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
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 Available published and unpublished data on the impact of community-based strategies and interventions on perinatal and neonatal health status outcomes were reviewed.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
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:
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.
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.
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.
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.
Discussion
Appropriate perinatal and neonatal care in any given circumstance in developing countries requires an integrated and holistic program of interventions at various levels. Interventions must not only include health-related measures that have a direct bearing on perinatal and/or neonatal outcomes but several other ancillary measures of equal importance. These measures include poverty alleviation; improved opportunities for female education; and improvement of women's social status, including empowerment and improvement of women's decision-making ability. Family size and short interpregnancy intervals are also critical factors in perinatal health.11–13
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 WHO14–16 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.
Effective interventions span maternal and neonatal care, as anticipated when one considers that pregnancy-related causes, delivery-related causes, and infections each account for approximately one third of neonatal deaths.18 This need for a continuum of care serves to illustrate the importance of integrating maternal and neonatal care while avoiding vertical programs for either the mother or the newborn. Moreover, although we emphasize impact on perinatal and neonatal outcomes (summarized in Tables 4–42), this review has further illustrated the principle that interventions in the antenatal and intrapartum periods frequently benefit both mother and newborn simultaneously.19 Moreover, a coordinated approach to postpartum care for mother and newborn would similarly benefit both. Thus, one would anticipate that an approach to maternal and neonatal health integrated within Safe Motherhood and Child Survival programs would not only foster continuity of care across the life cycle but also enhance the cost-effectiveness of packages of interventions.
Research Gaps
Although a number of interventions have been shown to reduce perinatal and/or neonatal mortality, there are fundamental gaps in our knowledge of how to most effectively improve perinatal and neonatal outcomes in developing-country communities. We know that implementation of comprehensive neonatal care programs can substantially reduce perinatal and/or neonatal mortality, but there is an urgent need to adapt and evaluate culturally and regionally appropriate packages of interventions in a variety of settings. Among these gaps in our knowledge is the critical issue of the determinants of family and community practices and their influence on newborn care and care-seeking behaviors. Better documentation of how behavior-change interventions are implemented and evaluation of these methods is needed to develop better tools for building individual, household, and community capacity for appropriate self-care and care seeking. In the context of the many parts of the developing world in which gender inequity and female feticide are major issues, this need for effective behavior-change approaches extends to newborn care and outcomes.
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:
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.
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.
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.
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.
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.
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.
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.
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
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
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:
All available electronic reference libraries of indexed medical journals and analytical reviews
Electronic reference libraries of nonindexed medical journals
Nonindexed journals not available in electronic libraries
Pertinent books, monographs, and theses
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
Maternal schooling/health education
Antenatal care packages
Protein supplementation
Balanced protein-energy supplementation
Iron supplementation
Folate supplementation
Iodine supplementation
Antenatal vitamin A supplementation
Zinc supplementation
Multiple micronutrient supplementation
Malaria chemoprophylaxis or intermittent presumptive treatment (IPT)
Malaria protection using insecticide-treated bed nets (ITNs)
Deworming
Syphilis screening and treatment
Antibiotics for asymptomatic bacteriuria
Antibiotics for bacterial vaginosis
Antibiotics for preterm labor
Antibiotics for preterm premature rupture of membranes (PPROM)
Tetanus toxoid (TT) immunization and clean delivery
Maternal pneumococcal immunization
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:
Maternal care packages
Intrapartum Interventions
Maternal vaginal and newborn skin antisepsis
Postnatal Interventions
Newborn resuscitation
Delayed umbilical cord clamping
Umbilical cord antisepsis
Hypothermia prevention and management
Hypoglycemia prevention and management
Breastfeeding
Prevention and treatment of ophthalmia neonatorum
Vitamin K prophylaxis
Hepatitis B vaccination
Neonatal vitamin A supplementation
Kangaroo mother care (KMC)
Topical emollient therapy
Hyperbilirubinemia screening
Traditional birth attendant (TBA)/CHW training
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:
Neonatal care packages
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:
Roles of skilled birth attendants
Family planning and birth spacing
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
HIV prevention and mother-to-child transmission reduction strategies
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:
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.
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.
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.
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
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 status53,54 (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
There are surprisingly few intervention studies on the specific impact of maternal health education on perinatal and newborn outcomes. Kramer57 evaluated the evidence, including that from an intervention trial in Greece,58 of the potential benefit of maternal nutritional advice during pregnancy on several outcomes. Although an increase in energy and protein intake during pregnancy was notable, the overall impact on maternal, perinatal, and neonatal outcomes was unclear.
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 practices59–62; 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 Theron66,67 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 Villar72,74 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
A recent systematic review of randomized trials also yielded no strong evidence that the content, frequency, or timing of currently recommended antenatal care visits has an effect on reducing the incidence of IUGR or preterm delivery.75 This systematic review of pooled data on alternative models of reduced numbers of antenatal care visits showed similar odds of multiple health outcomes compared with the standard care model, including pre-eclampsia (odds ratio [OR]: 0.91; 95% confidence interval [CI]: 0.66–1.26), UTIs (OR: 0.93; CI: 0.79–1.1), maternal mortality (OR: 0.91; CI: 0.55–1.51), incidence of LBW (OR: 1.04; CI: 0.93–1.17), and overall perinatal mortality (OR: 1.06; CI: 0.82–1.36).
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 stillbirth104,105 and perinatal mortality104,105,118 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).
In contrast to findings noted above regarding unbalanced protein supplementation alone in pregnancy,95 the impressive reduction in rates of stillbirths and perinatal mortality from this large trial provided strong evidence of the potential benefit of balanced protein-energy supplementation during pregnancy.
