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Community-Based Interventions for Improving Perinatal and Neonatal Health Outcomes in Developing Countries: A Review of the Evidence

Zulfiqar A. Bhutta, MBBS, FRCPCH, PhD^*, Gary L. Darmstadt, MD, MS, FAAP^,, Babar S. Hasan, MD^* and Rachel A. Haws, MHS

^* Department of Pediatrics and Child Health, Aga Khan University, Karachi, Pakistan
Saving Newborn Lives Initiative, Office of Health, Save the Children/USA, Washington, DC
Department of International Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD

	ABSTRACT

TOP ABSTRACT EXECUTIVE SUMMARY INTRODUCTION AND BACKGROUND METHODOLOGY USED FOR LITERATURE... REVIEW AND ANALYSIS OF... Intrapartum Interventions Postnatal Interventions COST-EFFECTIVENESS OF COMMUNITY... SUMMARY CONCLUSIONS REFERENCES

 
Background. Infant and under-5 childhood mortality rates in developing countries have declined significantly in the past 2 to 3 decades. However, 2 critical indicators, maternal and newborn mortality, have hardly changed. World leaders at the United Nations Millennium Summit in September 2000 agreed on a critical goal to reduce deaths of children <5 years by two thirds, but this may be unattainable without halving newborn deaths, which now comprise 40% of all under-5 deaths. Greater emphasis on wide-scale implementation of proven, cost-effective measures is required to save women’s and newborns’ lives. Approximately 99% of neonatal deaths take place in developing countries, mostly in homes and communities. A comprehensive review of the evidence base for impact of interventions on neonatal health and survival in developing-country communities has not been reported.

Objective. This review of community-based antenatal, intrapartum, and postnatal intervention trials in developing countries aimed to identify (1) key behaviors and interventions for which the weight of evidence is sufficient to recommend their inclusion in community-based neonatal care programs and (2) key gaps in knowledge and priority areas for future research and program learning.

Methods. Available published and unpublished data on the impact of community-based strategies and interventions on perinatal and neonatal health status outcomes were reviewed. Evidence was summarized systematically and categorized into 4 levels of evidence based on study size, location, design, and reported impact, particularly on perinatal or neonatal mortality. The evidence was placed in the context of biological plausibility of the intervention; evidence from relevant developed-country studies; health care program experience in implementation; and recommendations from the World Health Organization and other leading agencies.

Results. A paucity of community-based data was found from developing-country studies on health status impact for many interventions currently being considered for inclusion in neonatal health programs. However, review of the evidence and consideration of the broader context of knowledge, experience, and recommendations regarding these interventions enabled us to categorize them according to the strength of the evidence base and confidence regarding their inclusion now in programs. This article identifies a package of priority interventions to include in programs and formulates research priorities for advancing the state of the art in neonatal health care.

Conclusions. This review emphasizes some new findings while recommending an integrated approach to safe motherhood and newborn health. The results of this study provide a foundation for policies and programs related to maternal and newborn health and emphasizes the importance of health systems research and evaluation of interventions. The review offers compelling support for using research to identify the most effective measures to save newborn lives. It also may facilitate dialogue with policy makers about the importance of investing in neonatal health.

Abbreviations: ARI, acute respiratory infection • CCS, case-control study • CHW, community health worker • CI, confidence interval • CKMC, community-based application of kangaroo mother care • CQ, chloroquine • DBRCT, double-blind, randomized, controlled trial • DBRPCT, double-blind, randomized, placebo-controlled trial • EFA, essential fatty acid • EPI, Expanded Programme on Immunization • FHW, family health worker • Hb, hemoglobin • HBeAg, hepatitis B virus "e" antigen • HBsAg, hepatitis B surface antigen • HBV, hepatitis B virus • HDN, hemorrhagic disease of the newborn • IM, intramuscular • IMR, infant mortality rate • IPT, intermittent presumptive treatment • ITN, insecticide-treated bed net • IUGR, intrauterine growth restriction • IV, intravenous • IVH, intraventricular hemorrhage • KMC, kangaroo mother care • LBW, low birth weight • NIB, untreated bed net • NIH, National Institutes of Health • NMR, neonatal mortality rate • NTD, neural tube defect • OR, odds ratio • PCS, prospective cohort study • PMR, perinatal mortality rate • PROG, proguanil • PPROM, preterm premature rupture of membranes • PROM, premature rupture of membranes • QT, quasi-experimental trial • RCS, retrospective cohort study • RCT, randomized, controlled trial • RDA, recommended dietary allowance • RPCT, randomized, placebo-controlled trial • RPR, rapid plasma reagin • RR, relative risk • SEARCH, Society for Education, Action and Research in Community Health • SGA, small for gestational age • SP, sulfadoxine-pyrimethamine • STD, sexually transmitted disease • TBA, traditional birth attendant • TEWL, transepidermal water loss • TT, tetanus toxoid • UNICEF, United Nations Children's Fund • UTI, urinary tract infection • VLBW, very low birth weight • WHO, World Health Organization • WIC, Women, Infants, and Children Supplemental Nutrition Program • VHW, village health worker

	EXECUTIVE SUMMARY

TOP ABSTRACT EXECUTIVE SUMMARY INTRODUCTION AND BACKGROUND METHODOLOGY USED FOR LITERATURE... REVIEW AND ANALYSIS OF... Intrapartum Interventions Postnatal Interventions COST-EFFECTIVENESS OF COMMUNITY... SUMMARY CONCLUSIONS REFERENCES

 
Background
Although there has been considerable improvement in child health globally, it is increasingly evident that important gaps and disparities remain. In particular, it is apparent that a disproportionate burden of infant and under-5 childhood mortality relates to deaths within the neonatal period, which frequently occur within the first few days after birth. Moreover, the vast majority of perinatal and neonatal deaths occur in conditions of socioeconomic deprivation in developing countries. As the health of the newborn infant is inexorably tied to the health of the mother, strategies to improve the health and care of women in low-resource communities and countries are also expected to improve both pregnancy and neonatal health outcomes. However, although it is true that poverty, illiteracy, poor status and care of women, as well as dysfunctional health systems are critical underlying factors that adversely affect maternal and child health in many developing countries, these factors are relatively difficult to change in the short term. Moreover, in sub-Saharan Africa, the devastating epidemic of human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) threatens to reverse many of the gains achieved during decades of child health programming. This review does not attempt to evaluate the benefits of investing in social development, reducing inequity, and promoting economic growth among impoverished populations of developing countries. Although these are important long-term goals, pragmatic reality in most developing countries dictates the need for wide-scale implementation now of evidence-based, cost-effective health programs and interventions to improve child health outcomes. Moreover, achievement of Millennium Development Goal 4 to reduce under-5 mortality by two thirds by the year 2015 is critically dependent on a substantial reduction in neonatal mortality over the next decade.

