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 Available published and unpublished data on the impact of community-based strategies and interventions on perinatal and neonatal health status outcomes were reviewed.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.
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.
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.
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.
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.
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.
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 schooling/health education
Antenatal care packages
Balanced protein-energy supplementation
Antenatal vitamin A supplementation
Multiple micronutrient supplementation
Malaria chemoprophylaxis or intermittent presumptive treatment (IPT)
Malaria protection using insecticide-treated bed nets (ITNs)
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
In addition to the specific community-based interventions noted above, some studies evaluated packages of maternal interventions in community settings:
Maternal care packages
Maternal vaginal and newborn skin antisepsis
Delayed umbilical cord clamping
Umbilical cord antisepsis
Hypothermia prevention and management
Hypoglycemia prevention and management
Prevention and treatment of ophthalmia neonatorum
Vitamin K prophylaxis
Hepatitis B vaccination
Neonatal vitamin A supplementation
Kangaroo mother care (KMC)
Topical emollient therapy
Traditional birth attendant (TBA)/CHW training
Pneumonia case management
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
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
Maternal Schooling/Health Education
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”).
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
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
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).
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.
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
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
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.
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.
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.
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
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.
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 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
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
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-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
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.
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
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
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 β-carotene supplementation on a number of associated maternal and neonatal health outcomes. Daily supplementation of married women (n = 44 646) with vitamin A or β-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 β-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
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 β-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.
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
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.
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
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.
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
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
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.
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.
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
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
Table 14 summarizes the major studies evaluating efficacy of ITN use among pregnant women in malaria-endemic areas. Overall, use of bed nets was effective,272,291 although not uniformly so,292 in reducing rates of maternal anemia. In Kenya, the incidence of severe maternal anemia (Hb <8 g/dL) was slightly lower in the bed-net group (15% vs 20%), but the overall incidence of anemia was the same (92% in the bed-net group and 91% in the control group).292
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
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
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.
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 × 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
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
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 perinatal and infant mortality in the African region.311,315–317 In Ethiopia, ∼6% of perinatal mortality was due to syphilis.318 In Zambia, almost 9% of infants seen at the University Teaching Hospital were found to have congenital syphilis,319 and in the Central Hospital of Maputo, Mozambique, ∼1% of neonates had congenital syphilis.320 The reported seroprevalence of syphilis among women attending antenatal clinics in African, Asian, and Latin American countries ranges from 4% to 19%.321–324 Some reports also indicate that the incidence of congenital syphilis may be increasing in many developing countries; to illustrate, a 10-fold increase in congenital syphilis was reported in the Brazilian Federal District from 1980 (0.17 cases per 100 000 inhabitants) to 1984 (1.7 per 1000).325 Early diagnosis and treatment sharply reduce the risk of fetal death due to syphilis.326
The potential benefits of large-scale population-based intervention strategies for the prevention, detection, and treatment of congenital syphilis is strengthened by the experience in developed countries. To illustrate, the prevalence of congenital syphilis was reduced by as much as 70% by a large screening and intervention program in Milwaukee.327
We identified 5 intervention trials in developing countries that addressed the issue of antenatal screening and treatment of syphilis and evaluated the impact on pregnancy outcomes (Table 16). Of these, only one316 was rural-based, and one was in a periurban/suburban setting328,329; the rest were urban hospital-based studies. We included these hospital-based studies in the current review because they were conducted in developing countries and represented typical catchment populations.
The data reviewed suggested that serologic and clinical testing for syphilis did not have sufficient sensitivity for case detection, especially when conducted by paramedical or nursing staff.316,330 One study reported sensitivity of 50% and specificity of 91% for on-site rapid plasma reagin (RPR) testing done by nurses.330 Universal screening, preferably on site, is the appropriate option,331 because it ensures immediate treatment. High-risk patients, however, should be rescreened in the third trimester.
The studies reviewed demonstrated a significant reduction in the incidence of congenital syphilis among cases identified and treated antenatally.316,328,329 Stillbirths and perinatal mortality328,329,332 were reduced in offspring of mothers diagnosed and subsequently treated for syphilis during pregnancy. An observational study also demonstrated that women who were diagnosed and treated for syphilis during pregnancy had lower risk (OR: 0.25; P < .0001) of giving birth to an LBW infant.332 Screening for and treatment of syphilis is thus a cost-effective means of reducing fetal deaths.332
Case identification and treatment of maternal syphilis have significant benefits in improving perinatal and neonatal outcomes, particularly in endemic areas such as sub-Saharan Africa. There are major challenges, however, in implementing diagnostic testing and treatment in programs while assuring quality and access. Additional operational research is needed on how to make accurate testing and effective treatment feasible and available at scale.
Antibiotics for Asymptomatic Bacteriuria
Although treatment for symptomatic UTIs in pregnancy is standard-of-care in developed countries, and the role of specific antimicrobial therapy in pregnancy is well established,333 there are no community-based studies of treatment for asymptomatic bacteriuria during pregnancy and its impact on pregnancy outcomes. Most available data are from facility-based cases and from developed countries. In a meta-analysis of the available evidence on benefits of antimicrobial therapy for asymptomatic bacteriuria in pregnancy, mostly from developed countries but also including poor populations, Smaill334 convincingly established a reduction in rates of pyelonephritis (OR: 0.25; CI: 0.19–0.32) and a pooled relative risk (RR) of 0.64 (CI: 0.50–0.82) for the composite outcome of preterm delivery or LBW based on 10 controlled clinical trials.