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
Although it is widely accepted that iron-deficiency anemia poses an increased risk of complications in pregnancy and of maternal and perinatal mortality,128 there is surprisingly little evidence to support this relationship. An association has been suggested by some epidemiologic studies,129–131 but other studies, in fact, have failed to demonstrate a relationship between iron-deficiency anemia and adverse pregnancy outcomes.132,133 Most of the evidence in the literature has been largely derived from retrospective studies and has not been controlled for ancillary factors such as overall nutrition, underlying health, and health service delivery.123 Several reviewers123,134–138 believe that anemia, which itself can be due to a variety of factors, is just one of a multitude of determinants of maternal and perinatal mortality and that there is no conclusive evidence of a link between maternal anemia and LBW or maternal or perinatal mortality. Moreover, there is little documentation that health status can be improved by treating anemia alone. There are no iron-supplementation trials with maternal mortality as a measured outcome, and all intervention trials that used perinatal mortality as the outcome involved nonanemic women,139 were poorly designed,140,141 or were too small to be conclusive about iron effects.142 However, despite the fragmentary nature of the data on the association between maternal anemia and mortality, one can infer that there is a steep rise in maternal mortality with increasing severity of anemia, especially Hb levels <5 g/dL.143 Nevertheless, the association may not be causal.128 There also seems to be a U-shaped relationship between maternal anemia and birth weight, because both low and high maternal Hb values are associated with an increased risk of LBW.135,144,145 Again, although no causal evidence has been established overall to support or refute the relationship between iron-deficiency anemia and LBW, the evidence from developing countries, in which iron-deficiency anemia is common, shows that maternal iron deficiency is positively associated with LBW and poor obstetric outcome.136 There is also evidence suggesting that a relationship exists between maternal anemia in early pregnancy and increased risk of preterm birth.146–149
Meta-analyses of iron-supplementation trials, conducted under the auspices of the Cochrane collaboration,150–152 concluded that although iron supplementation significantly reduced the prevalence of low Hb concentration (<105 g/L), it had no detectable effect on any other substantive measures of maternal or perinatal outcomes. Although iron reduces maternal anemia, there is no evidence that iron supplements administered alone or with folate have any effect on birth weight or fetal survival in developed countries. There are insufficient data from developing countries to draw conclusions; the few RCTs are inconclusive because of small sample size, problems with compliance, and large losses to follow-up. Small trials in The Gambia, Nigeria, and India showed no significant effects on birth weight,140,153–155 although 1 large trial in Niger showed a significant increase in birth length and Apgar scores and a reduction in PMR.156
There are several other reports of iron therapy in pregnancy from developing countries that are relatively less stringent in their inclusion and exclusion criteria.157–163 However, most of these studies were based in health facilities within developing countries and varied considerably in design. The overall effects of iron therapy in these studies were largely mixed and did not suggest a particular effect. A review of 9 RCTs of iron supplementation from health facilities in developing countries showed that the increment in Hb level for given amounts of supplementation was not greatest among those with the lowest Hb levels, suggesting that factors other than iron deficiency alone were operative.164
COMMUNITY-BASED EVIDENCE.
Few community-based iron-supplementation trials have resulted in improvement in either iron stores or measures of maternal and perinatal health.164–166 Among iron-supplementation trials conducted to date, 5 were in developing countries: 1 in a periurban setting and the other 4 in rural settings (Table 7). All 5 studies demonstrated a convincing effect of iron supplementation on reducing rates of maternal anemia.141,154–156,167,168
Several studies have evaluated the benefit of combining iron with other micronutrients in an effort to address multiple deficiencies. In a randomized, placebo-controlled trial (RPCT) in Indonesia, Suharno et al168 found a synergistic effect of vitamin A and iron supplementation in reducing rates of maternal anemia, with two thirds of the response attributable to vitamin A. Another study in India141 demonstrated a reduction in LBW rates and an increase in birth weight of infants born to women who were supplemented with both iron and folate. Increased birth weight, however, was seen only in offspring of women who began supplementation from 16 to 20 weeks' gestation but not in those supplemented after week 20 of gestation. Christian et al169 indicated that both iron-folate supplements and multiple micronutrients reduced the prevalence of LBW comparably among pregnant women in rural Nepal (16% vs 14%). A different study167 found a synergistic effect of antihelminthics with iron supplementation. However, this particular study also indicated that women who were supplemented for <17 weeks did not show any benefits, and there was no overall effect of supplementation on birth weight. One study154 showed an increase in birth weight but only in the offspring of women who had taken the iron supplement for a period of 80 days.
It must be pointed out also that there is evidence that administration of parenteral iron to iron-deficient women during pregnancy in malaria-endemic areas may be associated with an increase in the incidence of malarial infections and clinical episodes of disease.170,171 Thus, care must be exercised in administering iron supplements alone (without chemoprophylaxis) in malaria-endemic areas.
CONCLUSIONS.
Oral iron supplementation may improve maternal anemia, but there is no clear effect of iron supplementation on maternal and perinatal or neonatal outcomes. However, the evidence for impact of iron supplementation on health outcomes is inconclusive, primarily due to a paucity of adequately designed and robust trials of iron supplementation in developing countries rather than a demonstrated lack of effect.123,136 In any case, it seems that initiation of therapy early in gestation is important.
Pending the results of well-designed trials that might more definitely delineate the role and mode of iron supplementation in deficient populations, and given the apparent importance of anemia, especially severe anemia, as a risk factor for maternal mortality and morbidity,128 it would seem prudent (pending additional research, including meta-analyses) to continue with iron supplementation, concomitant with folate administration (see "Folate Supplementation"), during pregnancy and in at-risk populations of women of reproductive age. In malaria-endemic areas, routine iron supplementation during pregnancy must be accompanied by malaria chemoprophylaxis (see "Malaria Chemoprophylaxis or Intermittent Therapy"). Current WHO/UNICEF guidelines recommend universal iron-folate prophylactic supplementation of young children and pregnant women in areas where anemia is highly prevalent.172
Folate Supplementation
BACKGROUND.
