MD, MPH, Director of Pediatric Global Health, Department of Pediatrics, University of California Davis, Sacramento, California; herlihyj@gmail.com. 137 138 Table 8.1 Clinical Findings and Final Classification in Studies on Integrated Management of Fevers Level of health care Health facilities (outpatients) Community health workers (children < 5 years) Mukanga, Mukanga, Mukanga, D’Acremont D’Acremont D’Acremont Shao and Rowe and Tiono, and Tiono, and Tiono, and Gouws and Gouws and Gouws and and others and others and others others others Anyorigiya Anyorigiya Anyorigiya Reference others 2004 others 2004 others 2004 2011 2011 2014 2011 2001 2012 2012 2012 Year(s) of study 2000 2000 2002 2007–08 2007–08 2008 2011 1997–2002 2009 2009 2009 Country Tanzania Uganda Brazil Tanzania Tanzania Tanzania Tanzania Kenya Uganda Burkina Faso Ghana Reproductive, Maternal, Newborn, and Child Health Algorithm Original Original Original IMCI Usual care Usual care Modified Modified Original iCCM iCCM iCCM used IMCI IMCI IMCI IMCI IMCI Age group (years) <5 <5 <5 <5 >5 < 10 <5 <5 <5 <5 <5 Total number of patients 419 516 653 1,270 1,254 1,005 842 7,151 182 525 584 % with one or more danger signs — — — — — 5 — 10 — — — % who required referral — — — — — 8 — 17 — — — % with fever 76 81 29 84 74 100 73 88 — — — % positive RDT results among febrile patients — — — — — 10 3 — 78 74 84 % with cough 35 33 52 46 24 46 53 44 — 48 21 % with difficult breathing — — — 2 1 2 — — — — — table continues next page Table 8.1 Clinical Findings and Final Classification in Studies on Integrated Management of Fevers (continued) Level of health care Health facilities (outpatients) Community health workers (children < 5 years) Mukanga, Mukanga, Mukanga, D’Acremont D’Acremont D’Acremont Shao and Rowe and Tiono, and Tiono, and Tiono, and Gouws and Gouws and Gouws and and others and others and others others others Anyorigiya Anyorigiya Anyorigiya Reference others 2004 others 2004 others 2004 2011 2011 2014 2011 2001 2012 2012 2012 Year(s) of study 2000 2000 2002 2007–08 2007–08 2008 2011 1997–2002 2009 2009 2009 % with fast breathing among those with cough — — — — — 40 22 — — 44 24 % with chest indrawing among those with cough — — — — — 2 — — — — — % with pneumonia 28 31 3 — — 18 12 — 35 — — % with diarrhea 24 34 17 17 6 10 18 22 — 26 36 % with blood in stools among those with diarrhea — — — — — 5 1 — — — — % with ear pain — — — 2 1 1 1 — — — — % with measles — — — — 0.1 0 0.8 — — — — % with skin problems — — — 7 3 8 10 — — — — % with more than one diagnostic Diagnosis and Treatment of the Febrile Child classification — — — — — — — 36 29 33 22 Source: WHO 2013a. Reproduced with permission. Note: — = not available; iCCM = Integrated Community Case Management; IMCI = Integrated Management of Childhood Illness; RDT = rapid diagnostic test. 139 be most practical and cost-effective (DCP3 volume 6, conditions, classification and treatment strategies, and a Babigumira, forthcoming). In 2009, experts debated review of available diagnostic tests. In addition, different whether sufficient information was available to aban- health systems approaches to diagnosis and treatment of don presumptive treatment guidelines and move to an the febrile child at the community and health-facility levels emphasis on diagnosis before treatment (D’Acremont, are discussed, as is the evidence base for WHO-sponsored Lengeler, and Genton 2007; D’Acremont and others approaches such as IMCI and Integrated Community 2009; English and others 2009). Case Management (iCCM). Fever in adults and RDT use Mounting evidence demonstrated the decline of for malaria are discussed further in volume 6 (Holmes, Plasmodium falciparum infections in response to intense Bertozzi, Bloom, Jha, and Nugent, forthcoming). national and multinational initiatives to control malaria. In 2012 more than US$2.5 billion was invested from global partners, including the Global Fund to Fight ETIOLOGY OF FEVER IN CHILDREN UNDER AIDS, Tuberculosis and Malaria; the World Bank Malaria AGE FIVE YEARS Booster Program; the U.S. President’s Malaria Initiative; the Bill & Melinda Gates Foundation’s Malaria Control and Infectious etiologies of fever differ according to age and Evaluation Partnership in Africa; and the Roll Back Malaria geographic region. Recent evidence from multiple health Partnership (D’Acremont, Lengeler, and Genton 2010; care and low- and middle-income country (LMIC) settings Feachem and others 2010; Leslie and others 2012; WHO confirms that viral infections are predominantly responsi- 2013a). Countries with previously defined high-transmis- ble for fever within all age groups (Animut and others 2009; sion regions are reporting decreasing malaria incidence, Crump and others 2013; D’Acremont and others 2014; making the management of nonmalarial fevers critically Kasper and others 2012; Mayxay and others 2013). The important (Feachem and others 2010; WHO 2013a; Hertz studies described in table 8.2 used different study designs and others 2013; Ishengoma and others 2011). with significant variation in study population, case defi- In 2010, the WHO revised its fever treatment guide- nitions, and available diagnostics. Although these studies lines to recommend antimalarial treatment only for those are informative, they need to be interpreted in the context with a positive malaria test result, either point-of-care or of the individual study design and context. Following are microscopy (WHO 2010a). This new strategy is being common themes across the available research: implemented in the public sector in most Sub-Saharan African countries (Bastiaens and others 2011). However, • Predominance of acute respiratory infections (ARIs) many patients first present for care in the informal private in outpatient visits for fever sector, and more research is needed to better understand • Identification of multiple pathogens after molecu- treatment decision making in this context and how to lar laboratory investigations, making it difficult to reduce overuse of antimicrobials and ensure appropri- declare a specific diagnosis ate care. The epidemiology of pediatric febrile illness • High proportion of fever etiologies due to viral is undoubtedly shifting; understanding the etiology of pathogens when appropriate viral diagnostic tests are nonmalarial fevers in each context is the logical next step available; studies without viral diagnostics reveal a to improve pediatric clinical outcomes of other treatable high proportion of undiagnosed febrile illnesses serious febrile illnesses, such as pneumonia, sepsis, bacte- • Clinically overestimated malaria, compared with rial meningitis, enteric fever, rickettsioses, and influenza. RDT or microscopy-confirmed diagnosis. Given rampant and expanding antimicrobial drug resis- tance globally, care must be taken to use antibiotics only Although the available evidence suggests that most when indicated and to develop careful guidelines when viral and some specific bacterial diseases, such as rick- resources are limited. Present guidelines are based on ettsiosis and leptospirosis, are likely to be underdiag- clinical features that are unfortunately poorly predictive nosed, data are either not available or are limited from of the diseases causing fever. Low-cost, accurate, point-of- several countries where the fever burden is highest, care diagnostics are needed to determine which children such as the Democratic Republic of Congo, India, can benefit from antibacterial therapies to guide the most and Nigeria. Ongoing surveillance of fever etiology effective use of antibiotics. in multiple representative geographies to establish This chapter discusses the evidence that informs cur- trends in predominant pathogens and to identify rent etiologies of fever, stratified by regional geography. It emerging infections early would be ideal. Additionally, presents the clinical presentation, diagnosis, and treatment little research is available on fever etiology of young of the most common diseases, with special considerations infants (age 0–2 months); a concerted research effort for certain age groups, the burden of disease for different is underway to better understand the distribution 140 Reproductive, Maternal, Newborn, and Child Health Table 8.2 Summary of Evidence for Etiology of Fever Studies World Bank region Sub-Saharan Africa South Asia Study D’Acremont and Crump and others Animut and WHO 2013a Njama-Meya and Mayxay and WHO 2013a WHO 2013a Kasper and others (2014) (2013) others (2009) others (2007) others (2013) others (2012) Study setting Tanzania: One Tanzania, Four outpatient Zanzibar, Uganda, study Lao PDR, two Pakistan, small Cambodia, Cambodia, nine urban and one hospitalized clinics in Gojjam Tanzania clinic within a province-level peripheral clinic setting unknown outpatient clinics rural outpatient patients zone in northwest referral third- hospitals in south central clinic Ethiopia level hospital region Study design N = 1,005 N = 467 (ages N = 653 (ages N = 677 cases, N =1,602 (less N = 1,938 (ages N = 1,248 febrile N = 1,193 febrile N = 9,997 (younger than 2 months to 13 3–17 years) 200 controls than age 10 5 months to 49 episodes, all patients, all ages, patients with age 10 years years) (ages 2–59 years with fever years) with fever ages 282 controls fever, all ages, with fever) Diagnoses by months) in last 24 hours) Case definition Tested for median 13 years Computer- case definitions Diagnoses Clinical plus laboratory malaria, Lab algorithm- and convalescent by IMCI diagnoses investigations leptospirosis, investigations generated serum at four to classifications for RDT or rickettsial of respiratory diagnosis using six weeks post plus laboratory microscopy diseases, scrub secretions, blood, history, physical, discharge investigations negative for typhus, dengue, serum and wide array of malaria per local influenza, and lab investigations clinical guidelines bacteremia Most 62 percent ARI 1.3 percent 62 percent 26 percent 10 percent 8 percent dengue 47 percent ARI 32 percent 19.9 percent common (5 percent chest malaria malaria watery diarrhea diarrhea 7 percent scrub 23 percent RDT-confirmed PCR-confirmed diagnoses X-ray-confirmed 3.4 percent 7 percent clinical 2 percent bloody 93 percent typhus diarrhea or malaria influenza pneumonia) bacteremia pneumonia diarrhea ARIs: dysentery 68 percent 7.2 percent 6 percent 11.9 percent 0.9 percent Serologically 5 percent skin 47 percent URI Japanese 17 percent RDT-negative: microscopy- nasopharyngeal fungemia diagnosed: infections encephalitis virus enteric fever 76 percent URI confirmed viral infection 29 percent malaria Zoonotic: 5.8 percent 0.2 percent common cold 6 percent 2 percent 0.6 percent LRI 10.5 percent typhoid malaria leptospirosis bacteremia other 6.3 percent malaria 2 percent 12 percent 17 percent bacteremia brucellosis 5.1 percent 65 percent pharyngitis 2 percent than S. typhi enteric fever 10.3 percent typhus ARIs: bacteremia 0.5 percent UTI gastroenteritis 7.7 percent 4 percent leptospirosis 2.6 percent 57 percent pneumonia less than 3 0.4 percent 5.9 percent UTI brucellosis pneumonia percent malaria malaria 2.6 percent Q 1 percent otitis fever 9 percent media confirmed by microscopy or Diagnosis and Treatment of the Febrile Child tonsillitis RDT table continues next page 141 142 Table 8.2 Summary of Evidence for Etiology of Fever Studies (continued) World Bank region Sub-Saharan Africa South Asia 3.7 percent 7.4 percent 4 percent otitis 2 percent UTIs Six-month typhoid fever spotted fever 31 percent 8 percent skin testing for 1.5 percent rickettsial other ARI infections influenza: skin/mucosal disease 32 percent (54 percent infections 10 percent viral, 12 percent influenza-positive Reproductive, Maternal, Newborn, and Child Health 0.2 percent chikungunya virus bacterial, 18 meningitis percent unknown) Undiagnosed 3.2 64 Unknown Unknown 15 59 Unknown Unknown 62 (percent) Multiple 22.6 Unknown Unknown Unknown Unknown Unknown Unknown Unknown 3.5 more than diagnoses one pathogen (percent) identified Notes Availability of Limited viral Limited viral Of the viral ARIs Limited testing Role of influenza High proportion Clinical extensive viral testing. testing most common for bacterial during outbreak of enteric disease presentation and diagnostics High prevalence PCR results: illnesses such as lab diagnoses correlated with of zoonoses; 16 percent RSV typhoid did not always clinical diagnoses consider different correlate; many 9 percent pathogens found empiric antibiotic influenza (A/B) regimens in similar rates in 9 percent controls rhinovirus Note: ARI = acute respiratory infection; IMCI = Integrated Management of Childhood Illness; LRI = lower respiratory tract infection; PCR = polymerase chain reaction; RDT = rapid diagnostic test; RSV = respiratory syncytial virus; URI = upper respiratory tract infection; UTI = urinary tract infection. of infections in young infants via the Aetiology of studies report case fatality rates (CFRs) of 18 percent Neonatal Infection in South Asia research group, and 19 percent (Ganatra and Zaidi 2010). A systematic which is building on results from the WHO Young review that included 27 hospital-based studies of the Infants Study Group and the WHO Young Infants etiology of neonatal sepsis reports CFRs in children Clinical Signs Study Group (YICSSG) (WHO Young younger than 60 days as low as 3 percent in Europe and Infants Study Group 1999; YICSSG 2008). Infection- as high as 70 percent in South-East Asia (Waters and related neonatal deaths contributed at least 10 percent others 2011). to overall mortality in children under age five years in Although a positive blood culture is the gold stan- 2013 (Liu and others 2015). dard for diagnosing bacteremia, cultures are known to lack sensitivity, especially in children, and may take several hours to days before results are available; cultures DIAGNOSIS AND TREATMENT OF COMMON require significant laboratory infrastructure, which is a CHILDHOOD FEBRILE ILLNESSES challenge in low-resource settings. Total leukocyte count, leukocyte differential, levels of acute phase reactants (for Febrile Illnesses in Young Infants example, C-reactive protein), and screening panels using Infection-related mortality and morbidity for young a variety of cytokine markers may provide supportive infants from birth to age 59 days is one of the most evidence of infection when abnormal, but these mea- challenging health issues to address; signs and symp- sures have been shown to have limited value in diagnos- toms are often nonspecific, and illnesses can rapidly ing bacteremia (Remington and others 2006). progress to severe disease. Care seeking for young According to a systematic review of 27 studies per- infant illness often occurs too late or not at all, making formed by Waters and others (2011), the most com- community-based efforts critical to increasing access to mon documented pathogens for early-onset sepsis early treatment and addressing this disproportionate (N = 282 isolates) include Escherichia coli (16.3 percent), morbidity and mortality. Using the CHERG estimates, Staphylococcus aureus (11.7 percent), nonpneumo- sepsis (15 percent) and pneumonia (6 percent) are the coccal streptococcal species (8.5 percent), Klebsiella highest infection-related contributors to neonatal death, species (7.8 percent), Pseudomonas species (7.8 percent), with tetanus and diarrheal disease both contributing Group B streptococcus (GBS; 6.7 percent), Acinetobacter approximately 1 percent (chapter 4 in this volume, Liu species (6.7 percent), and Streptococcus pneumoniae and others 2016). None of the etiology studies discussed (4.6 percent). The distribution of pathogens for late- in table 8.2 captures the causes of fever in the young onset sepsis (N = 1,784) was similar to early onset but infant age group. with notably less GBS (1.7 percent) and a higher propor- tion of Serratia species (2.2 percent), Salmonella species Sepsis (1.5 percent), H. influenzae (1.7 percent), and Neisseria Sepsis in young infants presents in two varieties: meningitidis (0.7 percent). Overall, there was a similar early onset (fewer than seven days after birth) and proportion of gram-positive isolates (34.4 percent early late onset (seven days or more). Early-onset neo- onset, 34.6 percent late onset) compared with gram- natal sepsis is thought to be the result of exposure negative isolates (63.8 percent early onset, 60.5 percent to pathogens in the maternal birth canal; late-onset late-onset) (Waters and others 2011). These results sug- sepsis is thought to be secondary to environmental gest that empiric antibiotic regimens for both early- and exposures. Symptoms of bacteremia and related sep- late-onset sepsis should be broad spectrum to treat both sis in young infants are often vague and may include gram-positive and -negative infections. fever, hypothermia, poor tone, jaundice, or inability to suck. A decrease in urine production, poor perfu- Meningitis, Herpes Simplex Virus, and sion, bulging fontanelle, excessive sleepiness, or alter- Urinary Tract Infections natively, excessive irritability are signs of more serious In addition to bacteremia, a young infant presenting disease. Without antibiotic treatment, many young with a nonfocal fever should be evaluated for meningitis infants will rapidly progress to severe bacterial sepsis, and urinary tract infections (UTIs). A lumbar puncture which may prove fatal. to check for pleocytosis (an elevated number of white A review by Ganatra and Zaidi (2010) of five neona- blood cells in cerebral spinal fluid), elevated protein, or tal sepsis studies reports incidences of blood culture– low glucose levels can indicate whether infection is pres- confirmed early-onset sepsis ranging from 2.2 to 9.8 ent in the central nervous system. per 1,000 live births, and clinical sepsis incidence rang- Herpes simplex virus-2 (HSV-2) may cause enceph- ing from 20.7 to 50 per 1,000 live births. Two of these alitis, an infection more common in the first three Diagnosis and Treatment of the Febrile Child 143 weeks of life secondary to exposure via the birth canal. intrapartum prophylaxis were associated with lower HSV-2 is responsible for genital herpes, the prevalence incidence of early-onset GBS (0.23 per 1,000 live births of which is rising globally; it is of particular con- [95 percent confidence interval 0.13–0.59]) compared cern in HIV-endemic countries where genital ulcers with those with no prophylaxis (0.75 per 1,000 live increase risk of human immunodeficiency virus (HIV) births [95 percent confidence interval 0.58–0.89]). transmission. HSV-2 seroprevalence has been mea- Whether this practice would be beneficial in low- sured at roughly 50 percent in many LMICs (WHO, resource countries is difficult to determine because of UNAIDS, and LSHTM 2001). Many newborns are insufficient data on the burden of GBS disease in these exposed to HSV-2 in asymptomatic mothers, making contexts. surveillance for neonatal HSV-2 a challenge. Further research is needed to determine whether HSV-2 is a Acute Respiratory Infections major contributor to neonatal morbidity and mortal- ARIs in young infants (age 0–59 days) are particu- ity in LMICs. larly dangerous because immature immune systems UTIs are best evaluated by urine culture; in low- increase vulnerability for systemic spread, and the resource settings, point-of-care urinalysis can provide fatigue from the increased work of breathing is a major potentially valuable information. The presence of leuko- clinical concern. Liu and others (chapter 4 in this cyte esterase, blood, or nitrates may suggest a bacterial volume, 2016) estimate that ARIs contribute 6 percent urinary infection, however, only if the urine sample is to total all-cause neonatal mortality (0–28 days), and not contaminated. The difficulty of obtaining a sterile the WHO repository suggests 4 percent of children age sample from a young infant has made implementation 0–59 days die from ARI (WHO-CHERG 2011). It is of this test less feasible in the community setting. UTIs difficult to disentangle primary respiratory infections are the most common reason for nonfocal fever in young from sepsis and other pulmonary conditions related to infants; urinary vesicoureteral reflux is associated with premature lungs and congenital anomalies. Viral respi- higher risk (Byington and others 2003; Greenhow and ratory infections often infect the smallest of airways— others 2014). bronchioles—causing inflammation, bronchospasm, and difficulty breathing. Group B Streptococcus Disease GBS (Streptococcus agalactiae) is a bacterium that can cause bacteremia, sepsis, pneumonia, and meningitis Febrile Illnesses in Older Infants and Young Children in newborns. GBS may present as early-onset disease, Acute Respiratory Infections which is usually due to transmission from a colonized ARIs became the second largest killer of children under mother immediately before or during delivery, and age five years. Recent WHO-CHERG data describe late-onset disease (later than seven days of age), at which ARIs as responsible for approximately 15 percent of all time infection may be acquired from the mother or envi- under-five deaths and 24 percent of mortality for ages ronmental sources. Overall, the CFR tends to be high 1–59 months (chapter 4 in this volume, Liu and others (9.6 percent), with a higher case fatality in early-onset 2016). Estimates vary depending on the sources and infections (Edmond and others 2012). modeling approach, with ARI-related deaths among Although GBS is a common cause of neonatal sepsis children under five years of age ranging from 890,000 in high-income countries (HICs), the global burden (GBD 2013 Collaborators 2015) in 2013 to approxi- in LMICs is less established. Variable incidence levels mately 922,000 in 2015 (chapter 4 in this volume, Liu have been reported, with Sub-Saharan Africa reporting and others 2016). ARIs include upper respiratory tract rates almost threefold higher than North and South infections, such as the common cold, otitis media, America. In contrast, South-East Asian studies have sinusitis, and pharyngitis, as well as lower respiratory reported a low incidence and even no cases of GBS. tract infections (LRIs), such as laryngitis, tracheitis, This disparity may be due to differences in study design, bronchitis, bronchiolitis, and pneumonia. Bronchiolitis previous antibiotic use, and the severity of illness, with and pneumonia are the largest contributors to child young infants dying before they can be fully evaluated. ARI deaths through progressive respiratory failure In HICs, the standard of care is to conduct surveil- or systemic infection, inflammation, or toxins spread lance cultures for GBS at 36 weeks gestation. Pregnant from the lungs. women colonized with GBS receive intrapartum anti- Acute lower respiratory tract infections (ALRIs) biotics at least four hours before delivery to reduce in older infants and children under age five years the incidence of GBS neonatal illness. In the meta- are the most common reason for hospitalization. An analysis (Edmond and others 2012), studies that report assessment of the global burden of severe pneumonia 144 Reproductive, Maternal, Newborn, and Child Health estimated that in 2010, 11.9 million (95 percent mortality. Common viral etiologies of bronchiolitis confidence interval 10.3 million to 13.9 million) include respiratory syncytial virus, influenza (types A episodes of severe and 3.0 million (95 percent con- and B), parainfluenza, human metapneumovirus, rhino- fidence interval 2.1 million to 4.2 million) episodes virus, adenovirus, coronaviruses, and human bocavirus of very severe LRI resulted in hospital admissions in (García and others 2010). young children worldwide (Nair and others 2013). In 2012, the WHO updated the technical guidelines This analysis uses data from 37 hospital studies for treatment of pneumonia, based on available evidence reporting CFRs for severe ALRI to estimate that from studies reviewed by an expert panel. On the basis approximately 265,000 (95 percent confidence inter- of recent studies, the 2014 version of the IMCI guide- val 160,000–450,000) in-hospital deaths occurred in lines (table 8.3) recommends that pneumonia with fast young children; 99 percent of these deaths occurred breathing or chest indrawing but no other danger signs in developing countries. These data capture the be managed at the outpatient level, potentially reducing inpatient CFR; however, the at-home CFR is likely the number of children needing referral (WHO 2012b, higher in areas with poor access to care. Although 2014a). many children with ARI are diagnosed and treated Pulse oximetry, which measures a patient’s in the private sector, data on these ARI episodes and oxygen saturation, can provide important triage their outcome is sorely lacking; investment to better information—peripheral oxygen saturation of less understand the role of the informal sector in disease than 90 percent predicts clinical severity and need for diagnosis and treatment is paramount. supplemental oxygen (WHO 2013a). To reduce mor- In 2009, the WHO and UNICEF released a Global tality from ARIs, clear community-based algorithms Action Plan for Prevention and Control of Pneumonia to identify and refer children with severe pneumonia (WHO and UNICEF 2009a). In 2013, this plan was are needed, and referral-level facilities need to deliver updated to include diarrheal disease control and renamed supplemental oxygen. The cost-effectiveness of an the Integrated Global Action Plan for Prevention and oxygen systems strategy compares favorably with Control of Pneumonia and Diarrhoea (WHO and other higher-profile child survival interventions, such UNICEF 2013). These calls to action outlined the as new vaccines (Duke and others 2008). Although research and programming priorities for ARIs to include most portable oxygen systems lack sufficient oxygen the following: flow rates to provide adequate respite for increased work of breathing in infants with bronchiolitis, oxy- • Etiology research to better direct antimicrobial gen concentrators provide the most consistent and therapy least expensive source of oxygen in health facilities • Vaccine development with reliable power supplies. Future research efforts • Scale-up of community-based programming to rec- that focus on reducing the power needs of or using ognize and treat cases of severe ARI before disease alternative energy sources for oxygen concentrators progression. will facilitate their introduction to lower levels of the health care system. The capacity to perform routine The Pneumonia Etiology Research for Child Health maintenance and to source necessary replacement project was designed in response to the call for enhanced parts locally needs to be addressed if this technology understanding of the etiology of pneumonia. This mul- is to be sustainable at the community or facility level. ticountry case-control study of hospitalized pediatric patients in Bangladesh, The Gambia, Kenya, Mali, South Viral Exanthems Africa, Thailand, and Zambia will reflect the changes in A discussion of febrile illnesses in children is incomplete severe pneumonia etiology resulting from wider vac- without the mention of the myriad viruses that present cine availability, the HIV/AIDS epidemic and resulting nonfocally and ultimately declare themselves clinically opportunistic infections, and increasing antimicrobial with a characteristic exanthema or rash. For example, resistance. Results are expected in 2016–17. Annex 8A the clinical syndromes of roseola (HHV-6), varicella, provides a summary of the current understanding of measles, parvovirus B19, and coxsackievirus may ini- pneumonia etiology. tially present with fever before erupting into a rash. Of Respiratory viruses play a major role in infants these conditions, only measles is incorporated into the of all ages presenting with severe ALRI, clinically IMCI algorithms, which recommend treatment with known as bronchiolitis. Although these viruses exist vitamin A for uncomplicated infections, or urgent refer- in older children with ARIs, the clinical presentation ral, a first dose of an antibiotic, and vitamin A for severe in infants is associated with higher morbidity and complicated measles (Gove 1997). Many other classic Diagnosis and Treatment of the Febrile Child 145 Table 8.3 WHO IMCI Respiratory Illness Clinical Guidelines IMCI classification for children age 2–59 months Treatment Strength of recommendation Nonsevere pneumonia Without chest indrawing and Weak recommendation, moderate quality of a (fast breathing or chest HIV-negative: evidence indrawing without danger Amoxicillin 40 mg/kg twice daily for three days signs) Without chest indrawing and HIV-positive: Amoxicillin 40 mg/kg twice daily for five days With chest indrawing: Strong recommendation, moderate quality of Amoxicillin 40 mg/kg twice daily for five days evidence Severe pneumonia (fast Children age 2–59 months: Strong recommendation, moderate quality of breathing with danger Ampicillin 50 mg/kg IV every six hours for five days OR evidence signs, with or without chest indrawing) Benzyl penicillin 50,000 IU/kg every six hours for five days AND gentamicin 7.5 mg/kg IV daily for five days Third-generation cephalosporin as second-line therapyb Wheezing Inhaled salbutamol delivered via metered dose inhaler with Strong recommendation, low quality of spacer devices for up to three times 15–20 minutes apart, to evidence relieve bronchoconstriction and to assess the respiratory rate again and classify accordingly Oral salbutamol should not be used for treatment of acute or persistent wheezing, except where inhaled salbutamol is not availableb Source: WHO IMCI Chart Booklet 2014 (http://www.who.int/maternal_child_adolescent/documents/IMCI_chartbooklet/en/). Note: IMCI = Integrated Management of Childhood Illness; IU = international unit; IV = intravenous; mg/kg = milligrams per kilogram. a. Fast breathing is defined as respiratory rate ≥ 50 breaths per minute in infants age 2–12 months, and ≥ 40 breaths per minute in infants age 12–59 months. b. Expert consensus. viral exanthema are difficult to diagnose on darker reports a mortality burden of 190,000 for enteric fever skin, are typically self limited, and do not require treat- in the 2010 Global Burden of Diseases (Lozano and ment. Measles and, to a lesser extent, varicella are highly others 2012). In 2015, the IHME released updated mor- contagious viruses and have the potential for serious tality estimates with disaggregated cause of death; they sequelae. Parvovirus B19 is an important condition to report an estimated 54,262 paratyphoid-caused deaths consider in patients with sickle-cell disease because and 160,645 typhoid-caused deaths worldwide annually infection can lead to aplastic anemia. An emphasis on (GBD 2013 Collaborators 2015). These data come from identifying these syndromes and prophylactic vaccina- 73 Gavi, the Vaccine Alliance, countries within which tion for measles is warranted in refugee or displaced more than 70 percent of mortality burden comes from populations, and in HIV-endemic areas where outbreaks Asia and more than 50 percent comes from South Asia could spread rapidly. (Lozano and others 2012; GBD 2013 Collaborators 2015). CFRs, ranging from 10 percent to 30 percent Enteric Fever without antibiotic treatment, drop to less than 1 percent Enteric fever is an all-encompassing term for the dis- to 4 percent in the antibiotic-treated patient. As part of ease caused by several serovars of Salmonella enterica Millennium Development Goal (MDG) 7, improve- including S. typhi and S. paratyphi A. The clinical pic- ments in water, sanitation, and hygiene have reduced ture of typhoid is nonspecific with symptoms of severe environmental contamination exposure to typhoid. headache, nausea, and loss of appetite associated with However, treatment with antibiotics and prevention sustained, high fever and few other specific signs. The through vaccination are ultimately needed to reduce Institute for Health Metrics and Evaluation (IHME) typhoid mortality and morbidity (United Nations 2013). 