No studies were identified that reported data from developing-country community settings on the impact of antimicrobial therapy on asymptomatic bacteriuria in pregnancy. There is considerable evidence, however, that bacteriuria and occult UTIs are widespread in developing countries.335–337
Although there are no valid studies of screening and treatment strategies for maternal asymptomatic bacteriuria from community-based settings in developing countries, there is little reason to doubt the association of occult and overt UTIs in developing countries with increased risk of preterm/LBW births and neonatal infections, given the strength of the relationship in developed countries.338,339 Moreover, although the choice of antibiotics may vary, there is little reason to suggest that the findings of the main Cochrane review334 would not be applicable in diverse settings.340 Given the available evidence and biological plausibility, all clinically symptomatic UTIs must be appropriately treated, and attempts must be made to collect evidence from representative developing-country settings regarding the importance of treating asymptomatic bacteriuria. However, the logistics, technical requirements, and frequency of screening necessary for diagnosis of asymptomatic bacteriuria in developing-country settings are formidable barriers to wide-scale implementation of this intervention. Thus, pending additional evidence as to the feasibility and cost-effectiveness of this strategy, and require additional operational and cost-effectiveness research.
Antibiotics for Bacterial Vaginosis
Although reliable estimates of the global burden of bacterial vaginosis are unavailable, the disorder is known to affect a large proportion of women in developed countries (∼16%) and is associated with adverse pregnancy outcomes including increased risk of preterm (∼40%) or LBW birth and premature rupture of membranes (PROM).326,341–344 Some studies have found high rates of bacterial vaginosis in developing countries,345 but data are lacking on the attributable risk of bacterial vaginosis for LBW.
Despite strong epidemiologic evidence of an association between bacterial vaginosis and preterm birth, randomized trials of topical clindamycin, as well as systemic antibiotic treatments using any of a variety of agents (eg, erythromycin, amoxicillin, or metronidazole), have not shown clear evidence of benefit.302 This may be explained partly by heterogeneity in the patient populations studied. In the only published trial among low-risk (ie, no history of prior preterm birth) asymptomatic women, screening and treatment with oral clindamycin resulted in nearly a 50% reduction in the rate of preterm birth or PROM.346 It has been suggested, however, that data showing benefit from a prospective double-blind, placebo-controlled trial are needed before such an approach is undertaken routinely in low-risk pregnant women.347
Antibiotic treatment of bacterial vaginosis among high-risk pregnant women in developed countries who previously had a preterm delivery has significantly reduced the risk of subsequent preterm birth.348–351 Although Duff et al348 used oral amoxicillin for therapy, Hauth et al350 used a combination of metronidazole and erythromycin for 7 days, and others349,351 used a short course of metronidazole alone. However, in a recent large trial from the NIH Maternal-Fetal Medicine Network,352 a 2-dose regimen of oral metronidazole had no effect on rates of fetal and neonatal deaths, LBW, or VLBW. Moreover, a slightly increased risk of preterm birth was found for women with a prior history of preterm birth. Another recent publication from the same NIH network also reported an increased risk of preterm birth after treatment of women with asymptomatic trichomoniasis with metronidazole.353 Similarly, a combined intravenous (IV)-oral regimen of ampicillin/amoxicillin plus erythromycin had no impact on fetal or infant death rates.354 In the latter trial, however, treatment resulted in reduced incidence of neonatal necrotizing enterocolitis, intraventricular hemorrhage (IVH), respiratory distress, and early-onset sepsis. A single trial of treatment for reproductive tract infection due to chlamydia failed to reduce the risk of preterm birth.355 In a recent review of the impact of treatments for bacterial vaginosis, Joesoef et al347 concluded that women with symptomatic disease, whether pregnant or not, should be treated with metronidazole (500 mg, twice daily, for 7 days), clindamycin vaginal cream (2%, once daily as a nocturnal intravaginal application, for 7 days), or metronidazole vaginal gel (0.75%, twice daily, for 4 days), because these regimens have produced equivalent cure rates. For pregnant women with high risk of an adverse pregnancy outcome (ie, those with a prior preterm birth) but asymptomatic disease, intravaginal clindamycin is not recommended, because it has failed to reduce rates of preterm births. If screening of high-risk women is undertaken, it is best performed early in the second trimester, and treatment doses should be limited to 250 mg of metronidazole orally 3 times daily for 4 days to minimize any potential teratogenic effects of treatment.