Folate is critical for DNA synthesis, and folate deficiency is associated with dysfunction in rapidly dividing cells. Observational studies have suggested that lower maternal serum folate levels are associated with LBW and prematurity.173,174 A large US study suggests an association between higher maternal serum folate at 30 weeks' gestation and lower risk of IUGR, higher birth weight, and higher Apgar scores,175 although these results have not been corroborated by data from South America.176,177
There is a large body of literature, mainly from developed countries, reporting observational studies and RCTs of folic acid in pregnancy. These have been reviewed by Ramakrishnan et al,145 de Onis et al,86 and Mahomed.151,152 Some observational studies178 have shown positive associations between maternal folate status and birth weight, but the evidence is inconsistent. Twenty-one trials of folate supplementation were included in the Cochrane review,151 which concluded that, despite a significant reduction in maternal anemia, there was only a small and nonsignificant effect on the incidence of LBW (OR: 0.73; CI: 0.47–1.13). de Onis et al86 included 4 folate trials in their review of nutritional interventions to prevent IUGR and found a significant reduction in LBW, but they commented on the poor quality of much of the data. Although 2 studies from India179 and South Africa180 showed significant increases in birth weight of offspring of malnourished women, this result has not been confirmed in subsequent studies.
Folate deficiency in early pregnancy is an important factor underlying the occurrence of neural tube defects (NTDs) such as spina bifida, encephalocele, and anencephaly. Worldwide, NTDs (particularly the 2 major types, anencephaly and spina bifida) and encephalocele are estimated to affect 300 000 infants each year.181,182 A trial of periconceptional folate supplementation (400 μg of folic acid per day before and during the first 28 days after conception), conducted by the Medical Research Council183 in 33 centers among developed countries, showed a reduction of NTDs by 50% to 70%. Similar data were reported by Berry et al.184 Universal folic acid fortification of flour at 240 μg/100 g in consumed food products has been shown to significantly reduce NTD-affected conceptions and births.185 Currently, the benefits of periconceptional folate supplementation in terms of reducing the incidence of NTDs are well established, and this intervention should be made universally available.
Although there is little evidence of widespread folate deficiency, folic acid is commonly administered along with iron supplements during pregnancy. The benefit of periconceptional folate administration has been convincingly demonstrated in a large cohort (n = 23 491) in the United States.186 Prevalence ratio estimates of NTDs among women who took multivitamins containing folic acid during the first 6 weeks of pregnancy were 0.27 and 0.29, respectively, depending on whether they had a family history of an NTD.
Two meta-analyses undertaken by the Cochrane collaboration evaluated the impact of folate supplementation during either pregnancy151 or the periconceptional period.187 In the former review of 21 studies, folate supplementation during pregnancy was associated with a reduction in the proportion of women with low Hb levels in late pregnancy (OR: 0.61; CI: 0.52–0.71). Apart from the small, nonsignificant reduction in the incidence of LBW noted above (OR: 0.73; CI: 0.47–1.13), folate supplementation seemed to have no measurable effect on any other substantive measure of pregnancy outcome such as pregnancy-induced hypertension, placental abruption, or preterm delivery. Although folate administration significantly improved maternal Hb levels and folate status, there was insufficient evidence to evaluate whether folate supplementation during pregnancy had any effect, either beneficial or harmful, on clinical outcomes for mother and infant.
The second meta-analysis of periconceptional folate supplementation trials187 principally included 4 trials with 6425 women and concluded that periconceptional folate supplementation significantly reduced the incidence of NTDs (OR: 0.28; CI: 0.15–0.53). Of the 4 trials, 3 also evaluated different multivitamin combinations, including various micronutrients. Multivitamins or micronutrients alone were not associated with prevention of NTDs and did not produce any additive benefits when given with folate. There was no effect on rates of miscarriage (OR: 1.12; CI: 0.98–1.29) or stillbirth (OR: 0.78; CI: 0.34–1.78). There was some evidence that folate supplements increase the risk of multiple births (OR: 1.40; CI: 0.93–2.11); although not statistically significant, this was a consistent finding in 3 studies. None of these studies reported birth weight as an outcome. A trial of periconceptional and first trimester folic acid and multivitamins conducted by the Indian Council of Medical Research showed no effect on abortions or stillbirths and a nonsignificant effect on LBW (12.5% [folic acid] vs 15.6% [placebo]).188
We identified an additional 10 studies in developed countries that also evaluated the potential benefits of periconceptional folate administration; only 1 of these studies189 presented data on neonatal outcomes other than congenital malformations. This large study from Denmark189 showed a decrease in preterm, small-for-gestational-age (SGA), and LBW rates in neonates born to mothers who were supplemented with folate. Women who benefited were those supplemented with folate in the periconceptional period, compared with women who either were not supplemented or were supplemented during some other time of pregnancy. There was no difference in the effect of a 1-mg daily dose compared with a 2.5-mg daily dose of folate. Other studies revealed a significant reduction in the incidence of primary and recurrent cases of NTDs among neonates born to mothers supplemented with folate.190,191 Furthermore, these studies showed a decrease in the incidence of other congenital malformations (eg, limb defects, cardiovascular problems, urinary tract anomalies, orofacial abnormalities).191–195
Given the recent interest in the prevalence of maternal hyperhomocysteinemia among folate and B12-deficient populations and the potential relationship with adverse pregnancy outcomes,196,197 there is renewed emphasis on ensuring adequate maternal folate and B12 status during pregnancy. The serum concentrations of these nutrients have been shown to correlate with maternal pre-eclampsia,198 perinatal outcomes,199 and newborn measurements.200
COMMUNITY-BASED EVIDENCE.
Two studies from developing countries provide evidence for efficacy of folate supplementation (Table 8). In South Africa, there was a significant decrease in the incidence of LBW births among native African women supplemented with folic acid during pregnancy.180 In China, a large-scale intervention with optional folic acid supplementation given to women premaritally revealed a significant reduction in the incidence of NTDs in infants born to women who had received the folic acid supplements.184
CONCLUSIONS.
Based on the demonstrated impact of folic acid supplements given along with iron in improving Hb levels in iron-deficient populations, folate merits inclusion in antenatal supplementation programs in developing countries. Overall, the evidence also strongly supports the use of periconceptional folate supplementation to reduce NTDs, although the impact of folate supplementation on other pregnancy outcomes such as LBW and preterm births is not clear.