The objectives of this review of community-based antenatal, intrapartum and postnatal intervention trials in developing countries were to (1) identify key behaviors and interventions for which the weight of evidence is sufficient to recommend their inclusion in community-based neonatal care programs and (2) identify key gaps in knowledge and priority areas for future research and program learning.

Methods
Current practice of summarizing evidence for the impact of interventions through meta-analyses of randomized, controlled trials (RCTs), although of high scientific validity, has more limited relevance when applied to research in developing countries, because most studies meeting the rigorous criteria for inclusion in such analyses were conducted in developed-country settings. In addition, the evidence base made up of interventions deriving from effectiveness trials in health system settings is scanty. In this review, we evaluated the available evidence in the global literature for the benefits and impact of various community-based interventions during the antenatal, intrapartum, and postnatal periods on perinatal and neonatal health status outcomes. The selection of interventions was based on biological plausibility and inclusion as a component in programs of maternal and/or perinatal health care. We did not, however, review the evidence for impact of skilled birth attendants, because this is the subject of other reviews.^1–4 The scientific evidence available from individual interventions or combinations thereof was reviewed, and information from programs and effectiveness trials that used packages of interventions was specifically solicited and analyzed. Although our principal focus was to seek information from community-based RCTs, we extended the evaluation to include studies with a variety of other, less rigorous designs. A few studies with a quasi-experimental trial (QT) design were included, especially if they represented information from developing countries and pertained to an intervention with little other evidence base. Community was defined as extending from the household to the peripheral health facility level; in general, studies at secondary or tertiary referral-level health facilities were excluded. However, where evidence for key interventions from community-based settings was sparse or not available, information was included from facility-based settings in developing countries and occasionally from the developed world. The evidence from developed-country studies, however, was used primarily to provide perspective and context for conclusions drawn from developing-country data. Evidence from the Cochrane database of RCTs and the World Health Organization (WHO) Reproductive Health Library was also considered, and studies from developing countries that were included in the Cochrane Reference Library were specifically evaluated. We also complemented the review of the scientific evidence based on intervention trials in developing countries with an assessment of public health programs and interventions currently in place; recommendations from the WHO and other expert institutions and individuals; and biological plausibility and evidence from developed-country studies.

Sources for potentially eligible studies included journal articles, book chapters, technical reports, conference proceedings, and theses. The search for community-based evidence encompassed all available electronic health and social science reference libraries (including indexed and nonindexed journals), and manual reviews of Safe Motherhood and Child Survival books and technical reports. Additional details were solicited directly from most agencies and institutions involved in community-based care in developing countries, especially Reproductive Health, Safe Motherhood, or Child Survival programs. Most leading global public health researchers in the field of perinatal and maternal care were also individually approached for information and unpublished material. It is important to underscore that, although we specifically sought evidence from RCTs, we were cognizant of the danger of relying on RCTs as the sole source of evidence for interventions,⁵ especially in terms of consistency⁶ and external validity.⁷ This is especially true for those interventions that must be nested within health systems.⁸

The principal reviewers independently evaluated the data, and a common reporting matrix was used in summarizing the findings. Studies were evaluated for size, setting, quality, and design, ie, either efficacy or effectiveness trials.⁹ The final categorization and assessment of evidence for impact of the interventions was made by mutual agreement and consensus. Emphasis was placed on assessment of impact on perinatal or neonatal primary health status outcomes. However, for some interventions for which data on primary health status outcomes were lacking, other indicators were considered.

The evidence from various interventions was categorized as follows:

1. No evidence of benefit: These interventions had been evaluated and found to have no demonstrable benefit either singly or in combination with other measures. In some cases, there was evidence of an adverse effect of the intervention. Therefore, these interventions were not recommended for inclusion in neonatal health care strategies.
   
2. Uncertain evidence of benefit: This category included interventions for which there was some evidence of benefit, but contradictory evidence or issues such as study design, location, or size precluded any firm conclusions. These interventions merited additional evaluation or research in developing-country community settings using well-designed protocols.
   
3. Some evidence of benefit: These interventions had some positive impact on perinatal and/or neonatal outcomes, but the evidence remained preliminary or the location of studies was not representative of the developing world at large. Furthermore, the trial designs were mostly efficacy studies, and therefore their effectiveness, if any, in large-scale programmatic interventions remained to be assessed. Inclusion of interventions in this category in neonatal health programs was considered optional, but a recommendation was made to evaluate the benefits whenever these interventions were implemented.
   
4. Clear evidence of benefit: This category of interventions was of incontrovertible benefit to mothers and/or newborn infants, and thus it was recommended that they be included in community-based intervention programs for maternal and neonatal care.
   

This report principally presents the initial analysis of the data based on quality and availability of the evidence. We do not report the projections of the impact of these interventions, either singly or combined as packages, on the global or regional burden of neonatal mortality. A preliminary exercise of this nature on a limited number of maternal and neonatal interventions was conducted by the Bellagio Child Survival Study Group,¹⁰ and a comprehensive analysis is forthcoming in the Lancet Neonatal Survival Series in March 2005.

Results
We found a paucity of data from community-based settings in developing countries and a remarkable lack of large-scale effectiveness trials of a number of key interventions, especially in relevant health system settings. A total of 186 studies from developing countries were identified for in-depth review, of which only 64 were community-based studies reporting primary perinatal/neonatal health status outcomes such as stillbirths and perinatal and/or neonatal mortality, and 74 were community-based studies reporting secondary perinatal/neonatal health outcomes such as low birth weight (LBW) and/or anthropometrics, preterm birth, breastfeeding rates, and morbidities (Table 1). Of these studies reporting health outcomes, there were very few RCTs: 31 community-based RCTs reported primary neonatal health outcomes, and 40 reported secondary neonatal health outcomes. Only 10 studies were interventions conducted in health system settings, or effectiveness trials. Most interventions had been tested on relatively small numbers of individuals. There was also wide variation in the quality, size, location, design, and publication source of studies. This variability was considered while summarizing the information, although we refrain from direct comment on the quality of the evidence in individual studies, Table 2 (summarizing the strength of the evidence) represents a categorical ranking of interventions based on review of individual studies. In addition, however, as noted above, the evidence was placed in the context of biological plausibility and knowledge from developed countries, experience with the intervention in the context of health programs, and recommendations from the WHO and other leading maternal and child health agencies.