146 Reproductive, Maternal, Newborn, and Child Health Malaria Special Programme for Research and Training in Tropical Despite substantial control efforts since 2000, malaria Diseases 2009). No specific therapeutic agents exist for remains responsible for substantial morbidity and dengue fever apart from analgesics and medications to mortality worldwide; in 2015, there were an estimated reduce fever. Treatment is supportive; steroids, antivirals, 214 million cases and at least 438,000 deaths (WHO or carbazochrome, which decreases capillary permeability, 2015). Four species of Plasmodium are responsible for have no proven role. Mild or classic dengue is treated with most human cases (P. falciparum, P. vivax, P. ovale, antipyretic agents such as acetaminophen, bed rest, and and P. malariae), although P. knowlesi, a cause of pri- fluid replacement; most cases can be managed on an out- mate malaria, has been identified as a cause of human patient basis. The management of dengue hemorrhagic infections in Malaysia and other parts of South-East fever and dengue shock syndrome is purely supportive. Asia. Clinically, malaria ranges from asymptomatic par- Aspirin and other nonsteroidal anti-inflammatory drugs asitemia to uncomplicated malaria to severe malaria should be avoided, owing to the increased risk for Reye’s (typically manifested as cerebral malaria, severe ane- syndrome and hemorrhage (Simmons and others 2012). mia, hypoglycemia, and potentially multisystem organ Chikungunya, an alpha virus transmitted by mos- failure). Further detail on etiology and control strategies quitoes of the Aedes genus, is responsible for a clinical for malaria can be found in volume 6 (Holmes, Bertozzi, syndrome characterized by fever, rash, headache, myal- Bloom, Jha, and Nugent, forthcoming). gias, and arthralgias (Thiboutot and others 2010). It A paradigm shift has occurred in recent years, away can affect all ages, including young children; transpla- from the presumption that all fevers in endemic areas cental transmission with congenital infection has been should be treated as malaria toward the recommendation described (Gérardin and others 2008). Although past that laboratory testing should occur before treatment. outbreaks of chikungunya have primarily occurred in Although thick and thin blood smears have been the main- Sub-Saharan Africa and regions of South Asia and East stay of diagnosis, since 2005 the use of antigen-based RDTs Asia and Pacific, this vector-borne viral infection has with high sensitivity and specificity has increased. This emerged in Latin America and the Caribbean, where it recommendation has not been implemented in all regions spread rapidly from island to island. No specific antiviral given lack of resources to acquire RDTs or provider pref- therapy is available, and treatment is largely supportive. erence for relying on clinical diagnosis or blood smears, despite a convincing body of research to support RDTs as reliable and cost-effective diagnostic tools. Artemisinin- DIAGNOSTIC TOOLS AVAILABLE OR UNDER based combination therapy (ACT) is the preferred treat- DEVELOPMENT ment modality for uncomplicated and severe disease caused by P. falciparum; chloroquine remains the treat- Malaria ment of choice for the other three species in most regions. In many endemic areas, malaria accounts for a minority of fever episodes and is clinically indistinguishable from Dengue and Chikungunya Virus other common illnesses, including pneumonia, menin- Dengue fever, a mosquito-borne arbovirus of the genus gitis, typhoid, sepsis, and viral infections such as dengue Flavivirus, has become one of the most common and and chikungunya. The WHO recommends that malaria rapidly spreading vector-borne diseases after malaria and case management be based on parasitological diagnosis of is a major international public health concern. Dengue malaria infections before treatment (WHO 2010a, 2012a); is responsible for an estimated 50 million to 100 million the use of antigen-detecting RDTs is supportive of this illnesses annually, including 250,000 to 500,000 cases of strategy, particularly in areas where good quality micros- dengue hemorrhagic fever—a severe manifestation of copy cannot be maintained. The number of commercially dengue—and approximately 29,000 deaths (Lozano and available malaria RDTs that detect one or more of the others 2012; CDC 2012). Approximately 95 percent of three parasite antigens—histidine rich protein-2 (HRP-2), cases occur in children younger than age 15 years; infants parasite lactate dehydrogenase (pLDH), or aldolase—have constitute 5 percent of all cases. Dengue has mainly been increased substantially since their introduction in the late documented in Asia; data from Sub-Saharan Africa are 1990s (table 8.4). RDTs can play a key role in febrile ill- lacking, although reports from Gabon and elsewhere ness management, providing they are sensitive enough to are creating concern that it is an emerging disease or detect nearly all clinically significant cases of malaria and has been previously not recognized because of a lack of have a high specificity to rule out nonmalarial causes of diagnostic testing (Caron and others 2013). febrile illness. Multiple rounds of laboratory-based evalu- The grading of the severity of dengue can be based on ations have identified those RDTs that consistently detect a WHO classification system, updated in 2009 (WHO and malaria at low parasite densities (WHO 2012c). Diagnosis and Treatment of the Febrile Child 147 Table 8.4 Average Sensitivity and Specificity of Malarial Tests Test type Species detected Sensitivity (95% CI) Specificity (95% CI) Type 1 Plasmodium falciparum only 94.8% (93.1%–96.1%) 95.2% (93.2%–96.7%) Pf HRP-2 Type 2 Plasmodium falciparum, Plasmodium 96.0% (94.0%–97.3%) 95.3% (87.3%–98.3%) Pf HRP-2 and pan aldolase vivax, Plasmodium malariae and Plasmodium ovale Type 3 Plasmodium falciparum, Plasmodium vivax, 99.5% (71.0%–100%) 90.6% (80.5%–95.7%) Pf HRP-2 and pan pLDH Plasmodium malariae and Plasmodium ovale Sources: Baiden and others 2012; Abba and others 2011. Note: CI = confidence interval; Pf HRP2 = histidine rich protein-2; pLDH = parasite lactate dehydrogenase. However, the declining malaria burden in many Integrated Management of Childhood Illness endemic regions and an increasing programmatic focus The WHO developed the IMCI strategy in the 1990s on malaria elimination mean that novel target anti- to improve the quality of disease management and to gens, use of gold nanoparticles, or other diagnostic reduce mortality of children under age five years (Gove approaches may be needed to create point-of-care tests 1997). Using a series of algorithms and flow charts, with increased sensitivity. Several diagnostic approaches IMCI gives health care providers a systematic way to are based on selective microscopic detection of infected assess children for danger signs that trigger immediate blood cells by methods such as third-harmonic gener- referral or hospitalization; to classify the illness based on ation imaging (Bélisle and others 2008), photoacoustic the level of severity for pneumonia, diarrhea, measles, flowmetry (Samson and others 2012), and more recently, fever, otitis media, and malnutrition (Tulloch 1999); magneto-optical detection of the malaria pigment (Mens and to identify those requiring antibiotic treatment. and others 2010) hemozoin using hand-held devices The classifications are color coded, with pink calling with polarized light and laser pulse detection of vapor for hospital referral or admission, yellow for treat- nanobubbles generated by the parasite (Lukianova-Hleb ment at home, and green for children with mild illness and others 2014). who require only supportive care at home and can be counseled with return precautions (figure 8.1). IMCI Respiratory and Other Bacterial Illnesses has been adapted at the national level with increasing attention to HIV screening and management of illness A detailed discussion of diagnostic tools available and in infants under age two months. under development for ARI or other serious bacterial Several assessments of the quality of care delivered illnesses can be found in annex 8B (available online). by IMCI have been performed since the early 2000s. In Bangladesh, a systematic evaluation of 669 sick chil- HEALTH SYSTEMS APPROACHES TO dren age 2–59 months, using a gold-standard physician diagnosis and treatment decision, found a sensitivity of CHILDREN WITH FEBRILE ILLNESSES 78 percent and specificity of 47 percent for identifying Children with fever present to all levels and sectors of children with probable bacterial infections requiring the health system. Trials of algorithmic approaches have antibiotics (Factor and others 2001). In this low malaria been undertaken at the community and facility levels prevalence site, the majority of children with meningitis, to identify seriously ill children to indicate referral to a pneumonia, otitis media, and UTIs fulfilled IMCI crite- higher level of care. Two WHO-supported platforms to ria for at least one classification that would have resulted identify and treat children with fever and common pedi- in antibiotic initiation. However, many children with atric illnesses are IMCI for the facility level and iCCM bacteremia, skin infections, and dysentery would not for the community level. Further research is needed to have received antibiotics. This evaluation was based on identify best practice models for the formal and informal a comparison with an expert diagnosis that is subject to private sector to create a synergistic approach to provid- clinical subjectivity and the limited accuracy of available ing appropriate treatment and referral to more advanced diagnostic tools. A study assessing the safety of using a care, when needed. slightly modified version of IMCI showed that the rate 148 Reproductive, Maternal, Newborn, and Child Health Figure 8.1 Sample Fever Algorithm from 2014 IMCI Does the child have fever? (by history or feels hot or temperature 37.5˚Ca or above) If yes: • Any general danger sign or Pink: • Give first dose of artesunate or quinine for severe malaria Decide Malaria Risk: high or low High or Low Malaria • Stiff neck. • Give first dose of an appropriate antibiotic VERY SEVERE Risk • Treat the child to prevent low blood sugar Then ask: Look and feel: FEBRILE DISEASE • Give one dose of paracetamol in clinic for high fever (38.5°C • For how long? • Look or feel for stiff neck. or above) Classify FEVER • If more than 7 days, has • Look for runny nose. • Refer URGENTLY to hospital fever been present every • Look for any bacterial day? cause of feverb. • Malaria test POSITIVE. Yellow: • Give recommended first line oral antimalarial • Has the child had measles • Look for signs of MEASLES. • Give one dose of paracetamol in clinic for high fever (38.5°C MALARIA or above) within the last 3 months? • Generalized rash and • Give appropriate antibiotic treatment for an identified • One of these: cough, bacterial cause of fever runny nose, or red eyes. • Advise mother when to return immediately • Follow-up in 3 days if fever persists • If fever is present every day for more than 7 days, refer for assessment Do a malaria test c: If NO severe classification • In all fever cases if High malaria risk. • Malaria test NEGATIVE Green: • Give one dose of paracetamol in clinic for high fever (38.5°C • In Low Malaria risk if no obvious cause of fever present. • Other cause of fever PRESENT. FEVER: or above) • Give appropriate antibiotic treatment for an identified NO MALARIA bacterial cause of fever • Advise mother when to return immediately • Follow-up in 3 days if fever persists • If fever is present every day for more than 7 days, refer for assessment • Any general danger sign Pink: • Give first dose of an appropriate antibiotic. • Stiff neck. • Treat the child to prevent low blood sugar. VERY SEVERE FEBRILE No Malaria Risk and • Give one dose of paracetamol in clinic for high fever (38.5°C DISEASE No Travel to Malaria or above). Risk Area • Refer URGENTLY to hospital. • No general danger signs • Give one dose of paracetamol in clinic for high fever (38.5°C Green: If the child has measles • Look for mouth ulcers. • No stiff neck. or above) now or within the last Are they deep and FEVER • Give appropriate antibiotic treatment for an identified 3 months: extensive? bacterial cause of fever • Look for pus draining • Advise mother when to return immediately from the eye. • Follow-up in 2 days if fever persists • Look for clouding of the • If fever is present every day for more than 7 days, refer for cornea. assessment • Any general danger sign or Pink: • Give Vitamin A treatment If MEASLES now or within • Clouding of cornea or • Give first dose of an appropriate antibiotic • Deep or extensive mouth ulcers. SEVERE COMPLICATED • If clouding of the cornea or pus draining from the eye, apply last 3 months, Classify MEASLESd tetracycline eye ointment • Refer URGENTLY to hospital Yellow: • Give Vitamin A treatment • Pus draining from the eye or • Mouth ulcers. • If pus draining from the eye, treat eye infection with MEASLES WITH EYE tetracycline eye ointment OR MOUTH • If mouth ulcers, treat with gentian violet COMPLICATIONSd • Follow-up in 3 days • Measles now or within the Green: • Give Vitamin A treatment last 3 months. MEASLES a. These temperatures are based on axillary temperature. Rectal temperature readings are approximately 0.5°C higher. b. Look for local tenderness; oral sores; refusal to use a limb; hot tender swelling; red tender skin or bolls; lower abdominal pain or pain on passing urine in older children. c. If no malaria test available: High malaria risk - classify as MALARIA; Low malaria risk AND NO obvious cause of fever - classify as MALARIA. d. Other important complications of measles - pneumonia, stridor, diarrhoea, ear infection, and acute malnutrition - are classified in other tables. Source: IMCI Chart Booklet 2014 (http://www.who.int/maternal_child_adolescent/documents/IMCI_chartbooklet/en/). of clinical failure at day seven was very low (2.7 percent), studies also show that IMCI case management training and lower than in the control group (8.0 percent) in resulted in improved quality of care, especially when which routine care was used; only 15 percent received there were minimum standards of training quality and an antibiotic compared with 84 percent in the control sufficient coverage of trained health workers (Arifeen group (Shao and others 2015). and others 2005; Gouws and others 2004; Pariyo and A multicountry evaluation of IMCI effectiveness, others 2005; Nguyen and others 2013). The multicoun- cost, and impact was conducted in Bangladesh, Brazil, try evaluation also reveals that the IMCI approach pro- Peru, Tanzania, and Uganda (Bryce and others 2005). In vided many benefits in addition to improved quality of Tanzania, the survey results demonstrate that children care, including better record keeping and strengthened in IMCI districts received higher-quality care, includ- supervision. However, four of the five countries encoun- ing more thorough evaluations, a greater likelihood of tered challenges in expanding the IMCI strategy at the being properly diagnosed and correctly treated, and national level (Bryce and others 2005). better counseling and knowledge of caretakers of chil- A multicountry study finds that the quality of child dren in IMCI districts relative to comparison districts health care associated with IMCI training was simi- (Armstrong Schellenberg and others 2004). Several other lar across different cadres of health workers and that Diagnosis and Treatment of the Febrile Child 149 the duration and level of preservice training did not accordance with the guideline (incorrect choice of drug, appear to influence the quality of care (Huicho and dosage, and duration); missed opportunities for vac- others 2008). A cluster randomized controlled trial in cination; treatment with unnecessary and occasionally Bangladesh demonstrates that IMCI implementation dangerous medications; prescription of a large number resulted in improved health worker skills, increased oral of drugs for some children; and failure to perform coun- rehydration solution (ORS) utilization, and exclusive seling tasks, including how to administer medications breastfeeding, and it reduced stunting prevalence in (Rowe and others 2001). In Uganda, even after IMCI intervention areas relative to comparison areas (Arifeen training, only about 50 percent of the children classified and others 2009). IMCI implementation was also asso- as having malaria or pneumonia received complete and ciated with a nonsignificant 13 percent reduction in appropriate treatment (Pariyo and others 2005). New mortality in children under age five years. Mortality training strategies are necessary, especially for respiratory impact is examined in two other studies. In the first, a rate measurement and identification of danger signs. cluster randomized controlled trial in India that used In addition, the IMCI clinical algorithms have the Integrated Management of Neonatal and Childhood advantage of being highly sensitive but the drawback Illness (IMNCI) and community workers to conduct of having inadequate specificity. A prospective hospital- postnatal home visits, the infant mortality rate was 15 based study in Mozambique finds substantial symptom percent lower (adjusted hazard ratio 0.85, 95 percent overlap between malaria and severe pneumonia among confidence interval 0.77–0.94), and the neonatal mor- hospitalized children (Bassat and others 2011). Some tality rate after the first 24 hours was 14 percent 24 percent of children were classified using IMCI as lower (adjusted hazard ratio 0.86, 95 percent confidence having both malaria and severe pneumonia; however, interval 0.79–0.95) in intervention, relative to control when using stricter criteria based on radiological confir- clusters (Bhandari and others 2012). In the second, a mation of pneumonia and P. falciparum parasitemia, the retrospective pre/post analysis of IMCI implementation authors find that fewer than 1 percent had both malaria in the Arab Republic of Egypt found a nearly twofold and severe pneumonia. Similar to other studies, there reduction in under-five mortality (3.3 percent versus was a significant association between underlying HIV 6.3 percent) in one year (Rakha and others 2013). These infection and prevalence of severe pneumonia, duration three studies provide evidence to suggest that effective of hospitalization, and CFRs (Lanata 2004). scale-up and implementation of IMCI can help reduce For implementation of the IMCI guidelines, the infant and under-five all-cause mortality. WHO recommends an 11-day in-service training course In HIV-endemic countries such as South Africa, local for first-level (that is, primary care) health facilities, job adaptations of the IMCI algorithm have been created aids, and a follow-up visit to the facility at four to six to identify and manage HIV-infected children using a weeks to reinforce IMCI practices. As of 2009, 76 coun- set of common signs and symptoms that are predictive tries had scaled up IMCI beyond a few pilot districts; of HIV infection, for example, recurrent or persistent many countries have adapted the IMCI algorithm to diarrhea, persistent fever, or history of tuberculosis their local contexts. Some countries have started to use (Horwood and others 2003). The presence of three signs an electronic version of IMCI called ICATT that allows or a maternal report of HIV infection prompts testing easy and rapid country adaptation of the algorithm and for HIV in children. An evaluation of the IMCI HIV computer-based self training (http://www.icatt-impactt guidelines in South Africa finds that the algorithm cor- .org). Distance learning for IMCI has been developed rectly classified 71 percent of 76 HIV-infected children as as a strategy to increase IMCI training coverage (WHO suspected symptomatic HIV; approximately 20 percent 2014b). Other research into IMCI implementation high- were identified as HIV-exposed (Horwood and others lights challenges related to care seeking, resources and 2009). This approach missed only 9 percent of HIV- supply chain, training, and supervision requirements infected children. Unfortunately, the study also finds that to ensure implementation at large scale. Frequent staff this approach is not being used consistently in routine rotation and attrition require that countries revise clinical practice. preservice curricula to include training on the WHO Although the IMCI strategy has the potential to algorithms (WHO 2001, 2010b). increase the quality of care in health facilities, absolute levels of performance often are low, and adherence to the guidelines has been unsatisfactory. An assessment of Management of Sick Young Infants: IMNCI and health worker practices in Benin in 2000 revealed multi- Beyond ple problems with local adaptation of the IMCI guide- Given the need to strengthen the capacity of health lines. Problems included the failure to treat children in workers to identify young infants age 0–59 days with 150 Reproductive, Maternal, Newborn, and Child Health possible serious bacterial infections, two multicoun- rods, and 11 percent of S. aureus isolates were methi- try studies were performed to provide evidence to cillin resistant (Hamer and others 2015). Although strengthen the IMCI algorithm to include newborns and broad-spectrum cephalosporins show better sensitivities young infants. To obtain information on clinical signs to most pathogens, they are expensive and their use will of sepsis in young infants age 0–59 days, the WHO con- increase drug pressure. Recommended antimicrobial ducted a large study of the clinical features and etiologies therapies need to be regionally specific, and consider- of serious bacterial disease from 1990 to 1992 in the ations to empirically cover for HSV-2 infections must Philippines (Gatchalian and others 1999), The Gambia be considered in the youngest infants. The Aetiology (Mulholland and others 1999), Ethiopia (Muhe and oth- of Neonatal Infection in South Asia study will provide ers 1999), and Papua New Guinea (Lehmann and others even more current data for LMICs that reflect current 1999). This information contributed to the development epidemiology and antimicrobial susceptibilities (WHO of the IMCI algorithms during the mid-1990s, which Young Infants Study Group 1999; YICSSG 2008). standardized the management of sick young infants at A seminal study in India demonstrates a 16 percent first-level health facilities (Gove 1997; Tulloch 1999; reduction in neonatal sepsis case fatality and a Weber and others 2003). 62 percent reduction in overall neonatal mortality by Neonates in the first week of life were still not instituting a package of home-based newborn care ser- included. Accordingly, the YICSSG designed a multicen- vices by trained community health workers (CHWs); ter study to analyze recognition of young infants, includ- the services included an assessment for sepsis and ing neonates younger than seven days, requiring referral prereferral administration of injectable gentamicin if to higher levels of the health system. The YICSSG found indicated (Bang and others 1999). A more detailed dis- that 12 symptoms or signs showed statistical evidence of cussion of this study is provided in chapter 18 in this independent predictive value for severe illness requiring volume (Ashok, Nandi, and Laxminarayan 2016). In hospital admission in the first week of life. A decision Zambia, a cluster randomized controlled trial assessed rule requiring the presence of any of these 12 signs had the impact of training birth attendants to perform high sensitivity (87 percent) and specificity (74 percent). a modified neonatal resuscitation protocol for new- However, a simplified algorithm that required only seven borns with respiratory distress and to recognize a set signs—history of difficulty feeding, history of convul- of cardinal symptoms and signs of possible neonatal sions, movement only when stimulated, respiratory infection. If any signs of possible serious bacterial rate ≥ 60 breaths per minute, temperature ≥ 37.5°C or infection were observed in the first four weeks of life, < 35.5°C, and severe chest indrawing—had a similar intervention-trained birth assistants were to administer sensitivity (85 percent) and specificity (75 percent). This a 500 milligram dose of oral amoxicillin and facilitate seven-sign algorithm also performed well in infants age referral to the nearest rural health center. This combina- 7–59 days (sensitivity 74 percent, specificity 79 percent) tion of interventions resulted in a 45 percent reduction (WHO Young Infants Study Group 1999; Weber and in neonatal mortality for all live births in intervention as others 2003). This clinical algorithm was validated at compared with controls (Gill and others 2011). the community level during routine household visits in Several studies from India, Nepal, and Pakistan eval- rural Bangladesh (Darmstadt and others 2011). A sim- uate a variety of community-based perinatal packages plified six-sign algorithm had a sensitivity of 81 percent that deploy newborn home visitation; each trial has and specificity of 96 percent for screening neonates shown significant impact on neonatal mortality (Baqui requiring referral, and sensitivity of 58 percent and and others 2008; Bhutta and others 2008; Kumar and specificity of 94 percent for identifying newborns at risk others 2008). As a result of this growing body of evi- of dying. dence, the WHO and UNICEF released a joint statement The WHO IMCI guidelines recommend that any on home visits in 2009 (WHO and UNICEF 2009b). young infant presenting with danger signs should be Several countries have developed adaptations of IMNCI. referred to an appropriate level facility and treated with The Indian IMNCI program, which integrates home injectable gentamicin and ampicillin. Although data are visits for newborn care with improved treatment of limited, multiple reviews cite widespread resistance to illness, evaluated the effectiveness of this strategy in a ampicillin and gentamicin among sepsis-causing com- cluster randomized controlled trial. This study demon- mon pathogens E. coli, S. aureus, and Klebsiella species strated more optimal newborn care practices in inter- (Thaver, Ali, and Zaidi 2009; Waters and others 2011). vention clusters and a significant reduction of neonatal Similarly, data from the YICSSG, which represent com- mortality only among babies born at home receiving munity-acquired bacteremia in young infants, reveals the intervention (hazard ratio intervention/control 0.80 for wide distribution of multi-drug-resistant gram-negative home births [95 percent confidence interval 0.68–0.93] Diagnosis and Treatment of the Febrile Child 151 versus 1.06 for facility births [95 percent confidence by deploying diagnostics-guided, evidence-based pedi- interval 0.91–1.23]) (Bhandari and others 2012). atric treatment algorithms and improving early access to effective treatment, thereby decreasing the risk that a child’s illness will progress to severe disease. The WHO Integrated Community Case Management and UNICEF released a joint statement justifying the In many resource-limited countries, access to health need for iCCM and making recommendations on its facilities for prompt, appropriate management of com- implementation in 2012 (WHO and UNICEF 2012). mon childhood illnesses is limited and often compli- The effectiveness and feasibility of community-based cated by shortages of essential medicines and insufficient management of individual disease conditions have been human resources. Children in the lowest wealth quintile demonstrated for pneumonia, diarrheal disease, and are less likely to receive early and appropriate treat- malaria (Mubi and others 2011; Mukanga, Tiono, and ment for malaria, pneumonia, and diarrhea (Young and Anyorigiya 2012; Theodoratou 2010; Yeboah-Antwi Wolfheim 2012). To address this access gap and provide and others 2010). Home-based management of diar- early access to treatment, many countries have been rhea has been practiced for decades; the WHO’s Special testing and scaling up community-based programs for Programme for Research and Training in Tropical the treatment of common childhood infectious diseases. Diseases and others have extensively tested approaches iCCM provides an integrated algorithmic approach to to community-level management of malaria (Ajayi and identifying and treating ill children with limited access others 2008; Pagnoni 2009). Studies have been conducted to health facilities. These algorithms alert CHWs to signs to assess effectiveness of the full iCCM package for man- and symptoms of severe disease to indicate referral into agement of malaria, pneumonia, and diarrhea, which the formal health system while treating minor illness in is often coupled with screening for acute malnutrition. the community, serving as an extension of the formal This package generally consists of training either volun- health care system. This approach has several potential teer or paid cadres of community-based health workers benefits, including improving the rational use of drugs to follow a simple algorithm (figure 8.2) to classify and Figure 8.2 Sample Integrated Community Case Management Algorithm Yes Refer Danger signs Antimalarials and antibiotics immediately No Persisting symptoms Refer or signs of malnutrition for further assessment No Fever Cough Diarrhea Malaria Fast Blood in RDT breathing stool Positive Negative Yes No Yes No Malaria Unspecific fever Pneumonia Cold Dysentery Watery diarrhea ACT No antimicrobial Antibiotics No antimicrobial Refer ORS and zinc Source: WHO 2009. Note: ACT = artemisinin-based combination therapy; ORS = oral rehydration solution; RDT = rapid diagnostic test. 152 Reproductive, Maternal, Newborn, and Child Health treat children under age five years who present with fever, and an earlier evaluation in Kenya (Kelly and others cough, difficulty breathing, or diarrhea. Necessary equip- 2001) suggest problems with pneumonia evaluation, ment includes a timer for counting respiratory rates and emphasizing the need for ongoing supervision, train- a tape for measuring mid-upper arm circumference if ing, and quality measurement of CHWs. This issue is screening for acute malnutrition is performed; supplies further discussed in a systematic review of pneumonia include malaria RDTs, weight- and age-appropriate dose community case management (CCM), which suggests packs of an ACT, dispersible amoxicillin tablets (or cotri- that evidence on the efficacy and effectiveness of this moxaxole because supply of amoxicillin is a frequent approach in Sub-Saharan Africa is still lacking (Druetz challenge), zinc, and low osmolarity ORS. and others 2013). Several studies conducted in Benin, Tanzania, Uganda, Quality and Safety of iCCM delivery and Zambia demonstrate that febrile RDT-negative chil- Several studies show that CHWs can appropriately dren can be managed safely without antimalarial therapy classify and treat malaria, pneumonia, and diarrhea in (D’Acremont and others 2010; Faucher and others 2010; children. Studies in Cambodia, Sudan, and Zambia show Msellem and others 2009; Njama-Meya and others 2007; that with minimal training and job aids, CHWs can Yeboah-Antwi and others 2010). In the Zambian study, perform and interpret RDTs (Elmardi and others 2009; children were evaluated five to seven days after their visit Harvey and others 2008; Mayxay and others 2004). to the CHW; treatment failure at this point occurred in In contrast with some studies of health workers in 9.3 percent of children (N = 1,017) in the study arm that first-level health centers that demonstrate a tendency implemented an iCCM package of malaria RDTs, ACTs, to ignore malaria diagnostic test results and to overpre- and amoxicillin. Notably, only 0.4 percent of children scribe ACT, several other studies clearly highlight the were hospitalized and 0.2 percent died. These findings ability of CHWs to correctly perform RDTs and appro- provide additional confirmation that the WHO’s guide- priately not prescribe antimalarials for RDT-negative lines for malaria treatment (WHO 2010a), which rec- patients (Bisoffi and others 2009; Hamer and others ommend treatment based on a positive diagnostic test 2007; Harvey and others 2008; Reyburn and others for all patients, including children under age five years, 2007; Yasuoka and others 2010). Exceptions have been can also be safely implemented at the community level noted: Sudanese community volunteers have prescribed in malaria-endemic areas of Sub-Saharan Africa. ACT in 30 percent of subjects with fever but a negative All of the studies discussed focus on the management RDT result (Elmardi and others 2009), indicating that of children with nonsevere pneumonia at the commu- the inappropriate prescription of ACT may be an issue nity level. However, substantial evidence indicates that in some settings at the community level; lack of or children with the former WHO-defined severe pneu- inappropriate CHW training and supervision is one of monia (pneumonia with chest indrawing but no danger several possible reasons. signs) can be managed with oral amoxicillin at the com- A study in Zambia that evaluated two models of inte- munity level. In Pakistan, a five-day course of high-dose grated delivery of treatment for malaria and pneumonia amoxicillin was shown to be equivalent to parenteral demonstrates that CHWs correctly classified 1,017 ampicillin for 48 hours, followed by a three-day course children who presented with fever or fast or difficult of oral amoxicillin for children with severe pneumonia breathing as having malaria and pneumonia 94 percent (Hazir and others 2008). Subsequently, a multicountry to 100 percent of the time. Appropriate treatment based observational study conducted in Bangladesh, Egypt, on disease classification was correct in 94 percent to Ghana, and Vietnam demonstrated the safety and effi- 100 percent of episodes (Hamer and others 2012). In cacy of home-based management of severe pneumonia Uganda, a study that compared CHWs trained in inte- with oral high-dose amoxicillin (Addo-Yobo and oth- grated malaria and pneumonia management to those ers 2011). An average of 9.2 percent of children met a only trained in malaria case management demonstrated rigorous definition of treatment failure at day 6 and that CHWs with high illness knowledge scores used 2.7 percent relapsed by day 14, but all children survived; correct doses of medications for malaria and pneu- only one adverse drug reaction (among 823 children) monia, and correctly classified 75 percent of children was documented. Two parallel community-based stud- with pneumonia (Kalyango, Rutebemberwa, and Alfven ies in rural Pakistan provide further evidence of the 2012). However, the CHWs did not count respiratory effectiveness and safety of the home-based management rate accurately—only 49 percent measured respiratory of chest indrawing pneumonia with oral amoxicillin by rates within the bounds of the gold-standard criteria female health workers (Bari and others 2011; Soofi and of five breaths per minute of the physician. This study others 2012). Diagnosis and Treatment of the Febrile Child 153 Impact of iCCM however, this difference was not statistically significant iCCM has several benefits, including early care seeking (rate ratio = 0.79, 95 percent confidence interval 0.56– for illness; early access to appropriate treatment for chil- 1.12, P = 0.195). This study also showed reductions dren; reduced use of expensive antimalarial drugs when in anemia, severe anemia, and severe disease among RDTs are used; reductions in health center attendance, children in both study arms (Chinbuah and others which helps reduce the workload at primary health care 2013). Although this trial suggests a mortality benefit of centers; and probably decreased all-cause mortality for both an ACT alone and the combination of an ACT with children under age five years. an antibiotic, its design has several limitations, including Given the substantial workload at rural health cen- the lack of use of malaria RDTs and the empiric use of ters, which are often understaffed, iCCM offers a poten- antibiotics for all children with fever, regardless of the tial opportunity to increase access to effective therapy at respiratory rate in the combined arm (Chinbuah and the community level (Guenther and others 2012) while others 2012). decreasing the volume of health facility visits. In the A limited number of studies have evaluated the cost- Zambian study (Yeboah-Antwi and others 2010), cross- effectiveness of iCCM. An economic analysis of the study sectional household surveys on health care–seeking in Ghana that compared an ACT to ACT plus amoxicillin practices were performed before and immediately after (Chinbuah and others 2012) finds that the cost per DALY the 12-month integrated malaria and pneumonia inter- averted was US$90.25 for artesunate-amodiaquine and vention period. A significant increase was observed in US$114.21 for this ACT plus amoxicillin (Nonvignon the proportion of mothers who sought care from CHWs and others 2012). The authors conclude that both between baseline and poststudy in both groups (empiric approaches were cost-effective. However, the diagnosis ACT for fever plus referral of children with pneumonia of malaria did not involve the use of RDTs; all chil- versus RDT-based ACT for malaria and amoxicillin dren in the ACT plus amoxicillin arm with fever were for nonsevere pneumonia). Care seeking from CHWs given antibiotics, an approach that carries a high risk increased for all types of illness, and use of health facil- of antimicrobial resistance and potential adverse events ities and traditional healers decreased (Seidenberg and among children who do not require antibiotics. A cost- others 2012). This pattern was noted in both groups effectiveness analysis of malaria case management using for children presenting with fever, cough, and diarrhea; RDTs and artemether-lumefantrine in Zambia reveals however, there was a trend toward greater use of the that home-based management was more cost-effective CHWs that could provide amoxicillin for children with than facility-based management (US$4.22 per case at the fast breathing or difficulty breathing relative to those home versus US$6.12 at the facility) (Chanda and oth- CHWs who were trained to refer children with signs of ers 2011). A cost analysis from Pakistan that focuses on pneumonia. household costs of illness finds that home management Limited data are available on the impact of iCCM on of pneumonia by women health workers was associated child mortality under age five years. Some earlier studies with a substantially lower cost to the household than for of the home management of malaria, based on maternal children who were referred for treatment (Sadruddin recall of a history of fever, found that home management and others 2012). of malaria is associated with a reduction in the develop- ment of severe malaria by more than 50 percent and CHALLENGES AND FUTURE DIRECTIONS all-cause mortality by 40 percent (Kidane and Morrow 2000; Sirima and others 2003). More recently, a study in The Catalytic Initiative, an evaluation in six Sub-Saharan Ghana that used a stepped-wedge cluster-randomized African countries—Ethiopia, Ghana, Malawi, Mali, design evaluated the impact of adding amoxicillin to Mozambique, and Niger—provides a useful summary an antimalarial (artesunate-amodiaquine) for treating of challenges and lessons learned during the scale-up fever among children age 2–59 months on all-cause of iCCM. Some of the major challenges to delivery of mortality. In clusters in which artesunate-amodiaquine iCCM include the deployment, supervision, motivation, alone was used for fever treatment, mortality decreased and retention of CHWs; maintenance of reliable supply by 30 percent (rate ratio = 0.70, 95 percent confidence chains; demand-side barriers to utilization; inadequate interval 0.53–0.92, P = 0.011) and in clusters that used monitoring and evaluation systems; and a need for sup- both an ACT and amoxicillin, mortality was reduced portive government policies and engagement to achieve by 44 percent (rate ratio = 0.56, 95 percent confidence sustainable progress (UNICEF 2012). interval 0.41–0.76, P = 0.011) when compared with In 2009–10, a survey of 68 countries in the control clusters. A 21 percent mortality reduction was Countdown to 2015 initiative was conducted to assess observed with the addition of amoxicillin to the ACT; CCM of childhood illnesses (de Sousa and others 2012). 