Diagnostic methods for bacterial vaginosis in developing-country settings have not been standardized, and relatively few studies have explored the impact of potential interventions to screen and treat bacterial vaginosis on pregnancy outcomes (Table 17). A double-blind, randomized, placebo-controlled trial at 7 maternity clinics in Indonesia reported an 85.5% cure rate among women with bacterial vaginosis treated with 2% clindamycin vaginal cream, but rates of preterm delivery or LBW were not affected.344 It was suggested that systemic treatment may be needed to eradicate upper reproductive tract disease and to reduce preterm births. Treatment of women in South Africa in early preterm labor for 4 days with metronidazole and ampicillin (agents effective against, but not specifically targeted toward, bacterial vaginosis in this trial) increased pregnancy duration, but preterm birth rates were not reported, and no reduction was observed in either neonatal deaths or length of hospital stay.356
Broad-spectrum treatment for reproductive tract infections in rural Uganda with single doses of azithromycin, cefixime, and metronidazole resulted in a significant decrease in preterm birth rates (−23%) and early NMRs (−17%).345 In Kenya, a single oral dose of cefetamet-pivoxil given to women at 28–32 weeks of pregnancy with a prior history of stillbirth or an LBW infant resulted in significant reductions in the LBW rate (probably due largely to preterm birth) and postnatal endometritis and an increased birth weight.357 No effect was observed on stillbirths or preterm birth rates. Large losses to follow-up, however, suggest the need for cautious interpretation of these results. Finally, a recently published trial in pregnant women living in the Rakai district of Uganda revealed that those randomized to receive a single presumptive treatment dose of azithromycin, cefixime, and metronidazole had borderline significant reductions in risk of preterm birth (OR: 0.72; CI: 0.56–1.05) and early neonatal death (OR: 0.83; CI: 0.71–0.97).358 Each of these treatment regimens broadly decreased rates of maternal reproductive tract infections including bacterial vaginosis.
Available data suggest that antibiotic therapy effective for treatment of bacterial vaginosis may be beneficial in decreasing rates of LBW and, possibly, prematurity and neonatal mortality.345 Treatments that are effective against bacterial vaginosis may also decrease rates of other reproductive tract infections such as those due to chlamydia and gonorrhea. However, results have been mixed, with some studies showing increased risk for preterm births. Moreover, there are still major problems with operationalizing these interventions into programs, because simple, affordable diagnostic methods and additional large-scale effectiveness studies of simple treatment regimens, particularly in asymptomatic pregnant women, are needed. It is also unclear if the prevention of preterm births between 34 and 37 weeks' gestation will substantially improve perinatal and newborn survival in public health programs.359 These interventions merit additional exploration before their inclusion in routine antenatal care strategies.
Antibiotics for Preterm Labor
A major proportion of the burden of global perinatal mortality relates to preterm births. The WHO estimates that prematurity is responsible for nearly one fourth of neonatal deaths.29 Of ∼13 million annual preterm births globally,360 one third may be related to spontaneous preterm delivery,361 and in 30% to 40% of preterm births, labor may follow spontaneous rupture of membranes.362
Several studies have identified an association of subclinical chorioamnionitis (ie, intact membranes) with spontaneous preterm labor.363–365 Pathogens were identified from the amniotic fluid in 10% to 15% of cases presenting with preterm labor.366 A meta-analysis by the Cochrane collaboration of available RCTs of antibiotic therapy in preterm labor with intact membranes367 identified that antibiotic treatment in this situation prolonged pregnancy (weighted mean difference: 5.4 days; CI: 0.9–9.8 days). There was no effect on reduction of preterm births or on respiratory distress syndrome or neonatal sepsis, but a significant reduction in neonatal necrotizing enterocolitis (OR: 0.33; CI: 0.13–0.88) was noted. The meta-analysis also revealed, however, an increase in mortality related to preterm birth or its sequelae (OR: 2.43; CI: 0.92–6.43) and an increase in perinatal mortality in the group receiving antibiotics (OR: 3.36; CI: 1.21–9.32). With regard to maternal effects, antibiotic treatment significantly reduced maternal infection (chorioamnionitis/endometritis) (OR: 0.68; CI: 0.48–0.98). Still, overall evidence for the benefit of antibiotic therapy in preterm labor with intact membranes is lacking.
This large meta-analysis has been supplemented by the large multicenter ORACLE II trial in several developed countries, including almost 6300 pregnant women randomized into 1 of 4 groups to receive (1) erythromycin, (2) amoxicillin/clavulanic acid, (3) both, or (4) placebo.368 The primary outcome measure was a composite of neonatal death, chronic lung disease, or major cerebral abnormality on ultrasonography before discharge from hospital. There was no evidence that any of the antibiotic regimens improved maternal or neonatal outcomes; length of pregnancy, length of maternal hospital stay, mode of delivery, birth weight, proportion of infants admitted to intensive care or ventilated, proportion of infants with a positive blood culture, or composite neonatal outcome were not different among the treatment groups.
Most of the trials of antibiotic therapy for preterm labor have been conducted in developed countries; none have been reported from community settings. Table 18 illustrates the 2 studies of antibiotic therapy for preterm labor in developing-country settings.356,369 The overall conclusions from these studies were consistent with the results of the Cochrane meta-analysis367 and the ORACLE II study.368
No clear overall benefit for routine antibiotic therapy for preterm labor with intact membranes has been demonstrated in trials in urban settings in developed or developing countries. Thus, this intervention cannot be recommended routinely. Evidence indicates that antibiotic administration in preterm labor should be considered only when there are clear indications of associated infection, or, as indicated in the next section, in the presence of other risk factors.