Implications for Programs
This review of evidence from developing-country community-based trials for impact of antenatal, intrapartum, and postnatal interventions on perinatal and neonatal outcomes highlights the paucity of available information, particularly from RCTs. Cost-effectiveness data were found to be almost entirely unavailable. The relative paucity of evidence for impact of interventions on neonatal mortality was also apparent in the recent analysis of the Bellagio Child Survival Study Group,¹⁰ which nevertheless included several neonatal interventions because of their proven impact on infant and child survival. Not withstanding the above exercise, to broaden the relevance of the conclusions that can be drawn from the available data, we attempted to place the evidence in the context of biological plausibility, data from studies in developed countries, programmatic experience, and recommendations by the WHO and other leading child health agencies. In so doing, it is clear that the evidence for benefit of a number of interventions (Table 2) warrants their broad programmatic implementation (Fig 1). Interestingly, this group of evidence-based interventions closely resembles those advocated by the WHO^14–16 and also identified recently through a strategic planning process at the international level and in multiple countries, led by the Saving Newborn Lives Initiative of Save the Children/USA.¹⁷ Thus, there seems to be broad convergence of expert opinion and the evidence base regarding priority interventions to advance perinatal and neonatal health and survival at the community level. Considering past experience of child health programs in implementation of various interventions and current recommendations of the WHO and leading child health agencies, a few additional interventions (marked with an asterisk) have been added to Fig 1 despite the lack of rigorous, prospective scientific evidence for their impact. These interventions include birth preparedness; recognition of and appropriate response to danger signs in the antenatal period; skilled health care at delivery (evidence reviewed elsewhere); recognition of and response to intrapartum danger signs; and early postnatal visitation for provision of anticipatory guidance and recognition/management of maternal and newborn illness. Many of these interventions have been included in comprehensive packages of maternal and newborn interventions but have not been evaluated per se for their specific contribution to the total impact of the package of care. Such evaluations must now be regarded as a priority, especially in health system settings.

View larger version (38K): [in this window] [in a new window]   Fig 1. Summary of priority antepartum, intrapartum, and postnatal interventions for inclusion in programs of maternal and neonatal health care, based on assessment of available evidence for impact on perinatal and neonatal health status. * indicates essential elements of the Saving Newborn Lives conceptual framework for advancing newborn health and survival, which either were not reviewed in this report or for which evidence is lacking (see "Methods").

Pivotal questions regarding implementation of neonatal health care programs that demand additional operational research include: Which cadre of health workers in various settings can most effectively deliver the needed services for newborns at the community level, and how can they be linked effectively with referral facilities to provide care for maternal and neonatal illness? How will these workers be trained and supervised in a sustainable manner at scale, and what are the most effective methods for preservice and in-service training? What will be the scope of their service delivery (eg, with regard to client age, breadth of services, and geographic reach)? Is a team of skilled birth attendants and newborn care providers needed at the community level to provide simultaneous care for the mother and newborn during the critical intrapartum period?

The Save the Children/USA conceptual framework for newborn care at the community level¹⁷ calls for provision of both preventive and curative care, particularly for birth asphyxia and infections. However, in many settings, provision of curative care for these major causes of neonatal mortality is beyond the capacity of current health care systems. Thus, critical unanswered questions are: Can effective implementation of a behavior-change communications package at the domiciliary level, without active identification and management of newborn illness, improve neonatal outcomes? What is the added benefit and cost-effectiveness of active identification and management of neonatal illness, particularly serious bacterial infections and intrapartum hypoxia/birth asphyxia? What are the most feasible and effective ways to deliver life-saving newborn resuscitation and antibiotic therapy in the community? How can barriers to care seeking for newborn illness be overcome most effectively so that home-based care and care seeking can be effectively linked with referral-level care at facilities? What is the impact and cost-effectiveness of postnatal visitation for promotion of healthful behaviors and recognition of neonatal illness? Can the same worker address the postnatal needs of both mothers and newborns? What is the optimal timing and number of routine visits with a health care provider?

Skilled care during delivery is universally recognized as a major long-term priority for improving the care of mothers and newborns, and plans for advancing health system capabilities for providing this care are paramount. Based on a consideration of the fact that most births and neonatal deaths occur at home during the early neonatal period, due to birth asphyxia and/or infections, and among LBW infants, the following emerge as major research gaps:

1. Understanding and improving household and community practices and their determinants: Local formative research is needed to better understand local beliefs and practices and the reasons behind them so that effective behavior-change strategies can be developed and evaluated.²³ This must be followed by appropriate research to develop intervention strategies to improve care-seeking behaviors at the household and community levels.
   
2. Improving health systems' capacity for providing essential preventive and special curative neonatal health care: As noted above, some of the most challenging questions in neonatal health care relate to how to most effectively deliver services to newborns in an integrated way within existing programs for maternal and child health.^20–22 Although difficult, determining the answers to these questions requires that many packages and combinations of interventions be tested through effectiveness trials in health system settings.
   
3. Preventing and improving recognition and management of birth asphyxia: Identification of sustainable interventions for management of intrapartum hypoxia/birth asphyxia is urgently needed at the community level.²⁴ Solutions must allow for immediate response at the time of delivery in a cost-effective manner and necessarily will require integration with skilled health care for mothers at delivery¹⁶ and links with referral facilities.
   
4. Preventing and improving recognition and management of infections: There is an urgent need to identify how the burden and severity of maternal infections relate to perinatal outcomes. These infections may range from subclinical intrauterine infection and bacterial vaginosis to overt genital tract infections that may lead to preterm labor. The true burden of bacterial neonatal infections in community settings is also unclear, because many clinical bacterial infections may represent viral infections. Narrowing this information gap is vital; to devise optimal antibiotic treatment strategies for neonatal infections,²⁵ we need to know the agents of life-threatening infections in the community and their antibiotic susceptibility patterns.²⁶ There is additional need for validated algorithms for accurate and rapid identification of infected neonates by community health workers (CHWs) and caregivers. We also must advance antibiotic-treatment strategies for serious infections, which may include simplified antibiotic-delivery systems and/or regimens. The potential development and evaluation of simplified oral treatment regimens that include oral administration will be a major advance for public health programs.
   