154 Reproductive, Maternal, Newborn, and Child Health Most (81 percent) of the 59 countries that responded Economic studies confirm that international had policies for CCM of diarrhea and malaria (75 guidelines for treatment of fever in children are also percent); only 54 percent had CCM policies for pneu- cost-effective. Community use of rectal artesunate monia. Only 17 (32 percent) of the 53 malaria-endemic for children with severe malaria during their refer- countries providing responses had policies for all ral to higher-level care has been shown to be cost- three of these conditions. According to the survey, effective. Similarly, RDTs for malaria are cost-effective CHWs administered the recommended treatments for if used appropriately (where P. falciparum is dominant diarrhea, malaria, or pneumonia in 34 percent (17 of and ACTs are the appropriate therapy, and where care 50), 100 percent (41 of 41), and 100 percent (34 of 34) providers abide by test results in their prescribing of the countries implementing CCM of these condi- behavior). Finally, IMCI was shown in one study to tions, respectively. Many programs identified similar be cost-effective (Armstrong Schellenberg and others implementation-related concerns, including problems 2004); however, precisely because it is effective, it can with drug supplies; quality of care; and CHW incen- increase costs to the health service as patients shift from tives, training, and supervision. Implementation issues using private clinics (needs Prinja and others 2013). around supervision, quality control, supply chain, and Future research needs for diagnosis and treatment remuneration of CHWs are important areas of research approaches for the febrile child are plentiful. Box 8.1 for iCCM because best practices will inform approaches highlights considerations for future research, policy, and to the scale-up of iCCM. programming. Box 8.1 Future Research Needs Epidemiology operated) for oxygen concentrators, pulse oxime- • Ongoing surveillance of febrile illness etiology, ters, and other tools that require power with particular emphasis on high burden coun- • Operational research to determine best practices tries, such as the Democratic Republic of Congo, for supply chain management, training, and Ethiopia, India, and Nigeria; on regions at high supervision for IMCI and iCCM when scaled up risk of zoonotic illness; on regions in conflict; and • Qualitative and quantitative research to better on neonatal infections understand the role of the private sector in influ- • Role of HSV-2 and GBS in neonatal illness, as encing care-seeking behaviors, diagnosis, and well as impact of HSV-2 and GBS prophylaxis on treatment neonatal outcomes • Patterns of antimicrobial resistance to direct Economics empiric therapies for pediatric serious bacterial • Cost analysis of diagnostic tools versus empiric infections therapy for common pediatric illnesses in new- born period, and for pneumonia, diarrheal dis- ease, and nonfocal fevers Implementation • Cost comparisons of investments in preventive • Field evaluation of commercially available diag- interventions (for example, vaccines, malnutri- nostic point-of-care tools to determine feasibility, tion treatment, exclusive breastfeeding) com- cost-effectiveness, and level of health system; pared with diagnosis and treatment for common various tools should be introduced pediatric illnesses • Creation and evaluation of innovative solutions Note: GBS = Group B streptococcus; HSV-2 = herpes simplex virus-2; iCCM = to reduce power needs or use of alternative integrated community case management; IMCI = Integrated Management of energy sources (for example, solar power, battery Childhood Illness. Diagnosis and Treatment of the Febrile Child 155 CONCLUSIONS ANNEXES Ample evidence suggests a shift in the etiology of The annexes to this chapter are as follows. They are avail- pediatric febrile illnesses, especially in countries with able at http://www.dcp-3.org/RMNCH. declining rates of malaria transmission. More etiology studies are needed in LMICs with high disease burdens • Annex 8A. Common Etiologies of Childhood (for example, Democratic Republic of Congo, Ethiopia, Pneumonia in Low- and Middle-Income Countries India, Nigeria, Pakistan), particularly for young infants. • Annex 8B. Diagnostic Tools Available and Under Ongoing surveillance is required to track epidemi- Development for ARI or Other Serious Bacterial ological shifts given that drug pressure and policies Illnesses influence which diseases are prominent in each region. The research evidence is concentrated in a few regions of the world; thus, advocacy for research in high bur- NOTE den countries, regions at high risk of zoonotic illness, For consistency and ease of comparison, DCP3 is using the regions in conflict, and neonatal infections is paramount World Health Organization’s Global Health Estimates (GHE) to shaping global, national, and region-specific policy. for data on diseases burden, except in cases where a relevant Many diagnostic tools are commercially available or data point is not available from GHE. In those instances, an are in the development pipeline, tools that could aid in alternative data source is noted. narrowing differential diagnoses and that could help World Bank Income Classifications as of July 2014 are as providers determine whether antimicrobials are indi- follows, based on estimates of gross national income (GNI) cated. However, these tools need to be evaluated in the per capita for 2013: field to assess the cost-effectiveness and utility in the clinical context. • Low-income countries (LICs) = US$1,045 or less • Middle-income countries (MICs) are subdivided: Finally, although both WHO-sponsored IMCI and a) lower-middle-income = US$1,046–US$4,125 iCCM offer promising health facility and community b) upper-middle-income (UMICs) = US$4,126–US$12,745 platforms for integrated service delivery, challenges • High-income countries (HICs) = US$12,746 or more. including adherence to guidelines, supply chain, super- vision, and scale up while maintaining quality are barriers to successful implementation. Adaptation of REFERENCES these models to reflect local epidemiology and available Abba, K., J. J. Deeks, P. L. Olliaro, C.-M. Naing, S. M. Jackson, resources is paramount. In areas without CHWs or and others. 2011. “Rapid Diagnostic Tests for Diagnosing regions with prominent informal private sectors, work Uncomplicated P. falciparum Malaria in Endemic needs to be done to determine how to align approaches Countries.” Cochrane Database of Systematic Reviews to children with fever to ensure appropriate treatment (7): CD008122. and decrease antibiotic overuse. The role of the private Addo-Yobo, E., D. D. Anh, H. El-Sayed, L. M. Fox, M. P. Fox, informal sector has been underestimated, and careful and others. 2011. “Outpatient Treatment of Children with thought is needed about how to motivate and partner Severe Pneumonia with Oral Amoxicillin in Four Countries: with private sector drug providers. The MASS Study.” Tropical Medicine and International Because febrile illnesses are still the predominant dis- Health 16 (8): 995–1006. ease presentation of most pediatric illnesses, high-quality Ajayi, I. O., E. N. Browne, F. Bateganya, D. Yar, C. Happi, impact and process research that can inform which models and others. 2008. “Effectiveness of Artemisinin-Based Combination Therapy Used in the Context of Home work best in which contexts is needed. This research, along Management of Malaria: A Report from Three Study Sites with expanded fever etiology surveillance and innovative in Sub-Saharan Africa.” Malaria Journal 7: 190. technologies for low-resource diagnostics and treatment Animut, A., Y. Mekonnen, D. Shimelis, and E. Ephraim. 2009. delivery, is critical for further reductions in child mortal- “Febrile Illnesses of Different Etiology among Outpatients ity and morbidity. A unified call for an organized agenda in Four Health Centers in Northwestern Ethiopia.” Japanese and framework that unites the pneumonia, malaria, mea- Journal of Infectious Disease 62 (2): 107–10. sles, other febrile illnesses, and neonatal illness agendas Arifeen, S. E., J. Bryce, E. Gouws, A. Baqui, R. E. Black, and would benefit the global child survival agenda. MDG 4 has others. 2005. “Quality of Care for Under-Fives in First-Level motivated numerous national-level planning efforts and Health Facilities in One District of Bangladesh.” Bulletin of now there is substantial country-specific programming. A the World Health Organization 83 (4): 260–67. forum to discuss evidence for best practices would further Arifeen, S. E., D. M. E. Hoque, T. Akter, M. Rahman, M. E. Hoque, and others. 2009. “Effect of the Integrated Management benefit this unmet need. 156 Reproductive, Maternal, Newborn, and Child Health of Childhood Illness Strategy on Childhood Mortality Care: Results from a Pilot Study in Rural Pakistan.” Bulletin and Nutrition in a Rural Area in Bangladesh: A Cluster of the World Health Organization 86 (6): 452–59. Randomised Trial.” The Lancet 374 (9687): 393–403. Bisoffi, Z., B. S. Sirima, A. Angheben, C. Lodesani, F. Gobbi, Armstrong Schellenberg, J., J. Bryce, D. de Savigny, and others. 2009. “Rapid Malaria Diagnostic Tests vs. T. Lambrechts, C. Mbuya, and others. 2004. “The Effect of Clinical Management of Malaria in Rural Burkina Faso: Integrated Management of Childhood Illness on Observed Safety and Effect on Clinical Decisions: A Randomized Quality of Care of Under-Fives in Rural Tanzania.” Health Trial.” Tropical Medicine and International Health 14 (5): Policy Planning 19 (1): 1–10. 491–98. Ashok, A., A. Nandi, and R. Laxminarayan. 2016. “The Benefits Bryce, J., C. G. Victora, J.-P. Habicht, R. E. Black, and of a Universal Home-Based Neonatal Care Package in Rural R. W. Scherpbier. 2005. “Programmatic Pathways to India: An Extended Cost-effectiveness Analysis.” In Disease Child Survival: Results of a Multi-Country Evaluation Control Priorities (third edition): Volume 2, Reproductive, of Integrated Management of Childhood Illness.” Health Maternal, Newborn, and Child Health, edited by R. Black, Policy Planning 20 (Suppl 1): i5–17. R. Laxminarayan, M. Temmerman, and N. Walker. Byington, C. L., K. K. Rittichier, K. E. Bassett, H. Castillo, Washington, DC: World Bank. T. S. Glasgow, and others. 2003. “Serious Bacterial Infections Baiden, F., J. Webster, M. Tivura, R. Delimini, Y. Berko, and oth- in Febrile Infants Younger Than 90 Days of Age: The ers. 2012. “Accuracy of Rapid Tests for Malaria and Treatment Importance of Ampicillin-Resistant Pathogens.” Pediatrics Outcomes for Malaria and Non-Malaria Cases among Under- 111 (5): 964–68. Five Children in Rural Ghana.” PLoS One 7 (4): e34073. Caron, M., G. Grard, C. Paupy, and I. Mombo. 2013. Bang, A. T., R. A. Bang, S. B. Baitule, M. H. Reddy, and “First Evidence of Simultaneous Circulation of Three M. D. Deshmukh. 1999. “Effect of Home-Based Neonatal Different Dengue Virus Serotypes in Africa.” PLoS One 8 Care and Management of Sepsis on Neonatal Mortality: (10): e78030. Field Trial in Rural India.” The Lancet 354 (9194): 1955–61. CDC (Centers for Disease Control and Prevention). 2012. Baqui, A. H., S. El-Arifeen, G. L. Darmstadt, S. Ahmed, “Fact Sheet: Dengue.” CDC, Atlanta, GA. www.cdc.gov E. K. Williams, and others. 2008. “Effect of Community- /Dengue/faqFacts/fact.html. Based Newborn-Care Intervention Package Implemented Chanda, P., B. Hamainza, H. Moonga, V. Chalwe, P. Banda, through Two Service-Delivery Strategies in Sylhet District, and F. Pagnoni. 2011. “Relative Costs and Effectiveness of Bangladesh: A Cluster-Randomised Controlled Trial.” The Treating Uncomplicated Malaria in Two Rural Districts in Lancet 371 (9628): 1936–44. Zambia: Implications for Nationwide Scale-Up of Home- Bari, A., S. Sadruddin, A. Khan, Iu Khan, A. Khan, and others. Based Management.” Malaria Journal 10: 159. 2011. “Community Case Management of Severe Pneumonia Chinbuah, M., M. Adjuik, F. Cobelens, K. A. Koram, M. Abbey, with Oral Amoxicillin in Children Aged 2–59 Months in and others. 2013. “Impact of Treating Young Children with Haripur District, Pakistan: A Cluster Randomised Trial.” Antimalarials with or without Antibiotics on Morbidity: The Lancet 378 (9805): 1796–803. A Cluster-Randomized Controlled Trial in Ghana.” Bassat, Q., S. Machevo, C. O’Callaghan-Gordo, B. Sigaúque, International Health 5 (3): 228–35. L. Morais, and others. 2011. “Distinguishing Malaria from Chinbuah, M., P. Kager, M. Abbey, M. Gyapong, E. Awini, Severe Pneumonia among Hospitalized Children Who Fulfilled and others. 2012. “Impact of Community Management of Integrated Management of Childhood Illness Criteria for Both Fever (Using Antimalarials with or without Antibiotics) on Diseases: A Hospital-Based Study in Mozambique.” American Childhood Mortality: A Cluster-Randomized Controlled Journal of Tropical Medicine and Hygiene 85 (4): 626–34. Trial in Ghana.” American Journal of Tropical Medicine and Bastiaens, G. J. H., E. Schaftenaar, A. Ndaro, M. Keuter, Hygiene 87 (5 Suppl): 11–20. T. Bousema, and others. 2011. “Malaria Diagnostic Testing Communicable Disease Surveillance and Response Vaccines and and Treatment Practices in Three Different Plasmodium Biologicals. 1997. “The Diagnosis, Treatment and Prevention falciparum Transmission Settings in Tanzania: Before and of Typhoid Fever.” World Health Organization, Geneva. after a Government Policy Change.” Malaria Journal 10: 76. Crump, J. A., A. B. Morrissey, W. L. Nicholson, R. F. Massung, Bélisle, J. M., S. Costantino, M. L. Leimanis, M.-J. Bellemare, R. A. Stoddard, and others. 2013. “Etiology of Severe Non- D. S. Bohle, and others. 2008. “Sensitive Detection of Malaria Febrile Illness in Northern Tanzania: A Prospective Malaria Infection by Third Harmonic Generation Imaging.” Cohort Study.” PLoS Neglected Tropical Diseases 7 (7): e2324. Biophysical Journal 94 (4): L26–28. D’Acremont, V., J. Kahama-Maro, N. Swai, D. Mtasiwa, Bhandari, N., S. Mazumder, S. Taneja, H. Sommerfelt, and B. Genton, and C. Lengeler. 2011. “Reduction of Anti- T. A. Strand. 2012. “Effect of Implementation of Integrated Malarial Consumption after Rapid Diagnostic Tests imple- Management of Neonatal and Childhood Illness (IMNCI) mentation in Dar es Salaam: A Before-After and Cluster Programme on Neonatal and Infant Mortality: Cluster Randomized Controlled Study.” Malaria Journal 10: 107. Randomised Controlled Trial.” British Medical Journal 344: D’Acremont, V., M. Kilowoko, E. Kyungu, S. Philipina, e1634. W. Sangu, and others. 2014. “Beyond Malaria: Causes of Bhutta, Z. A., Z. A. Memon, S. Soofi, M. S. Salat, S. Cousens, and Fever in Outpatient Tanzanian Children.” New England others. 2008. “Implementing Community-Based Perinatal Journal of Medicine 370: 809–17. Diagnosis and Treatment of the Febrile Child 157 D’Acremont, V., C. Lengeler, and B. Genton. 2007. “Stop Feachem, R. G., A. A. Phillips, J. Hwang, C. Cotter, B. Wielgosz, Ambiguous Messages on Malaria Diagnosis.” British and others. 2010. “Shrinking the Malaria Map: Progress and Medical Journal 334: 489. Prospects.” The Lancet 376 (9752): 1566–78. ———. 2010. “Reduction in the Proportion of Fevers Ganatra, H. A., and A. K. M. Zaidi. 2010. “Neonatal Infections Associated with Plasmodium falciparum Parasitaemia in in the Developing World.” Seminars in Perinatology 34 (6): Africa: A Systematic Review.” Malaria Journal 9: 240. 416–25. D’Acremont, V., C. Lengeler, H. Mshinda, D. Mtasiwa, García, C. G., R. Bhore, A. Soriano-Fallas, M. Trost, R. Chason, M. Tanner, and others. 2009. “Time to Move from and others. 2010. “Risk Factors in Children Hospitalized Presumptive Malaria Treatment to Laboratory-Confirmed with RSV Bronchiolitis versus Non-RSV Bronchiolitis.” Diagnosis and Treatment in African Children with Fever.” Pediatrics 126 (6): e1453–60. PLoS Medicine 6 (1): e252. Gatchalian, S., B. Quiambao, A. Morelos, L. Abraham, D’Acremont, V., A. Malila, N. Swai, R. Tillya, J. Kahama- C. Gepanayao, and others. 1999. “Bacterial and Viral Maro, and others. 2010. “Withholding Antimalarials in Etiology of Serious Infections in Very Young Filipino Febrile Children Who Have a Negative Result for a Rapid Infants.” Pediatric Infectious Disease Journal 18 (10 Suppl): Diagnostic Test.” Clinical Infectious Disease 51 (5): 506–11. S50–55. Darmstadt, G. L., A. H. Baqui, Y. Choi, S. Bari, S. M. Rahman, GBD (Global Burden of Disease) 2013 Mortality and Causes of and others. 2011. “Validation of a Clinical Algorithm Death Collaborators. 2015. “Global, Regional, and National to Identify Neonates with Severe Illness during Routine Age-Specific All-Cause and Cause-Specific Mortality for Household Visits in Rural Bangladesh.” Archive of Disease 240 Causes of Death, 1999–2013: A Systematic Analysis for in Childhood 96 (12): 1140–46. the Global Burden of Disease Study 2013.” The Lancet 385: de Sousa, A., K. E. Tiedje, J. Recht, I. Bjelic, and D. H. Hamer. 117–71. Epub December 17. 2012. “Community Case Management of Childhood Gérardin, P., G. Barau, A. Michault, M. Bintner, H. Randrianaivo, Illnesses: Policy and Implementation in Countdown to and others. 2008. “Multidisciplinary Prospective Study of 2015 Countries.” Bulletin of the World Health Organization Mother-to-Child Chikungunya Virus Infections on the 90: 183–90. Island of La Réunion.” PLoS Medicine 5 (3): e60. Druetz, T., K. Siekmans, S. Goossens, V. Ridde, and S. Haddad. Gething, P. W., V. C. Kirui, V. A. Alegana, E. A. Okiro, 2013. “The Community Case Management of Pneumonia A. M. Noor, and R. W. Snow. 2010. “Estimating the Number in Africa: A Review of the Evidence.” Health Policy Planning of Paediatric Fevers Associated with Malaria Infection 30 (2): 253–66. Presenting to Africa’s Public Health Sector in 2007.” PLoS Duke, T., W. Francis, J. Merilyn, M. Sens, K. Magdalene, and Medicine 7 (7): e1000301. others. 2008. “Improved Oxygen Systems for Childhood Gill, C. J., G. Phiri-Mazala, N. G. Guerina, J. Kasimba, Pneumonia: A Multihospital Effectiveness Study in Papua C. Mulenga, and others. 2011. “Effect of Training Traditional New Guinea.” The Lancet 372 (9646): 1328–33. Birth Attendants on Neonatal Mortality (Lufwanyama Edmond, K. M., C. Kortsalioudaki, S. Scott, S. J. Schrag, Neonatal Survival Project): Randomised Controlled Study.” A. K. M. Zaidi, and others. 2012. “Group B Streptococcal British Medical Journal 342: d346. Disease in Infants Aged Younger Than 3 Months: Systematic Gouws, E., J. Bryce, J.-P. Habicht, J. Amaral, G. Pariyo, and Review and Meta-Analysis.” The Lancet 379 (9815): 547–56. others. 2004. “Improving Antimicrobial Use among Health Elmardi, K. A., E. M. Malik, T. Abdelgadir, S. H. Ali, Workers in First-Level Facilities: Results from the Multi- A. H. Elsyed, and others. 2009. “Feasibility and Country Evaluation of the Integrated Management of Acceptability of Home-Based Management of Malaria Childhood Illness Strategy.” Bulletin of the World Health Strategy Adapted to Sudan’s Conditions Using Organization 82 (7): 509–15. Artemisinin-Based Combination Therapy and Rapid Gove, S. 1997. “Integrated Management of Childhood Illness by Diagnostic Test.” Malaria Journal 8: 39. Outpatient Health Workers: Technical Basis and Overview. English, M., H. Reyburn, C. Goodman, and R. W. Snow. The WHO Working Group on Guidelines for Integrated 2009. “Abandoning Presumptive Antimalarial Treatment Management of the Sick Child.” Bulletin of the World Health for Febrile Children Aged Less Than Five Years—A Case Organization 75 (Suppl 1): 7–24. of Running before We Can Walk?” PLoS Medicine 6 (1): Greenhow, T. L., Y.-Y. Hung, A. M. Herz, E. Losada, and e1000015. R. H. Pantell. 2014. “The Changing Epidemiology of Factor, S. H., J. A. Schillinger, H. D. Kalter, S. Saha, H. Begum, Serious Bacterial Infections in Young Infants.” Pediatric and others. 2001. “Diagnosis and Management of Febrile Infectious Disease Journal 33 (6): 595–99. Children Using the WHO/UNICEF Guidelines for IMCI Guenther, T., S. Sadruddin, T. Chimuna, B. Sichamba, in Dhaka, Bangladesh.” Bulletin of the World Health K. Yeboah-Antwi, and others. 2012. “Beyond Distance: An Organization 79 (12): 1096–105. Approach to Measure Effective Access to Case Management Faucher, J., P. Makoutode, G. Abiou, T. Beheton, P. Houze, for Sick Children in Africa.” American Journal of Tropical and others. 2010. “Can Treatment of Malaria Be Restricted Medicine and Hygiene 87 (5 Suppl): 77–84. to Parasitologically Confirmed Malaria? A School-Based Hamer, D. H., E. Brooks, K. Semrau, P. Pilingana, W. MacLeod, Study in Benin in Children with and without Fever.” and others. 2012. “Quality and Safety of Integrated Malaria Journal 9: 104. Community Case Management of Malaria Using Rapid 158 Reproductive, Maternal, Newborn, and Child Health Diagnostic Tests and Pneumonia by Community Health Kelly, J. M., B. Osamba, R. M. Garg, J. M. Hamel, J. J. Lewis, and Workers.” Pathology in Global Health 106 (1): 32–39. others. 2001. “Community Health Worker Performance in Hamer, D. H., G. L. Darmstadt, J. B. Carlin, A. K. M. Zaidi, the Management of Multiple Childhood Illnesses: Siaya K. Yeboah-Antwi, and others. 2015. “Etiology of Bacteremia District, Kenya, 1997–2001.” American Journal of Public in Young Infants in Six Countries.” Pediatric Infectious Health 91 (10): 1617–24. Disease Journal 34 (1): e1–8. Kidane, G., and R. H. Morrow. 2000. “Teaching Mothers to Hamer, D. H., M. Ndhlovu, D. Zurovac, M. Fox, K. Yeboah- Provide Home Treatment of Malaria in Tigray, Ethiopia: Antwi, and others. 2007. “Does Improving Coverage of A Randomised Trial.” The Lancet 356 (9229): 550–55. Parasitological Diagnostic Tests Change Malaria Treatment Kumar, V., S. Mohanty, A. Kumar, R. P. Misra, M. Santosham, Practices? An Operational Cross-Sectional Study in and others. 2008. “Effect of Community-Based Behaviour Zambia.” Journal of American Medicine 297: 2227–31. Change Management on Neonatal Mortality in Shivgarh, Harvey, S. A., L. Jennings, M. Chinyama, F. Masaninga, Uttar Pradesh, India: A Cluster-Randomised Controlled K. Mulholland, and others. 2008. “Improving Community Trial.” The Lancet 372 (9644): 1151–62. Health Worker Use of Malaria Rapid Diagnostic Tests in Lanata, C. F., I. Rudan, C. Boschi-Pinto, L. Tomaskovic, Zambia: Package Instructions, Job Aid and Job Aid-Plus- T. Cherian, and others. 2004. “Methodological and Training.” Malaria Journal 7: 160. Quality Issues in Epidemiological Studies of Acute Lower Hazir, T., L. M. Fox, Y. B. Nisar, M. P. Fox, Y. P. Ashraf, Respiratory Infections in Children in Developing Countries.” and others. 2008. “Ambulatory Short-Course High-Dose International Journal of Epidemiology 33 (6): 1362–72. Oral Amoxicillin for Treatment of Severe Pneumonia in Lehmann, D., A. Michael, M. Omena, A. Clegg, T. Lupiwa, Children: A Randomised Equivalency Trial.” The Lancet and others. 1999. “Bacterial and Viral Etiology of Severe 371 (9606): 49–56. Infection in Children Less Than Three Months Old in Hertz, J. T., O. M. Munishi, J. P. Sharp, E. A. Reddy, and the Highlands of Papua New Guinea.” Pediatric Infectious J. A. Crump. 2013. “Comparing Actual and Perceived Causes Disease Journal 18 (10 Suppl): S42–49. of Fever among Community Members in a Low Malaria Leslie, T., A. Mikhail, I. Mayan, M. Anwar, S. Bakhtash, and Transmission Setting in Northern Tanzania.” Tropical others. 2012. “Overdiagnosis and Mistreatment of Malaria Medicine and International Health 18 (11): 1406–15. among Febrile Patients at Primary Healthcare Level in Holmes, K. K., S. Bertozzi, B. Bloom, P. Jha, and R. Nugent, Afghanistan: Observational Study.” British Medical Journal editors. Forthcoming. Disease Control Priorities (third edi- 345: e4389. tion): Volume 6, HIV/AIDS, STIs, Tuberculosis, and Malaria. Liu, L., K. Hill, S. Oza, D. Hogan, Y. Chu, and others. 2016. Washington, DC: World Bank. “Levels and Causes of Mortality under Age Five Years.” Horwood, C., S. Liebeschuetz, D. Blaauw, S. Cassol, and S. Qazi. In Disease Control Priorities (third edition): Volume 2, 2003. “Diagnosis of Paediatric HIV Infection in a Primary Reproductive, Maternal, Newborn, and Child Health, edited Health Care Setting with a Clinical Algorithm.” Bulletin of by R. Black, R. Laxminarayan, M. Temmerman, and the World Health Organization 81 (12): 858–66. N. Walker. Washington, DC: World Bank. Horwood, C., K. Vermaak, N. Rollins, L. Haskins, P. Nkosi, Liu, L., H. L. Johnson, S. Cousens, J. Perin, S. Scott, and others. and others. 2009. “Paediatric HIV Management at Primary 2012. “Global, Regional, and National Causes of Child Care Level: An Evaluation of the Integrated Management Mortality: An Updated Systematic Analysis for 2010 with of Childhood Illness (IMCI) Guidelines for HIV.” BioMed Time Trends since 2000.” The Lancet 379 (9832): 2151–61. Central Pediatrics 9: 59. Liu, L., S. Oza, D. Hogan, J. Perin, I. Rudan, and others. Huicho, L., R. W. Scherpbier, A. M. Nkowane, and C. G. Victora. 2015. “Global, Regional, and National Causes of Child 2008. “How Much Does Quality of Child Care Vary between Mortality in 2000–13, with Projections to Inform Post-2015 Health Workers with Differing Durations of Training? Priorities: An Updated Systematic Analysis.” The Lancet 385 An Observational Multicountry Study.” The Lancet 372 (9966): 430–40. (9642): 910–16. Lozano, R., M. Naghavi, K. Foreman, S. Lim, K. Shibuya, and Ishengoma, D. S., F. Francis, B. P. Mmbando, J. P. A. Lusingu, others. 2012. “Global and Regional Mortality from 235 P. Magistrado, and others. 2011. “Accuracy of Malaria Rapid Causes of Death for 20 Age Groups in 1990 and 2010: Diagnostic Tests in Community Studies and their Impact A Systematic Analysis for the Global Burden of Disease on Treatment of Malaria in an Area with Declining Malaria Study 2010.” The Lancet 380 (9859): 2095–128. Burden in North-Eastern Tanzania.” Malaria Journal 10: 176. Lukianova-Hleb, E. Y., K. M. Campbell, P. E. Constantinou, Kalyango, J., E. Rutebemberwa, and T. Alfven. 2012. J. Braam, J. S. Olson, and others. 2014. “Hemozoin- “Performance of Community Health Workers under Generated Vapor Nanobubbles for Transdermal Reagent- Integrated Community Case Management of Childhood and Needle-Free Detection of Malaria.” Proceedings of Illnesses in Eastern Uganda.” Malaria Journal 11: 282. the National Academy of Sciences of the United States Kasper, M. R., P. J. Blair, S. Touch, B. Sokhal, C. Y. Yasuda, and 111 (9859): 900–95. others. 2012. “Infectious Etiologies of Acute Febrile Illness Mayxay, M., J. Castonguay-Vanier, V. Chansamouth, A. Dubot- among Patients Seeking Health Care in South-Central Pérès, D. H. Paris, and others. 2013. “Causes of Non- Cambodia.” American Journal of Tropical Medicine and Malarial Fever in Laos: A Prospective Study.” The Lancet Hygiene 86 (2): 246–53. Global Health 1 (3): e46–54. Diagnosis and Treatment of the Febrile Child 159 Mayxay, M., P. N. Newton, S. Yeung, T. Pongvongsa, Prinja, S., S. Mazumder, S. Taneja, P. Bahuguna, N. Bhandari, S. Phompida, and others. 2004. “Short Communication: and others. 2013. “Cost of Delivering Child Health Care An Assessment of the Use of Malaria Rapid Tests by Village through Community Level Health Workers: How Much Health Volunteers in Rural Laos.” Tropical Medicine and Extra Does IMNCI Program Cost?” Journal of Tropical International Health 9 (3): 325–29. Pediatrics 59 (6): 489–95. Mens, P. F., R. J. Matelon, B. Y. M. Nour, D. M. Newman, Rakha, M. A., A.-N. Abdelmoneim, S. Farhoud, S. Pieche, and H. D. Schallig. 2010. “Laboratory Evaluation on the S. Cousens, and others. 2013. “Does Implementation of Sensitivity and Specificity of a Novel and Rapid Detection the IMCI Strategy Have an Impact on Child Mortality? Method for Malaria Diagnosis Based on Magneto-Optical A Retrospective Analysis of Routine Data from Egypt.” Technology (MOT).” Malaria Journal 9: 207. British Medical Journal 3 (1): e001852. Msellem, M. I., A. Mårtensson, G. Rotllant, A. Bhattarai, Remington, J., J. O. Klein, C. B. Wilson, V. Nizet, and Y. Maldonado. J. Strömberg, and others. 2009. “Influence of Rapid Malaria 2006. Infectious Diseases of the Fetus and Newborn Infant, 6th Diagnostic Tests on Treatment and Health Outcome in edition. Philadelphia, PA: Elsevier Saunders. Fever Patients, Zanzibar: A Crossover Validation Study.” Reyburn, H., H. Mbakilwa, R. Mwangi, O. Mwerinde, R. Olomi, PLoS Medicine 6: e1000070. and others. 2007. “Rapid Diagnostic Tests Compared with Mubi, M., A. Janson, M. Warsame, A. Mårtensson, K. Källander, Malaria Microscopy for Guiding Outpatient Treatment and others. 2011. “Malaria Rapid Testing by Community of Febrile Illness in Tanzania: Randomised Trial.” British Health Workers Is Effective and Safe for Targeting Malaria Medical Journal 334 (7590): 403. Treatment: Randomised Cross-Over Trial in Tanzania.” Rowe, A. K., F. Onikpo, M. Lama, F. Cokou, and M. S. Deming. PLoS One 6: e19753. 2001. “Management of Childhood Illness at Health Facilities Muhe, L., M. Tilahun, S. Lulseged, S. Kebede, D. Enaro, and in Benin: Problems and Their Causes.” American Journal of others. 1999. “Etiology of Pneumonia, Sepsis and Meningitis Public Health 91 (10): 1625–35. in Infants Younger Than Three Months of Age in Ethiopia.” Sadruddin, S., S. Shehzad, A. Bari, A. Khan, Ibad-ul-Haque, Pediatric Infectious Disease Journal 18 (10 Suppl): S56–61. and others. 2012. “Household Costs for Treatment of Severe Mukanga, D., A. Tiono, and T. Anyorigiya. 2012. “Community Pneumonia in Pakistan.” American Journal of Tropical Case Management of Fever in Children Under Five Using Medicine and Hygiene 87 (5 Suppl): 137–43. Rapid Diagnostic Tests and Respiratory Rate Counting: A Samson, E. B., B. S. Goldschmidt, P. J. D. Whiteside, A. S. M. Multi-Country Cluster Randomized Trial.” American Journal Sudduth, J. R. Custer, and others. 2012. “Photoacoustic of Tropical Medicine and Hygiene 87 (5 Suppl): 21–29. Spectroscopy of β-Hematin.” Journal of Optics 14 (6): 065302. Mulholland, E. K., O. O. Ogunlesi, R. A. Adegbola, M. W. Weber, Seidenberg, P., D. H. Hamer, H. Iyer, P. Pilingana, K. Siazeele, A. Palmer, and others. 1999. “The Aetiology of Serious and others. 2012. “Impact of Integrated Community Infections in Young Gambian Infants.” Pediatric Infectious Case Management on Health-Seeking Behavior in Rural Disease Journal 18 (10 Suppl): S35–42. Zambia.” American Journal of Tropical Medicine and Hygiene Nair, H., E. A. F. Simões, I. Rudan, B. D. Gessner, E. Azziz- 87 (5 Suppl): 105–10. Baumgartner, and others. 2013. “Global and Regional Burden Shao, A., C. Rambaud-Althaus, S. Perri, N. Swai, J. Kahama- of Hospital Admissions for Severe Acute Lower Respiratory Maro, and others. 2011. “Safety of a New Algorithm for Infections in Young Children in 2010: A Systematic Analysis.” the Management of Childhood Illness (ALMANACH) The Lancet 381 (9875): 1380–90. to Improve Quality of Care and Rational Use of Drugs.” Nguyen, D. T. K., K. K. Leung, L. McIntyre, W. A. Ghali, In Abstracts of the 7th European Congress on Tropical and R. Sauve. 2013. “Does Integrated Management of Medicine and International Health, October 3–6, 2011, Childhood Illness (IMCI) Training Improve the Skills of Barcelona, Spain. Health Workers? A Systematic Review and Meta-Analysis.” Shao, A., C. Rambaud-Althaus, J. Samaka, A. F. Faustine, PLoS One 8 (6): e66030. S. Perri-Moore, and others. 2015. “Clinical Outcome and Njama-Meya, D., T. D. Clark, B. Nzarubara, S. Staedke, M. R. Antibiotic Prescription Rate Using a New Algorithm for Kamya, and others. 2007. “Treatment of Malaria Restricted the Management of Childhood Illnesses (ALMANACH) in to Laboratory-Confirmed Cases: A Prospective Cohort Tanzania.” PloS One 10 (7): e0132316. Study in Ugandan Children.” Malaria Journal 6: 7. Simmons, C., J. Farrar, N. van Vinh Chau, and B. Wills. Nonvignon, J., M. A. Chinbuah, M. Gyapong, M. Abbey, 2012. “Dengue.” New England Journal of Medicine E. Awini, and others. 2012. “Is Home Management of Fevers 15: 1423–32. a Cost-Effective Way of Reducing Under-Five Mortality in Sirima, S. B., A. Konaté, A. B. Tiono, N. Convelbo, S. Cousens, Africa? The Case of a Rural Ghanaian District.” Tropical and F. Pagnoni. 2003. “Early Treatment of Childhood Medicine and International Health 17 (8): 951–57. Fevers with Pre-Packaged Antimalarial Drugs in the Home Pagnoni, F. 2009. “Malaria Treatment: No Place Like Home.” Reduces Severe Malaria Morbidity in Burkina Faso.” Trends in Parasitology 25 (3): 115–19. Tropical Medicine and International Health 8 (2): 133–39. Pariyo, G. W., E. Gouws, J. Bryce, and G. Burnham. 2005. Soofi, S., S. Ahmed, M. P. Fox, W. B. MacLeod, D. M. Thea, “Improving Facility-Based Care for Sick Children in and others. 2012. “Effectiveness of Community Case Uganda: Training Is Not Enough.” Health Policy and Management of Severe Pneumonia with Oral Amoxicillin Planning 20 (Suppl 1): i58–68. in Children Aged 2–59 Months in Matiari District, Rural 160 Reproductive, Maternal, Newborn, and Child Health Pakistan: A Cluster-Randomised Controlled Trial.” The ———. 2014a. Integrated Management of Childhood Illnesses Lancet 379 (9817): 729–37. (IMCI) Chart Booklet. Geneva: WHO. Thaver, D., S. Ali, and A. Zaidi. 2009. “Antimicrobial Resistance ———. 2014b. Integrated Management of Childhood Illness among Neonatal Pathogens in Developing Countries.” Distance Learning Modules. Geneva: WHO. Pediatric Infectious Disease Journal 29 (1 Suppl): S19–21. ———. 2015. World Malaria Report: 2015. Geneva: WHO. Theodoratou, E., S. Al-Jilaihawi, F. Woodward, J. Ferguson, WHO-CHERG (Child Health Epidemiology Reference Group). A. Jhass, and others. 2010. “The Effect of Case Management 2011. “Global Health Observatory Data Depository.” on Childhood Pneumonia Mortality in Developing Geneva: WHO. Countries.” International Journal of Epidemiology WHO Division of Child Health and Development. 1997. 39 (Suppl. 1): i155–71. “Integrated Management of Childhood Illness: Thiboutot, M. M., S. Kannan, O. U. Kawalekar, D. J. Shedlock, Conclusions.” Bulletin of the World Health Organization 75 A. S. Khan, and others. 2010. “Chikungunya: A Potentially (Suppl 1): 119–28. Emerging Epidemic?” PLoS Neglected Tropical Diseases WHO and Special Programme for Research and Training in 4 (4): e623. Tropical Diseases. 