Antibiotics for PPROM
The most common antecedent of preterm labor is PPROM.362 The culture positivity rate of amniotic fluid for microbial organisms in such cases ranges from 32% to 35%.366 The mechanisms underlying PPROM may include local subclinical infection and inflammation leading to weakening of the amniotic membranes.370
A Cochrane meta-analysis of the benefits of antibiotic therapy in cases of PPROM concluded that maternal antibiotic therapy in this situation is effective in prolonging pregnancy and reducing maternal and neonatal infection-related morbidities.371 A subsequent large (n = 4826) multicenter RCT (ORACLE I)372 in urban centers in multiple developed and developing countries (eg, Argentina, Brazil, Lithuania, Malaysia, South Africa, Sri Lanka) corroborated the findings of the meta-analysis and suggested that administration of erythromycin to women with PPROM was associated with significant health benefits for the newborn. Fewer infants (P = .08) tended to have the primary composite outcome (ie, death, chronic lung disease, or major abnormality on cerebral ultrasonography) in the erythromycin group (151 of 1190 [12.7%]) than in the placebo group (186 of 1225 [15.2%]). Among the 2260 singletons in this comparison, significantly fewer had the composite primary outcome in the erythromycin group (125 of 1111 [11.2%] vs 166 of 1149 [14.4%]; P = .02). Use of erythromycin was also associated with prolongation of pregnancy beyond 48 hours of presentation (P = .004), reduction in neonatal treatment with surfactant (P = .05), reduced requirement for supplemental oxygen (P = .02), and fewer positive blood cultures (P = .02). An important additional finding among singletons was a lower rate of neonatal cranial ultrasonographic abnormalities at discharge (P = .04) and a probable reduction in childhood disability. Although co-amoxiclav only and co-amoxiclav plus erythromycin were associated with prolongation of pregnancy, they were also associated with a significantly higher rate of neonatal necrotizing enterocolitis (4-fold higher with co-amoxiclav alone versus placebo, 2.5-fold higher with any co-amoxiclav than with none).
The findings of 3 other studies373–375 conducted in developing countries largely corroborated findings from studies in developed countries, although data are very limited (Table 19). No trials of antibiotic therapy for PPROM, however, have been conducted solely in community settings in developing countries.
Although there are few systematic studies of antibiotic therapy for PPROM in developing countries and none in community settings, the evidence in support of the efficacy of this intervention in diverse settings is strong, and the practice is routine under certain circumstances (eg, early gestation). Thus, it is prudent to incorporate antibiotic therapy of PPROM in intervention programs wherever feasible, such as at referral-level health facilities. A domiciliary cadre of trained birth attendants potentially can be trained to recognize PPROM and provide referral and, possibly, initial antimicrobial therapy. However, this application of the intervention requires additional assessment and may be difficult in community settings.
TT Immunization and Clean Delivery
Despite major advances in understanding of the pathogenesis and risk factors for neonatal tetanus, it is still prevalent in many developing countries. A UNICEF/WHO/United Nations Population Fund survey in June 2000 indicated that 57 countries globally had not achieved elimination of neonatal tetanus (defined as <1 case of neonatal tetanus per 1000 live births in every district).376 Globally, only about half of women of reproductive age are adequately immunized, and it has been estimated that neonatal tetanus accounts for as much as 7% of neonatal deaths globally.29 Others point out that maternal tetanus may account for at least 5% of all maternal deaths.377 An additional 90 000 mothers die annually from puerperal infections caused by unclean delivery practices, and sepsis accounts for 14% of all obstetrical deaths.378 Thus, it is imperative that preventive strategies such as clean delivery and maternal tetanus immunization form a cornerstone of maternal care in any setting and that they go hand-in-hand.
Given the scientific basis for the importance of tetanus prevention and basic hygiene, it would now be unethical to conduct RPCTs assessing such approaches. Hence, much of the evidence for benefit of clean delivery practices and TT immunization comes from observational studies.
In addition to a host of descriptive studies, our search identified 8 trials conducted in rural settings in developing countries that provided pertinent information on perinatal and/or neonatal outcomes after various interventions to prevent tetanus and provide clean delivery (Table 20). These studies variably involved maternal TT immunization and/or preparation for clean delivery by equipping mothers and/or birth attendants with delivery kits and promoting hand-washing for delivery and newborn care. Thus, in general, it was not possible to determine the impact of individual interventions on outcomes.
Significant reductions in rates of neonatal tetanus, as well as associated case fatality and NMRs, were observed in newborns of mothers immunized for tetanus during pregnancy.379–385 Even partial immunization was found to be effective in decreasing mortality and tetanus morbidity.379,382 Hand-washing and use of clean instruments for cord cutting were associated with reduced neonatal tetanus incidence,381,386–389 neonatal mortality,380,384 and sepsis.271,384 Training TBAs in clean delivery and making clean delivery kits available were seen as important factors in infection control.380,385,390–392 In rural Nepal, failure to wash hands before cutting the cord or use of dirty cloths on the umbilical cord were associated with 60% and 70% increased risk of cord infection, respectively.393 Moreover, failure to use a boiled blade among nonusers of clean delivery kits led to a 2.3-fold increase in risk of cord infections above that of clean delivery kit users. However, use of a clean home-delivery kit did not affect cord infection rates, provided that a new or boiled blade was used to cut the cord.