Several other aspects of folate use in pregnancy remain unanswered, such as the optimal dosage, the role of genetic polymorphisms at a population level, and the considerable logistic difficulties in providing folic acid to susceptible women periconceptionally.201 Our review of the evidence on folate supplementation suggests that this intervention is important in areas of maternal malnutrition and endemic micronutrient deficiencies, and it already is used routinely in maternal health programs. Better targeting of this intervention, by ensuring that young women receive folic acid along with iron, may reduce rates of NTDs and other congenital malformations and improve pregnancy outcomes.
Iodine Supplementation
BACKGROUND.
Iodine-dependent thyroid hormones play a critical role in brain cell proliferation, synapse formation and microtubular assembly. The beneficial effect of iodine supplementation on endemic cretinism and goiter has been well established, and deficiency disorders are now understood to manifest across a spectrum ranging from subclinical iodine deficiency to overt hypothyroidism and goiter. The global importance of endemic iodine deficiency in many developing countries is well recognized.202 It is typically associated with mountainous areas but may pose a problem anywhere that iodine is leached from the soil by heavy rainfall or flooding. It is estimated that approximately 1 billion people live in high-risk areas, particularly China, India, Eastern Europe, and parts of Africa. Clinical effects of iodine deficiency are particularly serious during pregnancy, and can result in miscarriages, early infant death, LBW, and cognitive deficiencies.
Three trials involving 1551 women were included in the Cochrane review of data on the impact of maternal iodine supplementation on pregnancy outcomes, including cretinism and mortality of offspring.203 In these trials,204–207 which were conducted in areas of endemic iodine deficiency, the use of injectable iodized oil resulted in a significant reduction in mortality in infancy and childhood (OR: 0.71; CI: 0.56–0.90) and reduced risk of endemic cretinism by the age of 4 years (OR: 0.27; CI: 0.12–0.60). The trial from Zaire further revealed that administration of iodized-oil injections was effective in reducing infant mortality and improving neurologic outcome even when given in midpregnancy.207–209
COMMUNITY-BASED EVIDENCE.
Apart from the data from Zaire and Papua New Guinea, our search identified 1 additional community-based trial of iodine supplementation (Table 9). In rural China, administration of iodine in drinking water resulted in a significant (65%) reduction in neonatal mortality (see ref 715). However, no data on neurologic development or cognitive function were available from this intervention trial.
CONCLUSIONS.
Although limited data on the impact of iodine supplementation on pregnancy outcomes are available from developing-country communities, the potential benefits (ie, reduced neonatal mortality and neurologic deficits) are substantial. Moreover, these findings are in accord with a vast body of literature from developed countries that also establishes the crucial role of iodine in cognitive development. The evidence indicates the enormous potential of public health approaches to this problem, especially in countries with endemic iodine deficiency. Therefore, administration of adequate amounts of iodine during pregnancy to expectant mothers should be an important component of health care interventions during pregnancy. Although universal salt iodization is a well-established intervention to control endemic iodine deficiency, there is still a need to develop innovative means of providing iodine supplements to deficient populations.
Antenatal Vitamin A Supplementation
BACKGROUND.
Although there is conclusive evidence for reduction of childhood mortality after vitamin A supplementation,210 the corresponding evidence for impact of vitamin A supplementation in pregnancy on outcomes in the perinatal/neonatal period is less well established. In Nepalese women, night blindness in the third trimester was associated with a significantly increased risk of anemia, infections, and pre-eclampsia as well as maternal mortality.211 Similarly, maternal night blindness was associated with increased risk of mortality in early infancy.212 Although there is evidence of an association between serum vitamin A or carotenoids and birth weight,213,214 it has not been found consistently.173,175,215–217
COMMUNITY-BASED EVIDENCE.
Five trials performed in rural settings in developing countries provided information on vitamin A supplementation relevant to this review (Table 10). None of the trials reported birth weight as an outcome. In an RPCT in Indonesia in which women were supplemented with vitamin A, iron, or both, Suharno et al168 found that women given both supplements had maximal Hb increases and one third of this response was attributable to vitamin A supplementation, suggesting that vitamin A may help reduce rates of maternal anemia and subsequent adverse birth outcomes.
In Nepal, a recent series of double-blind, cluster-randomized trials examined the impact of low-dose vitamin A or -carotene supplementation on a number of associated maternal and neonatal health outcomes. Daily supplementation of married women (n = 44 646) with vitamin A or -carotene provided preconceptionally, during pregnancy, and during lactation resulted in a highly significant (44%) reduction in maternal mortality and reduced the maternal mortality ratio by 40%.218 There was no impact, however, on perinatal or neonatal mortality, nor was there any impact on rates of fetal loss (miscarriage, stillbirth, loss due to maternal death), preterm births, or early infant survival.219 However, the risk of early infant mortality was reduced among night-blind women supplemented with vitamin A.212 These trials in Nepal showed no broadly observed effect of vitamin A supplementation on neonatal mortality or mortality in the first 6 months,219 although subanalysis suggests that there may have been a trend toward an effect.212
Some of the most important data on the potential benefits of high-dose antenatal vitamin A supplementation are from studies in HIV-infected women. Trials among HIV-positive mothers in Tanzania220 and South Africa221,222 showed no effect of vitamin A alone on fetal growth or fetal loss. In an RCT, HIV-positive pregnant women supplemented with 5000 units of vitamin A and 30 mg of -carotene during the third trimester and 200 000 units of vitamin A at birth had a reduced incidence of preterm births of 11%, compared with 17% among unsupplemented women.222 In Malawi, administration of 10 000 units of vitamin A in HIV-positive women lowered the incidence of LBW compared with placebo-treated control women.223,224
CONCLUSIONS.
Data on the impact of antenatal vitamin A supplementation are limited, and the biological plausibility of the intervention has been questioned.88 The impact seems to be robust for maternal mortality, but evidence of benefit for perinatal or neonatal outcomes is lacking. There is an urgent need to undertake additional studies of antenatal vitamin A supplementation in areas of endemic or subclinical vitamin A deficiency. These trials must be designed with sufficient power to determine impact on maternal mortality, pregnancy outcomes, and mortality in infancy. Similarly, the strong evidence for efficacy of -carotene in reducing maternal mortality suggests that other forms of supplementation also merit consideration. However, all such trials must be designed as effectiveness trials, with sufficient information regarding appropriate process indicators to inform programs.