2009. Dengue Guidelines for Diagnosis, Tulloch, J. 1999. “Integrated Approach to Child Health in Treatment, Prevention and Control: New Edition. Geneva: Developing Countries.” The Lancet 354 (Suppl 2): 16–20. WHO. UNICEF (United Nations Children’s Fund). 2012. Review of WHO, UNAIDS, and LSHTM (London School of Hygiene Systematic Challenges to the Scale-Up of Integrated Community and Tropical Medicine). 2001. Herpes Simplex Virus Case Management. Emerging Lessons & Recommendations Type 2: Programmatic and Research Priorities of Developing from the Catalytic Initiative (CI/IHSS). New York: UNICEF. Countries. Geneva: WHO, UNAIDS, and LSHTM. United Nations. 2013. The Millennium Development Goals WHO and UNICEF. 2009a. Global Action Plan for Prevention Report 2013. New York: United Nations. and Control of Pneumonia. Geneva: WHO and UNICEF. Waters, D., I. Jawad, A. Ahmad, I. Lukšic, H. Nair, and others. ———. 2009b. “Joint Statement: Home Visits for the Newborn 2011. “Aetiology of Community-Acquired Neonatal Sepsis Child: A Strategy to Improve Survival.” Geneva: WHO and in Low and Middle Income Countries.” Journal of Global UNICEF. Health 1 (2): 154–70. ———. 2012. “Integrated Community Case Management: An Weber, M., J. Carlin, S. Gatchalian, D. Lehmann, L. Muhe, and Equity-Focused Strategy to Improve Access to Essential others. 2003. “Predictors of Neonatal Sepsis in Developing Treatment Services for Children.” Joint Statement, WHO Countries.” Pediatric Infectious Disease Journal 22 (8): and UNICEF, Geneva and New York. 711–27. ———. 2013. Ending Preventable Child Deaths from Pneumonia WHO (World Health Organization). 2001. Integrated and Diarrhoea by 2025: The Integrated Global Action Plan Management of Child Health: Guide to Planning for for Pneumonia and Diarrhoea. Geneva: WHO. Implementation of IMCI at District Level. Cairo: World WHO Young Infants Study Group. 1999. “Clinical Prediction Health Organization, Regional Office for the Eastern of Serious Bacterial Infections in Young Infants in Mediterranean. Developing Countries.” Pediatric Infectious Disease Journal ———. 2006. Guidelines for the Treatment of Malaria. 1st edition. 18 (10 Suppl): S23–31. Geneva: WHO. Yasuoka, J., K. Poudel, K. Poudel-Tandukar, C. Nguon, P. Ly, ———. 2009. Integrated Management of Adolescent and Adult and others. 2010. “Assessing the Quality of Service of Village Illness: Interim Guidelines for First-Level Facility Health Malaria Workers to Strengthen Community-Based Malaria Workers at Health Centre and District Outpatient Clinic: Control in Cambodia.” Malaria Journal 9: 109. Acute Care. Geneva: WHO. Yeboah-Antwi, K., P. Pilingana, W. B. Macleod, K. Semrau, ———. 2010a. Guidelines for the Treatment of Malaria. 2nd K. Siazeele, and others. 2010. “Community Case Management edition. Geneva: WHO. of Fever Due to Malaria and Pneumonia in Children Under ———. 2010b. IMCI Pre-Service Education: Guide to Five in Zambia: A Cluster Randomized Controlled Trial.” Evaluation. Geneva: WHO. PLoS Medicine 7 (9): e1000340. ———. 2012a. Recommendations for Management of Common YICSSG (Young Infants Clinical Signs Study Group). 2008. Childhood Conditions. Geneva: WHO. “Clinical Signs That Predict Severe Illness in Children ———. 2012b. Malaria Rapid Diagnostic Test Performance: Under Age 2 Months: A Multicentre Study.” The Lancet Results of WHO Product Testing of Malaria RDTs—Rounds 371 (9607): 135–42. 1–4. Geneva: WHO. Young, M., and C. Wolfheim. 2012. “World Health ———. 2013a. WHO Informal Consultation on Fever Organization/United Nations Children’s Fund Joint Management in Peripheral Health Care Settings: A Global Statement on Integrated Community Case Management: Review of Evidence and Practice. Geneva: WHO. An Equity-Focused Strategy to Improve.” American Journal ———. 2013b. World Malaria Report 2013. Geneva: WHO. of Tropical Medicine and Hygiene 87 (5 Suppl): 6–10. Diagnosis and Treatment of the Febrile Child 161 Chapter 9 Diarrheal Diseases Gerald T. Keusch, Christa Fischer Walker, Jai K. Das, Susan Horton, and Demissie Habte INTRODUCTION drinking water; sanitation; level of education, particularly of mothers; income; food security; nutrition; and access to The annual number of deaths from diarrheal diseases health care, both preventive and therapeutic. Continued among the 0–4 year age group in low- and middle-income progress depends on recognition that intersectoral inter- countries (LMICs) has dropped by 89 percent, from 4.6 ventions are integral to required measures to reduce or million in 1980 to 526,000 in 2015 (Liu, Hill and others eliminate diarrheal diseases as a public health concern. 2016). This striking improvement occurred without vac- This chapter explores the still-limited evidence on cines against the major pathogens, except for rotavirus, subclinical infections due to known microbial causes of which is now being scaled-up in LMICs. The incidence diarrhea, and impacts on intestinal physiology, nutrient of diarrhea has not significantly diminished, especially absorption, and nutritional status as plausible mecha- in young infants (Fischer Walker and others 2012). nisms underlying growth stunting and developmental Therefore, success in reducing mortality appears to be delays. The potential interventions for clinical and sub- driven largely by improved management rather than clinical intestinal infections are not necessarily identical, prevention (box 9.1). Each day, 4.7 million episodes of although they undoubtedly overlap. Accordingly, we diarrheal disease occur, including 100,000 cases of severe consider epidemiology, transmission, and mechanisms diarrhea, along with nearly 1,600 deaths, approximately of disease, as well as social and cultural factors instru- 9 percent of the mortality in children under age five years mental in determining outcomes. Nutritional needs of (chapter 4 in this volume, Liu, Oza, and others 2016). infants and young children, breastfeeding practices, use Increasing awareness of the adverse effects of nonfatal of complementary foods, and management of nutri- episodes of diarrhea on infant and childhood growth tional rehabilitation of acute malnutrition are covered in and development, particularly the role of repeated illness greater depth in Das and others (2016, chapter 12 of this and the potential impact of frequent subclinical infec- volume). tions with the same pathogens, presents a new challenge. Interventions will depend on enhanced understanding of causal pathways, pathogenesis, and sequelae of these DIARRHEAL DISEASES infections, with or without symptomatic diarrhea. Diarrheal diseases are good indicators of the stage of Definitions and Classification development of communities in LMICs because of the Diarrheal diseases are most prevalent in and cause greater impact of proximal and distal determinants of diarrheal morbidity and mortality in children younger than age five morbidity and mortality, including the availability of safe years in low-income countries (LICs). The term covers a Corresponding author: Gerald T. Keusch, Boston University School of Medicine, Boston, Massachusetts, United States, keusch@bu.edu. 163 Figure 9.1 Regional Burden of Diarrhea, Ages 0–4 Years, 2010 Box 9.1 Major Interventions in Diarrheal Disease • Early use of oral rehydration solutions Western Pacific • Appropriate use of antibiotics for bloody 256.3 Africa diarrhea and dysentery 437.6 • Continued breastfeeding • Nutritional interventions for persistent diarrhea • Rapid restoration of nutritional status in all South-East Asia 427.4 diarrhea patients The Americas 248.1 Europe Eastern multitude of infectious causes, ranging from viruses and Mediterranean 154.3 bacteria to protozoa and occasionally worms, each with 208.8 distinctive effects. There are three discernable epidemi- ological and clinical presentations with vastly different consequences for the individuals affected: Source: Fischer Walker and others 2013. • Acute dehydrating watery diarrhea disease severity, although few studies separately analyze • Acute inflammatory (bloody) diarrhea and dysentery severe episodes or identify bloody diarrhea or dysentery • Persistent diarrhea lasting 14 days or more. or episodes that become persistent. One systematic review of the limited data available suggests that 5 percent to Burden of Infection 15 percent of watery diarrhea cases progress to persistent diarrhea (Lamberti, Fischer Walker, and Black 2012). Children younger than age five years in LMICs in South More than 50 percent of severe episodes occur in Sub- Asia and Sub-Saharan Africa experience an average of Saharan Africa and South-East Asia (figure 9.2). 2.7 (uncertainty range: 2.1–3.2) episodes of diarrhea per year (Fischer Walker and others 2012). Most are mild and self-limited, lasting an average of 4.3 days. From Mortality 0.5 percent to 2 percent are severe, and last an average The 2015 estimated number of deaths due to of 8.4 days (Lamberti, Fischer Walker, and Black 2012). diarrhea—526,000 under age five years—represents an Incidence rates vary but are higher in children in LICs 89 percent decline from 1980 and a striking 58 percent and lower-middle-income countries, and highest in Sub- reduction from 2000 to 2015 (Liu, Oza, and others Saharan Africa (3.3 episodes per child per year) (Fischer 2016, chapter 4 in this volume), even though the total Walker and others 2013) (figure 9.1). population in this age group increased by approximately 11 percent (figure 9.3). Because 72 percent of diarrhea deaths occur in the first two years of life, targeting this Incidence age group will yield the greatest future impact on mor- Despite targeted investments, estimated global diarrhea tality (Fischer Walker and others 2013). A thorough incidence rates have not changed significantly since 1980 discussion of the cause-of-death structure and mortal- (Bern and others 1992; Fischer Walker and others 2013; ity decline is presented in Liu, Hill, and others (2016, Kosek, Bern, and Guerrant 2003; Snyder and Merson chapter 4 in this volume); Sub-Saharan Africa and South 1982). Incidence consistently varies by age, peaking Asia account for 90 percent of the total. between 6 and 11 months, as immunity transferred from the mother in utero and via breastfeeding wanes; poten- tially contaminated complementary foods are intro- Etiologies duced; and infant mobility increases, allowing for greater Although many agents cause diarrheal disease, a few contact with sources of pathogens (Fischer Walker and account for a major portion of the burden. In one others 2012). The consequences are also determined by study, almost 40 percent of cause-specific attributable 164 Reproductive, Maternal, Newborn, and Child Health Figure 9.2 Regional Burden of Severe Diarrhea Episodes, to severe illness identified four pathogens—rotavirus, Ages 0–4 Years, 2010 Cryptosporidium, enterotoxigenic E. coli, and Shigella— responsible for most attributable episodes of moderate to severe diarrhea (Kotloff and others 2013). Rotavirus was the leading cause during the first year of life, followed by Cryptosporidium. Rotavirus remained Western Pacific first in the age 12–23 month cohort, followed by Shigella; 5.5 Africa among children ages 24–59 months, that ranking 9.6 reversed. The odds of dying for children with moderate to severe diarrhea were 8.5 times higher (95 percent con- fidence interval 5.8–12.5, p < 0.0001) than for control subjects, with 33 percent of deaths occurring 21 days to South-East Asia 90 days following enrollment in the study. Most deaths 9.3 The Americas were in infants (56 percent) and toddlers (32 percent); 4.8 55 percent of the deaths occurred at home or outside a medical facility. Certain pathogens, such as rotavi- Eastern rus, Shigella, Vibrio cholerae, and adenovirus sero- Europe Mediterranean 2.5 4.3 types 40/41, were more commonly isolated in children with moderate to severe illness. Almost three-quarters (72 percent) of controls without diarrhea also harbored one or more putative pathogens, and 31 percent had two Source: Fischer Walker and others 2013. or more, reflecting the fecally contaminated environment in which they live (Kotloff and others 2013). Future stud- ies that include diagnostic capacity for noroviruses and Figure 9.3 Regional Burden of Diarrhea Mortality, Ages 0–4 other emerging pathogens may change these rankings. Years, 2015 East Asia and Pacific 15,553 Transmission and Epidemiology Understanding transmission routes and epidemiology is critical for effective prevention and mitigation. Although transmission is fundamentally the same for all agents (fecal-oral transmission), there are diverse pathways and South Asia routes involved, including direct person-to-person trans- 138,715 mission mediated through feces-contaminated fingers or inanimate objects (fomites); and indirect transmission Sub-Saharan Africa via contaminated food or water in or outside the home, 278,141 including agricultural fields or seafood sources irrigated Europe Eastern or contaminated with pathogen-laden sewage. Microbial 4,399 Mediterranean characteristics determine the number of organisms 80,759 required to cause illness (the inoculum size); small inoc- ulum pathogens are readily transmitted directly from person to person, whereas high inoculum pathogens first need to multiply in food or water. Host characteristics, Latin America and the Caribbean such as immunity, often interplay with microbial charac- 8,740 teristics. Pathogens also must survive diverse nonspecific Source: Liu, Hill, and others 2016. host defenses, such as stomach acid. Some pathogens, for example, Shigella, are inherently acid resistant, so small inocula survive into the duodenum; others, like diarrhea mortality was due to two organisms: rotavi- V. cholerae, are acid sensitive, and large inocula are rus (27.8 percent) and enteropathogenic Escherichia essential to survive passage through the stomach. coli (11.1 percent) (Lanata and others 2013). Another Reduced gastric acidity significantly reduces the large, multisite, clinic-based prospective case-control required inoculum size for acid-sensitive pathogens, for study of children under age five years with moderate example, in individuals with peptic ulcer disease treated Diarrheal Diseases 165 by gastric surgery or drugs to reduce acid secretion. potentially life-threatening when in excess of 10 percent. Infants, including preterm, produce acid, but the amounts With increasing fluid losses, intravascular volume dimin- and response to stimuli are diminished compared with ishes and blood pressure drops. Without replacement of older children, potentially increasing their susceptibility. fluids (rehydration), hypotension can progress to circu- Malnutrition (Gilman and others 1988) and Helicobacter latory failure, dysfunction of critical organs, and death. pylori infection of the stomach (Windle, Kelleher, and Early initiation of rehydration, for example, using oral Crabtree 2007) also impair gastric acid production in rehydration solutions (ORS), can mitigate or prevent pro- young children. Sustained early infection with H. pylori gression to more severe dehydration. Such interventions in Gambian infants under age one year was associated are not only life saving; they can also reduce duration of with subsequent growth faltering, even though they had illness and extent of nutrient losses. access to good primary health care, treatment of acute childhood illness, and nutritional supplements (Thomas Inflammatory Diarrhea and Dysentery and others 2004). Some pathogens cause inflammation of the bowel wall, Other factors include lack of refrigeration for food, or with leukocyte (white blood cell) infiltration and dam- flies that can transfer pathogens from feces in the envi- age resulting in mucosal ulcers; bleeding; leukocyte ronment to unprotected food or water in households exudates; production of peptide cytokines that mediate (Farag and others 2013; Lindsay and others 2012). A risk dramatic, often prolonged, changes in appetite and factor study for Shigella infection in Thailand identified metabolism; and direct nutrient losses. Bacterial patho- poor breastfeeding practices; poor water supply; unsafe gens causing inflammatory diarrhea and dysentery sanitation; lack of fly control; and inadequate personal (a clinical syndrome of frequent small-volume bloody hygiene, in particular handwashing, as major targets for mucoid stools, abdominal cramps, and tenesmus [the interventions (Chompook and others 2006). Multiple urgency to pass stool]) generally require antibiotics routes of transmission exist; hence any single interven- to treat the infection, resolve inflammation, allow the tion may have limited impact. mucosa to heal, and reverse nutritional deterioration. Early effective antibiotic treatment shortens duration of these illnesses, limits acute complications, and reduces Natural History longer-term impacts. Exposure to pathogens does not necessarily lead to infec- tion, and infection does not necessarily result in clinical Persistent Diarrhea illness. Several factors explain the differences: Diarrhea episodes lasting from 7 days to 13 days, termed prolonged, impair growth and increase the risk • The inoculum size and the biology of the pathogen, of progression to persistent diarrhea (Moore and others in particular, its virulence attributes 2010). Moore and others (2010) find that prolonged • The susceptibility of the host, including previous diarrhea accounted for only 11.7 percent of episodes exposure and preexisting immunity, including pas- but 25.2 percent of all days of diarrhea; persistent diar- sively acquired immunity in utero or from breast milk rhea accounted for only 4.7 percent of episodes but consumption 24.5 percent of days with diarrhea. Progression from • The health and nutritional status of the individual at acute to prolonged diarrhea increased the overall risk of the time of exposure. persistent diarrhea from 4.8 percent to 29.0 percent (rel- ative risk 6.09, 95 percent confidence interval 4.96–7.45). As a result, natural history following infection can Once diarrhea is persistent, mortality rates increase vary from no symptoms, to mild-moderate self-limited sharply (Grimwood and Forbes 2009), in some settings illness, to severe life-threatening disease. Individuals who accounting for as much as 50 percent of overall diar- are healthier and better nourished at exposure are less rhea mortality. Continuing reductions in acute diarrhea likely to develop severe illness after a given inoculum of deaths has increased attention to mortality associated a specific pathogen. Early and appropriate management with persistent diarrhea, which is relatively heightened of clinical manifestations improves outcomes and can be as a consequence. effectively promoted at the community level. A few pathogens have been particularly associated with persistence or are preferentially identified when Watery Diarrhea an episode becomes persistent, including a subgroup of Watery diarrhea is classified according to stool volume: diarrhea-causing E. coli designated enteroaggregative, mild when less than 5 percent of body weight, moder- Cryptosporidium parvum, S. flexneri, S. dysenteriae type 1, ate between 5 percent and 10 percent, and severe and and Giardia intestinalis (lamblia). Serial exposure to these 166 Reproductive, Maternal, Newborn, and Child Health or other pathogens may also be involved. As the duration in Peruvian infants are also associated with slower of illness extends, malnutrition becomes increasingly weight gain compared with uninfected infants, albeit to prominent because of ongoing mucosal injury, anorexia, a lesser extent than infants with symptomatic infections malabsorption, and nutrient losses (Newman and others (Checkley and others 1997). However, because asymp- 2000). Shigella infection, characterized by intense tis- tomatic infections were twice as common as diarrhea, sue catabolism and nutrient losses, almost doubles the their ultimate effects might exceed those of clinical diar- risk of persistent diarrhea (Ahmed and others 2001). rhea. Moreover, infants infected with Cryptosporidium As the frequency of Shigella infection dropped from during the first six months of life remained stunted at age 1991 to 2010 in Bangladesh, the frequency of persistent one year, despite some interval catch-up growth (Bushen diarrhea diminished as well (Das and others 2012). and others 2007; Checkley and others 1998). Early coloni- Mucosal injury also explains why the manifestations of zation with H. pylori has also been identified as a precur- persistent diarrhea are primarily those of malabsorption sor of growth faltering in children under age five years in and malnutrition, and why careful dietary and nutri- The Gambia (Thomas and others 2004). tional management is needed until mucosal damage is reversed and new, normally functioning epithelial cells are regenerated. Environmental Enteric Dysfunction Intestinal biopsy studies of the upper small intestine from asymptomatic adults in tropical countries reported NEW FRONTIERS: SUBCLINICAL INFECTIONS 30 years to 40 years ago documented structural differ- AND ENVIRONMENTAL ENTERIC ences compared with healthy adults from temperate DYSFUNCTION countries, including shorter blunted villi, which reduced the surface area covered by epithelial cells, and increased Subclinical Infections inflammatory cells, accompanied by diminished abil- Mounting and diverse evidence suggests that subclinical ity to absorb test sugars, fat, or vitamin B12 (Baker infections with diarrhea pathogens can cause physiologi- 1976). Limited biopsies from infants and young children cal and structural alterations of the gut with adverse con- revealed normal, slender finger-like villi at birth, but sequences on child nutrition and growth. For example, a jejunum of older infants and children resembled the handwashing intervention not only reduced the number adult gut, suggesting these changes were acquired after of diarrhea episodes by 31 percent (4.3 versus 3.0 epi- birth (Baker 1976). Similar changes occurred over one sodes, p < 0.05) and days of diarrhea by 41 percent (9.67 to two years in healthy young adult expatriates living versus 16.33, p = 0.023) (Langford, Lunn, and Panter- in Bangladesh (Lindenbaum, Kent, and Sprinz 1966) Brick 2011) but also showed that, independent of clinical and Thailand (Keusch, Plaut, and Troncale 1972), with diarrhea, infants with the highest values of a biomarker few or no symptoms other than soft stools and mild of mucosal damage (lactose-to-creatinine ratio) indica- weight loss. This constellation of findings was called tive of abnormal mucosal permeability had significantly tropical or subclinical enteropathy/jejunitis/malabsorp- lower height-for-age z-scores (p = 0.01), weight-for-age tion, and normalized after the subjects returned home z-scores (p < 0.001), and weight-for-height z-scores (Lindenbaum, Gerson, and Kent 1971). The same res- (p = 0.034) (Langford, Lunn, and Panter-Brick 2011). olution was observed in healthy South Asians living in This finding suggests that subclinical infections may the United States or the United Kingdom the longer reduce nutrient absorption and impair growth by many they resided outside their home countries (Gerson and of the same mechanisms present during clinical episodes. others 1971; Wood, Gearty, and Cooper 1991). However, Although the malabsorption may be limited, chronicity the significance of enteropathy remained unclear, and may be sufficient to produce overt malnutrition over interest waned because no relationship to pathogenesis time, especially when dietary nutrient intake is marginal. of tropical sprue, a real disease, was apparent. Subclinical infections with intestinal pathogens have In retrospect, the extent of the weight loss associated been shown to underlie growth faltering (Guerrant and with enteropathy in adults was dismissed too quickly; others 1999). Giardia intestinalis, which causes diarrhea the same decrement occurring in young infants would associated with growth retardation in infants (Newman raise concerns about incipient malnutrition. Recently, and others 2001), is often identified in the stools of investigators in Sub-Saharan Africa, using newer assess- asymptomatic children in endemic areas, and a cor- ments of intestinal permeability, identified alterations in relation between asymptomatic Giardia infection and young infants associated with altered gut histology and growth faltering has been reported (Prado and others poor growth in early childhood (Campbell, Lunn, and 2005). Asymptomatic first Cryptosporidium infections Elia 2002; Campbell and others 2004). Inflammatory Diarrheal Diseases 167 cells present in the intestinal mucosa were identified as or immune activation have been identified (Kosek immunoreactive T cells (Veitch and others 1991), linked and others 2013). A composite activity score of three to strong pro-inflammatory local cytokine responses stool biomarkers of intestinal inflammation (neopterin, (Campbell and others 2003). These findings have rekin- alpha1-antitrypsin, and myeloperoxidase) during peri- dled interest in their physiological significance, anal- ods without diarrhea is inversely correlated with linear ogous to inflammatory bowel disease. Although the growth. Children with the highest score grew 1.08 cen- mechanisms have remained uncertain, a nexus of micro- timeters less than children with the lowest score during bial exposure, mucosal pathology, increased permeabil- the subsequent six months, even controlling for the ity and malabsorption, immune activation leading to incidence of diarrheal disease. Similarly, fecal levels of poor response to mucosal vaccines, and growth stunt- REG1B protein, which plays a role in cell differentiation ing has been postulated (Prendergast and Kelly 2012). and proliferation in the intestinal tract and is reported Inadequacy of dietary intake, especially when diet qual- to be increased in other gut inflammatory conditions, ity is also marginal, would likely exacerbate the impact was predictive of linear growth in three-month-old of any level of malabsorption. birth cohorts in Bangladesh and Peru, independent of In parallel, growth stunting, a marker of chronic under- their length-for-age z-score at the time the sample was nutrition that is common among infants and children taken (Peterson and others 2013). If confirmed, such living in poverty in LMICs, is associated with increased assessments of intestinal health may become important childhood morbidity and mortality and poor longer-term biomarkers of EED and a predictor of growth (box 9.2). functional outcomes, including cognitive development; If EED leads to malnutrition, impaired immune reduced years of schooling; and diminished productivity function, and increased susceptibility to and severity of in adulthood, measured by income attained and other subsequent diarrheal episodes in early infancy, it may be a economic productivity markers (Dewey and Begum major force for stunting, particularly when recurrent epi- 2011). If changes in intestinal structure and function sodes restrict the capacity for catch-up growth (Salomon, develop in young infants in impoverished communities Mata, and Gordon 1968). The effects of diarrheal diseases early in life, presumably due to environmental exposure can be both short term and long term. In the short term, to still-unknown inciting factors, the consequence may patients experience adverse systemic impacts on appetite, be initial malabsorption leading to early malnutrition, metabolism, and nutrition due to the infection. In the growth faltering, and increased susceptibility to diarrheal longer term, mucosal changes can alter digestion, absorp- disease (Keusch and others 2013). This has been termed tion, and assimilation of nutrients from food. In bloody environmental enteric dysfunction (EED) to stress the diarrhea and dysentery, structural mucosal damage leads importance of the functional alterations. to protein-losing enteropathy as blood proteins leak Although systematic serial observations of intesti- into the gut lumen (Bennish, Salam, and Wahed 1993). nal structure in these young infants remains limited, a These effects can continue for weeks after shigellosis number of surrogate biomarkers of gut inflammation (Alam and others 1994; Raqib and others 1995), resulting Box 9.2 Biomarkers to Assess Environmental Enteric Dysfunction Category Potential biomarkers Intestinal absorption and mucosal D-Xylose, mannitol, or rhamnose absorption; lactulose paracel- permeability lular uptake; α1-antitrypsin leakage into gut lumen Enterocyte mass and function Plasma citrulline, conversion of alanyl-glutamine to citrul- border line, or both; lactose tolerance test (as a marker of microvillus damage) Inflammation Plasma cytokines, stool calprotectin, myeloperoxidase, or lactoferrin Microbial translocation and Stool neopterin; plasma lipopolysaccharide (LPS) core anti- immune activation body, LPS binding protein, or both; circulating soluble CD14 168 Reproductive, Maternal, Newborn, and Child Health in progressive malnutrition rather than convalescence and repair. As a consequence, mortality over the three months Box 9.3 following successful discharge from an expert treatment center in Bangladesh almost doubled (2.8 percent versus Interventions for Diarrheal Diseases 4.9 percent) in children with documented shigellosis compared with watery diarrhea without evidence of Category Options Shigella (Bennish and Wojtyniak 1991). Therapeutic Oral rehydration solutions The early effects of EED can lead to repeated infec- tion because of similar risk factors, including increased Antimicrobials for bloody exposure to enteric pathogens, limited and poor quality diarrhea or dysentery water, lack of sanitary facilities, poor household hygiene, Nutritional treatment of per- and poor diets. Understanding the pathogenesis of EED sistent diarrhea is a prerequisite to the selection of optimal interventions. Zinc supplementation Preventive Protected safe water INTERVENTIONS FOR DIARRHEAL DISEASES Handwashing Sanitary disposal of fecal waste Interventions for diarrheal diseases can be divided into therapeutic and preventive (box 9.3). Some interven- Vaccines tions, such as nutritional support and zinc supplemen- Improved nutrition: tation, can be beneficial for both purposes. Interventions vitamin A, zinc can also be classified by scale: individuals, households, or communities. Some depend on infrastructure; others are behavioral, determined by understanding and compli- ance at the level of the household, community, or health contradictory, of poor reliability, or difficult to interpret. care system. Although most interventions are not new, Similarly, the use of drugs to restore physiological func- innovations to make them more accessible or effective tions of the intestine is not considered because of limited can have adverse unintended consequences, such as reliable data in target human populations. increased and inappropriate use of antibiotics. Oral Rehydration Solutions ORS may prevent as many as 93 percent of diarrheal Therapeutic Interventions deaths (Munos, Fischer Walker, and Black 2010). The Treatment with therapeutic interventions focuses on therapy works because the co-absorption of glucose and reversing dehydration, providing antibiotics for inflam- sodium is preserved during watery diarrheas; hence, ORS matory bacterial diarrhea and dysentery, and special containing optimal concentrations of glucose and salt nutritional interventions to overcome malabsorption results in net uptake of sodium and chloride, effectively associated with persistent diarrhea, although general expanding the intravascular compartment regardless of dietary interventions to mitigate nutritional deteriora- age, and significantly reduces the need for intravenous tion during and after diarrhea are relevant to all diar- fluids for all but the most severely dehydrated patients rheal diseases. Two analyses of a package of interventions or those with intractable vomiting. New formulations individually shown to have an impact on mortality with lower concentrations of glucose and sodium reduce (ORS; zinc; antibiotics for dysentery; rotavirus vacci- the likelihood of hypernatremia during treatment of nation; vitamin A supplementation; improved access to noncholera dehydration, reduce total stool output and safe water, sanitation, and hygiene; and breastfeeding) vomiting, and reduce the need for supplementary intra- estimate a reduction in mortality of 54 percent to venous fluids (Hahn, Kim, and Garner 2002); the World 78 percent if implemented to a feasible level, and by Health Organization (WHO) now recommends such 92 percent to 95 percent if universally applied (Bhutta formulations (WHO and UNICEF 2004). and others 2013; Fischer Walker and others 2011). Further modifications have been proposed, for exam- Other strategies, including pre- and probiotics to ple, rice-based formulations or the addition of certain counter adverse changes in intestinal microecology, or amino acids (glycine, alanine, or glutamine) to further fecal transplants to reconstitute a healthy microbiota increase sodium absorption and hasten intestinal repair after illness or antibiotic treatment, are not discussed (Atia and Buchman 2009), or supplementation with zinc further because available efficacy data are limited, often to improve outcomes (Awasthi and IC-ZED Group 2006; Diarrheal Diseases 169 Lazzerini and Ronfani 2013). However, the primary goal and attitudes reduce inappropriate use (Clavenna and of ORS remains enhancing salt and water absorption. Bonati 2011). Although simple home-prepared ORS may be sufficient Despite repeated pleas for more evidence-based use in mild diarrhea, the WHO formulation is preferred for of antibiotics, better education of practitioners and the more severely dehydrated patients. public, and systematic surveillance of antibiotic use Cholera and cholera-like enterotoxigenic E. coli and resistance, more than 50 percent of all medicines infections raise additional issues because of prodigious are still inappropriately prescribed, dispensed, or sold, volume losses; vomiting; and comorbidities, such as and 50 percent of patients use them incorrectly (WHO pneumonia, that affect outcomes. When intravenous 2010). Examples abound. Government health centers in rehydration is required because of shock, switching The Gambia ordered antibiotics for 45 percent of young to maintenance ORS when clinical status improves children with simple diarrhea without dehydration (Risk is effective. Interest in antiemetic drugs, for example, and others 2013). In the Democratic Republic of Congo, ondansetron, is limited because safety and efficacy data more practitioners relied on pharmaceutical companies in poorly nourished children under age five years are for prescribing recommendations (73.9 percent) than not available, and because of the added cost (Ciccarelli, on professional guidelines (66.3 percent) or university Stolfi, and Caramia 2013). training (63.6 percent), and more practitioners used Unfortunately, use of ORS for clinic- and home-based the Internet for guidance (45.7 percent) than used treatment has stagnated in most countries reaching, on WHO publications (26.6 percent) (Thriemer and others average, 30 percent to 38 percent of the children who 2013). Although 85 percent of caregivers in a peri-urban should receive it (Santosham and others 2010; WHO slum in Lima, Peru, expressed confidence in decisions and UNICEF 2009). This absence of use is due in part made by physicians, even withholding antibiotics when to a lack of parental understanding of the benefit of advised, 65 percent of caregivers still believed antibiotics ORS, because stool volumes may remain high even as were necessary for acute