Thus, tetanus immunization of pregnant women in combination with promotion of hand-washing and clean delivery, including clean umbilical cord care, was protective against neonatal tetanus and resulted in reduced neonatal mortality and morbidity. Among these interventions, the most persuasive data on efficacy are in support of tetanus vaccination strategies. In Sri Lanka, the introduction of the Expanded Programme on Immunization (EPI) vaccination strategy in 1978 led to a dramatic reduction in neonatal tetanus infection rates, which declined from 2.16 to 0.06 cases per 1000 live births.394 Similar data were reported from Burma,384 showing that neonatal tetanus mortality rates in non-EPI areas were threefold higher than in EPI areas (9 vs 3 per 1000 live births). Similarly, in Bangladesh, national TT-immunization programs reduced the incidence of deaths from neonatal tetanus by 90% (from 41 to 4 deaths per 1000 live births) over a decade.29 One study (in 2 sites) compared the efficacy of 3 intervention strategies for reducing neonatal tetanus: maternal TT administration, hospital-based delivery (to promote clean delivery), and home delivery by a trained birth attendant.395,396 Overall, maternal tetanus vaccination is most effective and seems to offer the single best option for reducing neonatal tetanus in developing countries (Table 21).
Evidence for the benefits of maternal tetanus immunization on neonatal outcomes is incontrovertible. Maternal TT immunization must be an essential part of antenatal care packages as well as mass-vaccination programs. Similarly, the importance of clean delivery practices, including clean umbilical cord care, must be underscored. Available community-based data suggest that the best gains may be obtained from implementation of a combination of maternal immunization and clean delivery and cord-cutting practices. On the other hand, there is no evidence that as a single intervention, use of a clean delivery kit is necessarily the most appropriate way of ensuring that caregivers and birth attendants pay sufficient attention to antisepsis, nor is there evidence that kit use impacts umbilical cord infection or NMRs. To the contrary, behavior-change communications strategies to promote clean delivery practices, including clean cord cutting, should be implemented in tandem with introduction of clean delivery kits.
We would underscore the need to undertake an evaluation of the most appropriate, cost-effective, and sustainable clean delivery strategies in community and rural settings in developing countries. If clean delivery kits are promoted, it should be done in the context of broader behavior-change communications regarding clean delivery practices.
Maternal Pneumococcal Immunization
The high incidence of infectious diseases in young infants in developing countries suggests that, in many cases, maternally derived antibodies fail to provide adequate protection. For example, infection with Streptococcus pneumoniae accounts for 10% of deaths (220 000 deaths per year) globally in infants <90 days old.397 Although live vaccines are contraindicated in pregnancy, killed or toxoid-based vaccines can be administered safely to pregnant women. These strategies may be particularly useful in circumstances in which background rates of routine vaccinations in childhood and adolescence are low or available vaccines are contraindicated or ineffective in young infants. Thus, although the benefits of maternal immunization against tetanus are well established, there is very little information about the impact of other vaccines administered during pregnancy on pregnancy outcomes.
One study of maternal pneumococcal vaccination has been reported (Table 22).398 Although the study took place in an urban hospital setting, we included it in our evaluation because it was based in a developing country and evaluated neonatal outcomes. Infants born to mothers who had been immunized had higher blood levels of antibodies sufficiently protective against pneumococcal antigens. However, the newborn antibody levels depended primarily on the duration between immunization and delivery. Although the level of antibodies decreased at 22 weeks of age postnatally, levels were still higher than those found among control infants. Additional data on clinical outcomes and long-term protection were not available.
Although limited and preliminary, these data provide intriguing information on the possibility of maternal immunization as a strategy for addressing early neonatal pneumococcal infections. Development of maternal immunizations against group B streptococcus and Haemophilus influenzae is similarly of great interest and under active investigation.
Promotion of Smoking Cessation During Pregnancy
Inhalation of smoke by pregnant women may occur through several modes of exposure and has been consistently associated with IUGR and LBW in offspring. It is widely recognized that smoking increases the risk of LBW births almost twofold399 and significantly increases perinatal mortality.400
Infants born to women who smoke during pregnancy weigh, on average, 200 g less than infants born to comparable women who do not smoke.399 Smoking has been shown to double the risk of LBW births among those mothers who smoke, compared with those who do not. In addition to LBW, increased risk of spontaneous abortion, as well as increased risk of perinatal and neonatal mortality, have also been associated with maternal smoking.401 Recently, new evidence has shown an association of indoor air pollutants with LBW and increased infant and perinatal mortality.402,403 One study reported an association of LBW with use of wood as cooking fuel.401,402 The study by Boy et al,402 using a retrospective cohort design, evaluated the association between LBW and exposure to wood smoke by asking women at the time of delivery about the type of cooking fuel they used. The study results were potentially confounded, however, failing to control for differences in nutritional and socioeconomic variables associated with different fuel types. The study also included a combination of hospital and home deliveries but excluded women living in remote areas due to inaccessibility.