5. Preventing and improving care for LBW infants: Given that the majority of newborns who die in many developing countries are LBW, improved strategies for both prevention of and care for LBW infants are urgently needed. These strategies include interventions to reduce preterm births and the incidence of intrauterine growth restriction (IUGR) or combinations thereof. Prevention may be achieved by improved maternal nutrition and detection and treatment of maternal infections. Improved postnatal care of LBW infants may be achieved in part by behavior-change communications, topical emollient therapy, breastfeeding promotion, and widespread implementation of culturally adapted methods for skin-to-skin care (or variations thereof) with the mother and (when indicated) other household members. The development, validation, and availability of low-cost technology for the care of LBW infants in primary and secondary health care facilities is an important adjunct to community-based management strategies.
   
6. Improving information on the magnitude and causes of neonatal mortality: Lack of accurate global, regional, and country-specific data on the magnitude and causes of perinatal and neonatal morbidity and mortality currently is limiting advocacy and program planning in newborn health. Strengthening of information systems, including birth and death registration, and dissemination of information at local levels about causes of newborn morbidity and mortality (and their determinants), are needed to guide resource allocation and program and research priorities. Moreover, as programs incorporate newborn care, their impact must be monitored and accurate data fed back to those involved in health policy and program decision-making to enable them to use scarce resources more effectively. Integral to documenting and monitoring newborn health status is the need for improved verbal autopsy instruments to enable more accurate determination of causes of perinatal and neonatal deaths in the community and to assess the contribution of sociocultural and logistic factors. Perinatal audit may also be a powerful tool for identifying avoidable factors in deaths and mobilizing change in communities to improve maternal and neonatal health care.
   
7. Cost-effectiveness analyses: Assessment of cost-effectiveness must be incorporated into neonatal health research to guide selection of interventions and stimulate investment in neonatal health.
   
8. Development of indicators and simple management tools for assessing and monitoring health system performance for perinatal and newborn care at the national level: An important impediment to wider implementation of neonatal health programming is lack of inclusion of perinatal and neonatal health indicators among global indicators for measuring progress in child survival (eg, Millennium Development goals). Moreover, programs too often fail to monitor adequately and demonstrate the effectiveness of their programs. Tools for rapidly assessing the situation, prioritizing program activities, and accurately monitoring and documenting program effectiveness are urgently needed.
   

A major factor currently limiting our ability to identify effective interventions is the wide variation in study designs and indicators for assessing impact and the almost complete absence of cost-effectiveness data. In 2001, a group of neonatal health researchers met to discuss a common agenda and methodologies for neonatal health research in developing-country communities.²⁷ Our review further highlights the need, as recommended at that time, for dialogue among researchers, policy makers, program managers, and donors in the selection of research priorities, use of common (and, whenever possible, rigorous) study designs, and for sharing of data-collection instruments and research results.

Conclusions
A paucity of community-based data are available from developing countries on health status impact of many interventions that are currently considered for inclusion in health programs for newborns. However, a review of the evidence and consideration of the broader context of knowledge, experience, and recommendations regarding these interventions enabled us to categorize the interventions according to the strength of the evidence base and confidence that the intervention could be implemented widely and would improve perinatal and/or neonatal survival. As a result, a package of priority interventions for inclusion in programs was identified, and research priorities for advancing the state-of-the-art in neonatal health care were formulated. Thus, this review can serve as a guide for development of evidence-based maternal and newborn health care programming at the community level and for selection of research to advance community-based neonatal care. It also may facilitate dialogue with policy makers about the importance of investing in newborn health.

Clearly, there is ample evidence for benefit of several interventions, and, in many cases, operational questions of how to implement the intervention(s) in an affordable and acceptable manner at scale were of overriding concern. Thus, although there is great need for continued research on the cost-effectiveness of a number of interventions, it must not hamper implementation now of many interventions of known impact at wider scale. However, it is important that these intervention packages be structured as integrated maternal and newborn care strategies that can be implemented in appropriate health system settings. Close communication between program managers as they gain experience with intervention implementation, the researchers who can provide answers to operational questions, and the donors who fund the work will be critical to advancing maternal and neonatal health care at the community level.

	INTRODUCTION AND BACKGROUND

TOP ABSTRACT EXECUTIVE SUMMARY INTRODUCTION AND BACKGROUND METHODOLOGY USED FOR LITERATURE... REVIEW AND ANALYSIS OF... Intrapartum Interventions Postnatal Interventions COST-EFFECTIVENESS OF COMMUNITY... SUMMARY CONCLUSIONS REFERENCES

 
Infant and under-5 childhood mortality rates in developing countries have declined significantly in the past 2 to 3 decades, whereas neonatal mortality rates (NMRs) have remained relatively static.^18,20,24,28 Neonatal mortality, amounting to an estimated 4 million deaths worldwide each year, now comprises nearly two thirds and two fifths of infant and under-5 childhood mortality, respectively, in developing countries,²⁹ and 98% of global neonatal mortality occurs in developing countries.³⁰ An equal number of deaths are thought to occur during the last trimester of pregnancy, although data precisely quantifying the burden of stillbirths are lacking. Unfortunately, most of the countries with high rates of perinatal and neonatal deaths also have the lowest rates of vital registration of births and deaths.^31,32 Moreover, the likelihood of missing live births is highest for very low birth weight (VLBW) infants,³³ and rates of LBW are highest in developing countries, especially Asia.¹⁸ In addition, neonatal health indicators are seldom included in Safe Motherhood or Child Survival program evaluations, nor are they among the outcomes of interest of global agencies and initiatives. Thus, current estimates of perinatal and neonatal mortality, although startlingly high, may nevertheless underestimate the true burden.

It is now recognized that reducing perinatal and neonatal mortality is of paramount importance for additional gains in child survival to be realized.^{20,26,32,34,35} Moreover, because the majority of perinatal and neonatal deaths in developing countries occur in the home, there is an urgent need to identify solutions at the community level.^18,20,22,26 To achieve Millennium Development Goal 4 of halving child mortality by the year 2015, major advances in neonatal survival must be achieved through wide-scale implementation of cost-effective interventions in the community.²²

There is little debate that perinatal and neonatal mortality are profoundly affected by proximal factors that influence maternal health such as socioeconomic deprivation, gender bias, illiteracy, and high fertility rates, and redress of these factors is critical to improving maternal and neonatal health in developing countries.^4,36 However, these elements are relatively resistant to change in the short term.^37–42 Moreover, as a consequence of such systematic neglect, a sense of fatalism and inevitability of adverse fetal and neonatal outcomes sets in and further impedes care seeking.^22,43,44 This in itself is a major barrier to improvement in perinatal and neonatal outcomes. The concept that all people possess equal rights to health, education, and social services is a key factor in creating demand for better allocation of health care resources for women and newborns. This must be coupled with greater participation of individuals and communities in planning and meeting their own health care needs, particularly women within traditional societies through empowering them to participate in decision-making processes.