diarrhea, and nearly 25 percent hydration improves. Parental expectations of treatment reporting leftover antibiotics at home said they would are also influenced by previous experience. For exam- use them for a future illness (Ecker and others 2013). ple, Brazilian physicians recommend intravenous fluids In Nigeria, 47 percent of young children with diarrhea for most children with moderate dehydration, which seen at a third-level hospital had already received anti- sends the wrong message to caregivers about profes- biotics without a clinician’s recommendation (Ekwochi sionals’ trust in the efficacy of ORS (Costa and Silva and others 2013). Caregivers in India and Kenya ranked 2011). Community-based initiatives, such as home visits antibiotics higher than ORS for diarrhea by more than by community health workers, and community-based two to one, partially explaining the low use of ORS delivery mechanisms have increased the use of ORS by and the high use of antibiotics (Zwisler, Simpson, and an average of 160 percent, with an 80 percent increase Moodley 2013). in the use of zinc-ORS, as well as a 75 percent reduc- tion in antibiotic use (Das, Lassi, and others 2013). Inappropriate use of antibiotics. Experts agree that anti- Limited information precludes rigorous assessment of biotics are usually unnecessary for acute watery diar- the impact of community case management on mortal- rhea; most episodes are mild and self-limited, and many ity, but trends suggest a decrease of 63 percent among are due to viruses, especially among young children children ages 0–4 years (95 percent confidence interval (Kotloff and others 2013). It is time to abandon rou- 7–85 percent) and 92 percent (95 percent confidence tine use of antibiotics to shorten duration of illness in interval 13–100 percent) among children age 0–1 year. moderate to severe dehydration. Although V. cholerae has remained sensitive to most antibiotics, the long- Antibiotics term tradeoff of antibiotic use is selection for drug The pervasive, indiscriminate overuse of antibiotics is resistance, which is now increasing among V. cholerae dangerous because it promotes emergence of drug resis- strains (Ghosh and Ramamurthy 2011) and is poten- tance. Overuse is fostered by multiple causes: caregiver tially transferable to other enteric pathogens as well expectations; lack of knowledge; prescriber behavior; (Kruse and others 1995). The emergence of resistance lack of etiology-specific point-of-care diagnostics; fail- in V. cholerae to quinolone (Kim and others 2010), the ure of regulation and its enforcement to control quality most useful antibiotic for grossly bloody diarrhea and of and access to medicines; and availability without dysentery, further raises the level of concern about rou- prescription in pharmacies, shops, and markets even tine inclusion of antibiotics for cholera. Routine use of when prescriptions are required (Adriaenssens and oth- quinolone may be appropriate in certain circumstances. ers 2011). Improved practitioner and parent knowledge These include treatment of the most severely purging 170 Reproductive, Maternal, Newborn, and Child Health cases (Harris and others 2012), during epidemics that Preventive Interventions overwhelm clinical capacity (Ernst and others 2011), or Preventive measures to reduce exposure to enteric patho- when elimination of viable V. cholerae in stool would gens involve improving the quality of water for drinking diminish the potential for spread within or between and cooking; the quantity of water available for personal countries (MacPherson and others 2009; Tatem, Rogers, and household hygiene; safe storage of food; hand- and Hay 2006). washing; and sanitary disposal of fecal waste, including treatment of sewage to inactivate microbial pathogens. Appropriate use of antibiotics. Morbidity and mortality Vaccines to improve immunity are presently limited due to inflammatory diarrheas, most often caused by to rotavirus, the only vaccine approved and increas- Shigella invading the intestinal mucosa, are not caused ingly available to prevent moderate to severe rotavirus by dehydration but rather by tissue damage. Large num- diarrhea. Improving health and immune function by bers of leukocytes are recruited to the invasion site, lead- improving nutritional status is another effective measure. ing to epithelial cell death and ulceration, with release of cytokine mediators of metabolism that result in nutri- tional deterioration. These metabolic responses persist Vaccines for weeks after acute infection, and drive continuing For public health, prevention is always preferable to malnutrition (Raqib and others 1995), a major reason treatment, but effective treatment is necessary when why post-shigellosis mortality remains high for months prevention fails. Immunization is among the more after bloody diarrhea or dysentery ceases. The clinical cost-effective public health tools when deployed at hallmarks of inflammatory diarrhea for which antibiot- scale (WHO, UNICEF, and World Bank 2009). The ics are indicated include grossly bloody stools or dysen- complexity for diarrheal disease is that vaccines are tery, usually with accompanying fever. Most episodes are pathogen specific and often serotype or serogroup bacterial in etiology, and Shigella or sometimes-related specific. For example, different formulations would be enteroinvasive E. coli serotypes are most common. necessary for V. cholerae O1 and O139; even if com- Without point-of-care diagnostics to identify spe- bined in the final product, a vaccine for each would cific causes, the pragmatic assumption is that bloody be required. Unfortunately, vaccines for diarrheal diarrhea is bacterial in origin and antibiotics appro- diseases have met with developmental challenges, in priate for shigellosis should be initiated. This regimen part because the basis of effective immunity is poorly will likely be adequate for other possible bacterial eti- understood, and because diarrheal disease is most ologies. However, resistance of Shigella species to some, problematic in LICs where resources to purchase or multiple, antibiotics is increasing (Bhattacharya and vaccines is limited, thereby reducing incentives for others 2011; Mota and others 2010), but the pattern is research and development. locale specific and dynamic (Das, Ahmed, and others 2013). Ongoing drug sensitivity surveillance is essen- Rotavirus. Two vaccines produced by Merck and tial to guide therapeutic decisions (O’Ryan, Prado, GlaxoSmithKline are widely used in high-income and Pickering 2005). Because such surveillance is not countries and many middle-income countries but are yet feasible in most LMICs, empiric treatment deci- only beginning to be introduced in LICs. Other rotavi- sions remain the norm. Ciprofloxacin, azithromycin, rus vaccines have been licensed in China or Vietnam for or pivmecillinam, where available, are reasonable initial local use only. A less expensive Indian-manufactured choices, reserving ceftriaxone for treatment failures, vaccine named ROTAVAC® (Bharat Biotech) has been defined as lack of clinical improvement within 48 hours prequalified by the WHO and is approved for use to 72 hours (Erdman, Buckner, and Hindler 2008; Traa in India. In efficacy trials, it reduced severe episodes and others 2010). by more than 56 percent in the first year of life, by ORS may be useful but insufficient, because dehy- nearly 49 percent in the second year of life, and over- dration is minor and, unlike inflammation, does not all by 55 percent (Bhandari and others 2014). It was drive severity or mortality. Mild shigellosis, typically also safe. The most important adverse event associated associated with S. sonnei infection, without grossly with rotavirus vaccines, intussusception, was assessed bloody stools is generally self-limited and can be treated through active surveillance. Eight events occurred in like other watery diarrheas with ORS alone, even if stool India between 112 days and 587 days after vaccination, microscopy reveals some red or white blood cells. The well beyond the known timing of vaccine-related intus- challenge is to increase adherence to current principles susception, and so were unlikely to be vaccine related. and guidelines to limit the use of antibiotics unless Continued monitoring subsequent to introduction is clinical criteria are met. necessary and is planned (Bhandari and others 2014). Diarrheal Diseases 171 Delayed introduction of rotavirus vaccines in LICs, In contrast to endemic cholera, the experience in where the vast majority of severe rotavirus infection and Haiti following the introduction of cholera in 2010 is most mortality occurs, is a consequence of several factors: enlightening. In the first two years, 604,634 cases—with 329,697 hospitalizations and 7,436 deaths—were reported • Price to the Ministry of Health (Barzilay and others 2013). With • Lower reported efficacy than in high-income international support to improve case management, the countries case fatality rate rapidly decreased; within three months • Uncertainty about the risk of complications, such as it was approximately 1 percent, a threshold indicator of intussusception effective case management for cholera (WHO 2012). • National policy failures to prioritize national child- Mass immunization was under consideration as hood vaccine programs. a way to prevent cholera from becoming endemic in Haiti. However, analyses concluded it should not be Gavi, the Vaccine Alliance has added rotavirus to deployed because of serious obstacles, including lim- its support program, and 19 of the 35 Gavi-eligible ited vaccine availability, complex logistics, operational countries now include rotavirus vaccine in their rou- challenges of a multidose regimen, and population tine immunization programs; this number is expected displacement and potential civil unrest (Kashmira and to increase to 30 during 2015 (Gavi Alliance 2014). others 2011). Cholera has indeed become endemic in ROTAVAC may ultimately be marketed outside of India Haiti and is the leading etiology of diarrhea in hospi- in LICs. Universal implementation of rotavirus vaccine talized patients (Steenland and others 2013). A subse- could prevent many episodes of severe diarrhea (Fischer quent vaccine demonstration trial in Haiti showed that Walker and Black 2011) and reduce the number of high coverage with two doses of vaccine was, in fact, diarrhea deaths under age five years by 70,000–85,000 feasible (Rouzier and others 2013). This paved the way per year, and reduce hospitalizations and associated for an ambitious immunization program, justified by costs by an average of 94 percent (Munos, Fischer the dreadful state of water and sanitation facilities in Walker, and Black 2010). The cost of hospital admis- the country. The potential of vaccines to mitigate the sion for rotavirus diarrhea in India may be as much as extent of epidemic cholera and improve the impact 5.8 percent of annual household income (Mendelsohn of effective case management for dehydration has led and others 2008), or about US$66 per hospitalization to a proposal for an oral cholera vaccine stockpile (Sowmyanarayanan and others 2012). that would be available for use in future emergency and humanitarian disaster settings (Waldor, Hotez, Cholera. The global burden of morbidity and mortality and Clemens 2010); this plan is being implemented of cholera is high; an estimated 2.8 million cases and through the WHO and the International Coordinating 91,000 deaths occur annually in endemic countries (Ali Group (WHO 2013). and others 2012). Incidence is highest in children under age five years, who may account for as much as 50 percent Other pathogens. Vaccines for other enteric pathogens of cholera mortality. It is notable that 67 percent of inpa- remain under research and development; no licensed tient cholera deaths in Bangladesh were actually associ- products are available, particularly for agents highly ated with pneumonia rather than dehydration (Ryan and associated with moderate to severe diarrhea, including others 2000), increasing to 80 percent in children under enterotoxigenic E. coli, Shigella, and Cryptosporidium. age one year. Identification and appropriate treatment of More recently, norovirus has been identified as a poten- these patients will reduce mortality. tial significant cause of global diarrhea morbidity and Inexpensive oral killed whole bacteria cholera vaccines mortality and a target for vaccine development (Patel developed in India and Vietnam are effective (Clemens and others 2008). Vaccines for these infections are a high 2011); the former is WHO prequalified. Production and priority, but it will be many years before licensed prod- use of these vaccines remains limited, even for domestic ucts become available for scale up in LICs. needs, although widespread introduction could reduce It has long been recognized that measles immuniza- incidence by as much as 52 percent (Das, Tripathi, tion also reduces incidence and mortality from diarrheal and others 2013). Modeling based on clinical trials in disease (Feachem and Koblinsky 1983), presumably Bangladesh suggests a herd immunity effect with as high because measles is immunosuppressive and exacer- as a 93 percent reduction in incidence if only 50 percent bates malnutrition. The current campaign for measles of the population is immunized (Longini and others elimination through universal immunization not only 2007). Reduced incidence would also reduce the use of addresses measles, but has additional beneficial effects antibiotics (Okeke 2009). on diarrheal disease mortality and morbidity. 172 Reproductive, Maternal, Newborn, and Child Health Nutrition may curtail the severity of diarrheal episodes (Haider General Nutritional Support and Bhutta 2009) and prevent future episodes because Nutritional support is both a therapeutic and a preventive it is vital for protein synthesis, cell growth and dif- intervention. Malnutrition is a consequence of and a risk ferentiation, and immune function, and promotes factor for diarrheal disease (Mondal and others 2012). intestinal transport of water and electrolytes (Castillo- Nutritional support during diarrhea and nutritional Duran and others 1987; Shankar and Prasad 1998). rehabilitation during convalescence reduce the severity A systematic review of 13 studies from LMICs of of associated nutritional deficits and improves resis- zinc supplementation in diarrhea finds a significant tance to and recovery from future diarrheal episodes. 46 percent (relative risk 0.64, 95 percent confidence Improving nutrition enhances the ability to respond interval 0.32–0.88) reduction in all-cause mortality to future exposure to diarrhea pathogens and miti- and 23 percent (relative risk 0.77, 95 percent confi- gates the severity of nutritional losses when diarrhea dence interval 0.69–0.85) reduction in diarrhea-related occurs. Dietary management of acute diarrhea with hospital admissions (Fischer Walker and Black 2010). locally available age-appropriate foods is effective for the No statistically significant impact on diarrhea-related majority of acute diarrhea episodes, even in the presence mortality and subsequent prevalence was found; how- of lactose malabsorption; commercial preparations or ever, it was not possible to completely separate the specialized diets are not necessary (Gaffey and others effect of zinc from that of ORS in large-scale effective- 2013). Recent studies of community management of ness trials, because introduction of zinc also increased severe or moderate acute malnutrition using commer- ORS use rates. Zinc supplementation for more than cial ready-to-use therapeutic foods (RUTFs), which are three months was associated with a 13 percent (relative energy dense, solid or semisolid, low-moisture-content risk 0.87, 95 percent confidence interval 0.81–0.94) preparations of peanut butter enriched with dried reduction in incidence of diarrhea in children under skimmed milk, sugar, vegetable oil, vitamins, and min- age five years in LMICs (Yakoob and others 2011). erals that can be eaten direct from the package, have had Efficacy has also been documented in children younger positive effects (Santini and others 2013). Such products than age six months (Mazumder and others 2010). can also be locally made and will facilitate community There have been no reports of severe adverse reactions management of malnutrition (Choudhury and others from any form of zinc supplementation used in the 2014; Schoonees and others 2013). Local production has treatment of diarrhea, and the WHO recommends certain benefits over imported commercially produced therapeutic zinc supplementation for children with RUTF, which are more costly, can exert adverse impacts acute diarrhea for 10 days to 14 days. on breastfeeding, may medicalize and commercialize Zinc supplementation may also be useful in the malnutrition treatment, and may be difficult to scale up treatment of persistent diarrhea. A randomized con- to meet global needs (Latham and others 2010). trolled trial in children ages 6–18 months showed that Exclusive breastfeeding is another fundamental nutri- persistent diarrhea led to depletion of zinc whereas tional support modality for very young infants, with oral zinc administration improved zinc status (Sachdev, many health impacts beyond improved nutrition and Mittal, and Yadav 1990). A pooled analysis of the effect reduced susceptibility to diarrheal disease and other of supplementary oral zinc in children under age five infections (Bhutta and others 2013; Dey and others years with persistent diarrhea reduced the probability 2013; Strand and others 2012). Alternating breastfeed- of continuing diarrhea by 24 percent (relative risk 0.76, ing and ORS during acute watery diarrhea in infants 95 percent confidence interval 0.63–0.91) and decreased combines the nutrient and resistance factors in breast the rate of treatment failure or death by 42 percent (rel- milk with the impact of ORS on dehydration, but faces ative risk 0.58, 95 percent confidence interval 0.37–0.90) common cultural biases against feeding during diarrhea (Bhutta and others 2000). (Chouraqui and Michard-Lenoir 2007; King and others Zinc also plays a vital role in normal growth and 2003). Strand and others (2012) conclude that breast- development of children, with or without diarrhea. feeding is the most important modifiable risk factor to Preventive zinc supplementation at a dose of 10 milli- reduce the frequency of prolonged diarrhea. grams per day for 24 weeks leads to a net gain of 0.19 (±0.08) centimeters in height in children under age five Zinc Supplementation years (Imdad and Bhutta 2011). Zinc sulfate is low cost, Zinc deficiency is associated with increased risk of diar- safe, and efficacious, and tablets can be crushed and fed rhea, adversely affects intestinal structure and function, to children or dispersed in breast milk, ORS, or water. and impairs immune function (Bhan and Bhandari Baby zinc sulfate tablets and formulations in syrup form 1998; Gebhard and others 1983). Zinc administration are also available. Diarrheal Diseases 173 Although many countries have changed diarrhea and the WHO estimated that the global cost of water and management policies by adding zinc to ORS, a gap sanitation projects to meet Millennium Development remains between policy change and effective program Goal (MDG) targets would be US$42 billion and US$142 implementation (Bhutta and others 2013). Bottlenecks billion in 2005 dollars through 2014 for water and san- include limited knowledge among care providers itation, respectively, exclusive of programmatic costs and parents, price, and availability. Scaling-up use of beyond the intervention delivery point (Hutton and zinc, including promotion and distribution through Bartram 2008). This investment equates to US$4 billion community programs, can increase use by 80 percent and US$14 billion per year for water and sanitation proj- (Das, Lassi, and others 2013). Free distribution, social ects, respectively, or US$8 and US$28 per capita, respec- marketing, education of caregivers, and provision of zinc tively. When maintenance, the cost of replacing existing through both government and private providers at the infrastructure and facilities, and the extension of coverage community level, and copackaging of zinc and ORS are to include future population growth are added, expen- additional strategies to increase coverage. ditures increase to US$360 billion for each intervention. Once built, however, water and sanitation infrastructure need to be maintained; this ongoing requirement leads to Water, Sanitation, and Hygiene substantial additional financial as well as human capacity Because diarrhea is ultimately transmitted from infected investments, without which infrastructure deteriorates stools, clean water and safe disposal of feces have major and the initial investment can be lost. Further economic impacts on diarrhea incidence. If, as suspected, EED analysis of WASH interventions is provided in Hutton is also a consequence of continuing ingestion of fecal and Chase (forthcoming). microorganisms, water and sanitation improvements Limited evidence suggests that combining develop- should also reduce EED as a cause of early malnutrition. ment and health interventions results in facilities that are Reductions in diarrhea risk of 17 percent and 36 percent better built and maintained, and used more effectively. have been shown for improved water quality and excreta Six years after completion of a project in Bolivia, the use disposal, respectively (Cairncross and others 2010). of facilities in intervention communities was 44 percent Demographic and Health Surveys between 1986 and higher than in control communities; from 66 percent 2007 also suggest that access to improved water reduces to 86 percent of intervention households continued to risk of diarrhea (odds ratio 0.91, 95 percent confidence practice four promoted maternal and child health behav- interval 0.88–0.94) and mild or severe stunting (odds iors compared with 14 percent to 30 percent of house- ratio 0.92, 95 percent confidence interval 0.89–0.94), holds in control communities (Eder and others 2012). while improved sanitation reduces diarrhea mortal- Unfortunately, current assessments indicate that the ity (odds ratio 0.77, 95 percent confidence interval 2015 MDG 7 for water and sanitation targets will not be 0.68–0.86), incidence (odds ratio 0.87, 95 percent confi- met in five of nine regions (WHO and UNICEF 2013). dence interval 0.85–0.90), and risk of mild to moderate stunting (odds ratio 0.73, 95 percent confidence interval 0.71–0.75) (Fink, Günther, and Hill 2011). Behavioral Interventions Water, sanitation, and hygiene interventions are col- Many actions or decisions by caregivers, health care lectively known as WASH. Somewhat surprisingly, a providers, and public health officials require behavior 2005 meta-analysis of WASH interventions failed to changes and the decision to act. If improved practices document greater effectiveness of combinations over became the norm, risk of diarrhea and morbidity and single interventions (Fewtrell and others 2005). Current mortality rates would diminish. Each of these behaviors assessments are not sufficiently robust to influence may be difficult to sustain, but each would have a major investment decisions in one strategy over another, impact. although all make sense and improve quality of life (Arnold and others 2013). Handwashing As infrastructure projects, water and sanitation The transfer of infectious agents via the hands directly improvements can be built at the community, neighbor- between individuals or indirectly through contamination hood, or individual household levels; may be more or less of inanimate objects (fomites), such as dishes, utensils, and technically complex; and may be more or less expensive. other objects (Abad and others 2001), is a common route Unfortunately, the majority of sanitation systems fail to for the transmission of low inoculum diarrhea pathogens treat sewage to render it safe; as a result, irrigation water or (as well as respiratory infections). Contaminated hands seafood sources may become contaminated (Hutton and readily inoculate food or water, allowing high inoculum Chase, forthcoming, volume 7). In 2008, the World Bank pathogens to multiply. Simple handwashing procedures 174 Reproductive, Maternal, Newborn, and Child Health significantly reduce transmission rates in health care or water disinfection groups. When reenrolled in a facilities (Bolon 2011); households (Bloomfield 2003); follow-up surveillance 18 months later, handwashing schools (Lee and Greig 2010); and even day care and pre- intervention households were still 1.5 times more likely school settings, which are notoriously difficult environ- to wash with soap and water (79 percent versus ments in which to enforce good hygiene (Churchill and 53 percent, p = 0.001) and 2.2 times (50 percent versus Pickering 1997). Handwashing has an additional benefit 23 percent, p = 0.002) more likely to rub their hands in also reducing transmission of respiratory infections together compared with controls (Bowen and others (Luby and others 2005). 2013). During weekly follow-up throughout the 14 Provision of soap to an urban squatter community months without active educational intervention there in Karachi, Pakistan, supported by weekly meetings with was no difference between the groups in the proportion trained health care workers from the same communities of person-days with diarrhea (1.59 percent versus to reinforce the behavior, reduced days with diarrhea by 1.88 percent, p = 0.66) or the amount of soap purchased. 39 percent (95 percent confidence interval −61 percent Three years later, however, the investigators reengaged to −16 percent) among infants compared with controls 461 original households (69 percent) and found the over one year (Luby and others 2004). Even severely mal- original intervention households were 3.4 times more nourished children (weight-for-age z-score < −3.0) had likely than controls to have soap available (97 percent 42 percent (95 percent confidence interval −69 percent versus 28 percent, p < 0.0001), more commonly reported to −16 percent) fewer days of diarrhea, compared with handwashing before cooking (relative risk 1.2, 95 percent equally malnourished children in the control group. confidence interval 1.0–1.4) and before meals (relative An additional benefit was a 50 percent reduction in the risk 1.7, 95 percent confidence interval 1.3–2.1), and incidence of pneumonia (95 percent confidence interval purchased more soap per person per month (0.91–1.1 −65 percent to −34 percent). bars versus 0.65 for controls, p < 0.0001). Handwashing with water alone is also worthwhile. In The critical question is not whether improving hand- Bangladesh, the risk of diarrhea diminished when care- washing practices is effective, but rather how to best givers washed both hands with water before preparing promote consistent behavior. The behavior requires food (odds ratio 0.67, 95 percent confidence interval availability of water and household handwashing stations 0.51–0.89); the effect was greater if one or both hands designed and located to facilitate rather than inhibit the were washed with soap (odds ratio 0.30, 95 percent con- practice (Hulland and others 2013). Educational support fidence interval 0.19–0.47) (Luby and others 2011). Risk from health care workers is useful, but how much is was also reduced when caregivers washed hands with feasible and affordable remains in question. Increasingly, soap after defecation, but not with water alone (odds integrated behavioral models will be needed to improve ratio 0.45, 95 percent confidence interval 0.26–0.77). the outcome of WASH interventions (Dreibelbis and Five key times for handwashing were identified: after others 2013). defecation, after handling children’s feces or cleaning the anus, before preparing food, before feeding children, and Health Care Seeking before eating. Direct observations identified more than To ensure optimal care of infants and children with 20 opportunities per day for handwashing, a frequency diarrheal disease, caregivers must recognize there is a considered impossible to achieve, especially when the problem, know what to do and do it, be alert to signs added cost of soap is considered. Handwashing after of clinical deterioration needing professional care, and contact with feces is poorly practiced globally (Freeman know how to access such care without delay. Knowledge and others 2014), and Luby and others (2011) recom- and experience are necessary but not sufficient; caregivers mended prioritizing handwashing before food prepara- must also have the authority to act promptly. Initiatives tion because it was the single most effective opportunity to scale up prompt decision making and action generally to reduce diarrhea risk. focus on technical details and acquisition of practical How feasible is it to embed handwashing in daily skills, but frequently overlook social and cultural dimen- behavior? A randomized intervention in Pakistan com- sions. These factors may influence whether a caregiver pared provision of soap for handwashing with a method recognizes that fluid losses are beyond normal limits, are to disinfect water or no intervention, including weekly becoming dangerous, and require professional interven- visits over nine months to encourage either practice tion (Larrea-Killinger and Muñoz 2013). (Luby and others 2006). The study documented a Higher levels of education promote quicker care- 55 percent reduction in diarrhea (95 percent confidence seeking action; however, cultural influences, for example, interval 17 percent to 80 percent) compared with con- gender discrimination, can delay action for female infants trol neighborhoods, but no difference between the soap (Malhotra and Upadhyay 2013). In rural Burkina Faso Diarrheal Diseases 175 caregivers failed to recognize mild diarrhea, especially toddlers must be handled safely as well. Because water among infants, and made intervention choices that were and sanitation improvements are often implemented not clinically based and recommended (Wilson and together, separating the influence of each, and under others 2012). Only 55 percent of caregivers sought care which circumstances, can be difficult. Community-Led outside of the household, and 22 percent of these were Total Sanitation (CLTS) is a participatory approach to with traditional healers or drug vendors, only 12 percent improving sanitation in communities, in which com- of whom recommended ORS. In rural Kenya, where munities mobilize to achieve total abandonment of open caregivers understood the significance of diarrhea and defecation and replace it with subsidized construction of dehydration, their primary concern was stopping the facilities, household by household. The goal is to gener- diarrhea, preferring antibiotics or antidiarrheals over ate social pressure on all members of a community to ORS (Blum and others 2011). Cost of treatment is the understand the health implications of open defecation, major pragmatic impediment to care seeking outside and convince the community to join together, without of the home (Nasrin and others 2013). Anthropological external resources except guidance and facilitation, to and ethnographic approaches may help improve edu- agree on and act to completely eliminate open defe- cational messaging and responses, but cost, travel and cation and build a community sanitary infrastructure access to facilities, and wait times are likely to be critical (Kar 2003). Its relevance is suggested by an analysis of determinants of behavior, and these require very differ- Demographic and Health Survey data indicating that ent inputs to address. open defecation explains almost twice as much (54 versus 29 percent) of the international variation in child Community-Based Interventions height compared with gross domestic product (Spears Limited access to health facilities with trained primary 2013). A 20 percent reduction in open defecation pre- care workers means that many children fail to receive dicted a 0.1 standard deviation increase in child height. simple but effective early interventions when diarrhea CLTS begins with a facilitator engaging a commu- develops. However, a systematic review (Das, Lassi, nity or village to promote understanding of the link and others 2013) concludes that community-based between open defecation and illness. Initial engagement interventions improve care seeking by 9 percent (rela- is followed by a survey and mapping of actual practices, tive risk 1.09, 95 percent confidence interval 1.06–1.11), often led by motivated school-age children. Finally, increase ORS use by 160 percent (relative risk 2.6, community deliberations lead to communal decisions 95 percent confidence interval 1.59–4.27), produce a to make the necessary changes. In the process, the 29-fold increase in use of zinc supplements (relative risk facilitator may “provoke people through… tactics that 29.8, 95 percent confidence interval 12.33–71.97), and trigger powerful emotions such as disgust, shame and reduce antibiotic use by 75 percent (relative risk 0.25, fear… [to] enable local people to confront an unpleasant 95 percent confidence interval 0.12–0.51). reality, and in doing this deliberately shocks, provokes, Because diarrheal disease risk not only depends on jokes and teases. Sparking these emotions and affects the behavior of individuals and households but also on is key to triggering CLTS” (Deak 2008, 11). Although the practices of neighbors and communities, a systems some have criticized the use of shame or social stigma approach to increase “attention to multiple transmis- to promote compliance (Bartram and others 2012), sion pathways, and highlight the need to widen the others have noted that shame, social pressure, and peer causal lens and pay more conceptual attention to socio- monitoring with government subsidies to build latrines economic status, gender, remoteness, and ecosystem markedly increases the adoption of improved sanitation changes” (Eisenberg and others 2012, 242) can improve (Pattanayak and others 2009). outcomes. However, measuring these effects will require Many tensions continue to surround the CLTS innovative study designs that reveal social patterns of movement because organizations, government interaction and the movement of pathogens through the ministries, and development funders may be committed environment. to different models of improving sanitation infrastruc- ture; yet many examples of success and the spread of Community-Led Total Sanitation CLTS exist. This juxtaposition of tensions and successes Interventions to improve the safe disposal of human indicates the need for careful analysis of the role of excreta can be difficult to implement and maintain, and CLTS and how and where to introduce it most effec- documenting a positive result is challenging, especially tively. A number of issues must be considered, such as in rural settings in LMICs (Clasen and others 2010). For how to promote learning by doing; careful training of full impact, children and adults must learn to consistently facilitators; cultural changes in institutional environ- use improved sanitation, and stools from infants and ments to a more participatory, responsive, transparent, 176 Reproductive, Maternal, Newborn, and Child Health and downward-accountability approach; and changing The following is a brief discussion of the from a top-down to a bottom-up development model cost-effectiveness of selected diarrhea interventions. that is sensitive to local context and the longer time Details are presented in table 10.1 (Feikin and others horizon required (Deak 2008). 