Smoking and use of tobacco in other forms are widespread in developing countries. Moreover, exposure to outdoor air pollution, indoor air pollution, and indoor smoke (either from cooking or secondary inhalation of cigarette smoke) is widespread and may impact the mother as well as the young infant, leading to increased risk for asthma and respiratory infections.404
A systematic review of RCTs evaluating the impact of cessation of smoking during pregnancy405 found that there were significant reductions in the incidence of LBW (OR: 0.8; CI: 0.67–0.95) and preterm births (OR: 0.83; CI: 0.69–0.99) and an increase in mean birth weight of 28 g (CI: 9–49 g). However, there was no difference in the incidence of VLBW births or overall perinatal mortality, and the largest cluster-randomized trial reviewed showed no evidence of an impact of reduction in smoking on adjusted mean birth weight.406
Measures to reduce environmental exposure to smoke may improve pregnancy outcomes, but this has not been systematically studied in developing countries. In light of this lack of data, evidence available concerning the impact of smoking cessation on pregnancy outcomes is presented from developed countries in an attempt to evaluate the impact of this potential intervention.
We identified 8 additional studies, the majority of which were undertaken in the United States, primarily in urban settings, that reported on the impact of smoking cessation on pregnancy outcomes (Table 23). No rural-based study could be identified. The studies included several smoking-cessation counseling methods ranging from individual counseling by midwives to counseling by a trained professional counselor, often supplemented with literature about the potential adverse effects of smoking on the developing fetus. In all but 1 study,407 interventions to promote smoking cessation in pregnant women were found to be significantly effective in increasing smoking-cessation rates408–411 and reducing the number of cigarettes smoked by mothers.410,412 In most studies, however, no impact was seen on pregnancy outcomes, including birth weight,407,408,410,413,414 rates of LBW or preterm delivery,407–410,413,414 or perinatal mortality.409,413,414 Some studies, however, demonstrated an increase in birth weight and/or length in subgroups that stopped smoking due to the intervention.409,411,412
Overall, smoking-cessation programs have produced mixed results on pregnancy outcomes such as preterm birth or LBW rates and have failed to impact fetal, perinatal, or infant mortality despite success in reducing smoking rates. Few studies have evaluated the impact of environmental smoke and indoor air pollution on pregnancy outcomes in developing countries or interventions to redress them. However, a recent review by the WHO has highlighted the potential adverse health consequences from indoor air pollution.403
Clearly, it is prudent to discourage maternal smoking due to the general harm that smoking does to health. It is important, however, that additional studies on reducing exposure to tobacco and indoor air pollution be conducted in developing countries with direct assessment of pregnancy outcomes and health of the young infant, because evidence for the impact of interventions on health status of newborns in developing countries is currently unavailable. Presently, despite the paucity of studies from community settings in developing countries, there is enough information from developed countries to decry the use of any form of tobacco (smoked or chewed) and addictive drugs such as alcohol, cocaine, and narcotics in pregnancy.
Maternal Care Packages
The aforementioned studies and interventions largely evaluated solitary maternal interventions. In most programmatic settings, however, such interventions typically are provided in combinations and as part of a package of care. Although most such studies have examined maternal outcomes, data also exist on the impact of packages of maternal interventions on perinatal outcomes.
Our review yielded 2 studies that provided maternal care packages in a rural community-based setting and reported information on perinatal outcomes (Table 24). These programs were directed toward identification of high-risk patients and their early referral to a higher-level facility and provided a multilayered series of measures including essential antenatal care, improved referral systems, and facility-based care. The community-based maternal care programs showed significant reductions in perinatal (34%) and neonatal (43%) mortality.415 Recent data from a perinatal intervention trial in Macedonia indicate that it may be possible to reduce perinatal and neonatal mortality at the national scale through a concerted perinatal education and health worker–training program within the health system setting.416 Similarly, the introduction of a structured primary care program in Bolivia,417 coupled with maternal care, led to a dramatic reduction in infant and young child mortality. In 1992–1993, the annual rates of mortality of children <5 years old were 205.5 per 1000 and 98.5 per 1000 in the comparison and intervention areas, respectively. The absolute difference in mortality of 107.0 deaths per 1000 (CI: 72.7–141.3 per 1000) represented 52.1% (CI: 35.2–68.8%) lower mortality among children <5 years old in the intervention areas, compared with the control areas.
Available evidence suggests that much of the improvement in perinatal and neonatal health in the West preceded the advent of neonatal intensive care and is largely owed to better and comprehensive maternal care and reproductive health.418 In developing countries, the dependence of infant survival on the survival and health of the mother has been clearly demonstrated.14 Data on the impact of maternal interventions on perinatal and neonatal outcomes are scarce but robust. Investing in improved maternal health must form the cornerstone of strategies aimed at improving perinatal and neonatal outcomes.
Maternal Vaginal and Newborn Skin Antisepsis
Maternal intrapartum and postpartum infections are a major cause of maternal morbidity and mortality in developing countries. A large proportion of early-onset neonatal infections in developing countries may also be related to vertically transmitted infections from the maternal genital tract.21,25,419 Thus, there is interest in evaluating low-cost strategies for preventing and reducing infectious complications of maternal infections, particularly for settings in which antenatal care may be suboptimal.