Because the health of the mother and newborn are intimately entwined, they must be considered together when planning strategies to improve perinatal and neonatal outcomes. It is important to highlight that the peak period of vulnerability for both the mother and newborn is around pregnancy and childbirth. Thus, interventions must largely focus on addressing joint outcomes. There is evidence, however, that this has not been widely adopted, that Safe Motherhood interventions have not adequately addressed the newborn period, and that newborn interventions rarely focus on integration with existing maternal care programs and services.

To redress the burden of perinatal and neonatal mortality, several factors are required: (1) political commitment to newborn health at the global, regional, national, and local levels; (2) increased focus on the newborn within existing Safe Motherhood and Child Survival programs; (3) efficient allocation of resources; (4) effective implementation of cost-effective interventions; and (5) clear documentation of impact.¹⁸ To aid in garnering political and programmatic will and action to improve perinatal and neonatal health care and status, the magnitude of the problem and evidence for effectiveness of interventions to prevent and manage adverse outcomes must be documented clearly. A recent analysis of the neonatal burden of disease in south Asia and sub-Saharan Africa, in which approximately three fourths of neonatal deaths occur, highlighted the dearth of information available on neonatal outcomes in developing countries, particularly at the community level.²⁸ Similarly, a recent meeting of neonatal health researchers highlighted the need for a review of available evidence for impact of interventions on perinatal and neonatal health and survival.²⁷

Neonatal health experts agree that improving neonatal health and survival in developing countries depends in large measure on more effectively implementing what has already been shown to work.^18,26,34,35 Moreover, a number of health interventions for the mother and her newborn have been proposed by the WHO and others as global priorities for programmatic implementation.^{14,18,26,34,35,45,46} Although many advances in obstetric and neonatal care are costly and require technologies that are unavailable in resource-poor countries, a substantial proportion of perinatal and neonatal morbidity and mortality in developing countries could be prevented through appropriate adaptations and applications of inexpensive, relatively simple methods to improve antenatal, obstetric, and neonatal care. The fact remains that improvements in care are often limited more by lack of adequate knowledge and its appropriate application than by technologic barriers. In other cases, however, additional research is needed to devise, adapt, and evaluate sustainable solutions, particularly at the community level. Although reviews of the impact of certain antepartum, intrapartum, and postnatal interventions have been conducted, evidence for proven benefit, or lack thereof, of the many interventions that one might include in a neonatal health program at the community level has never been systematically evaluated and summarized. Major evidence gaps include lack of objective data on the methodologies of introducing interventions within health system settings and evaluating hard outcomes through effectiveness-trial designs. The limitations of the strictly randomized-trial design have been recognized in health systems research and interventions.⁸

This review of community-based antenatal, intrapartum, and postnatal intervention trials in developing countries was undertaken to (1) identify key behaviors and interventions for which the weight of evidence is sufficient to recommend their inclusion in community-based neonatal care programs and (2) identify key gaps in knowledge and priority areas for future research and program learning. We did not focus on long-term solutions of established and indisputable value in improving maternal and perinatal outcomes, such as poverty reduction, gender equity, fertility regulation and control, and improved health system performance. Rather, the focus of this review was on specific targeted interventions that may impact perinatal and neonatal health status outcomes, primarily perinatal and neonatal mortality.

	METHODOLOGY USED FOR LITERATURE SEARCH AND REVIEW

TOP ABSTRACT EXECUTIVE SUMMARY INTRODUCTION AND BACKGROUND METHODOLOGY USED FOR LITERATURE... REVIEW AND ANALYSIS OF... Intrapartum Interventions Postnatal Interventions COST-EFFECTIVENESS OF COMMUNITY... SUMMARY CONCLUSIONS REFERENCES

 
This review aimed to consider all available published and unpublished data on the impact of community-based strategies and interventions on perinatal and neonatal health status outcomes. The community was defined as extending from the household to peripheral health facilities.

The search methodology included review of the following sources of information:

1. All available electronic reference libraries of indexed medical journals and analytical reviews
   
2. Electronic reference libraries of nonindexed medical journals
   
3. Nonindexed journals not available in electronic libraries
   
4. Pertinent books, monographs, and theses
   
5. Project documents and reports
   

Electronic Reference Sources
The following principal sources of electronic reference libraries were searched to access the available data on community-based intervention studies: Cochrane Reference Libraries, the WHO Reproductive Health Libraries, Medline, PubMed, ExtraMed, Embase, and Popline. Several search strategies were employed using key words, combinations, and medical subject headings (MeSH) words including "community-based care," "community care," "newborn or neonatal care," "perinatal care," "interventions," "intervention strategies," "perinatal or newborn care programs," "newborn survival," "perinatal outcomes," and "neonatal outcomes," among others.

Manual Literature Search
A detailed examination of cross-references and bibliographies of available data and publications was performed to identify additional sources of information. In particular, this search extended to reviewing the gray literature in nonindexed and nonelectronic sources. The bibliographies of 37 recently published textbooks or books with sections pertaining to community-based maternal and/or newborn care were also searched manually. Requests for information were sent to major development and aid agencies including the World Bank, United Nations Children's Fund (UNICEF), WHO, Department for International Development, United Nations Development Programme, United States Agency for International Development, MotherCare, JHPIEGO, the Wellcome Trust, LINKAGES, John Snow Inc, National Institute of Child Health and Human Development, National Institutes of Health (NIH) Institute of Medicine, CARE, Save the Children/USA, and several other nongovernmental organizations. In particular, requests for information were made to regionally active development agencies and research councils. In addition, personal requests for information on community-based perinatal and neonatal interventions were made to leading public health scientists in the field.

For in-depth review, we selected 186 studies from developing countries that directly related to the research question of health status impact of community-based perinatal and neonatal health care. These studies were analyzed in detail and summarized in the tables according to a standardized, prearranged evaluation format as to their location, size, design, nature of intervention, and outcome. The information was categorized according to whether the target group consisted of mothers, newborn infants, or both.