2016, chapter 10 in this volume). Das and others (2016, chapters 10 and 12 in this volume), and Stenberg and others (2016, chapter 16 in this volume) provide relevant COST AND COST-EFFECTIVENESS OF information on vaccines and nutrition. The most cost-effective interventions currently avail- INTERVENTIONS able for diarrhea (as measured in 2012 U.S. dollars per Several cost-effective and low-cost interventions are disability adjusted life year [DALY] averted) are prophy- available to help prevent and treat diarrhea (table 9.1). lactic zinc supplementation (alone and as an adjunct Since the analysis of cost-effectiveness of interventions to ORS), ORS, rotavirus vaccine, and household-level for diarrhea in LMICs in the second edition of Disease water treatment (primarily in rural areas using chlori- Control Priorities in Developing Countries (Keusch and nation or solar disinfection) (see table 10.1). The sec- others 2006), the ranking of various modalities has ond most cost-effective group includes rural sanitation, changed because of new evidence on the benefits of piped water, and in selected countries, cholera vaccine. zinc as adjunct therapy for diarrhea (optimally in com- Nutrition interventions are the least cost-effective for bination with ORS), substantial decreases in the cost of diarrhea; however, they have other major benefits, and rotavirus vaccine, and additional research separating the cost-effectiveness of community management of severe cost-effectiveness of water supply from that of sanitation. acute malnutrition is addressed in Lenters, Wazny, and The large gains in measles immunization have stopped Bhutta (2016, chapter 11 in this volume). additional work on its cost-effectiveness for diarrhea Table 9.1 includes just one study of behavior change, because it has become standard care. Although it is self identified through a focused search in PubMed. Such evident that breastfeeding promotion reduces diarrhea, interventions tend to have very heterogeneous results; this practice has not been as high on the research and the one reviewed here (see table 10.1 for further details), policy agenda. a handwashing education intervention in Burkina Faso Table 9.1 Cost-Effectiveness and Unit Cost of Interventions for Diarrheal Diseases Cost-effectiveness Intervention Region (US$/DALY averted) Unit cost (US$) Oral rehydration solution (versus no ORS) AFR-E < 200 2.20/diarrhea episode Prophylactic zinc with ORS (versus ORS alone) AFR-E and SEA-D < 100 0.61/diarrhea episode Rotavirus vaccine (versus no vaccine) Low-income countries < 200 at 5/dose 5/dose for two doses (Gavi price); Gavi-eligible (less at 0.20/dose) countries pay 0.20/dose for two doses Clean water (at household: chlorination or AFR-E and SEA-D < 200 0.07/person/year SEA-D solar disinfection versus untreated water) 0.13/person/year AFR-E (in 2000 U.S. dollars) Improved rural water and sanitation (versus AFR-E and SEA-D < 2,000 28/household (well); 52/household (latrine) unimproved) Piped water and sewer connection (versus AFR-E < 2,000 136/household (water); 160/household (sewer) no connections) SEA-D < 3,000 Cholera vaccine (versus no vaccine) High-endemicity countries 2,000–10,000 1.33/person Behavior change Low-income countries Large variation Large variation RUTF added to standard rations (versus AFR-E > 10,000 considering only 527/child/year standard rations) benefits for diarrhea Source: See Horton and Levin 2016, chapter 17, on cost-effectiveness in this volume. Note: AFR-E = high-mortality Africa (WHO subregion); DALY = disability adjusted life year; Gavi, the Vaccine Alliance; ORS = oral rehydration solution; RUTF = ready-to-use therapeutic foods; SEA-D = high-mortality South-East Asia (WHO subregion). Costs and cost per DALY averted are higher in other regions. Interventions costing less than US$240 per DALY in 2012 would be very cost-effective even in the poorest low-income country; those costing less than US$720 would be cost-effective even in the poorest low-income country (Burundi’s per capita gross national income was US$240 in 2012) (World Bank 2014). All costs converted to 2012 U.S. dollars (except as noted otherwise). Diarrheal Diseases 177 (Borghi and others 2002), falls into the most cost-effective Most of the results in tables 9.1 and 10.1 describe group. Well-designed behavior change interventions to the cost-effectiveness of implementing a single increase use of clean water, latrines, ORS, prophylactic intervention. If interventions are combined, the incre- zinc, and vaccines could all be cost-effective. Neither mental cost-effectiveness of each additional intervention table 9.1 nor table 10.1 contains cost-effectiveness results can decline. Fischer Walker and others (2011) estimate the for drug treatment of dysentery because focused searches combined effect of 10 interventions designed to reduce in PubMed returned no relevant citations. Typically, diarrhea in 68 countries with high child mortality, using cost-effectiveness studies are performed when a drug is the Lives Saved Tool. Two scenarios were modeled: an new or is being tested for a new use, which is not the case ambitious strategy designed to reach MDG 4 goals (to here. Drug treatment for dysentery is known to be highly reduce child mortality) in a realizable way; and a universal effective if the pathogens are sensitive; the high case strategy designed to bring coverage of many interventions fatality rates for dysentery indicate that drug treatment to 90 percent or more of the target population, and water, is extremely likely to be cost-effective. sanitation, and handwashing interventions to 55 percent It is not sufficient for an intervention to be cost-effective or more. Both strategies were scaled up from current cov- to be adopted. Cost or affordability in relation to health erage to the target over five years. The ambitious strategy expenditures also matters. One major advance has been saved 3.8 million lives during a five-year period, at a cost of the addition of zinc as a complementary therapy to ORS; US$52.5 billion, or US$13,700 per death averted, approx- as an adjunct to an existing treatment, it appears to be imately US$432/DALY averted assuming one life saved particularly cost-effective and affordable. Robberstad in infancy or early childhood is about 32 DALYs averted. and others (2004) estimate that zinc tablets cost approx- The universal strategy saved 5 million lives at a cost of imately US$0.61 for a three-week course of treatment, in US$20,752 per death averted, or US$648 per DALY averted. addition to the US$2.20 in recurrent costs per course of Although these rates would be considered cost-effective or treatment with ORS, excluding personnel costs in deliv- very cost-effective for most countries, affordability is still an ering the intervention. obstacle. The main issue is the water and sanitation com- Introduction of rotavirus vaccine is progressing as ponents, which account for 84 percent of the cost of the a result of Gavi interventions, although the negotiated ambitious package and 87 percent of the universal strategy. price for the vaccine at US$5 per dose for the two-dose Extended cost-effectiveness analysis provides further course remains a substantial addition to current costs insight. Chapters 18 and 19 in this volume (Ashok, of the WHO’s Expanded Program on Immunization. Nandi, and Laxminarayan 2016; Verguet and others Gavi provides the vaccine at a highly subsidized price to 2016) present extended cost-effectiveness analyses of the eligible countries (US$0.40 for two doses); countries that introduction of rotavirus vaccine in India and water and graduate from eligibility are required to pay 20 percent sanitation improvements in Ethiopia. These interven- of the Gavi cost in the first year, increasing by US$1 per tions are pro-poor—the poor benefit disproportionately year until the full price of US$5 per dose is paid (Verguet from reduced child mortality and from out-of-pocket and others 2016, chapter 19 in this volume). Given that savings on treatment costs, because they bear a dispro- diarrhea rates and mortality rates are higher in LICs, the portionately higher burden of ill health from diarrhea. vaccine is particularly cost-effective in these countries. They have less access to clean water and improved san- Sanitation and, to a lesser extent, water supply inter- itation, and therefore their children have poorer nutri- ventions, are subject to affordability considerations. tional status and are at higher risk of mortality from Initial investment costs per household for standard diarrhea-related illness. urban requirements—water piped to the house and a sewer connection—are US$136 and US$160, respec- CONCLUSIONS tively. The lowest-cost clean water interventions in rural areas are still substantial at US$28 per household for The burden of diarrheal diseases in children under a dug well, US$31 per household for a borehole, and age five years in LMICs has been reduced dramatically. US$52 per household for a pit latrine (Haller, Hutton, These reductions are the result of focused attention and Bartram 2007). Household point-of-use disin- and resources applied, originally through vertical pro- fection of water (using chlorine or solar disinfection) grams and advocacy through the WHO and interna- costs pennies per capita per year in recurrent costs, but tional donor agencies, and more recently through more requires behavior change. Although improved water integrated programs for primary care and community- supply and sanitation are essential in the long term to based programming. Although there are no magic decrease diarrhea, intestinal parasites, and stunting, the bullets to control the incidence of diarrheal diseases, investment costs mean the transition is likely to be slow. the following are highly effective: improved nutrition 178 Reproductive, Maternal, Newborn, and Child Health of young children to increase their ability to respond REFERENCES to infection; water and sanitation improvements to Abad, F. X., C. Villena, S. Guix, S. Caballero, R. M. Pintó, reduce the number of microorganisms in the environ- and others. 2001. “Potential Role of Fomites in the ment; handwashing; and implementation of simple but Vehicular Transmission of Human Astroviruses.” Applied highly effective interventions, such as ORS, that have Environmental Microbiology 67 (9): 3904–07. enabled early treatment and mitigation of dehydration Adriaenssens, N., S. Coenen, A. Versporten, A. Muller, G. Minalu, due to watery diarrhea. and others. 2011. “European Surveillance of Antimicrobial When antibiotics are used appropriately for inflam- Consumption (ESAC): Outpatient Antibiotic Use in Europe matory diarrheas, survival is enhanced; however, tar- (1997–2009).” Journal of Antimicrobial Chemotherapy 66 geting only those individuals who truly need antibiotic (Suppl 6): vi3–12. doi:10.1093/jac/dkr453. treatment remains problematic. Most uses of antibiotics Ahmed, R., M. Ansaruzzaman, E. Haque, M. R. Rao, and are not only ineffective, for example, in the treatment of J. D. Clemens. 2001. “Epidemiology of Postshigellosis viral infections, but counterproductive, due to selective Persistent Diarrhea in Young Children.” Pediatric Infectious Diseases Journal 20 (5): 525–30. pressure for drug resistance. Indeed, many important Alam, A. N., S. A. Sarker, K. A. Wahed, M. Khatun, and diarrheal disease agents now exhibit serious resistance M. M. Rahaman. 1994. “Enteric Protein Loss and Intestinal to multiple medications. Improved understanding of Permeability Changes in Children during Acute Shigellosis the pathogenesis of persistent diarrhea has helped the and after Recovery: Effect of Zinc Supplementation.” Gut development of nutritional interventions to address 35 (12): 1707–11. the malabsorption and malnutrition that characterize Ali, M., A. L. Lopez, Y. A. You, Y. E. Kim, B. Sah, and others. persistent diarrhea and lead to serious morbidity and 2012. “The Global Burden of Cholera.” Bulletin of the World increased mortality. Health Organization 90: 209–18. This chapter reviews interventions and policy strat- Arnold, B. F., C. Null, S. P. Luby, L. Unicomb, C. P. Stewart, egies that are effective, can often be packaged together, and others. 2013. “Cluster-Randomised Controlled and can be delivered at the community level. Many of Trials of Individual and Combined Water, Sanitation, Hygiene and Nutritional Interventions in Rural these interventions have impacts far beyond diarrheal Bangladesh and Kenya: The WASH Benefits Study Design disease, and these additional rationales for implemen- and Rationale.” BMJ Open 3: e003476. doi:10.1136 tation enhance their cost-effectiveness. Some are both /bmjopen-2013-003476. effective and highly inexpensive, for example, the early Ashok, A., A. Nandi, and R. Laxminarayan. 2016. “The use of ORS, so there is no reason not to promote them. Benefits of a Universal Home-Based Neonatal Care Package Continued attention to delivering an appropriate pack- in Rural India: An Extended Cost-Effectiveness Analysis.” age of interventions, coupled with monitoring and In Disease Control Priorities (third edition): Volume 2, continuous quality improvement of health care delivery Reproductive, Maternal, Newborn, and Child Health, edited services, can be expected to continue to drive down by R. Black, R. Laxminarayan, M. Temmerman, and the mortality and sequelae of diarrheal diseases in the N. Walker. Washington, DC: World Bank. coming decade. In addition to the development of point- Atia, A. N., and A. L. Buchman. 2009. “Oral Rehydration Solutions in Non-Cholera Diarrhea: A Review.” American of-care diagnostics, medications, and vaccines, many Journal of Gastroenterology 104 (10): 2596–04. issues need continuing study, including better water and Awasthi, S., and IC-ZED (INCLEN Childnet Zinc Effectiveness safe sanitation methods, food and water safety behavior for Diarrhea) Group. 2006. “Zinc Supplementation in within households and along the food chain, and the Acute Diarrhea Is Acceptable, Does Not Interfere with Oral cause and role of EED and asymptomatic infection on Rehydration, and Reduces the Use of Other Medications: A intestinal function and nutrition. Randomized Trial in Five Countries.” Journal of Pediatric Gastroenterology and Nutrition 42 (3): 300–05. Baker, S. J. 1976. “Subclinical Intestinal Malabsorption in Developing Countries.” Bulletin of the World Health NOTE Organization 54 (5): 485–94. World Bank Income Classifications as of July 2014 are as fol- Bartram, J., K. Charles, B. Evans, L. O’Hanlon, and S. Pedley. lows, based on estimates of gross national income (GNI) per 2012. “Commentary on Community-Led Total Sanitation capita for 2013: and Human Rights: Should the Right to Community-Wide Health Be Won at the Cost of Individual Rights?” Journal of • Low-income countries (LICs) = US$1,045 or less Water and Health 10 (4): 499–503. • Middle-income countries (MICs) are subdivided: Barzilay, E. J., N. Schaad, R. Magloire, K. S. Mung, J. Boncy, a) lower-middle-income = US$1,046–US$4,125 and others. 2013. “Cholera Surveillance during the Haiti • b) upper-middle-income (UMICs) = US$4,126–US$12,745 Epidemic—The First 2 Years.” New England Journal of • High-income countries (HICs) = US$12,746 or more. Medicine 368: 599–609. Diarrheal Diseases 179 Bennish, M. L., M. A. Salam, and M. A. Wahed. 1993. “Enteric Transactions of the Royal Society of Tropical Medicine and Protein Loss during Shigellosis.” American Journal of Hygiene 101 (4): 378–84. Gastroenterology 88 (1): 53–57. Cairncross, S., C. Hunt, S. Boisson, K. Bostoen, V. Curtis, Bennish, M. L., and B. J. Wojtyniak. 1991. “Mortality Due to and others. 2010. “Water, Sanitation and Hygiene for Shigellosis: Community and Hospital Data.” Reviews of the Prevention of Diarrhoea.” International Journal of Infectious Diseases 13 (Suppl 4): S245–51. Epidemiology 39 (Suppl 1): i193–205. Bern, C., J. Martines, I. de Zoysa, and R. I. Glass. 1992. “The Campbell, D. I., P. G. Lunn, and M. Elia. 2002. “Age-Related Magnitude of the Global Problem of Diarrhoeal Disease: A Association of Small Intestinal Ucosal Enteropathy with Ten-Year Update.” Bulletin of the World Health Organization Nutritional Status in Rural Gambian Children.” British 70: 705–14. Journal of Nutrition 88 (5): 499–505. Bhan, M. K., and N. Bhandari. 1998. “The Role of Zinc and Campbell, D. I., G. McPhail, P. G. Lunn, M. Elia, and Vitamin A in Persistent Diarrhea among Infants and D. J. Jeffries. 2004. “Intestinal Inflammation Measured by Young Children.” Journal of Pediatric Gastroenterology and Fecal Neopterin in Gambian Children with Enteropathy: Nutrition 26 (4): 446–53. Association with Growth Failure, Giardia lamblia, and Bhandari, N., T. Rongsen-Chandola, A. Bavdekar, J. John, Intestinal Permeability.” Journal of Pediatric Gastroenterology K. Antony, and others. 2014. “Efficacy of a Monovalent and Nutrition 39 (2): 153–57. Human-Bovine (116E) Rotavirus Vaccine in Indian Campbell, D. I., S. H. Murch, M. Elia, P. B. Sullivan, Children in the Second Year of Life.” Vaccine 32 (Suppl 1): M. S. Sanyang, and others. 2003. “Chronic T Cell-Mediated A110–16. doi:10.1016/j.vaccine.2014.04.079. Enteropathy in Rural West African Children: Relationship Bhattacharya, D., S. A. Purushottaman, H. Bhattacharjee, with Nutritional Status and Small Bowel Function.” R. Thamizhmani, S. D. Sudharama, and others. 2011. Pediatric Research 54 (3): 306–11. “Rapid Emergence of Third-Generation Cephalosporin Castillo-Duran, C., G. Heresi, M. Fisberg, and R. Uauy. Resistance in Shigella sp. Isolated in Andaman and Nicobar 1987. “Controlled Trial of Zinc Supplementation dur- Islands, India.” Microbial Drug Resistance 17 (2): 329–32. ing Recovery from Malnutrition: Effects on Growth and Bhutta, Z. A., S. M. Bird, R. E. Black, K. H. Brown, J. M. Gardner, Immune Function.” American Journal of Clinical Nutrition and others. 2000. “Therapeutic Effects of Oral Zinc in 45 (3): 602–8. Acute and Persistent Diarrhea in Children in Developing Checkley, W., L. D. Epstein, R. H. Gilman, R. E. Black, Countries: Pooled Analysis of Randomized Controlled L. Cabrera, and others. 1998. “Effects of Cryptosporidium Trials.” American Journal of Clinical Nutrition 72 (6): parvum Infection in Peruvian Children: Growth Faltering 1516–22. and Subsequent Catch-Up Growth.” American Journal of Bhutta, Z. A., J. K. Das, N. Walker, A. Rizvi, H. Campbell, Epidemiology 148 (5): 497–506. and others. 2013. “Interventions to Address Deaths from Checkley, W., R. H. Gilman, L. D. Epstein, M. Suarez, J. F. Diaz, Childhood Pneumonia and Diarrhoea Equitably: What and others. 1997. “Asymptomatic and Symptomatic Works and at What Cost?” The Lancet 381 (9875): 1417–29. Cryptosporidiosis: Their Acute Effect on Weight Gain in Bloomfield, S. F. 2003. “Home Hygiene: A Risk Approach.” Peruvian Children.” American Journal of Epidemiology 145 International Journal of Hygiene and Environmental Health (2): 156–63. 206 (1): 1–8. Chompook, P., J. Todd, J. G. Wheeler, L. von Seidlein, Blum, L. S., P. A. Oria, C. K. Olson, R. F. Breiman, and J. Clemens, and others. 2006. “Risk Factors for Shigellosis P. K. Ram. 2011. “Examining the Use of Oral Rehydration in Thailand.” International Journal of Infectious Diseases Salts and Other Oral Rehydration Therapy for Childhood 10 (6): 425–33. Diarrhea in Kenya.” American Journal of Tropical Medicine Choudhury, N., T. Ahmed, M. I. Hossain, B. N. Mandal, M. and Hygiene 85 (6): 1126–33. Golam, and others. 2014. “Community-Based Management Bolon, M. 2011. “Hand Hygiene.” Infectious Disease Clinics of of Acute Malnutrition in Bangladesh: Feasibility and North America 25: 21–43. Constraints.” Food and Nutrition Bulletin 35 (2): 277–85. Borghi, J., L. Guinness, J. Ouedraogo, and V. Curtis. 2002. Chouraqui, J. P., and A. P. Michard-Lenoir. 2007. “Feeding “Is Hygiene Promotion Cost-Effective? A Case Study in Infants and Young Children with Acute Diarrhea.” Archives Burkina Faso.” Tropical Medicine and International Health of Pediatrics 14 (Suppl 3): S176–80. 7 (11): 960–69. Churchill, R. B., and L. K. Pickering. 1997. “Infection Control Bowen, A., M. Agboatwalla, T. Ayers, T. Tobery, M. Tariq, and Challenges in Child-Care Centers.” Infectious Disease Clinics others. 2013. “Sustained Improvements in Handwashing of North America 11 (2): 347–65. Indicators More Than 5 Years after a Cluster-Randomised, Ciccarelli, S., I. Stolfi, and G. Caramia. 2013. “Management Community-Based Trial of Handwashing Promotion in Strategies in the Treatment of Neonatal and Pediatric Karachi, Pakistan.” Tropical Medicine and International Gastroenteritis.” Infection and Drug Resistance 6: 133–61. Health 18 (3): 259–67. Clasen, T. F., K. Bostoen, W. P. Schmidt, S. Boisson, I. C. Fung, Bushen, O. Y., A. Kohli, R. C. Pinkerton, K. Dupnik, and others. 2010. “Interventions to Improve Disposal R. D. Newman, and others. 2007. “Heavy Cryptosporidial of Human Excreta for Preventing Diarrhoea.” Cochrane Infections in Children in Northeast Brazil: Comparison of Database of Systematic Reviews Jun 16: (6): CD007180. Cryptosporidium hominis and Cryptosporidium parvum.” doi:10.1002/14651858.CD007180.pub2. 180 Reproductive, Maternal, Newborn, and Child Health Clavenna, A., and M. Bonati. 2011. “Differences in Antibiotic Sanitation Interventions in Bolivia Six Years Post-Project.” Prescribing in Paediatric Outpatients.” Archives of Disease Revista Panamericana de Salud Pública 32: 43–48. in Childhood 96 (6): 590–95. Eisenberg, J. N., J. Trostle, R. J. Sorensen, and K. F. Shields. Clemens, J. 2011. “(1579).” Philosophical Transactions of the 2012. “Toward a Systems Approach to Enteric Pathogen Royal Society B 366: 2799–805. Transmission: From Individual Independence to Costa, A. D., and G. A. Silva. 2011. “Oral Rehydration Therapy Community Interdependence.” Annual Review of Public in Emergency Departments.” Jornal de Pediatria 87 (2): Health 33: 239–57. 175–79. Ekwochi, U., J. M. Chinawa, I. Obi, H. A. Obu, and S. Agwu. Das, J. K., Z. S. Lassi, R. A. Salam, and Z. A. Bhutta. 2013. 2013. “Use and/or Misuse of Antibiotics in Management “Effect of Community Based Interventions on Childhood of Diarrhea among Children in Enugu, Southeast Nigeria.” Diarrhea and Pneumonia: Uptake of Treatment Modalities Journal of Tropical Pediatrics 59 (4): 314–16. and Impact on Mortality.” BMC Public Health 13 (Suppl 3): Erdman, S. M., E. E. Buckner, and J. F. Hindler. 2008. “Options S29. doi:10.1186/1471-2458-13-S3-S29. for Treating Resistant Shigella Species Infections in Children.” Das, J. K., R. A. Salam, A. Imdad, and Z. A. Bhutta. 2016. “Infant Journal of Pediatric Pharmacology and Therapeutics 13: and Young Child Growth.” In Disease Control Priorities 29–43. (third edition): Volume 2, Reproductive, Maternal, Newborn, Ernst, S., C. Weinrobe, C. Bien-Aime, and I. Rawson. 2011. and Child Health, edited by R. Black, R. Laxminarayan, “Cholera Management and Prevention at Hôpital Albert M. Temmerman, and N. Walker. Washington, DC: Schweitzer, Haiti.” Emerging Infectious Diseases 17: 2155–57. World Bank. Farag, T. H., A. S. Faruque, Y. Wu, S. K. Das, A. S. Hossain, and Das, J. K., A. Tripathi, A. Ali, A. Hassan, C. Dojosoeandy, and others. 2013. “Housefly Population Density Correlates with others. 2013. “Vaccines for the Prevention of Diarrhea Shigellosis among Children in Mirzapur, Bangladesh: A Due to Cholera, Shigella, ETEC and Rotavirus.” BMC Time Series Analysis.” PLoS Neglected Tropical Diseases 7: Public Health 13 (Suppl 3): 511. https://www.biomedcentral e2280. doi:10.1371/journal.pntd.0002280. .com/1471-2458/13/S3/S11. Feachem, R. G., and M. A. Koblinsky. 1983. “Interventions Das, S. K., S. Ahmed, F. Ferdous, F. D. Farzana, M. J. Chisti, and for the Control of Diarrhoeal Diseases among Young others. 2013. “Etiological Diversity of Diarrhoeal Disease in Children: Measles Immunization.” Bulletin of the World Bangladesh.” Journal of Infection in Developing Countries 7 Health Organization 61 (4): 641–52. (12): 900–9. Feikin, D. R., B. M. J. Flannery Hamel, M. Stack, and P. Hansen. Das, S. K., A. S. Faruque, M. J. Chisti, M. A. Malek, M. A. Salam, 2016. “Vaccines for Children in Low- and Middle-Income and others. 2012. “Changing Trend of Persistent Diarrhoea in Countries.” In Disease Control Priorities (third edition): Young Children over Two Decades: Observations from a Large Volume 2, Reproductive, Maternal, Newborn, and Child Diarrhoeal Disease Hospital in Bangladesh.” Acta Paediatrica Health, edited by R. Black, R. Laxminarayan, M. Temmerman, 101 (10): e452–57. doi:10.1111/j.1651-2227.2012.02761.x. and N. Walker. Washington, DC: World Bank. Deak, A. 2008. “Taking Community-Led Total Sanitation to Fewtrell, L., R. B. Kaufmann, D. Kay, W. Enanoria, L. Haller, and Scale: Movement, Spread and Adaptation.” Working Paper others. 2005. “Water, Sanitation, and Hygiene Interventions 298, Institute of Development Studies at the University of to Reduce Diarrhoea in Less Developed Countries: A Sussex, Brighton, UK. Systematic Review and Meta-Analysis.” The Lancet Infectious Dewey, K. G., and K. Begum. 2011. “Long-Term Consequences Diseases 5 (1): 42–52. of Stunting in Early Life.” Maternal and Child Nutrition 7 Fink, G., I. Günther, and K. Hill. 2011. “The Effect of Water and (Suppl 3): 5–18. Sanitation on Child Health: Evidence from the Demographic Dey, S. K., M. J. Chisti, S. K. Das, C. K. Shaha, F. Ferdous, and and Health Surveys 1986–2007.” International Journal of others. 2013. “Characteristics of Diarrheal Illnesses in Epidemiology 40 (5): 1196–204. Non-Breast Fed Infants Attending a Large Urban Diarrheal Fischer Walker, C.L., and R. E. Black. 2010. “Zinc for the Disease Hospital in Bangladesh.” PLoS One 8 (3): e58228. Treatment of Diarrhoea: Effect on Diarrhoea Morbidity, doi:10.1371/journal.pone.0058228. Mortality and Incidence of Future Episodes.” International Dreibelbis, R., P. J. Winch, E. Leontsini, K. R. Hulland, Journal of Epidemiology 39 (Suppl 1): i63–69. P. K. Ram, and others. 2013. “The Integrated Behavioural Fischer Walker, C. L., and R. E. Black. 2011. “Rotavirus Vaccine Model for Water, Sanitation, and Hygiene: A Systematic and Diarrhea Mortality: Quantifying Regional Variation Review of Behavioural Models and a Framework for in Effect Size.” BMC Public Health 11 (Suppl 3): S16. Designing and Evaluating Behaviour Change Interventions doi:10.1186/1471-2458-11-S3-S16. in Infrastructure-Restricted Settings.” BMC Public Health Fischer Walker, C. L., I. K. Friberg, N. Binkin, M. Young, N. Walker, 13: 1015. doi:10.1186/1471-2458-13-1015.48. and others. 2011. “Scaling Up Diarrhea Prevention and Ecker, L., T. J. Ochoa, M. Vargas, L. J. Del Valle, and J. Ruiz. Treatment Interventions: A Lives Saved Tool Analysis.” PLoS 2013. “Factors Affecting Caregivers’ Use of Antibiotics Medicine 8: e1000428. doi:10.1371/journal.pmed.1000428. Available without a Prescription in Peru.” Pediatrics 131 (6): Fischer Walker, C. L., J. Perin, M. J. Aryee, C. Boschi-Pinto, and e1771–79. doi:10.1542/peds.2012-1970. R. E. Black. 2012. “Diarrhea Incidence in Low- and Middle- Eder, C., J. Schooley, J. Fullerton, and J. Murguia. 2012. Income Countries in 1990 and 2010: A Systematic Review.” “Assessing Impact and Sustainability of Health, Water, and BMC Public Health 12: 220. doi:10.1186/1471-2458-12-220. Diarrheal Diseases 181 Fischer Walker, C. L., I. Rudan, L. Liu, H. Nair, E. Theodoratou, and Child Health, edited by R. Black, R. Laxminarayan, and others. 2013. “Global Burden of Childhood Pneumonia M. Temmerman, and N. Walker. Washington, DC: and Diarrhoea.” The Lancet 381 (9875): 1405–16. World Bank. Freeman, M. C., M. E. Stocks, O. Cumming, A. Jeandron, Hulland, K. R., E. Leontsini, R. Dreibelbis, L. Unicomb, A. Afroz, J. P. Higgins, and others. 2014. “Hygiene and Health: and others. 2013. “Designing a Handwashing Station for Systematic Review of Handwashing Practices Worldwide Infrastructure-Restricted Communities in Bangladesh and Update of Health Effects.” Tropical Medicine and Using the Integrated Behavioural Model for Water, International Health 19 (8): 906–16. Sanitation and Hygiene Interventions (IBM-WASH).” BMC Gaffey, M. F., K. Wazny, D. G. Bassani, and Z. A. Bhutta. 2013. Public Health 13: 877. doi:10.1186/1471-2458-13-877. “Dietary Management of Childhood Diarrhea in Low- and Hutton, G., and J. Bartram. 2008. “Global Costs of Attaining Middle-Income Countries: A Systematic Review.”BMC Public the Millennium Development Goal for Water Supply and Health 13 (Suppl 3): S17. doi:10.1186/1471-2458-13-S3-S17. Sanitation.” Bulletin of the World Health Organization 86: Gavi Alliance. 2014. “Rotavirus Vaccine Support.” http://www 13–19. .gavialliance.org/support/nvs/rotavirus/. Hutton, G., and C. Chase. “Water Supply, Sanitation, and Gebhard, R. L., R. Karouani, W. F. Prigge, and C. J. McClain. Hygiene.” Forthcoming. In Disease Control Priorities (third 1983. “The Effect of Severe Zinc Deficiency on Activity of edition): Volume 7, Injury Prevention and Environmental Intestinal Disaccharidases and 3-Hydroxy-3-Methylglutaryl Health, edited by C. N. Mock, O. Kobusingye, and R. Nugent. Coenzyme A Reductase in the Rat.” Journal of Nutrition 113 Washington, DC: World Bank. (4): 855–89. Imdad, A., and Z. A. Bhutta. 2011. “Effect of Preventive Gerson, C. D., T. H. Kent, J. R. Saha, N. Siddiqi, and Zinc Supplementation on Linear Growth in Children J. Lindenbaum. 1971. “Recovery of Small-Intestinal Structure under 5 Years of Age in Developing Countries: A Meta- and Function after Residence in the Tropics. II. Studies in Analysis of Studies for Input to the Lives Saved Tool.” Indians and Pakistanis Living in New York City.” Annals of BMC Public Health 11(Suppl 3): S22. doi:10.1186/ Internal Medicine 75 (1): 41–48. 1471-2458-11-S3-S22. Ghosh, A., and T. Ramamurthy. 2011. “Antimicrobials and Kar, K. 2003. “Subsidy or Self-Respect? Participatory Total Cholera: Are We Stranded?” Indian Journal of Medical Community Sanitation in Bangladesh.” Working Paper 184, Research 133: 225–31. Institute for Development Studies, Brighton, UK. Gilman, R. H., R. Partanen, K. H. Brown, W. M. Spira, Kashmira, A., K. A. Date, A. Vicari, T. B. Hyde, E. Mintz, and S. Khanam, and others. 1988. “Decreased Gastric Acid others. 2011. “Considerations for Oral Cholera Vaccine Use Secretion and Bacterial Colonization of the Stomach during Outbreak after Earthquake in Haiti, 2010–2011.” in Severely Malnourished Bangladeshi Children.” Emerging Infectious Diseases 17 (11): 2105–12. Gastroenterology 94 (6): 1308–14. Keusch, G. T., O. Fontaine, A. Bhargava, C. Boschi-Pinto, Grimwood, K., and D. A. Forbes. 2009. “Acute and Persistent A. A. Bhutta, and others. 2006. “Diarrheal Diseases.” Diarrhea.” Pediatric Clinics of North America 56 (6): In Disease Control Priorities in Developing Countries, 2nd 1343–61. ed., edited by D. T. Jamison, J. G. Breman, A. R. Measham, Guerrant, R. L., A. A. Lima, M. Barboza, S. Young, T. Silva, G. Alleyene, M. Claeson, D. B. Evans, P. Jha, A. Mills, and and others. 1999. “Mechanisms and Impact of Enteric P. Musgrove, 371–88. Washington, DC: World Bank and Infections.” Advances in Experimental Medicine and Biology Oxford University Press. 473: 103–12. Keusch, G. T., A. G. Plaut, and F. J. Troncale. 1972. “Subclinical Hahn, S., S. Kim, and P. Garner. 2002. “Reduced Osmolarity Malabsorption in Thailand: II. Intestinal Absorption in Oral Rehydration Solution for Treating Dehydration Caused American Military and Peace Corps Personnel.” American by Acute Diarrhoea in Children.” Cochrane Database of Journal of Clinical Nutrition 25 (10): 1067–73. Systematic Reviews 1: CD002847. Keusch, G. T., I. H. Rosenberg, D. M. Denno, C. Duggan, Haider, B. A., and Z. A. Bhutta. 2009. “The Effect of Therapeutic R. L. Guerrant, and others. 2013. “Implications of Acquired Zinc Supplementation among Young Children with Selected Environmental Enteric Dysfunction for Growth and Infections: A Review of the Evidence.” Food and Nutrition Stunting in Infants and Children Living in Low- and Bulletin 30 (Suppl 1): S41–59. Middle-Income Countries.” Food and Nutrition Bulletin 34 Haller, L., G. Hutton, and J. Bartram. 2007. “Estimating (3): 357–64. the Costs and Health Benefits of Water and Sanitation Kim, H. B., M. Wang, S. Ahmed, C. H. Park, R. C. LaRocque, Improvements at Global Level.” Journal of Water and Health and others. 2010. “Transferable Quinolone Resistance in 5 (4): 467–80. Vibrio cholerae.” Antimicrobial Agents and Chemotherapy 54 Harris, J. B., R. C. LaRocque, F. Qadri, E. T. Ryan, and (2): 799–803. S. B. Calderwood. 2012. “Cholera.” The Lancet 379 (9835): King, C. K., R. Glass, J. S. Bresee, and C. Duggan. 2003. 2466–76. “Managing Acute Gastroenteritis among Children: Oral Horton, S., and C. Levin. 2016. “Cost-Effectiveness of Rehydration, Maintenance, and Nutritional Therapy.” Interventions for Reproductive, Maternal, Neonatal, Morbidity and Mortality Weekly Reports. Recommendations and Child Health.” In Disease Control Priorities (third and Reports 52 (RR16): 1–16. http://www.cdc.gov/mmwr edition): Volume 2, Reproductive, Maternal, Newborn, /preview/mmwrhtml/rr5216a1.htm. 182 Reproductive, Maternal, Newborn, and Child Health Kosek, M., C. Bern, and R. L. Guerrant. 2003. “The Global Lindenbaum, J., T. H. Kent, and H. Sprinz. 1966. “Malabsorption Burden of Diarrhoeal Disease, as Estimated from Studies and Jejunitis in American Peace Corps Volunteers in Published between 1992 and 2000.” Bulletin of the World Pakistan.” Annals of Internal Medicine 65 (6): 1201–09. Health Organization 81 (3): 197–204. Lindsay, S. W., T. C. Lindsay, J. Duprez, M. J. Hall, B. A. Kosek, M., R. Haque, A. Lima, S. Babji, S. Shrestha, and oth- Kwambana, and others. 2012. “Chrysomya Putoria, a Putative ers. 2013. “Fecal Markers of Intestinal Inflammation and Vector of Diarrheal Diseases.” PLoS Neglected Tropical Permeability Associated with the Subsequent Acquisition Diseases 6: e1895. doi:10.1371/journal.pntd.0001895. of Linear Growth Deficits in Infants.” American Journal of Liu, L., K. Hill, S. Oza, D. Hogan, S. Cousens, and others. 2016. Tropical Medicine and Hygiene 88 (2): 390–96. “Levels and Causes of Mortality under Age Five Years.” Kotloff, K. L., J. P. Nataro, W. C. Blackwelder, D. Nasrin, In Disease Control Priorities (third edition): Volume 2, T. H. Farag, and others. 2013. “Burden and Aetiology Reproductive, Maternal, Newborn, and Child Health, edited of Diarrhoeal Disease in Infants and Young Children in by R. Black, R. Laxminarayan, M. Temmerman, and Developing Countries (the Global Enteric Multicenter N. Walker. Washington, DC: World Bank. Study, GEMS): A Prospective, Case-Control Study.” The Liu, L., S. Oza, D. Hogan, J. Perin, I. Rudan, and others. Lancet 382 (9888): 209–22. 2015. “Global, Regional, and National Causes of Child Kruse, H., H. Sørum, F. C. Tenover, and O. Olsvik. 1995. Mortality in 2000–13, with Projections to Inform Post-2015 “A Transferable Multiple Drug Resistance Plasmid from Priorities: An Updated Systematic Analysis.” The Lancet 385 Vibrio cholerae O1.” Microbial Drug Resistance 1 (3): 203–10. (9832): 430–40. Lamberti, L. M., C. L. Fischer Walker, and R. E. Black. 2012. Longini, I. M. Jr, A. Nizam, M. Ali, M. Yunus, N. Shenvi, and “Systematic Review of Diarrhea Duration and Severity in J. D. Clemens. 2007. “Controlling Endemic Cholera with Children and Adults in Low- and Middle-Income Countries.” Oral Vaccines.” PLoS Medicine 4: e336. BMC Public Health 12: 276. doi:10.1186/1471-2458-12-276. Luby, S. P., M. Agboatwalla, D. R. Feikin, J. Painter, W. Billhimer, Lanata, C. F., C. L. Fischer Walker, A. C. Olascoaga, C. X. Torres, and others. 