A number of antiseptic solutions or preparations may be used for cleansing the maternal genital tract. However, the largest body of evidence and greatest measure of support is available for chlorhexidine. This agent has been used successfully in developed countries for prophylaxis against newborn colonization and infection with group B streptococcus.420–426
A study of the impact of chlorhexidine cleansing was undertaken in Malawi at an urban hospital, at a cost of $0.10 for each maternal-infant pair treated (Table 25). 427,428 Cleansing of the maternal vaginal canal and the newborn skin with a 0.25% chlorhexidine solution resulted in significant reductions in serious postpartum maternal infections (P = .02), neonatal admissions (OR: 0.8; CI: 0.79–0.97), neonatal sepsis (OR: 0.5; CI: 0.32–0.76), overall neonatal mortality (28.6 vs 36.9 per 1000; P < .05), and neonatal mortality due to infections (OR: 0.5; CI: 0.29–0.88; 2.4 vs 7.3 per 1000; P < .005).428 Among women with rupture of membranes for >4 hours, the HIV transmission rate was decreased by 40% (OR: 0.6; CI: 0.4–0.9). In another study in Kenya comparing intrapartum vaginal lavage with 0.2% and 0.4% chlorhexidine, there was no overall effect on transmission of HIV, but risk of transmission was significantly reduced (OR: 0.1; CI: 0.0–0.9) in the subgroup that had not had rupture of membranes before treatment.429
Chlorhexidine cleansing of both the maternal vaginal canal and the newborn skin has significant potential for reducing maternal and neonatal postnatal infections and improving neonatal (and perhaps maternal) survival. Additional efficacy trials are needed to confirm these results in different facility-based settings, to determine the relative contribution of vaginal cleansing versus newborn skin cleansing, and, thence, to evaluate potential applications and feasibility of the intervention within the community. Evaluation of higher-concentration formulations of chlorhexidine to prevent sepsis with pathogens from the skin34 and to prevent maternal-to-child transmission of HIV (1%) is also warranted.
Intrapartum hypoxia and birth asphyxia are widely regarded as major causes of morbidity and mortality in developing countries.18,430,431 “Birth asphyxia,” or failure to establish breathing at birth, comprises just a portion of the burden of early death from hypoxia. For every neonatal death from asphyxia, there seems to be ∼1 additional fresh stillbirth that occurs due to intrapartum hypoxia,430,432 although the precise burden of stillbirths is not yet well defined.24 Evidence for birth asphyxia as a major cause of neonatal mortality is well established; however, the contribution of intrapartum hypoxia and birth asphyxia to cerebral palsy and the overall burden of handicap in developing countries is unclear.433 Previously, it was estimated that for every case of mortality due to asphyxia or intrapartum hypoxia, another 4 newborns survived but suffered sequelae.434 However, more recent data suggest that this may be a gross overestimation of the burden of handicap, because most newborns in developing countries with severe asphyxia die.435
Approaches to improving birth asphyxia-related outcomes may include prevention through improved antenatal care such as birth preparedness; intrapartum care such as the presence of a skilled birth attendant and fetal monitoring (eg, use of a partograph); or improved management (eg, resuscitation) of newborns who do not breathe adequately at birth. The effects of antenatal and intrapartum interventions on birth asphyxia outcomes are thoroughly covered in another recent review24 and are not included here. The important role of neonatal resuscitation in immediate newborn care is well accepted and forms a cornerstone of immediate newborn care in developed countries,17 but there are particular challenges to making this intervention feasible in developing-country settings.24 Recent treatment modalities and interventions such as cerebral hypothermia436,437 therapy and the role of medications after asphyxia are experimental and have been evaluated only in controlled facility-based situations in developed countries. This latter group of interventions is not evaluated further in this review.
In addition to a host of descriptive studies, we identified 13 studies from developing countries that evaluated various aspects of neonatal resuscitation, including the feasibility of primary care staff undertaking the interventions (Table 26, see also Table 39). The reported literature suggests that TBAs who are trained and supervised in newborn resuscitation are capable of learning and properly using simple resuscitation techniques431,438–442 and that resuscitation may be performed successfully by trained health providers using relatively simple equipment (eg, mouth-to-mask breathing)443,444 and room air.445,446 Training hospital staff in India447 and China448 in newborn resuscitation has been shown to reduce asphyxia-related deaths.
It has been suggested that neonatal mortality may be reduced after training of TBAs in resuscitation,431,449 although little objective data have been provided. Daga et al449 reported 41% and 62% reductions in NMR and PMR, respectively, over a 3-year period after introduction of a TBA training program that included mouth-to-mouth resuscitation of asphyxiated infants as a central component of the intervention. Successful resuscitation was reported in 83% of cases of asphyxia. Kumar and Aggarwal431,442 reported a 70% reduction in asphyxia-specific mortality (P < .05) among infants delivered by selected TBAs in rural India trained in advanced resuscitation using a mucus sucker and bag-and-mask compared with TBAs trained in mouth-to-mouth resuscitation. Newborns delivered by TBAs with advanced training also had a 19% lower PMR and a 20% lower case-fatality rate, although neither outcome effect was significant. A recent meta-analysis of the impact of TBA training programs found that neonatal mortality due to asphyxia was reduced 11% (CI: 2–21%).3 It was uncertain, however, which aspects of the training programs were responsible for the impact. Most programs did not describe neonatal resuscitation as an important part of training; thus, the impact seemed to be due to interventions other than resuscitation.