The following categorization of interventions was made:

Maternal Interventions

1. Maternal schooling/health education
   
2. Antenatal care packages
   
3. Protein supplementation
   
4. Balanced protein-energy supplementation
   
5. Iron supplementation
   
6. Folate supplementation
   
7. Iodine supplementation
   
8. Antenatal vitamin A supplementation
   
9. Zinc supplementation
   
10. Multiple micronutrient supplementation
    
11. Malaria chemoprophylaxis or intermittent presumptive treatment (IPT)
    
12. Malaria protection using insecticide-treated bed nets (ITNs)
    
13. Deworming
    
14. Syphilis screening and treatment
    
15. Antibiotics for asymptomatic bacteriuria
    
16. Antibiotics for bacterial vaginosis
    
17. Antibiotics for preterm labor
    
18. Antibiotics for preterm premature rupture of membranes (PPROM)
    
19. Tetanus toxoid (TT) immunization and clean delivery
    
20. Maternal pneumococcal immunization
    
21. Promotion of smoking cessation during pregnancy
    

Composite Interventions
In addition to the specific community-based interventions noted above, some studies evaluated packages of maternal interventions in community settings:

1. Maternal care packages
   

Intrapartum Interventions

1. Maternal vaginal and newborn skin antisepsis
   

Postnatal Interventions

1. Newborn resuscitation
   
2. Delayed umbilical cord clamping
   
3. Umbilical cord antisepsis
   
4. Hypothermia prevention and management
   
5. Hypoglycemia prevention and management
   
6. Breastfeeding
   
7. Prevention and treatment of ophthalmia neonatorum
   
8. Vitamin K prophylaxis
   
9. Hepatitis B vaccination
   
10. Neonatal vitamin A supplementation
    
11. Kangaroo mother care (KMC)
    
12. Topical emollient therapy
    
13. Hyperbilirubinemia screening
    
14. Traditional birth attendant (TBA)/CHW training
    
15. Pneumonia case management
    

Composite Interventions
Apart from community interventions focusing on the aforementioned specific areas, some studies evaluated packages of postnatal interventions or the functioning of hospitals in the community and interventions performed within them, including use of alternative methods of care to compensate for meager resources and facilities:

1. Neonatal care packages
   
2. Care in peripheral health facilities
   

Exclusions
Some interventions were excluded from this review because other investigators were evaluating the evidence base for their impact. Interventions excluded included the following:

1. Roles of skilled birth attendants
   
2. Family planning and birth spacing
   
3. Safe Motherhood strategies such as prevention and treatment for pre-eclampsia, pregnancy-induced hypertension, and antepartum hemorrhage; newer strategies for prevention of preterm labor (eg, magnesium, calcium, fish oil); emergency obstetric care; emergency transport services; communications strategies; community waiting homes; and use of fetal partograph
   
4. HIV prevention and mother-to-child transmission reduction strategies
   
5. Maternal tuberculosis treatment
   

Synthesis of Evidence
The principal reviewers independently evaluated all the data, and a common reporting matrix was used in summarizing the findings. Emphasis was placed on assessment of impact on perinatal or neonatal primary health status outcomes. For some interventions, however, for which data on primary health status outcomes were lacking, other indicators were considered.

The final categorization of the interventions was done by mutual agreement and consensus as follows:

1. No evidence of benefit: These interventions had been evaluated and found to have no demonstrable benefit either singly or in combination with other measures. In some cases, there was evidence of an adverse effect of the intervention. Therefore, these interventions were not recommended for inclusion in any neonatal health care strategy.
   
2. Uncertain evidence of benefit: This category included interventions for which there was some evidence of benefit, but contradictory evidence or issues such as study design, quality, location or size precluded any firm conclusions. These interventions merited additional evaluation or research using well-designed protocols and designs.
   
3. Some evidence of benefit: These interventions had some positive impact on perinatal or neonatal outcomes, but the evidence remained preliminary or the location of the studies was not representative of the developing world at large. Furthermore, the trial designs were mostly efficacy studies; therefore, their effectiveness, if any, in large-scale programmatic interventions remained to be assessed. Their inclusion in intervention programs was considered optional, but a recommendation was made to include an evaluation of benefits whenever they were included.
   
4. Clear evidence of benefit: This category of interventions was of incontrovertible benefit to mothers and/or newborn infants, and thus it was recommended that they be included in community-based intervention programs for maternal and perinatal care.
   

When categorizing the evidence for impact of interventions, we considered a variety of factors including the study size, location, and rigor of design; consistency and magnitude of impact reported, particularly on perinatal or neonatal mortality; biological plausibility of the intervention; evidence from relevant developed-country studies; experience with implementing the intervention in health care programs; and recommendations from the WHO and other leading agencies in maternal and child health. Thus, the evidence was put into a broader context to reach a composite assessment that was agreed on by the principal investigators (Z.A.B. and G.L.D.).

	REVIEW AND ANALYSIS OF AVAILABLE DATA

TOP ABSTRACT EXECUTIVE SUMMARY INTRODUCTION AND BACKGROUND METHODOLOGY USED FOR LITERATURE... REVIEW AND ANALYSIS OF... Intrapartum Interventions Postnatal Interventions COST-EFFECTIVENESS OF COMMUNITY... SUMMARY CONCLUSIONS REFERENCES

 
Antenatal Interventions
Maternal Schooling/Health Education
BACKGROUND.
The relationship between maternal antenatal education and perinatal and neonatal outcomes is well established. Caldwell and McDonald⁴⁷ demonstrated the close relationship between maternal education level (ie, schooling) and infant mortality from observations in Nigeria. Since then, this association has been borne out through a number of reviews.^40,48–51 Victora et al,³⁹ in a review of cause-specific infant mortality rates (IMRs) in Pelotas, Brazil, found a significant inverse relationship between maternal schooling and deaths from perinatal conditions, particularly infectious diseases. The association between increased maternal education and decreased infant mortality, particularly in reducing postneonatal deaths, was further strengthened by a review of 34 cross-sectional World Fertility Surveys between 1974 and 1980,⁵² although the association was weakened when the data were corrected for socioeconomic status^53,54 (Table 3). The association between maternal education and neonatal survival was also corroborated by analysis of data from 11 Demographic and Health Surveys; in this review, the association held even after correction for socioeconomic status.^38,55 More recently, the importance of maternal education in reducing birth weight–specific perinatal mortality in Nigeria was further stressed by Harrison,⁴² and the association between educational level of the maternal grandmother and utilization of health services for prenatal care and delivery by a skilled attendant was also demonstrated.⁵⁶

Reasons for improved survival of neonates born to more highly educated mothers is not clear, but the association is only partly explained by the economic advantages and access to health care afforded by education. Potential links between maternal education and reduced perinatal and neonatal mortality also include appropriate birth spacing and health-seeking behavior, particularly for prenatal care. There is strong evidence supporting the importance of community- and hospital-based maternal education and support programs on breastfeeding practices^59–62; these programs are reviewed below (see "Breastfeeding").