2005. “Effect of Handwashing on Child Health: M. J. Aryee, and others. 2013. “Child Health Epidemiology A Randomised Controlled Trial.” The Lancet 366 (9481): Reference Group of the World Health Organization and 225–33. UNICEF. Global Causes of Diarrheal Disease Mortality Luby, S. P., M. Agboatwalla, J. Painter, A. Altaf, W. Billhimer, in Children <5 Years of Age: A Systematic Review.” and others. 2006. “Combining Drinking Water Treatment PLoS One September 4: 8:e72788. doi:10.1371/journal. and Hand Washing for Diarrhoea Prevention: A Cluster pone.0072788. Randomised Controlled Trial.” Tropical Medicine and Langford, R., P. Lunn, and C. Panter-Brick. 2011. “Hand- International Health 11 (4): 479–89. Washing, Subclinical Infections, and Growth: A Luby, S. P., M. Agboatwalla, J. Painter, A. Altaf, W. L. Billhimer, Longitudinal Evaluation of an Intervention in Nepali and R. M. Hoekstra. 2004. “Effect of Intensive Handwashing Slums.” American Journal of Human Biology 23 (5): 621–29. Promotion on Childhood Diarrhea in High-Risk Larrea-Killinger, C., and A. Muñoz. 2013. “The Child’s Body Communities in Pakistan: A Randomized Controlled Trial.” without Fluid: Mother’s Knowledge and Practices about Journal of the American Medical Association 291 (21): Hydration and Rehydration in Salvador, Bahia, Brazil.” 2547–54. Journal of Epidemiology and Community Health 67 (6): Luby, S. P., A. K. Halder, T. Huda, L. Unicomb, and R. B. Johnston. 498–507. 2011. “The Effect of Handwashing at Recommended Times Latham, M. C., U. Jonsson, E. Sterken, and G. Kent. 2010. with Water Alone and with Soap on Child Diarrhea in “RUTF Stuff: Can the Children Be Saved with Fortified Rural Bangladesh: An Observational Study.” PLoS Med 8: Peanut Paste?” World Nutrition 2 (2): 62–85. e1001052. doi:10.1371/journal.pmed.1001052. Lazzerini, M., and L. Ronfani. 2013. “Oral Zinc for Treating MacPherson, D. W., B. D. Gushulak, W. B. Baine, S. Bala, Diarrhoea in Children.” Cochrane Database of Systematic P. O. Gubbins, and others. 2009. “Population Mobility, Reviews 1: CD005436. doi:10.1002/14651858.CD005436. Globalization, and Antimicrobial Drug Resistance.” pub4. Emerging Infectious Diseases 15 (11): 1727–32. Lee, M. B., and J. D. Greig. 2010. “A Review of Gastrointestinal Malhotra, N., and R. P. Upadhyay. 2013. “Why Are There Delays Outbreaks in Schools: Effective Infection Control in Seeking Treatment for Childhood Diarrhoea in India?” Interventions.” Journal of School Health 80 (12): 588–98. Acta Paediatrica 102 (9): e413–18. doi:10.1111/apa.12304. Lenters, L., K. Wazny, and Z. A. Bhutta. 2016. “Management Mazumder, S., S. Taneja, N. Bhandari, B. Dube, R. C. Agarwal, of Severe and Moderate Acute Malnutrition in Children.” and others. 2010. “Effectiveness of Zinc Supplementation In Disease Control Priorities (third edition): Volume 2, Plus Oral Rehydration Salts for Diarrhoea in Infants Aged Reproductive, Maternal, Newborn, and Child Health, edited Less than 6 Months in Haryana State, India.” Bulletin of the by R. Black, R. Laxminarayan, M. Temmerman, and World Health Organization 88: 754–60. N. Walker. Washington, DC: World Bank. Mendelsohn, A. S., J. R. Asirvatham, D. Mkaya Mwamburi, Lindenbaum, J., C. D. Gerson, and T. H. Kent. 1971. “Recovery T. V. Sowmynarayanan, and others. 2008. “Estimates of Small Intestinal Structure and Function after Residence of the Economic Burden of Rotavirus-Associated and in the Tropics: I. Studies in Peace Corps Volunteers.” Annals All-Cause Diarrhoea in Vellore, India.” Tropical Medicine of Internal Medicine 74 (2): 218–22. and International Health 13 (7): 934–42. Diarrheal Diseases 183 Mondal, D., J. Minak, M. Alam, Y. Liu, J. Dai, and others. Raqib, R., A. A. Lindberg, B. Wrwetlind, P. K. Bardhan, 2012. “Contribution of Enteric Infection, Altered Intestinal U. Andersson, and others. 1995. “Persistence of Local Barrier Function, and Maternal Malnutrition to Infant Cytokine Production in Shigellosis in Acute and Malnutrition in Bangladesh.” Clinical Infectious Diseases Convalescent Stages.” Infection and Immunity 63 (1): 289–96. 54 (2): 185–92. Risk, R., H. Naismith, A. Burnett, S. E. Moore, M. Cham, and Moore, S. R., N. L. Lima, A. M. Soares, R. B. Oriá, R. C. Pinkerton, S. Unger. 2013. “Rational Prescribing in Paediatrics in a and others. 2010. “Prolonged Episodes of Acute Diarrhea Resource-Limited Setting.” Archives of Disease in Childhood Reduce Growth and Increase Risk of Persistent Diarrhea in 98 (7): 503–9. Children.” Gastroenterology 139 (4): 1156–64. Robberstad, B., T. Strand, R. E. Black, and H. Sommerfelt. 2004. Mota, M. I., M. P. Gadea, S. González, G. González, L. Pardo, “Cost-Effectiveness of Zinc as Adjunct Therapy for Acute and others. 2010. “Bacterial Pathogens Associated with Childhood Diarrhoea in Developing Countries.” Bulletin of Bloody Diarrhea in Uruguayan Children.” Revista Argentina the World Health Organization 82 (7): 523–31. de Microbiologia 42 (2): 114–17. Rouzier, V., K. Severe, M. A. Juste, M. Peck, C. Perodin, and Munos, M. K., C. L. Fischer Walker, and R. E. Black. 2010. “The others. 2013. “Cholera Vaccination in Urban Haiti.” American Effect of Oral Rehydration Solution and Recommended Journal of Tropical Medicine and Hygiene 89 (4): 671–81. Home Fluids on Diarrhoea Mortality.” International Journal Ryan, E. T., U. Dhar, W. A. Khan, M. A. Salam, A. S. Faruque, of Epidemiology 39 (Suppl 1): 175–87. and others. 2000. “Mortality, Morbidity, and Microbiology Nasrin, D., Y. Wu, W. C. Blackwelder, T. H. Farag, D. Saha, and of Endemic Cholera among Hospitalized Patients in Dhaka, others. 2013. “Health Care Seeking for Childhood Diarrhea Bangladesh.” American Journal of Tropical Medicine and in Developing Countries: Evidence from Seven Sites in Hygiene 63 (1–2): 12–20. Africa and Asia.” American Journal of Tropical Medicine and Sachdev, H. P., N. K. Mittal, and H. S. Yadav. 1990. “Oral Zinc Hygiene 89 (Suppl 1): 3–12. Supplementation in Persistent Diarrhea in Infants.” Annals Newman, R. D., S. R. Moore, A. A. Lima, J. P. Nataro, of Tropical Paediatrics 10 (1): 63–69. R. L. Guerrant, and others. 2001. “A Longitudinal Study of Salomon, J. B., L. J. Mata, and J. E. Gordon. 1968. “Malnutrition Giardia lamblia Infection in North-East Brazilian Children.” and the Common Communicable Diseases of Childhood Tropical Medicine and International Health 6 (8): 624–34. in Rural Guatemala.” American Journal of Public Health 58 Newman, R. D., C. L. Sears, J. P. Nataro, D. P. Fedorko, T. Wuhib, (3): 505–16. and others. 2000. “Persistent Diarrhea Signals a Critical Santini, A., E. Novellino, V. Armini, and A. Ritieni. 2013. “State Period of Increased Diarrhea Burdens and Nutritional of the Art of Ready-to-Use Therapeutic Food: A Tool for Shortfalls: A Prospective Cohort Study among Children in Nutraceuticals Addition to Foodstuff.” Food Chemistry 140 Northeastern Brazil.” Journal of Infectious Diseases 181 (5): (4): 843–49. doi:10.1016/j.foodchem.2012.10.098. 1643–51. Santosham, M., A. Chandran, S. Fitzwater, C. Fischer Walker, O’Ryan, M., V. Prado, and L. K. Pickering. 2005. “A Millennium A. H. Baqui, and others. 2010. “Progress and Barriers for Update on Pediatric Diarrheal Illness in the Developing the Control of Diarrhoeal Disease.” The Lancet 376 (9734): World.” Seminars in Pediatric Infectious Diseases 16 (2): 63–67. 125–36. Schoonees, A., M. Lombard, A. Musekiwa, E. Nel, and Okeke, I. N. 2009. “Cholera Vaccine Will Reduce Antibiotic J. Volmink. 2013. “Ready-to-Use Therapeutic Food for Use.” Science 325 (5941): 326. Home-Based Treatment of Severe Acute Malnutrition Patel, M. M., M. A. Widdowson, R. I. Glass, K. Akazawa, in Children from Six Months to Five Years of Age.” J. Vinjé, and others. 2008. “Systematic Literature Review of Cochrane Database of Systematic Reviews 6: CD009000. Role of Noroviruses in Sporadic Gastroenteritis.” Emerging doi:10.1002/14651858.CD009000.pub2. Infectious Diseases 14 (8): 1224–31. Shankar, A. H., and A. S. Prasad. 1998. “Zinc and Immune Pattanayak, S. K., J. C. Yang, K. L. Dickinson, C. Poulos, Function: The Biological Basis of Altered Resistance S. R. Patil, and others. 2009. “Shame or Subsidy Revisited: to Infection.” American Journal of Clinical Nutrition 68 Social Mobilization for Sanitation in Orissa, India.” Bulletin (Suppl 2): 447S–63S. of the World Health Organization 87 (8): 580–87. Snyder, J. D., and M. E. Merson. 1982. “The Magnitude of the Peterson, K. M., J. Buss, R. Easley, Z. Yang, P. S. Korpe, and Global Problem of Acute Diarrhoeal Disease: A Review others. 2013. “REG1B as a Predictor of Childhood Stunting of Active Surveillance Data.” Bulletin of the World Health in Bangladesh and Peru.” American Journal of Clinical Organization 60 (4): 605–13. Nutrition 97 (5): 1129–33. Sowmyanarayanan, T. V., T. Patel, R. Sarkar, S. Broor, Prado, M. S., S. Cairncross, A. Strina, M. L. Barreto, S. D. Chitambar, and others. 2012. “Direct Costs of A. M. Oliveira-Assis, and others. 2005. “Asymptomatic Hospitalization for Rotavirus Gastroenteritis in Different Giardiasis and Growth in Young Children: A Longitudinal Health Facilities in India.” Indian Journal of Medical Study in Salvador, Brazil.” Parasitology 131 (Pt 1): 51–56. Research 136 (1): 68–73. Prendergast, A., and P. Kelly. 2012. “Review: Enteropathies in Spears, D. 2013. “How Much International Variation in Child the Developing World: Neglected Effects on Global Health.” Height Can Sanitation Explain?” Policy Research Working American Journal of Tropical Medicine and Hygiene 86 (5): Paper WPS 6351, World Bank, Washington, DC. http:// 756–63. go.worldbank.org/SZE5WUJBI0. 184 Reproductive, Maternal, Newborn, and Child Health Steenland, M. W., G. A. Joseph, M. A. Lucien, N. Freeman, Diplomatic Resource.” New England Journal of Medicine M. Hast, and others. 2013. “Laboratory-Confirmed Cholera 363 (24): 2279–82. and Rotavirus among Patients with Acute Diarrhea in Four WHO (World Health Organization). 2010. “Medicines: Hospitals in Haiti, 2012–2013.” American Journal of Tropical Rational Use of Medicines.” Fact Sheet 338. http://www Medicine and Hygiene 89 (4): 641–46. .wiredhealthresources.net/WHO-FS_MedicinesRational Stenberg, K., K. Sweeny, H. Axelson, and P. Sheehan. 2016. Use.pdf. “Returns on Investment in the Continuum of Care for ———. 2012. “Cholera.” Fact Sheet 107. http://www.who.int Reproductive, Maternal, Newborn, and Child Health.” /mediacentre/factsheets/fs107/en. In Disease Control Priorities (third edition): Volume 2, ———. 2013. “Oral Cholera Vaccine Stockpile.” http://www Reproductive, Maternal, Newborn, and Child Health, edited .who.int/cholera/vaccines/ocv_stockpile_2013/en/index by R. Black, R. Laxminarayan, M. Temmerman, and .html. N. Walker. Washington, DC: World Bank. WHO and UNICEF (United Nations Children’s Fund). 2004. Strand, T. A., P. R. Sharma, H. K. Gjessing, M. Ulak, Clinical Management of Acute Diarrhoea. New York: WHO R. K. Chandyo, and others. 2012. “Risk Factors for Extended and UNICEF. Duration of Acute Diarrhea in Young Children.” PLoS One ———. 2009. Diarrhoea: Why Children Are Still Dying and 7: e36436. doi:10.1371/journal.pone.0036436. What Can Be Done. Geneva: WHO and UNICEF. Tatem, A. J., D. J. Rogers, and S. I. Hay. 2006. “Global Transport ———. 2013. Progress on Sanitation and Drinking-Water, Networks and Infectious Disease Spread.” Advances in 2013 Update: Joint Monitoring Programme for Water Supply Parasitology 62: 293–343. and Sanitation. Geneva: WHO and UNICEF. http://www Thomas, J. E., A. Dale, J. E. Bunn, M. Harding, W. A. Coward, .who.int/water_sanitation_health/publications/2013/jmp and others. 2004. “Early Helicobacter pylori Colonisation: _report/en/index.html. The Association with Growth Faltering in The Gambia.” WHO, UNICEF, and World Bank. 2009. State of the World’s Archives of Disease in Childhood 89 (12): 1149–54. Vaccines and Immunization. 3rd ed. Geneva: WHO. Thriemer, K., Y. Katuala, B. Batoko, J. P. Alworonga, H. Devlieger, Wilson, S. E., C. T. Ouédraogo, L. Prince, A. Ouédraogo, and others. 2013. “Antibiotic Prescribing in DR Congo: S. Y. Hess, and others. 2012. “Caregiver Recognition of A Knowledge, Attitude and Practice Survey among Medical Childhood Diarrhea, Care Seeking Behaviors and Home Doctors and Students.” PLoS One 8: e55495. doi:10.1371 Treatment Practices in Rural Burkina Faso: A Cross- /journal.pone.0055495. Sectional Survey.” PLoS One 7: e33273. doi:10.1371/journal Traa, B. S., C. L. Fischer Walker, M. Munos, and R. E. Black. .pone.0033273. 2010. “Antibiotics for the Treatment of Dysentery in Windle, H. J., D. Kelleher, and J. E. Crabtree. 2007. “Childhood Children.” International Journal of Epidemiology 39 Helicobacter pylori Infection and Growth Impairment in (Suppl 1): i70–74. Developing Countries: A Vicious Cycle?” Pediatrics 119 (3): Veitch, A. M., P. Kelly, I. S. Zulu, I. Segal, and M. J. Farthing. e754–59. 1991. “Tropical Enteropathy: A T-Cell-Mediated Wood, G. M., J. C. Gearty, and B. T. Cooper. 1991. “Small Crypt Hyperplastic Enteropathy.” European Journal of Bowel Morphology in British Indian and Afro-Caribbean Gastroenterology and Hepatology 13 (10): 1175–81. Subjects: Evidence of Tropical Enteropathy.” Gut 32 (3): Verguet, S., C. Pecenka, K. A. Johansson, S. T. Memirie, 256–59. I. K. Friberg, and others. 2016. “Health Gains and Financial Yakoob, M. Y., E. Theodoratou, A. Jabeen, A. Imdad, T. P. Eisele, Risk Protection Afforded by Treatment and Prevention of and others. 2011. “Preventive Zinc Supplementation in Diarrhea and Pneumonia in Ethiopia: An Extended Cost- Developing Countries: Impact on Mortality and Morbidity Effectiveness Analysis.” In Disease Control Priorities (third Due to Diarrhea, Pneumonia and Malaria.” BMC Public edition): Volume 2, Reproductive, Maternal, Newborn, Health 11 (Suppl 3): S23. doi:10.1186/1471-2458-11-S3-S23. and Child Health, edited by R. Black, R. Laxminarayan, Zwisler, G., E. Simpson, and M. Moodley. 2013. “Treatment M. Temmerman, and N. Walker. Washington, DC: of Diarrhea in Young Children: Results from Surveys on World Bank. the Perception and Use of Oral Rehydration Solutions, Waldor, M. K., P. J. Hotez, and J. D. Clemens. 2010. “A National Antibiotics, and Other Therapies in India and Kenya.” Journal Cholera Vaccine Stockpile—A New Humanitarian and of Global Health 3 (1): 010403. doi:10.7189/jogh.03.010403. Diarrheal Diseases 185 Chapter 10 Vaccines for Children in Low- and Middle-Income Countries Daniel R. Feikin, Brendan Flannery, Mary J. Hamel, Meghan Stack, and Peter M. Hansen INTRODUCTION global initiatives (PHR 2014; WHO 2012a). Vaccination is central to the health goal included in the post-2015 Vaccination is the centerpiece of preventive care of Sustainable Development Goals, which is on a critical the well child. Vaccination has been one of the singular pathway to delivering on its targets. public health successes of the past half century, and its full In addition to the clear health benefits, vaccination potential remains unrealized. Pneumonia and diarrhea, has been one of the most cost-effective public health two of the leading causes of child mortality, account for interventions (Brenzel and others 2006; WHO, UNICEF, approximately 1.4 million deaths annually (Liu and others and World Bank 2002). Based on 2001 data, the cost 2016); vaccination with currently available vaccines has per death averted through routine vaccination with the potential to prevent 59 percent of pneumonia-related the six original antigens in the Expanded Program on deaths and 29 percent of diarrhea-related deaths (Fischer Immunization (EPI) was US$205 in South Asia and Sub- Walker, Munos, and Black 2013). Other leading causes of Saharan Africa; estimated cost per disability-adjusted life childhood deaths are already preventable through avail- year (DALY) averted was US$7 to US$16 (Brenzel and able and effective vaccines, such as measles and menin- others 2006). New vaccines, although more expensive, gitis, and other diseases, such as malaria, may become have also been determined to be cost-effective in Gavi- vaccine preventable in the near future (Agnandji and eligible countries (Atherly and others 2012; Sinha and others 2011; Liu and others 2012). Forecasts for vaccine others 2007) (see box 10.1). use in the 73 countries supported by Gavi, the Vaccine This chapter describes the epidemiology and burden Alliance, project that 17.7 million deaths will be averted of vaccine-preventable diseases and provides estimates in children under age five years as a result of vaccinations of the value of vaccines in health impact as well as administered from 2011 to 2020 (Lee and others 2013). broader economic benefits. The focus is on vaccination Childhood vaccination contributed greatly to prog- of infants during routine well-child visits and not on ress made toward achieving the fourth United Nations other important vaccines for older children and young Millennium Development Goal, a two-thirds reduc- adults, such as human papillomavirus vaccine, typhoid tion in childhood mortality between 1990 and 2015 vaccine, and dengue vaccines. (UN 2015), and the centerpiece of several other major Corresponding author: Daniel R. Feikin, Chief, Epidemiology Branch/Division of Viral Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, United States; drf0@cdc.gov. 187 Box 10.1 Gavi, The Vaccine Alliance Disparities exist in vaccination status between coun- Advanced Market Commitment tries and within the same country, where some An innovative financing mechanism called the regions or sectors of society remain substantially Advanced Market Commitment was established undervaccinated. For example, in Nigeria’s 2008 to accelerate the introduction of and scale up the Demographic and Health Survey, the coverage of pneumococcal conjugate vaccine through Gavi the third dose of the diphtheria-tetanus-pertussis (Cernuschi and others 2011). The Advanced vaccine varied from 67 percent in the southeast to Market Commitment secured US$1.5 billion 9 percent in the northwest (NPC and ICF Macro from six donor countries and the Bill & Melinda 2009). Disparities are largely driven by socioeco- Gates Foundation, which provided a finan- nomic status; the poorest children, with the highest cial commitment to purchase pneumococcal disease burden, are the least vaccinated (Cutts, conjugate vaccine for introduction and scale-up Izurieta, and Rhoda 2013). in Gavi-supported countries at predetermined To address low coverage and inequitable access to terms. life-saving vaccines, Gavi, the Vaccine Alliance was launched in 2000 to increase access to immuniza- Eligibility and Transition to Self-Financing tion in poor countries. Gavi is a public-private part- As of January 2014, per capita gross national income nership involving the World Health Organization in 17 of 73 Gavi-supported countries had risen (WHO), the United Nations Children’s Fund, above the eligibility threshold, resulting in a five- and the World Bank; civil society organizations; year transition period during which such countries public health institutes; donors and implementing finance an increasingly larger share of their vaccines country governments; major private philanthro- each year. These countries need to mobilize domes- pists, such as the Bill & Melinda Gates Foundation; tic resources to sustainably finance their vaccines vaccine manufacturers; and the financial commu- when they complete the transition to self-financing. nity (Gavi 2013). Gavi’s support for 2011–15 has focused on 73 countries based on eligibility crite- Vaccine Investment Strategy ria determined through per capita gross national Gavi uses a vaccine investment strategy to determine income. which vaccines to add to its portfolio of support to Gavi has expanded its initial support for hepatitis B, countries every five years, taking into account the pentavalent, and yellow fever vaccines to include selection criteria and the date when different vac- measles vaccine second dose and those against pneu- cines will be available. The Gavi Board decided in mococcus, rotavirus, meningococcus serogroup A, 2014 that Gavi will undertake the following: measles-rubella, human papillomavirus, Japanese encephalitis, and inactivated polio vaccine. Gavi • Yellow fever. Increase support for additional has approved a contribution to the global cholera yellow fever campaigns. stockpile for use in epidemic and endemic settings. • Cholera. Contribute to a global vaccine stockpile From its inception through 2014, Gavi has commit- from 2014 to 2018 to increase access in outbreak ted US$8.8 billion in program support to eligible situations and further a learning agenda on its countries; 75 percent of the total commitment is for use in endemic settings. the purchase of vaccines. From 2000 through early • Malaria. Consider supporting the vaccine that is 2015, Gavi-supported vaccines have helped coun- now in development when it is licensed, WHO- tries vaccinate approximately 500 million children prequalified, and recommended for use by the through routine programs. Annex table 10A.3 shows joint meeting of the WHO Strategic Advisory the vaccine introduction status in 73 Gavi-eligible Group of Experts on Immunization and the countries. Malaria Policy Advisory Committee. box continues next page 188 Reproductive, Maternal, Newborn, and Child Health Box 10.1 (continued) • Rabies and influenza. Recommend further minimize the cost of vaccines, and ensure the assessment of the impact and operational fea- availability of quality and innovative products. sibility of supporting rabies and influenza Improved vaccine delivery strategies are needed to vaccines for pregnant women, fund an observa- ensure that immunization programs and health sys- tional study to address critical knowledge gaps tems are able to implement programs of increasing around access to rabies vaccine, and monitor size and complexity at high levels of coverage and the evolving evidence base for maternal influ- equity. It will be necessary to build on the unprece- enza vaccination. dented momentum achieved in new vaccine intro- duction and market shaping to take to scale innovative By forecasting and pooling demand from eligible approaches to generating demand for immunization; countries and purchasing large volumes of vaccines, upgrading country supply chain management systems; Gavi has created a reliable market for vaccines strengthening country health information systems; and in these settings. Gavi’s market-shaping strategy enhancing political will and country capacity related to aims to ensure adequate supply to meet demand, leadership, management, and coordination. METHODS were codified in 1984, with the goal of reaching every child with vaccines against six diseases: diphtheria, per- We describe vaccines in three categories: tussis, tetanus, measles, poliomyelitis, and tuberculosis (Hadler and others 2004; Mitchell and others 2013). The • Vaccines among the six original EPI antigens: Bacille fulcrum of the EPI program is the fixed health facility, Calmette-Guérin (BCG); diphtheria, tetanus, and where parents bring their children to be immunized. pertussis (DTP); and measles and polio The immunization visit has been expanded into the well- • Vaccines classified as new or underutilized and sup- child visit, where the contact with the health system is used ported by Gavi since its inception in 2000 to add other preventive interventions (for example, vita- • New vaccines that might be introduced into routine min A and growth monitoring). Vaccination is also deliv- immunization for infants at the well-child visit in the ered in many low- and middle-income countries (LMICs) next decade. through modes and mechanisms outside the well-child visit, such as mobile outreach clinics, supplemental immu- For the epidemiology and vaccine characteristics, nization activities as part of eradication and elimination we used a nonsystematic review of the published campaigns, and mass vaccination for control of outbreaks. literature, recommendations of the World Health Organization (WHO), and a search of relevant updated websites on vaccines. For the impact of vaccination VACCINE-PREVENTABLE DISEASES: using the original EPI vaccines, we referenced exist- EPIDEMIOLOGY, BURDEN, AND VACCINES ing models. For the new vaccines, we used a method- This section describes the epidemiology, burden, and ology adopted through an expert process, with leading vaccines available for vaccine-preventable diseases modeling groups co-convened by Gavi and the Bill & among children in LMICs. The section is divided into Melinda Gates Foundation, to estimate the number the six original EPI vaccines, new and underutilized of future deaths and DALYs averted attributable to vaccines introduced since 2000, and vaccines that might vaccinations administered in the 73 Gavi-supported become more widely used in young children during the countries (annex 10A and table 10A.1). next decade (summarized in annex table 10A.2). EXPANDED PROGRAM ON IMMUNIZATIONS Original EPI Vaccines The EPI program was created in 1974 to improve vaccine Bacille Calmette-Guérin Vaccine availability globally (WHO 1974). Global policies and Tuberculosis is caused by the bacterium Mycobacterium recommended schedules based on immunologic data tuberculosis and is spread from person to person through Vaccines for Children in Low- and Middle-Income Countries 189 the air; it primarily causes disease in the lung, although Diphtheria, Tetanus, and Pertussis Vaccine it can spread to many parts of the body. Infection with Despite progress, these three bacterial diseases of infancy M. tuberculosis may lie dormant for years. In 2012, the and early childhood remain endemic in some countries. WHO estimated a global burden of 8.6 million cases Diphtheria is a respiratory illness characterized by mem- and 1.3 million deaths due to tuberculosis; 55,000 of branous inflammation of the upper respiratory tract these were in children under age five years, 95 percent caused by toxin-producing Corynebacterium diphtheriae of which occurred in LMICs. Co-infection with human and is transmitted through respiratory droplets and immunodeficiency virus (HIV) greatly increases the coughing. Before vaccination, an estimated 1 million risk of developing active tuberculosis. The treatment cases and 50,000–60,000 deaths occurred annually of tuberculosis worldwide is becoming more compli- (Walsh and Warren 1979). In 2008, only 7,000 cases of cated because of the rise of multidrug-resistant strains diphtheria were reported; more than 85 percent of these (Bloom and others, forthcoming; Connelly Smith, occurred in India (WHO and UNICEF 2014). Tetanus Orme, and Starke 2013; WHO 2015a). is caused by a toxin produced by Clostridium tetani, a BCG vaccine is a live-attenuated strain of a related ubiquitous organism found in the soil and transmitted mycobacterium, Mycobacterium bovis, originally iso- through contamination of wounds or unsterile proce- lated from an infected cow and attenuated through dures, including care of the umbilical cord. Neonatal repeated passage. BCG is most effective against tuber- tetanus is mostly present in LMICs, resulting in an esti- culous meningitis and disseminated (miliary) tuber- mated 34,481 deaths in 2015 in children in LMICs, which culosis. However, BCG vaccination does not prevent account for 99 percent of all under-five tetanus deaths M. tuberculosis infection in childhood, when most worldwide (Liu and others 2016). Pertussis, or whoop- infections occur, or reactivation of latent infection and ing cough, is a highly communicable respiratory illness pulmonary tuberculosis later in life, which is the princi- caused by Bordetella pertussis and characterized by par- pal source of community transmission (WHO 2004). In oxysmal cough that may last for many weeks. Estimates 2012, BCG was included in routine infant immunization from the WHO suggest that about 63,000 children died schedules in 159 of 194 WHO member states; world- from this disease in 2008, 95 percent of them in LMICs wide coverage was estimated to be 90 percent in 2012 (Black and others 2010). (WHO, UNICEF, and World Bank 2002). Approximately DTP vaccines are composed of inactivated diphtheria 100 million infants receive BCG annually; more than and tetanus toxins (referred to as toxoids) and pertussis 4 billion people have been vaccinated (Connelly Smith, antigens, either killed, whole-cell Bordetella pertussis or Orme, and Starke 2013). The 100 million BCG vacci- purified antigens (acellular pertussis [aP] vaccine). Whole- nations given worldwide to infants in 2002 prevented cell pertussis acts as a potent adjuvant that improves the approximately 30,000 cases of tuberculous meningitis immune response to diphtheria and tetanus toxoids, and 11,000 cases of miliary tuberculosis (Trunz, Fine, but periodic boosting is required because of waning and Dye 2006). immune responses; waning may occur more quickly with Vaccination is recommended for all infants in coun- aP vaccines (Edwards and Decker 2013). DTP vaccines tries with high tuberculosis disease burden and infants at combined with hepatitis B and Haemophilus influenzae high risk of exposure in low-burden countries. Because type b (Hib) antigens are widely used in LMICs, while it is a live-attenuated vaccine, BCG is not recommended combination vaccines with aP are common in upper- for immunocompromised children, including those with middle- and high-income countries. Because the risk of congenital severe combined immunodeficiency syndrome pertussis complications is highest in infants too young and those with symptomatic HIV infection. to be vaccinated, maternal vaccination is a strategy that Tuberculosis will not be eliminated without new, could protect young infants (CDC 2011). more effective tuberculosis vaccines (Connelly Smith, DTP vaccine coverage is an important indicator Orme, and Starke 2013). For the prevention of severe of immunization program performance. Initiatives to childhood diseases, a single BCG dose is recom- strengthen routine immunization services often monitor mended as soon as possible after birth (WHO 2004). progress as measured by coverage with the third DTP BCG is the only vaccine in the EPI program routinely dose (DTP3) in infancy, which requires multiple immu- administered by intradermal injection, which requires nization visits in the first year of life. The difference specific injection supplies and health care worker between coverage with the first versus the third DTP training. BCG is produced by a large number of coun- dose, often called dropout, measures loss to follow-up tries using different vaccine seed strains, which may and challenges to completion of infant vaccinations. contribute to the variability in effectiveness observed Many newer vaccines, including pneumococcal, menin- in different studies. gococcal, and rotavirus vaccines, have adapted to DTP 190 Reproductive, Maternal, Newborn, and Child Health immunization schedules to reach the maximum number countries, the WHO recommends four doses beginning of children during scheduled immunization visits. as soon as possible after birth, with at least one dose of DTP vaccines are included in routine childhood IPV at age 14 weeks if only one IPV dose is given. immunization programs in all 194 WHO member There are several steps to the Polio Eradication and states. Global DTP3 coverage rose from 20 percent Endgame Strategic Plan 2013–2018, and this transition in 1980 to 84 percent in 2013 (WHO and UNICEF in polio vaccination strategy has several phases. First, 2014), preventing 76,000 deaths from diphtheria and all OPV-using countries should introduce at least one 1.6 million deaths from pertussis annually. In conjunc- dose of IPV (containing inactivated polioviruses of all tion with improved maternal immunization against three types) to boost immunity to poliovirus type 2 tetanus, the vaccines prevented approximately 408,000 (WHO 2014b). Then, trivalent OPV will be replaced deaths from tetanus (WHO 2013a). Despite increased with more immunogenic bivalent OPV containing type coverage, more than 20 million infants remained unvac- 1 and 3 viruses. IPV introduction will pave the way for cinated in 2013 (WHO and UNICEF 2014). More future total cessation of all OPV use after eradication than 80 percent of these children live in Gavi-eligible has been achieved. Most high-income countries adopted countries. If these countries achieved and maintained routine childhood immunization with IPV to prevent their DTP3 coverage at 90 percent between 2015 and rare cases of paralytic polio caused by OPV. However, 2020, 439,000 deaths and 16 million cases of pertussis achieving high coverage with IPV will require strength- could be averted during the 10 years from the scale-up ening of routine immunization services. (Stack and others 2011). Measles Vaccine Polio Vaccine Measles is one of the most contagious diseases of humans The goal of universal polio vaccination is eradication. In (Fine and Mulholland 2013). It is caused by a paramyxo- 1988, when the Global Polio Eradication Initiative was virus, manifesting as a febrile rash illness, which can result established, poliomyelitis crippled more than 350,000 in multiple life-threatening complications, including children each year, with transmission of wild poliovi- pneumonia, diarrhea, and encephalitis. In 2000, measles rus serotypes (1, 2, and 3) reported from 125 countries was the leading vaccine-preventable cause of childhood (WHO 2014c). From January to December 2015, only deaths and the fifth leading cause of under-five mor- 66 cases of wild poliovirus type 1 were reported world- tality; that year, measles alone accounted for 5 percent wide, compared with 359 cases in January to December of the estimated 10.9 million deaths among children 2014, and no cases of wild poliovirus had been reported under age five years (Strebel and others 2012). By 2010, on the African continent for 12 months; wild type 2 measles-related deaths had declined by 75 percent follow- polioviruses have not been identified since 1999; and ing accelerated measles control activities in Sub-Saharan the last case of wild type 3 poliovirus occurred in 2012 Africa and other regions (Simons and others 2012); (Global Polio Eradication Initiative 2013; WHO 2014b). declines in measles-related deaths accounted for almost Implementation of routine childhood immunization 10.1 percent of overall declines in childhood mortality and supplemental immunization activities with oral from 2000 to 2015 (Liu and others 2016). Further prog- polio vaccine (OPV) containing attenuated polioviruses ress is expected as countries implement measles elim- of all three types substantially decreased cases in LMICs ination strategies; as of 2014, all six WHO regions had and eliminated poliovirus circulation in the WHO established target dates for measles elimination. regions of the Americas, Europe, Western Pacific, and Measles vaccination can prevent illness and death South-East Asia. Clinical trials showed that three doses of directly among vaccinated persons and indirectly among OPV were needed for greater than 90 percent protection unvaccinated persons as a result of decreased transmission. against paralytic poliomyelitis. However, the immune In countries with ongoing transmission of measles and high response was lower among children in LMICs, requiring risk of measles among infants, the WHO recommends vac- more vaccine doses to achieve the high levels of popula- cination at age nine months when protection provided by tion immunity necessary for elimination (Estívariz and maternal antibody wanes and seroconversion rates improve others 2012; Grassly and others 2007). In 2014, the WHO among infants. In countries with low rates of measles trans- recommended that all countries using OPV include at mission, the WHO recommends the first dose of vaccine at least one dose of inactivated polio vaccine (IPV) in their age 12 months to take advantage of higher seroconversion routine immunization schedule (WHO 2014c). Most rates achieved at this age (Strebel and others 2012). immunization schedules in LMICs include a three-dose Between 1980 and 2011, global measles vaccination primary polio immunization schedule, and many include coverage rose from 18 percent to 84 percent globally booster doses in the second year of life. For high-risk (WHO 2013d; WHO, UNICEF, and World Bank 2002). Vaccines for Children in Low- and Middle-Income Countries 191 In one analysis, a projected 624 million children in Gavi- countries receiving support from Gavi, with a focus on eligible countries would be vaccinated with one dose 10 new and previously underutilized vaccines. Expected of measles-containing vaccine between 2011 and 2020, impact is shown separately for vaccinations adminis- averting 10.3 million deaths relative to a hypothetical sce- tered from 2001 to 2012 and vaccinations forecasted to nario in which countries were not administering measles be administered from 2013 to 2020. The total expected vaccine (Lee and others 2013). impact is shown as estimated numbers of persons Because of its high risk of contagion, high levels of immunized, as well as future deaths and DALYs averted. immunity are needed to interrupt measles transmis- Estimates of future deaths and DALYs averted are based sion. A two-dose strategy is deemed essential for mea- on a comparison of the number of deaths and DALYs sles elimination, to immunize children who missed the expected over the lifetime of vaccinated cohorts relative first dose and protect up to 15 percent of children who to a hypothetical scenario in which the cohorts do not do not seroconvert after primary immunization (WHO receive the vaccinations in question. 