Notwithstanding the above, the data on reduction of maternal mortality are compelling. Thus, it makes sense to ensure that pregnant women in areas of endemic subclinical vitamin A deficiency and night blindness receive at least the recommended dietary allowance (RDA) of vitamin A during pregnancy from both dietary sources and supplements.
Zinc Supplementation
BACKGROUND.
Because zinc is a critical nutrient involved in immunocompetence, growth, and development, there has been much interest in its role in pregnancy. King225 and Keen et al226 reviewed the evidence for an association between zinc deficiency and adverse outcomes in pregnancy. They concluded that, although evidence for the critical nature of zinc in pregnancy is based largely on animal studies, there were data to suggest that zinc was indeed an important nutrient in human pregnancy. A review of 17 studies published from 1977 to 1994 also indicated an association between maternal indicators of zinc status and birth weight of offspring, although several others were inconclusive.175 A further in-depth review of 10 zinc-supplementation trials conducted up to 1996 revealed that birth weight increased after zinc supplementation in 4 of the 10 trials.145 However, the Cochrane review on maternal zinc supplementation227 revealed no significant differences in maternal or neonatal outcomes after zinc supplementation, although there was a small effect of supplementation on reduction of preterm delivery rates. It was concluded, however, that there was insufficient evidence to fully evaluate the effect of zinc supplementation during pregnancy. Moreover, it is important to point out that most of the studies in the Cochrane review were from developed countries with relatively few malnourished women, and there have been a number of more recent studies from developing countries that may shed more light on this subject (reviewed below). On the other hand, other reviewers94,228 have also concluded that it is unlikely that zinc supplementation alone will influence birth weight or improve pregnancy outcomes in developing countries. Recent studies have focused also on combinations of zinc with other nutrients such as vitamin A. However, the results have been inconsistent. In 1 instance, although a positive impact of either zinc or vitamin A supplementation on maternal iron status during pregnancy was observed, the combination of the 2 failed to improve serum ferritin or Hb concentrations.229
COMMUNITY-BASED EVIDENCE.
Our search identified 6 studies for additional review, only 1 of which took place in a rural setting (Table 11). The majority of the studies were undertaken in urban slums and were comprised of subjects who had low zinc intake and were considered to be at high risk of zinc deficiency during pregnancy.
The additional studies of zinc supplementation in pregnancy reviewed here also produced mixed results. Only 1 study from Chile230 showed a decrease in prematurity rates in the supplemented group, along with a reduction in rate of LBW; the latter result was also seen in a study from the United States.231 Overall, the majority of the studies failed to show a significant impact of zinc supplementation on birth weight, preterm delivery rate, and either neonatal or perinatal mortality. A study from the urban slums of Bangladesh,232,233 however, showed a significant impact of zinc supplementation on rates of infectious disease morbidity (eg, diarrhea, dysentery, and impetigo) during the first 6 months of life among LBW infants born to zinc-supplemented mothers.
There are also ancillary studies that have evaluated the effect of zinc supplementation on maternal and infant outcomes that may be of value. Sazawal et al234 showed a significant (68%) reduction in mortality during the first 9.5 months of life among SGA infants born to zinc-supplemented women in urban India. Thus, although it is unlikely that isolated zinc supplementation among malnourished women will impact LBW rates, it is possible that zinc supplementation may improve infectious disease morbidity and boost immunity beyond the neonatal period. Recent data on combined vitamin A and zinc supplementation of pregnant women in central Java indicate that this combination supplement may significantly reduce anemia and rates of puerperal sepsis,229 highlighting the need to address multiple micronutrient deficiencies in at-risk populations. Moreover, data from Bangladesh showed that offspring of women supplemented with zinc from 4 months' gestation to delivery had lower scores on mental and psychomotor development indices at 13 months of age.235,236 These findings suggest the need for caution in addressing micronutrient deficiencies in malnourished populations with single-nutrient solutions.
CONCLUSIONS.
It is highly unlikely that isolated zinc deficiency exists in at-risk populations; significant iron deficiency, among other nutrient deficiencies, frequently coexists with subclinical zinc deficiency. Evidence for benefit of isolated zinc supplementation on pregnancy outcome is relatively weak, and at present we cannot recommend isolated zinc supplementation in pregnancy. However, all attempts should be made to replenish zinc stores or provide at least the RDA of zinc in malnourished populations. Whenever possible, this must be done through formulations that address other key micronutrient deficiencies that coexist with zinc deficiency, such as iron and vitamin A deficiencies, and implemented through multiple program pathways.237
Multiple-Micronutrient Supplementation
BACKGROUND.
With the emerging evidence of multiple micronutrient deficiencies in pregnancy, especially in HIV-endemic areas,238,239 there has been much interest recently in interventions employing multiple micronutrient supplements in pregnancy by using the standard UNICEF multiple-micronutrient supplements. Randomized trials of multiple micronutrient interventions in pregnancy are currently underway in a number of developing countries with malnourished populations, such as Nepal, Pakistan, Guinea Bissau, Bangladesh, and Indonesia.