COMMUNITY-BASED EVIDENCE.
Although there are data available from developed countries on maternal educational strategies specifically aimed to improve perinatal and neonatal outcomes,^63–65 there are few systematic studies that have prospectively evaluated their impact,⁵⁷ particularly from developing countries. Woods and Theron^66,67 in South Africa demonstrated a significant improvement in cognitive knowledge of midwives who participated in an extended perinatal education program; however, impact on perinatal outcomes was not reported. In contrast, providing postnatal maternal education in Nepal through a limited didactic educational interaction met with little success in improving knowledge and practices, except for family-planning practices.⁶⁸ Although the impact of the didactic form of education was not found to be effective, the authors of the latter study subsequently concluded that community participation was a key to the success of educational strategies. These intervention strategies include the development of intervention strategies by community members themselves, based on their understanding of barriers to care seeking for newborn care.^69,70

CONCLUSIONS.
Maternal educational level is clearly associated with improved perinatal and neonatal survival. Thus, building the capacity of mothers through basic education is a key long-term strategy to improve perinatal and neonatal health in developing-country communities. More work is needed, however, to develop and test shorter-term maternal educational strategies targeted toward improving pregnancy outcomes in developing countries, particularly at the community level. The exact nature and content of the educational package, roles of different cadres of health workers, and ways to convey the messages at the community level most effectively may best be developed and evaluated considering the principles of appropriate and participatory community-based research.⁷¹

Antenatal Care Packages
BACKGROUND.
Antenatal care is well regarded as 1 of the 4 main pillars of Safe Motherhood by the WHO.¹⁴ Although the beneficial effects of antenatal care for maternal health and outcomes are well recognized and the practice is well established, there have been few systematic studies of the impact of "standardized" antenatal care programs on perinatal and neonatal outcomes.^72,73 No intervention studies are available that directly compared groups of women who received antenatal care and those who did not, thus limiting conclusions regarding the extent to which antenatal care improves perinatal/neonatal outcomes.

The benefits of antenatal care for maternal and newborn outcomes, including assessment of the most effective components, were addressed in systematic analyses by Bergsjo and Villar^72,74 and Carroli et al.⁷⁵ Some of the major interventions introduced during antenatal care and their impact on pregnancy outcomes are detailed in Table 4. TT immunization, iron-folate supplementation, detection and management of pre-eclampsia, screening and treatment for bacteriuria, and where appropriate, screening and treatment for syphilis and malaria are priority activities. Although some studies have indicated that antenatal care alone may be insufficient for the identification of pregnant women at risk of obstetric complications and emergencies,^76–78 there is observational evidence from a variety of geographic settings that lack of antenatal care is associated with increased risk for late fetal death.^79,80 Although the evidence is somewhat mixed, the overall consensus is that quality antenatal care provided by a trained attendant within a functional health system reduces the risk of maternal mortality and adverse pregnancy outcomes.⁸¹

Although there is some evidence that antenatal care works, there is little consensus on critical related issues such as the minimum number of visits and the most cost-effective components of antenatal care. In an evaluation of antenatal care models in the United States, McDuffie et al⁸² found comparable pregnancy outcomes among women who had attended a modified program of 2.7 fewer visits, on average, compared with the traditional program of 7 antenatal visits. To further evaluate whether a reduced system of 4 antenatal care visits was as effective as a program with more frequent visits, the WHO organized a multicenter trial involving urban centers in Saudi Arabia, Argentina, Cuba, and Thailand (Table 5).^83,84 No impact was observed in this large trial on either preterm birth or IUGR.⁸⁴ Women who received information about breastfeeding antenatally were more likely to initiate breastfeeding after birth. Those assigned to the reduced-visit model had similar maternal (ie, morbidity index, urinary tract infection [UTI], and anemia rates) and neonatal (ie, perinatal mortality rate [PMR], NMR, LBW rate) outcomes as those who were given standard antenatal care, although women who had >4 antenatal visits were more likely to feed their infants colostrum. The participants of the trials were generally satisfied with the quality of care in the new, modified system of antenatal care.⁸⁵

CONCLUSIONS.
The benefits and importance of antenatal care in improving maternal health and pregnancy outcomes are widely accepted, yet little direct evidence of impact exists from intervention trials. An antenatal care package that consists of fewer but qualitatively better and more goal-oriented visits is recognized to be more cost-effective than the "conventional" antenatal care packages promoted previously, which involved more frequent visits. However, this evaluation was also not undertaken as an effectiveness trial in health system settings. It is also important to point out that there are no studies evaluating different community-based models of antenatal care using primary heath care workers and CHWs.

The exact margin of improvement in neonatal mortality after antenatal care is unclear, and we could not cite a specific figure based on objective evidence and controlled trials. Moreover, a controlled trial to determine the level of effect would now be unethical. The exact contents of such a package would need to be based on evidence of the efficacy of each individual component of the package plus the cost-effectiveness and relative ease of implementation by primary care workers. Based on the available evidence elaborated in this review, the antenatal care package should contain, at a minimum, TT immunization, iron-folate supplementation, and promotion of clean delivery and exclusive breastfeeding. Based on health system capacity, the package should also include supplementation with iodine and screening and treatment for bacteriuria, pre-eclampsia, and syphilis.

Nutrition Interventions in Pregnancy
Maternal malnutrition is widespread in developing countries and is an underlying factor in fetal malnutrition and LBW as well as other adverse pregnancy outcomes such as premature births, abruptio placentae, and stillbirths.^86,87 A large proportion (16%) of births in developing countries are LBW, which is a major underlying risk factor for morbidity and mortality in the perinatal and neonatal periods and later in infancy.^86,88 Poor maternal nutritional status is associated with adverse birth outcomes,^11,89 but the association with fetal mortality is less clear. Given the recognized association between maternal malnutrition and LBW, there has been considerable interest in nutritional interventions that may improve birth weight as well as other adverse pregnancy outcomes.⁸⁷ With the emerging evidence of the long-term implications of fetal malnutrition, nutrition transition, and adverse metabolic outcomes such as diabetes,⁹⁰ it becomes even more imperative to improve maternal and fetal nutrition in developing countries. Two recent reviews evaluated the impact of nutrition interventions on prematurity⁹¹ and pregnancy outcomes⁹² and underscored the fact that few studies have addressed this problem in community settings in developing countries.