2013d). Childhood immunization schedules in many countries include two doses. In countries with poor Hepatitis B Vaccine access to preventive services, the second opportunity Hepatitis B vaccine is included in routine infant immu- for measles vaccination is most often provided through nization schedules to prevent serious disease and death nationwide supplementary immunization activities or later in life caused by chronic infection with hepatitis mass campaigns. B virus, a member of the hepadnavirus family. Hepatitis B virus is a blood-borne pathogen that may also be trans- mitted sexually. Hepatitis B, one of five viruses known to New and Underutilized Vaccines or Vaccine cause hepatitis in humans, is responsible for most of the Strategies Supported by Gavi worldwide hepatitis burden: more than 2 billion people Table 10.1 summarizes the large impact of vaccination have been infected with hepatitis B virus, and 360 mil- for averting death and reducing disease burden in 73 lion have become chronically infected (WHO 2010b). Table 10.1 Impact of Vaccination: Children Immunized and Deaths Averted in 73 Gavi-Supported Countries, Based on Strategic Demand Forecast Version 9 Estimates for 2001–12 Projections for 2013–20 Children Deaths DALYs Children Future deaths Future DALYs immunized averted averted immunized averted averted Hepatitis B 377,000,000 3,400,000 99,000,000 480,000,000 3,700,000 109,000,000 Haemophilus influenzae type B 160,000,000 830,000 52,000,000 440,000,000 1,800,000 126,000,000 Japanese encephalitis (campaign) 83,000,000 19,000 1,000,000 71,000,000 9,000 1,100,000 Japanese encephalitis (routine) 21,000,000 6,000 840,000 93,000,000 20,000 3,300,000 Measles (routine 2nd dose) 71,000,000 90,000 6,000,000 350,000,000 220,000 14,000,000 Measles (campaign) 1,000,000,000 2,800,000 167,000,000 800,000,000 1,900,000 117,000,000 Meningitis A (campaign) 103,000,000 140,000 7,700,000 215,000,000 310,000 14,000,000 Meningitis A (routine) n.a. n.a. n.a. 70,000,000 6,000 430,000 Pneumococcus 11,000,000 70,000 4,900,000 260,000,000 1,500,000 105,000,000 Rotavirus 4,000,000 4,000 320,000 230,000,000 380,000 24,000,000 Rubella (campaign) 105,000,000 20,000 1,800,000 650,000,000 190,000 18,000,000 Rubella (routine) 21,000,000 5,000 500,000 210,000,000 50,000 5,300,000 Yellow fever (campaign) 70,000,000 260,000 8,000,000 140,000,000 170,000 4,400,000 Yellow fever (routine) 84,000,000 540,000 21,000,000 120,000,000 570,000 23,000,000 Sources: Children immunized derived from the World Health Organization–United Nations Children’s Fund Estimates of National Immunization Coverage and United Nations Population Division; vaccine introduction and scale-up scenario based on Gavi Strategic Demand Forecast Version 9; future deaths averted derived from Lee and others (2013); future DALYs averted derived from personal communication with S. Ozawa. Note: Gavi = Gavi, the Vaccine Alliance; n.a. = not applicable; DALY = disability-adjusted life year. 192 Reproductive, Maternal, Newborn, and Child Health Chronic hepatitis B virus infection is the leading cause severe pneumonia; Hib accounted for 25 percent of of cirrhosis and cancer of the liver, which result in severe pneumonia in The Gambia and 22 percent in approximately 600,000 deaths annually (Goldstein and Chile (Levine and others 1999; Mulholland and others others 2005). Hepatitis B virus transmission may occur 1997). Hib pneumonia rates are higher than Hib men- prenatally and during early childhood, adolescence, and ingitis rates; consequently, pneumonia accounted for adulthood. Vaccination is more than 95 percent effective the majority (79 percent) of the approximately 200,000 in infants and more than 72 percent effective in prevent- Hib-related deaths worldwide in children ages 1–59 ing perinatal transmission. Vaccination must be part of a months in 2010 (WHO 2013h). comprehensive prevention strategy. Humans are the only The multiple formulations of Hib conjugate vaccines reservoir of hepatitis B virus, making disease elimination include several different conjugated proteins and com- possible (WHO 2010b). bination vaccines, such as the most widely used pen- Modern hepatitis B vaccines containing recombi- tavalent vaccine (DTP–Hepatitis B–Hib). Hib conjugate nant hepatitis B virus surface antigen (HBsAg) were vaccines are more than 80 percent effective against Hib introduced in 1986 (Van Damme and others 2013). meningitis, sepsis, and bacteremic pneumonia; in most The WHO has recommended routine infant vaccination Sub-Saharan African countries that have introduced Hib against hepatitis B since 1992. In 2013, hepatitis B vac- vaccine into the national program, Hib disease has vir- cine was included in routine infant immunization sched- tually disappeared (Adegbola and others 2005; Cowgill ules in 94 percent of 194 WHO member states. Infant and others 2006; WHO 2006b). However, Hib vaccines immunization schedules include at least three doses likely have reduced efficacy in HIV-infected children, of hepatitis B vaccine, which may be combined with and evidence from South Africa suggests a booster dose other antigens, such as DTP and Haemophilus influenzae might be required (Mangtani and others 2010). In many type b. In 2013, worldwide coverage with three doses settings, three doses of Hib vaccine in infancy may of hepatitis B vaccine was estimated to be 81 percent. control the disease and do not appear to increase rates In countries with a high prevalence of hepatitis B virus of H. influenzae disease caused by serotypes other than infection, the WHO recommends administering the type b (Ribeiro and others 2007; Zanella and others first dose within 24 hours of birth to prevent perinatal 2011). By 2013, 186 countries had introduced Hib vac- transmission. In 2013, 93 countries included hepatitis cines, and as of 2014, all 73 Gavi countries vaccinated B birth dose in their routine immunization schedules, against Hib alongside hepatitis B, diphtheria, tetanus, with global coverage estimated to be 38 percent. Better and pertussis through the pentavalent vaccine as part of birth dose coverage and monitoring are needed; timely their routine infant immunization programs. delivery of birth dose should be a performance measure Future needs include introduction of Hib vaccine of immunization programs (WHO 2013h). into countries that have not yet introduced it, particu- larly in Asia. Haemophilus influenzae Type b Vaccine Haemophilus influenzae is a Gram-negative bacterium Pneumococcal Conjugate Vaccine surrounded by a polysaccharide capsule, which is a Streptococcus pneumoniae, the pneumococcus, is a major virulence factor. While six serotypes (a, b, c, d, Gram-positive encapsulated bacterium commonly found e, f) and unencapsulated strains cause disease—including in the respiratory tract. Pneumococci are surrounded meningitis, pneumonia, septicemia, epiglottitis, cellulitis, by polysaccharide capsules that confer serotype; more septic arthritis, osteomyelitis, and otitis media (mainly than 90 pneumococcal serotypes have been identi- due to unencapsulated H. influenzae)—Hib was the lead- fied, although a limited number cause most disease. ing cause of meningitis in children under age five years in Pneumococcal disease is the leading bacterial cause of most countries before widespread vaccination (Bennett pneumonia in children and also causes meningitis and and others 2002). The mean case fatality rate (CFR) of septicemia. The CFR of pneumococcal disease worldwide Hib meningitis was 67 percent (44 percent to 75 percent) is approximately 5 percent (range 4 percent to 9 percent), in Sub-Saharan Africa and 43 percent (23 percent to but it is more than double that rate in Sub-Saharan Africa 55 percent) globally. In 2000, before widespread Hib (CFR 11 percent; range 7 percent to 18 percent) (O’Brien vaccination, Hib caused an estimated 371,000 deaths and others 2009). About 90 percent of pneumococcal (Watt and others 2009). By 2008, Hib vaccines were deaths are due to pneumonia. Pneumococcal meningi- used in 136 countries, and estimated deaths had fallen to tis, though rare, has a higher CFR of 59 percent (range 203,000 (Black and others 2010; WHO 2013b). 27 percent to 80 percent); it can be as high as 73 percent Evidence from several clinical trials of Hib conjugate in Sub-Saharan Africa. Before widespread pneumococ- vaccine demonstrated the importance of Hib in causing cal conjugate vaccination, pneumococcus caused an Vaccines for Children in Low- and Middle-Income Countries 193 estimated 826,000 deaths (O’Brien and others 2009) in (WHO 2009). Lower-cost rotavirus vaccines are still 2000, and 541,000 deaths among children younger than needed (Bharat Biotech 2011). Infants who receive age five years worldwide in 2008 (WHO 2013b). rotavirus vaccines have a slightly elevated risk of a rare Pneumococcal conjugate vaccines are at least 80 but serious condition called intussusception, which can percent effective against meningitis, septicemia, and bac- result in potentially fatal bowel obstruction, although teremic pneumonia (Lucero and others 2009); like Hib increased incidence of intussusception is small relative vaccines, pneumococcal conjugates likely have reduced to the overall impact of the vaccine (Patel and others efficacy in HIV-infected children (Klugman and oth- 2012; Patel and others 2011). Future needs include ers 2003). Two pneumococcal conjugate vaccines are development of vaccines with improved efficacy in high- currently commercially available; one contains the con- burden countries and introduction of rotavirus vaccine jugated polysaccharides of 10 serotypes, and the other into high-burden Asian countries. contains 13 serotypes. Evidence suggests that declines in disease caused by vaccine serotypes with pneumococcal Rubella Vaccine conjugate vaccine use may be partially offset by increased The rubella virus, a member of the togavirus family, disease due to nonvaccine serotypes (referred to as serotype is one of the most teratogenic viruses known. In the replacement); however, according to one meta-analysis of absence of vaccination, rubella is a common cause of invasive pneumococcal disease in high-income countries, febrile rash illness in children, often misdiagnosed as childhood vaccination resulted in 50 percent reductions measles. Infection of susceptible women early in preg- in pneumococcal disease overall, despite some serotype nancy can result in miscarriage, fetal death, or a constel- replacement (Feikin and others 2013). Introduction of lation of congenital defects known as congenital rubella pneumococcal conjugate vaccine into Asian countries has syndrome (CRS) in up to 90 percent of infected infants. lagged Gavi-supported introduction into Africa. The incidence of rubella and CRS has been reduced in many high-burden countries following implementation Rotavirus Vaccine of rubella vaccination strategies. Rotavirus, a member of the reovirus family, causes watery The goal of rubella vaccination in high-burden diarrhea that can lead to dehydration and death. It is the countries is to prevent the substantial disease bur- leading cause of childhood diarrhea-related mortality den associated with CRS. It is estimated that more worldwide (Parashar and others 2003), responsible for than 100,000 CRS cases occur worldwide each year an estimated 453,000 deaths in 2008 (Tate and others (Vynnycky, Gay, and Cutts 2003). Through 2013, 137 2012). Rotavirus accounts for 35 percent to 50 percent countries have included rubella-containing vaccines of acute severe diarrhea in children, varying by region in national immunization schedules; the introduction (Mwenda and others 2010), with the highest propor- of rubella vaccination in Asia and Sub-Saharan Africa tions in children younger than age one year (Kotloff lags other regions (WHO 2011b). Live-attenuated and others 2013). Unlike bacterial and parasitic causes rubella virus vaccines were first licensed in 1970, of diarrhea, the occurrence of rotavirus diarrhea is but they were not included in EPI programs because not higher in settings with poor water, sanitation, and of concerns that suboptimal vaccine coverage could hygiene. A recent study of moderate-to-severe diarrhea delay age at natural rubella virus infection and result in seven low-income settings found a CFR from rotavi- in higher incidence among women of childbearing rus presenting to a health facility of 2.5 percent (Kotloff age, paradoxically increasing the risk of CRS. Since and others 2013). This figure is higher in areas without 2011, the WHO has recommended introduction of good access to health care (Feikin and others 2012) rubella vaccination strategies as part of measles con- (see Keusch and others 2016, chapter 9 in this volume). trol and elimination activities, taking advantage of Two rotavirus vaccines are commercially available the availability of combined measles-rubella (MR) (WHO 2009). Both have been efficacious in random- and measles-mumps-rubella (MMR) vaccines (WHO ized controlled trials in low-income settings, with effi- 2011b). cacies generally ranging from 50 percent to 80 percent The preferred strategy for the introduction of rubella against rotavirus diarrhea; the lowest efficacy was vaccination is to begin with MR/MMR vaccine in a seen in lower-socioeconomic, higher-mortality coun- campaign targeting a wide range of ages, in combination tries (Armah and others 2010; Madhi and others 2010). with universal childhood vaccination (Reef and Plotkin Nonetheless, because of higher rates of disease in these 2013). The first dose of combined MR vaccine can be deliv- countries, the number of serious rotavirus infections ered at age 9 months or 12 months, depending on the level prevented is likely to be higher, and the WHO strongly of measles virus transmission (WHO 2011b). The effec- recommends rotavirus vaccine use in these countries tiveness is at least 95 percent, even at age 9 months; only 194 Reproductive, Maternal, Newborn, and Child Health one dose of rubella vaccine is required to achieve rubella occur in 31 endemic Sub-Saharan African countries with elimination if high coverage is achieved (WHO 2011b). a total population of 610 million, more than 33 percent of whom live in urban settings. Since the 1980s, yellow Meningococcal Meningitis Serogroup A fever has reemerged in some areas or appeared for the Conjugate Vaccine first time in others. Neisseria meningitidis, also referred to as the menin- Yellow fever vaccines contain live-attenuated virus gococcus, is a Gram-negative encapsulated bacterium and have been used since the 1930s (Monath and others transmitted by respiratory droplets that can cause severe 2013). Routine infant immunization against yellow fever bloodstream infections and meningitis; it is the leading is only recommended in 44 at-risk countries and terri- cause of bacterial meningitis in many LMICs. Explosive tories, of which 35 included yellow fever vaccine in their outbreaks of meningococcal meningitis occur with high routine infant immunization schedules in 2013. A single attack rates and case fatality across broad age ranges. dose of yellow fever vaccine at age nine months or later Six N. meningitidis serogroups (A, B, C, W, X, Y) cause is assumed to provide lifelong immunity. almost all cases, although prevalence varies temporally and geographically. Sub-Saharan African countries from Japanese Encephalitis Vaccine Senegal to Ethiopia in a zone referred to as the meningitis Japanese encephalitis (JE) is the most common cause belt have experienced frequent and devastating epidem- of viral encephalitis in Asia (WHO 2013c). JE virus, ics of meningococcal meningitis, most often caused a flavivirus, is transmitted by mosquitoes in natural by serogroup A meningococcal strains. From 1993 to cycles involving domestic pigs or water birds; human 2012, countries in the meningitis belt reported nearly disease is common in areas with rice cultivation and 1 million meningitis cases, including 100,000 deaths pig farming. Of the estimated 67,900 annual cases in (WHO 2013f). the 24 endemic countries, 51,000 (75 percent) occur Meningococcal vaccines prevent diseases caused by in children ages 0–14 years, resulting in about 10,000 specific serogroups: vaccines against serogroups A, C, W, deaths and 15,000 cases of long-term neuropsychiat- and Y contain purified polysaccharide alone or conju- ric sequelae (Campbell and others 2011). Reported gated to carrier proteins (based on diphtheria or tetanus cases underestimate geographic distribution of risk toxoids), while serogroup B vaccines contain outer mem- because of underreporting and occurrence of disease brane vesicles extracted from outbreak strains with the in less than 1 percent of human infections (Halstead, addition of recombinant proteins. Conjugate vaccines Jacobson, and Dubischar-Kastner 2013). In recent provide better long-lasting immunity, particularly in chil- decades, outbreaks have occurred in several previously dren younger than age two years, and indirect protection nonendemic areas. of unvaccinated groups through the reduction of dis- The WHO recommends the introduction of JE ease transmission. Meningococcal conjugate vaccines have immunization through EPI programs in areas where been introduced into routine immunization programs JE constitutes a public health problem (WHO 2006a). In in many high-burden countries. In 2010, a serogroup 2012, JE vaccines were used in immunization programs A meningococcal conjugate vaccine developed by the in 11 (46 percent) of 24 at-risk countries (WHO 2013c). Meningitis Vaccine Project, with funding from the Bill & The most effective strategy for controlling JE has been to Melinda Gates Foundation, was licensed for use in coun- conduct wide age-range (catch-up) vaccination followed tries in the meningitis belt (LaForce and Okwo-Bele 2011). by routine infant immunization. In upper-middle- and In the Sub-Saharan African meningitis belt, the WHO high-income economies—including Japan; the Republic recommends mass vaccination of the population ages of Korea; and Taiwan, China—routine immunization 1–29 years (WHO 2011a), a highly effective strategy for since 1965 using inactivated, mouse-brain-derived vac- prevention of serogroup A meningococcal disease (Novak cine has successfully controlled the disease (Halstead, and others 2012), followed by routine childhood vaccina- Jacobson, and Dubischar-Kastner 2013). However, dis- tion with a single dose at age 9–18 months (WHO 2015b). advantages of the mouse-brain vaccine include the need for multiple doses, frequent boosting, and high Yellow Fever Vaccine prices (WHO 2006a). In 2013, the WHO and the United Yellow fever is a viral hemorrhagic fever that was one of Nations Children’s Fund approved a live-attenuated JE the most feared epidemic diseases in the world before vaccine from a Chinese manufacturer based on the SA vaccination. Despite the availability of an effective vac- 14-14-2 strain, which induces protection for several cine, yellow fever continues to cause an estimated 84,000 years after one or two doses (WHO 2013g). Approval of to 170,000 severe cases annually, with 29,000 to 60,000 the live-attenuated JE vaccine should increase access in deaths (WHO 2013e). Most reported cases and deaths endemic countries. Vaccines for Children in Low- and Middle-Income Countries 195 Additional and Future Vaccines with Potential Public safety signals to the vaccine (WHO 2015d). The WHO is Health Impacts in Young Children considering these recommendations and was expected to Malaria Vaccine provide guidance in early 2016. RTS,S/AS01 may become Approximately 198 million malaria cases and 584,000 the first malaria vaccine licensed for use in children in malaria deaths occurred globally in 2013; most deaths Sub-Saharan African countries (RTS,S Clinical Trials were in young children living in Sub-Saharan Africa Partnership 2015). (WHO 2015c). Plasmodium falciparum is the most vir- ulent of the five Plasmodium species that cause human Influenza Vaccine malaria. The RTS,S/AS01 candidate malaria vaccine Influenza viruses are orthomyxoviruses that cause respi- is a partially effective vaccine that targets the pre- ratory illness, ranging from mild febrile illness to severe erythrocytic stage of the P. falciparum parasite resulting pneumonia. Because influenza viruses change rapidly, in a reduction in the number of clinical malaria episodes vaccines are reformulated and delivered annually through experienced. RTS,S/AS01 recently underwent testing in a routine immunization or seasonal campaigns. Influenza large phase 3 clinical trial, the final stage before licensure. viruses infecting humans are transmitted person to per- In total, 15,460 children and young infants participated son, mostly by droplets and aerosols from the respiratory in the trial, which was conducted at 11 sites in seven Sub- secretions of infected people. Influenza viruses cause sea- Saharan African countries across a wide range of malaria sonal influenza epidemics, mostly in the winter months transmission levels (RTS,S Clinical Trials Partnership in temperate climates, with less distinct seasonality in the 2015). Among children ages 5–17 months at first vacci- tropics. Influenza has an annual attack rate of 5 percent to nation followed for a median of 48 months, RTS,S/AS01 10 percent in adults and 20 percent to 30 percent in chil- vaccine efficacy against clinical malaria was 37 percent dren. When complicated by subsequent bacterial pneu- (95 percent confidence interval 32–41) when the pri- monia, influenza infections can have high mortality rates. mary vaccination series of three doses administered In general, the role of influenza in LMICs has been under- monthly was followed by a booster given 18 months estimated. A review suggests that 6.5 percent of hospital after the primary vaccination series, and 28 percent admissions for respiratory illness among Sub-Saharan (95 percent confidence interval 23–33) when no booster African children were due to influenza (Gessner, Shindo, was given. Vaccine efficacy was lower in young infants and Briand 2011). Another meta-analysis estimates that who received the primary vaccination series coadmin- 28,000 to 111,500 influenza-associated deaths occur istered with EPI vaccines beginning at ages 6–12 weeks: annually in children, with 99 percent occurring in LMICs 26 percent (95 percent confidence interval 20–32) with (Nair and others 2013). a booster and 18 percent (95 percent confidence interval Licensed influenza vaccines include inactivated or 12–24) without. Despite modest efficacy estimates, the live-attenuated influenza type A and B viruses. Inactivated impact was substantial: 1,774 cases of clinical malaria influenza vaccines (IIVs) are administered by injection; were averted per 1,000 children vaccinated when a live-attenuated virus vaccines are delivered as nasal spray. booster was administered; 1,363 cases were averted with- Only IIV is licensed for children younger than age two out a booster. The number of cases averted per 1,000 years. Two doses of influenza vaccine given four weeks young infants was 983 in those who received a booster apart are recommended during the first season a child is and 558 in those who did not. Meningitis and febrile vaccinated. Vaccine effectiveness varies annually accord- seizures were reported more frequently in those who ing to protection provided against circulating influenza received the RTS,S/AS01 primary vaccination series than viruses, but in general, vaccination has provided signifi- in those in the comparator group. cant protection in children (Jefferson and others 2012), In July 2015, the European Medicines Agency issued although few studies of vaccine effectiveness have been a positive scientific opinion on RTS,S/AS01 for the conducted among children in LMICs (WHO 2012b). prevention of malaria in children in Sub-Saharan Maternal influenza immunization has gained support as Africa. Subsequently, the WHO’s Strategic Advisory a way of protecting infants too young to be vaccinated Group of Experts on Immunization and the Malaria against influenza disease. A study in Bangladesh shows Policy Advisory Committee reviewed the evidence on that giving influenza vaccine to pregnant women led to an RTS,S/AS01 efficacy and safety as well as other relevant efficacy of 63 percent against lab-confirmed influenza and information surrounding vaccine implementation. In 29 percent against febrile respiratory illness in their infants’ October 2015, the WHO advisory groups recommended first six months of life (Zaman and others 2008). Maternal the implementation of the vaccine through pilot projects influenza vaccination with IIV is now recommended in designed to better understand how well the vaccine can some countries and is being studied in LMICs as a method be implemented and to further assess the relationship of for preventing influenza in young infants (CDC 2013; 196 Reproductive, Maternal, Newborn, and Child Health WHO 2012a). No cost-effectiveness data on the use of COST AND COST-EFFECTIVENESS OF influenza vaccine in LMICs are available. The WHO VACCINATIONS suggests that countries make their respective decisions on influenza vaccines based on local disease burden, resources, Cost capacity, and other health priorities (WHO 2012a). Despite the relatively low cost of traditional EPI vaccines, more than 20 million infants did not receive the third Oral Cholera Vaccine dose of DTP-containing vaccine in 2013; the majority Cholera is caused by ingestion of toxigenic serogroups of these children lived in five countries: the Democratic (O1 and O139) of Vibrio cholerae bacteria, leading to Republic of Congo, Ethiopia, India, Nigeria, and Pakistan. diarrhea, dehydration, and rapid death. Periodically, National EPI programs have evolved in the past 15 years; new strains of V. cholerae emerge to cause pandemics. the WHO universally recommends vaccines against 11 In 1970, the seventh pandemic strain appeared in Sub- different diseases for infants—tuberculosis, hepatitis B, Saharan Africa, where it is now endemic and accounts for polio, diphtheria, tetanus, pertussis, Hib, pneumococ- the majority of cholera mortality (Mintz and Guerrant cus, rotavirus, measles, and rubella. As more countries 2009). Cholera incidence and mortality is greatest in chil- increase coverage of new and underutilized vaccines, the dren (Ali and others 2012; Deen and others 2008), who cost of fully immunizing a child increases. account for 50 percent of all cholera deaths. Globally, The costs of delivering existing and new vaccines to cholera kills at least 45,000 children under age five years beneficiary populations can be challenging to quan- annually; this number is likely to be twice as high when tify, especially over time with the introduction of new considering out-of-hospital mortality (Ali and others vaccines. Early studies of the principal EPI vaccines 2012; Sack 2014). In 2010, cholera was introduced into estimated the cost of fully immunizing a child to range Haiti following a massive earthquake, causing more than from US$10 to $US20, depending on the region and 500,000 cases (Barzilay and others 2013). Although the place of vaccine delivery (Brenzel and Claquin 1994). cholera CFR can be less than 1 percent in settings with Using more recent immunization financing data after good access to health care and proper treatment, these the advent of Gavi (from Financial Sustainability Plans), conditions rarely exist in most LMICs, where CFRs often the cost of fully immunizing a child in 50 of the poorest exceed 5 percent and can be as high as 50 percent during Gavi-eligible countries was estimated to increase from outbreaks (Gaffga, Tauxe, and Mintz 2007; WHO 2010a). US$6.00 to US$17.50 per infant with the addition of There are two WHO-approved oral cholera vaccines, hepatitis B and Hib vaccines and increased coverage which contain formalin-inactivated or heat-killed whole- (Lydon and others 2008). An updated estimate in Gavi- cell V. cholerae. One vaccine showed greater than 80 eligible countries based on financial data from the WHO percent effectiveness against cholera for at least the first six (Comprehensive Multi-Year Plans) increased the cost to months after administration (Clemens, Sack, and Ivanoff US$23 per infant for 2008–11, increasing to a projected 2001; van Loon and others 1996); the second showed cost of US$42 per infant in 2016 (Brenzel, Young, and 67 percent effectiveness against cholera during the first Walker 2015). There was substantial variability by WHO two years of follow-up among children vaccinated at ages region, with Europe having the highest costs and South- 1–4 years (Sur and others 2011). East Asia and the Western Pacific regions the lowest; These vaccines were cost-effective in a crowded city more than one-third of the total projected cost of vacci- like Kolkata, India, at US$1 per dose; they would likely nation from 2011 to 2020 (US$57.5 billion) is expected be cost-effective in other settings, such as Sub-Saharan to be spent in India, Nigeria, and Pakistan (Gandhi and Africa, if significant herd protection occurs with the others 2013). Non-vaccine delivery costs can account for vaccine, as has been hypothesized. In 2010, the WHO nearly half of the total costs of vaccination (Brenzel 2015; recommended use of oral cholera vaccines in addition Gandhi and others 2013; Lydon and others 2008). to other preventive strategies, such as provision of safe As highly effective yet more expensive vaccines water, in cholera-endemic countries or areas likely to become available, many countries with already-strained experience outbreaks, with priority for vaccination given resources will have to find the right balance between to children in settings of limited vaccine supply (Jeuland increasing coverage with available vaccines in often and others 2009; Longini and others 2007; WHO 2010a). hard-to-reach areas or introducing new vaccines into the For vaccination during large outbreaks like those in national immunization schedule. Haiti and Zimbabwe (Ahmed and others 2011; Barzilay A systematic review of cost-effectiveness analyses and others 2013), the WHO plans to create an emer- from 44 published articles of 23 vaccines in 51 countries gency stockpile of 2 million doses of cholera vaccine finds that vaccines cost less than US$100 per DALY (Martin, Costa, and Perea 2012). averted in more than half of the articles, and less than Vaccines for Children in Low- and Middle-Income Countries 197 US$1,000 per DALY averted in nearly 90 percent of the first six months of life, for example, pertussis and Hib. articles (Horton, Wu, and Brouwer 2015). Additionally, timely vaccination ensures maximal herd Table 10.2 shows the relative cost-effectiveness of immunity and protects those who are too young to different vaccines using the accepted metric of cost per be fully vaccinated (Akmatov and others 2008; Clark DALY averted. For comparison, if the cost per DALY and Sanderson 2009; Patel and others 2011). A review averted for an intervention is less than per capita gross of immunization timeliness in 45 countries found national income (GNI), it is very cost-effective; if less a median delay of six weeks for receipt of DTP3; in than three times per capita GNI, it is cost-effective (WHO countries with the greatest delays, 25 percent of chil- 2001). Those vaccines in the third column are very dren received DTP3 at least 19 weeks late (Clark and cost-effective in upper-middle-income countries, as long Sanderson 2009). as cost per DALY does not exceed US$4,087, the cutoff in Fully immunized children who receive on-time 2012 between lower-middle- and upper-middle-income vaccinations obtain the greatest protection and great- countries, per the World Bank. A more detailed analysis est reduction of the risk of mortality in the first six of cost-effectiveness of vaccines is presented in chapter 17 months of life from preventable childhood diseases. in this volume (Horton and Levin 2016). Such immunization also conveys broader direct social and economic benefits, leading to greater adult pro- ductivity and contributing to economic development. Direct Social and Economic Benefits Directly averting illness through immunization can Immunization coverage has traditionally been moni- lead to lower medical costs and missed wages by tored using DTP3 coverage or measles vaccine coverage caretakers. Vaccines that prevent diseases that cause as indicators. Most countries now deliver DTP through disabilities have improved school enrollment and newer combination vaccines—for example, as of 2014, all attainment rates (Simmerman and others 2006) and 73 Gavi countries were using the pentavalent vaccine that cognitive ability linked to test scores (Bloom, Canning, combines Hib and hepatitis B with DTP. However, even and Seiguer 2011), thereby increasing a population’s though DTP3 coverage in 2013 was high—84 percent human capital in the long term (Bloom, Canning, globally and 76 percent in the 73 Gavi countries— and Jamison 2004). Ozawa and others (2012) quantify fewer than 5 percent of children received all 11 WHO- the impact of vaccination on health care cost saving, recommended immunizations. Clearly, immunization care-related productivity gains, and outcome-related platforms are effective in reaching many children with productivity gains. some vaccines, but large gaps in protection remain. Most of the evidence on the economic benefit of vac- The timeliness of vaccination is critical, particularly cines has been for health care savings and care-related for diseases for which most mortality occurs in the productivity gains that directly affect the finances of Table 10.2 Approximate Range of Cost-Effectiveness of Various Childhood Vaccines, Various Contexts (2012 U.S. dollars per DALY averted) < US$100/DALYa US$100 to