The 10-year observational Camden Study on the impact of multivitamin supplementation on pregnancy and perinatal outcomes was conducted in a poor US urban setting240 and included 1430 pregnant women in various stages of pregnancy. Risk of LBW was reduced approximately twofold with supplement use during the first (OR: 0.63; CI: 0.39–1.0) and/or second (OR: 0.57; CI: 0.38–0.86) trimester. The use of prenatal supplements during the first and second trimester was also associated with an approximately twofold reduction in risk of preterm delivery (ORs: 0.53 and 0.71; CIs: 0.35–0.81 and 0.5–1.01; for first and second trimester use, respectively). Thus, it seemed that the decrease in rates of LBW or VLBW was not due to a decrease in rates of IUGR but rather to a decrease in the rates of preterm infants. In another large trial in the United States reported in 1989, use of multivitamins lacking in folic acid content had no impact on prevalence of NTDs.186
In contrast to the above-mentioned studies, which focused on micronutrient supplementation, there are a large number of studies that have used combinations of food and energy supplements and micronutrients. Most of these data are derived from programs and interventions in developed countries. The US government's Women, Infants, and Children Supplemental Nutrition Program (WIC) provides low-income mothers with vouchers for milk, eggs, cheese, fruit juice, cereals, legumes, and peanut butter.241 Although this intervention has not been assessed prospectively in a randomized trial, it has been estimated retrospectively242 that participation in the WIC program was associated with reduced preterm delivery and fetal death and small but significant increases in mean birth weight (+22.7 g) and head circumference. Retrospective analyses of mothers with poor diets who had received supplemental milk, eggs, and oranges revealed a higher mean birth weight compared with siblings (+107 g).243 These effects were relatively greater in thinner mothers. In a large Hungarian trial of micronutrient supplementation,192 there was no impact on birth weight.
Data from developing countries are limited and relate to disparate programs of varying sizes. In some cases, the trial design does not allow for clear conclusions to be drawn regarding the contribution of multiple micronutrients to the impact of the intervention. Two large trials in Guatemala115 and Taiwan108 evaluated the benefit to pregnant women of increased energy intake as well as multiple mineral and vitamin supplements. The trial in Guatemala administered 2 supplements, 1 caloric and 1 protein-caloric, to malnourished pregnant women during pregnancy to examine effects of supplementation on birth weight. Both supplements were fortified with comparable amounts of micronutrients including vitamin C (4 mg), calcium (0.0–0.4 g), phosphorus (0.0–0.3 g), thiamine (1.1 mg), riboflavin (1.5 mg), vitamin A (18.5 mg), iron (5 mg), and fluoride (0.2 mg). There was no difference in birth weight between the 2 intervention groups, but infants born to the subgroup of mothers who had consumed >83 750 J of either supplement during pregnancy had a correspondingly greater increment in birth weight. In contrast, the increment in birth weight was comparable in Taiwan, where the supplements were given to well-nourished women and were not significantly fortified with micronutrients.108 Although the results from the Guatemala trial have been attributed to increased energy intake, there may also have been an effect of the micronutrients present in both supplements. However, because of the open study design, it is difficult to measure the attributable effects of micronutrient supplementation on birth weight in this trial.
A small trial in a poor rural population of Thailand studied the effect on birth weight of improving the mothers' dietary quality.110 Mothers (n = 43) were randomized into 3 groups to receive either extra food (preprepared cooked food containing legumes, sesame, peanuts, and sugar; or rice, oil, peanuts, shrimp, and sugar) or no extra food. Newborn infants born to mothers who had received the food-based interventions were 250 g heavier than infants born to controls. In the Narangwal Study from Indian Punjab,244 villages were assigned to 1 of 4 groups, receiving (1) nutrition care, (2) health care, (3) both, or (4) neither. In nutrition villages, pregnant mothers received bulgar wheat porridge, sugar, milk powder, and oil. Although birth weight was not recorded, stillbirths were reduced by 40% compared with control villages.
COMMUNITY-BASED EVIDENCE.
As indicated above, several community trials of multiple micronutrients are currently underway. Preliminary results from a community-based cluster-randomized trial of multiple micronutrient supplements in Pakistan suggest a significant impact on birth weight (Z.A.B., unpublished observations, 2004).
The major published data available on efficacy of multiple micronutrient supplementation in developing countries currently derive from a study in HIV-infected women in Tanzania220 and another trial in The Gambia of high-energy biscuits that also contained extra micronutrients, calcium and iron104 (see Tables 6 and 12). The results of the Gambian study have been presented already (see "Balanced Protein-Energy Supplementation"). In Tanzania, after micronutrient supplementation, the mean birth weight was higher among HIV-negative infants (+100 g; P < .01), and there were significant reductions in rates of LBW (–44%), preterm births before 34 weeks' gestation (–39%), and IUGR (10% vs 18%; P = .002). Moreover, use of multiple micronutrients and multivitamins resulted in significantly fewer fetal deaths (5.9% vs 9.6%; P = .02). Recent unpublished data from the same group indicate that multiple RDAs of multivitamins and micronutrients may be required in HIV-infected pregnant women (W. Fawzi, MD, DrPH, verbal communication, 2002).
In a trial in Chile,100 mothers received either powdered milk or milk fortified with vitamins and minerals. Mean birth weight was higher in the fortification group (+73 g; P < .05), and the percentage of IUGR infants was lower (32% vs 44%; P < .05). In Bogotá, Colombia, birth weight was greater (+95 g) in urban slum families who were randomly allocated to receive extra food (milk, fortified bread, and vegetable oil).245 Similarly, infants born to women in South Africa who received a supplement of maize porridge and skim milk fortified with vitamins A, B1, B2, and calcium were an average of 300 g heavier than infants born to unsupplemented women.246 However, in Mexico, other studies of multiple-micronutrient supplementation during pregnancy have failed to demonstrate any benefit regarding increased birth weight250 or maternal hematologic parameters.251
CONCLUSIONS.
Although benefit from supplementing pregnant women with multiple vitamins and micronutrients seems plausible, particularly due to increased nutritional requirements during pregnancy and lactation,94 there has been concern that multiple-micronutrient–supplement formulations designed for developed countries may be inappropriate for women in developing countries with significantly different staple diets.247 It is thus very important that these studies be undertaken with full attention to potential adverse outcomes. Recent data from Nepal on the use of multiple micronutrients suggest that multiple micronutrients may confer no additional advantage over iron-folate supplements but rather may alter the distribution of birth weight, leading to higher PMR and NMR due to obstructed labor.169,248,249 Current field trials of multiple micronutrient supplementation in pregnancy will provide useful data on efficacy, impact on LBW and other perinatal outcomes, and potential interactions of micronutrients. Pending these data, however, the widespread use of these multiple micronutrients cannot be recommended.