Evidence for impact of nutritional interventions on maternal, perinatal, and neonatal outcomes has been reviewed extensively, largely within the Cochrane collaboration using meta-analyses of RCTs. Available data have also been reviewed recently as part of an evaluation of the evidence base for Safe Motherhood strategies⁹³ and a review of the efficacy and effectiveness of nutrition interventions.⁹⁴ Our evaluation of the evidence was drawn largely from these sources, especially the individual community-based studies in developing countries within the Cochrane reviews. In addition, we evaluated recent studies that have not yet been included in the Cochrane reviews and others with a quasi-experimental design that were not considered as part of the meta-analyses.

Protein Supplementation
BACKGROUND.
Benefits of unbalanced protein supplementation in pregnancy were largely refuted recently in a meta-analysis of available evidence.⁹⁵ Such interventions have been tried historically in a variety of malnourished and at-risk populations including poor communities in developed countries.^96,97 In 3 studies among Asian women in the United Kingdom and Chile, where the usual maternal energy intake was isocalorically replaced with 10% to 11% protein,^98–100 there was no effect on pregnancy outcomes, although there was a trend toward reduced birth weight. Even higher levels of protein supplementation (>25% of energy) in relatively well-nourished populations failed to show any benefit on pregnancy outcomes and birth weight.^101,102 Thus, protein supplementation alone is no longer viewed as a viable intervention during pregnancy.¹⁰³

CONCLUSIONS.
Based on a large body of evidence, pure or high levels of dietary protein supplementation cannot be recommended as an antenatal intervention, nor is additional research warranted on this intervention.

Balanced Protein-Energy Supplementation
BACKGROUND.
Balanced protein-energy supplements, by definition, provide <25% of their total energy content in the form of protein. A systematic review done by the Cochrane collaboration on the effect of antenatal maternal balanced protein-energy supplementation⁹⁵ concluded that this intervention significantly improved fetal growth and reduced the risk of fetal and neonatal death. The findings of this review, however, were largely influenced by 1 large trial undertaken in The Gambia that indicated a significant reduction in perinatal mortality.¹⁰⁴ However, this efficacy study also included micronutrient supplementation in addition to balanced protein-energy intake. Excluding this single study drastically altered the conclusions of this meta-analysis, leaving no demonstrable impact.

COMMUNITY-BASED EVIDENCE.
A review of the literature identified 19 studies, 12 of which were undertaken in community settings and discussed pregnancy outcomes, thus fulfilling our criteria for selection. The details of these studies are given in Table 6. These trials were largely conducted in developing countries and inner-city populations in industrialized countries. Inconsistent results may have been related to the variability in the background rates of maternal malnutrition in the different study settings and the relative size of the individual studies. Of the trials included in this review, only 4 reported preterm birth rates.^{97,101,105–107} Supplementation was not associated with an increase in mean gestational age (mean difference: –0.1 week; CI: –0.2 to +0.1 week) or a significant reduction in preterm birth (OR: 0.83; CI: 0.65–1.06). Supplementation generally resulted in increased birth weight and/or a reduction in the LBW rate.^{104,105,108–115} Overall, however, balanced energy-protein supplementation seems to have only a modest effect on mean birth weight (weighted mean difference: 25 g; CI: –4 to +55 g) but a more substantial effect on reducing IUGR (OR: 0.68; CI: 0.57–0.80). No evidence was found that these effects were greater in undernourished than in well-nourished women. However, the magnitude of the birth weight increase was substantially larger (136 g) in the Gambian study,¹⁰⁴ in which the supplement provided an additional 3780 kJ per day, as compared with an 840- to 1050-kJ-per-day increase in most of the other trials. Although a trend toward increased weight gain of the supplemented mothers was observed in 2 studies, the differences were nonsignificant.^105,114 Moreover, other studies showed no impact on maternal weight gain.^116,117 In the few studies that examined effects on the stillbirth^104,105 and perinatal mortality^104,105,118 rates, reductions were seen. The largest of these studies¹⁰⁴ was undertaken in The Gambia, where, in an RCT, chronically undernourished pregnant women were provided a higher-energy supplement (3780 kJ), largely toward the last trimester, with little micronutrient content. Results from this Gambian study¹⁰⁴ reported significant reductions in rates of stillbirths (53% reduction), early neonatal deaths (46% reduction), and LBW (39% reduction).

CONCLUSIONS.
Although Kramer⁹⁵ did not find a differential effect of balanced protein-energy supplements according to the degree of maternal malnutrition, the weight of evidence is strong in favor of improving perinatal mortality and birth weight through balanced protein-energy supplementation of malnourished pregnant women. Most of the evidence, however, comes from strict efficacy trials conducted under intense supervision, and the overall results are largely driven by a single trial from The Gambia. No effectiveness trials have been undertaken to evaluate the benefit of balanced-energy protein supplementation at the community level nor of using home-available diets to provide these supplements. We believe that balanced protein-energy supplementation merits additional field evaluation in diverse geographic locations and may be cautiously included in intervention programs in malnourished populations. However, if such a program is instituted, data must be collected to evaluate the program's benefit and cost-effectiveness. Ideally, the benefit of improved protein-energy intake in pregnancy may be achieved through dietary diversification strategies as well as targeted supplementation in at-risk populations, although the cost may be substantial.

Iron Supplementation
BACKGROUND.
Global estimates by the WHO indicate that 55% of all pregnant women living in developing countries and 18% of those in developed countries are anemic (hemoglobin [Hb] concentration <11 g/dL).¹¹⁹ It is also recognized that anemia underlies some 8% to 15% of maternal deaths in developing countries.^120–122 Although the exact contribution of maternal anemia to maternal mortality may be unclear,^123,124 it is also widely recognized as a major determinant of maternal morbidity in developing countries. The majority of such cases of anemia are related to iron deficiency, although malaria and hookworm infestation, as well as protein and other micronutrient deficiencies, may play a role also.¹²¹

Iron-deficiency anemia is highly prevalent in developing countries, affecting an estimated 2 billion people, including one fourth of the world's women and children.^125,126 Thus, there has been much interest in interventions geared toward improving iron intake and status during pregnancy. Despite the evidence that gastrointestinal iron absorption increases during pregnancy, it is highly unlikely that sufficient amounts can be absorbed from the diet during this period to compensate for the increased requirement of the body. Thus, supplementation with iron generally is required, especially where diets may be deficient in iron and body stores of iron may be inadequate to meet requirements.¹²⁷