Infection Control and Prevention
Interventions in Malaria-Endemic Areas
Malaria continues to be a major health problem in endemic countries and a matter of concern within the global community. Globally, malaria affects almost 10% of the world's population, and of the nearly 500 million cases, 1 million may die annually.252 In areas of high malarial transmission, chronic and repeated malaria infections greatly increase the risk of maternal anemia.253–257 In areas of low malarial transmission, immunity is low, and malaria in pregnancy can rapidly progress to complications such as severe anemia, cerebral malaria, and death.258–262 Primigravidae also tend to have a much higher prevalence and density of parasitemia than both nonpregnant women and multigravidae.256,263 Where malaria is endemic, women become more susceptible to infection during pregnancy, but this susceptibility decreases with successive pregnancies.256,264 Given the propensity of parasitized red blood cells to sequester in the placenta, malaria is associated with maternal anemia, increased risk of preterm birth, LBW, and neonatal mortality.265–268 The estimated population attributable risk of LBW among primigravidae with malaria is 10% to 40%.269 Recent data also suggest that HIV infection may impair the ability to acquire pregnancy-specific immunity, thus increasing the likelihood of complications of malaria among HIV-positive multigravidae in endemic areas.258–262,270
Malaria Chemoprophylaxis or IPT
BACKGROUND.
Although malaria chemoprophylaxis with chloroquine (CQ) has been the main strategy for management of malaria in endemic areas, there is uncertainty about its efficacy in comparison with IPT. A review of 15 trials by the Cochrane collaboration271 revealed that women who were given regular, routine antimalarial drugs had less risk of developing severe anemia and had fewer episodes of fever antenatally than those who did not receive prophylactic therapy. Newborn infants of these women also had higher birth weight compared with those born to women who did not receive prophylaxis; this effect was principally seen among primigravidae. However, there was no overall benefit of antimalarial chemoprophylaxis on perinatal and neonatal mortality.
Several studies indicated that IPT can be given under directly observed therapy in antenatal clinic programs and achieve high program effectiveness.272 Additional support for the effectiveness of IPT was given in a meta-analysis by Newman et al,273 which found that the 7 most promising drug regimens for malaria prevention in terms of program effectiveness and efficacy, were all IPT as opposed to chemoprophylaxis because of their ease of delivery and lower cost. IPT with sulfadoxine-pyrimethamine (SP) in areas without SP-resistant strains was ranked highest in terms of effectiveness due to the low cost, wide availability, easy deliverability, and acceptability of SP.
COMMUNITY-BASED EVIDENCE.
A variety of antenatal antimalarial chemotherapy drugs (eg, SP, CQ, proguanil [PROG], and Maloprim [pyrimethamine-dapsone]) given for prophylaxis have been evaluated in developing countries (Table 13). Decreases in rates of stillbirths and perinatal, neonatal, and/or infant mortality were observed in some instances,274–277 but overall, the impact on these outcomes was not significant. The preterm birth rate also was not impacted. An increase in birth weight, however, was observed in nearly all studies155,258–262,275,277–284; thus, the evidence for a beneficial effect of chemoprophylaxis on birth weight in endemic areas is strong. Chemoprophylaxis also had a uniformly significant effect in reducing maternal anemia, parasitemia, and/or placental parasite load.
Studies comparing various drug regimens revealed that mefloquine was of particular benefit in clearance of parasitemia and in some neonatal health outcomes (eg, reduction in LBW rate) in areas with high rates of CQ resistance.258–262,285 Another study by van Eijk286 in Kenya found IPT (at least 1 dose of SP) during pregnancy was associated with a significant reduction in the LBW rate (OR: 0.65; CI: 0.45–0.95).
A growing body of research evaluates the cost-effectiveness of different drug prophylaxis/IPT regimens. In Malawi, Schultz et al287 found that 2 doses of trimethroprim/sulfamethoxazole during pregnancy were equally effective as 1 dose. Another study evaluated the cost-effectiveness of 3 approaches to malaria chemoprophylaxis compared with case management of malarial disease in areas with variable HIV prevalence and high malaria endemicity.283 In malaria-endemic areas with high HIV prevalence (>10%), administering 1 dose of SP prophylaxis per month was more cost-effective, whereas in malaria-endemic areas with low HIV prevalence (<10%), administering 2 doses of SP prophylaxis during pregnancy was more cost-effective. In any setting, the monthly and the 2-dose strategies were more cost-effective than the case management approach.
CONCLUSIONS.
Malaria prophylaxis during pregnancy is an important intervention in community settings in malaria-endemic areas, because it serves to reduce maternal anemia and parasitemia and improve birth weight. In general, however, little improvement in survival of offspring (eg, stillbirths, PMRs, and NMRs) has been demonstrated, although most studies lacked sufficient power to evaluate mortality outcomes. Case management strategies alone are less effective than continuous or intermittent prophylaxis, and in areas with high rates of CQ resistance, alternative agents such as mefloquine are superior.
There is a real need to undertake concerted research in this area by means of large-scale effectiveness trials of various prophylaxis strategies for malaria, particularly IPT. Pending evidence to the contrary or for alternative strategies, the current policies of antimalarial prophylaxis in high-risk populations must continue.
Malaria Prevention Using ITNs
BACKGROUND.
Consistent use of bed nets impregnated with permethrin, an insecticide, reduces the frequency of bites from infected mosquitoes and can consequently reduce rates of malarial infection and parasitemia. A meta-analysis of RCTs evaluating ITNs showed that when ITNs were compared with untreated nets or no nets at all, the efficacy for prevention of moderate to severe malarial infection was 17%, and child mortality was reduced 23%.271 On average, 6 lives were saved annually for every 1000 children protected with ITNs. ITNs also reduced the incidence of mild malarial episodes by 48% and 34% compared with no net and untreated bed net (NIB) controls, respectively.
There is some evidence that the widespread use of ITNs, particularly in high-transmission, malaria-endemic areas, may reduce rates of maternal anemia and placental infection, consequently reducing the risk of adverse birth outcomes such as stillbirth and LBW due to prematurity and IUGR.288 There are also significant data showing that ITNs can reduce child morbidity and mortality, particularly in infants. In a high-transmission area of western Kenya, an RCT by Hawley et al289 reported that ITNs reduced all-cause postneonatal mortality (deaths of infants between 1 and 11 months old) by 23%. However, no single research study has had sufficient size to observe a specific significant impact of ITNs on neonatal mortality; benefits of ITNs on neonatal mortality have been largely inferred from pregnancy outcome data.290
COMMUNITY-BASED EVIDENCE.
The impact of ITNs on pregnancy outcomes was unclear, but overall, the results were not significant. The ITN intervention showed a trend toward reduced stillbirth rates and PMRs in Kenya,292 whereas a study in The Gambia failed to show an impact on perinatal mortality.272 This latter study, however, revealed a decrease in premature birth rate and a corresponding increase in birth weight, although only among primigravid women.272 Another study in Thailand showed no impact of ITN use on gestational age at birth,291 and overall, no study showed a significant impact on birth weight.272,291,292 The impact of the intervention on IMR also was mixed.291,293
CONCLUSIONS.
There is strong evidence for the efficacy of ITNs in reducing childhood mortality and morbidity from malaria. There is encouraging evidence for improved pregnancy outcomes and reduced perinatal or neonatal mortality from representative settings in developing countries. Some of the variability in data may be a result of the considerable heterogeneity in the treatment groups. Although the overall effect of this intervention shows promising trends, particularly in reducing rates of maternal anemia, the number of well-designed studies with the requisite power to assess outcomes of interest is limited. Cost-effectiveness studies and operations research are needed to help make this intervention more feasible at scale. Currently, we are able to recommend both chemoprophylaxis and PIB use in pregnancy in malaria-endemic areas, which, coupled with the recommendation for use in childhood, makes the case for family-centered approaches.10
Deworming
BACKGROUND.
A conservative estimate by the WHO suggests that at any given time, nearly 44 million pregnant women globally may be infected with hookworms.294 In endemic areas, hookworm infestation is known to be a major contributing factor in development of anemia in women of reproductive age.295
Although the current recommendation during pregnancy is to use a single-dose regimen of either mebendazole or albendazole for treating hookworm infestation,296 in combination with iron-folate supplements, there have been almost no systematic studies of the impact of this intervention on pregnancy outcomes.
COMMUNITY-BASED EVIDENCE.
Our review revealed little community-based information on the impact of maternal deworming. A recent intervention trial in rural India297 used a combination strategy with iron supplementation, deworming, and nutrition education using specially developed information, education, and communication materials (Table 15). Significant decreases in the prevalence of maternal iron-deficiency anemia and increases in mean Hb levels were seen and were greater the earlier the intervention was introduced in pregnancy.
Despite the lack of community-based data, there were a few smaller studies on the impact of deworming in developing-country settings. In a nonrandomized study in Sri Lanka167 women who received deworming along with iron folate as part of their antenatal care had better Hb and higher birth weight infants than women who did not. In Bangladesh, a randomized trial using a 2 x 2 factorial design tested the effects of iron and antihelminthic treatment on Hb and wormload in female tea-plantation workers.298 The group receiving both iron supplements and antihelminthics had the largest increments in Hb concentration compared with the controls. Prevalence and intensity of Ascaris, Trichuris trichiura, and hookworm infestation declined in the 2 groups that received antihelminthic treatment.
The only studies of the impact of deworming on neonates undertaken in developing countries were in Nepal and Sri Lanka299 (Table 15). This retrospective observational study in an urban hospital setting in Sri Lanka found that antihelminthic therapy (mebendazole) was associated with significantly lower stillbirth rates and PMRs (OR: 0.55; CI: 0.4–0.77). Taking medication was also associated with a decrease in the proportion of women delivering a VLBW infant (1.1% vs 2.3%). Women who took mebendazole during the first trimester, however, had a higher proportion of congenital malformations compared with the untreated women. In Nepal, another study found that 2 doses of albendazole during pregnancy was associated with a 46% decrease in neonatal mortality (RR: 0.54; CI: 0.37–0.78).300
CONCLUSIONS.
These data suggest that deworming in areas of high endemicity may reduce rates of maternal anemia and lead to improved pregnancy outcomes (eg, stillbirth, PMR, and LBW rates). However, there is a need to formally evaluate the benefits and potential complications of antihelminthic therapy in community-based effectiveness trials in diverse programmatic settings and locations.
UTIs and Reproductive Tract Infections
Ascending bacterial infections of the genitourinary tract can be a significant underlying factor in many late fetal deaths301 as well as spontaneous onset of preterm labor.302 Although colonization of the lower genital tract by fecal flora can occur commonly without adverse consequences,303,304 infection of the amniotic fluid, the interior of the placenta, and/or the fetus is associated with serious complications.301 Chorioamnionitis or amniotic fluid infection has been identified as an important cause of fetal death in several studies from developing countries.305–309 The following section will review the evidence of interventions pertaining to common genitourinary infections in pregnancy.
Syphilis Screening and Treatment
BACKGROUND.
Although syphilis is widely recognized as an important cause of morbidity among the adult population, there are few reliable estimates of the exact contribution of syphilis to the burden of perinatal and neonatal mortality in developing countries. Congenital syphilis continues to be a major public health problem in developing countries.310
Untreated syphilis was found to cause fetal death in 22% of pregnancies among infected African mothers; the risks for antepartum and intrapartum stillbirths among infected women were 18-fold and 8-fold higher, respectively.311 In Malawi, a longitudinal population-based study revealed a population-attributable risk for syphilis of 26% among all fetal deaths and 38% for antepartum fetal deaths.312 Syphilis was the attributed cause of 10% of 315 late fetal deaths in a case-control study (CCS) in Port Moresby, Papua New Guinea.79 Syphilis is particularly common in Africa, with prevalence estimates around 10%.313–315 Syphilis is also recognized as a major contributor to peri