In northern India, CHWs were trained in essential newborn care (clean cord cutting, maintenance of warmth, breastfeeding promotion); identification and special care, including referral when indicated, of at-risk infants; and mouth-to-mouth resuscitation of asphyxiated infants.438 The NMR fell 25%, from 51.9 to 38.8 per 1000 live births, during the 2 years of the study, with 18% of deaths attributed to asphyxia. In another trial of home-based neonatal essential and emergency care, including resuscitation of asphyxiated newborns by trained CHWs, Bang et al439 reported a 48% reduction in asphyxia-specific neonatal mortality. Training of grassroots-level health providers in a Chinese province in methods of newborn resuscitation resulted in a reduction in the case fatality rate from 7.1% to 0.45%.450
No data exist on the role of family members in neonatal resuscitation.
Our review suggests that, although objective evidence for the impact of community-based resuscitation efforts is sparse, there are promising approaches and techniques that seem effective in preliminary trials. Trained TBAs or CHWs seem to be capable of learning resuscitation skills and saving newborn lives; however, the feasibility of scaling up this approach is unclear. Supervision and maintenance of skills are critical to success, yet formidable challenges exist at the community level. One of the areas of greatest need is to define feasible and cost-effective approaches by which community-level providers (eg, CHWs, community midwives) can prevent fresh stillbirths and neonatal deaths due to intrapartum hypoxia/birth asphyxia. There is evidence that mouth-to-mask and bag-and-mask resuscitation are comparable techniques with regards to neonatal mortality and morbidity443; however, the former was deemed more difficult for the providers. Thus, where feasible, bag-and-mask ventilation has become the preferred modality.439 The evidence that room air could be satisfactorily used for neonatal resuscitation suggests that staff training alone and basic equipment may be sufficient for resuscitation of asphyxiated newborns in developing-country communities.
Additional large-scale effectiveness trials of such intervention strategies with defined criteria and endpoints are clearly required. More precise definitions of “birth asphyxia” at the community level and improved verbal autopsy instruments for identification of fresh stillbirths and neonatal deaths due to acute intrapartum hypoxia are urgently needed. The cost-effectiveness and sustainability of resuscitation using various modalities and the impact of resuscitation on disability rates have not been documented. The various components of resuscitation, such as the role of pharyngeal suction, the need for oxygen therapy, and the role of ventilation by bag-and-mask (as opposed to other modalities such as tube-and-mask, mouth-to-mask, or mouth-to-mouth), also require additional scientific scrutiny. Meanwhile, it is reasonable to promote the basic elements of newborn resuscitation (namely, drying, stimulation, and warming) as a routine part of newborn care and to further evaluate the potential role of trained TBAs and CHWs in using equipment such as the bag-and-mask to ventilate nonbreathing newborns. In addition, all skilled attendants should be trained to provide proper newborn stimulation and ventilation.
Delayed Umbilical Cord Clamping
There is little evidence as to whether the current practice of umbilical cord clamping soon after birth, to prevent polycythemia on the one hand or anemia on the other, is based on solid scientific criteria. Some studies have demonstrated that delayed cord clamping (after the cord stops pulsating) may increase neonatal blood volume by approximately one third.451,452 Thus, delayed cord clamping may increase the newborn infant's iron reserves and reduce the incidence of iron-deficiency anemia in infancy, an issue of considerable public health importance.453
In the course of introducing a program to reduce tetanus incidence in Haiti, it was observed that nearly half of families ceased cutting the cord at home after delivery and instead bundled the infant, placenta, and cord and sought cord care at the hospital.385 Despite delays in cord cutting for up to several hours, neonatal mortality declined dramatically and no adverse effects on neonatal outcomes were noted.
We identified only 1 comparative trial from a developing country that evaluated this issue in an urban hospital setting (Table 27). Delaying umbilical cord clamping until the cord ceased pulsating was associated with an increase in red blood cell count in the neonatal circulation regardless of whether the infant was level with or below the level of the placenta.454
Despite the potential importance of the timing of cutting the cord, there are little data on its relationship to neonatal health. No data are available from developing countries on whether the common practice of waiting until after the placenta has been delivered to cut the cord has a beneficial or adverse impact on neonatal circulation and health. However, the scarce available evidence does indicate that delayed cord clamping may be beneficial, because it may allow for greater transfer of placental blood to the newborn's circulation before cutting the cord. Additional studies are needed to resolve this issue, because it may have important implications for prevention of anemia in infancy in susceptible populations in developing countries.
Umbilical Cord Antisepsis
The importance of clean cord cutting for the prevention of neonatal tetanus was considered in the section on tetanus prevention (see “TT Immunization and Clean Delivery” and Table 20). Studies of the impact of topical applications of antiseptics to the umbilical cord in the postnatal period generally have shown reductions in bacterial colonization compared with no treatment.34 However, impact has varied with the specific antimicrobial compound, the mode or frequency of application, and the degree of contamination in the environment. In general, chlorhexidine seems to be the most favorable choice of antiseptic because of its broad spectrum of activity, residual effects on the skin, low toxicity, and results showing overall reductions in cord colonization after treatment.34,455
Evidence for the effect of topical antiseptic treatment of the cord in reducing local cord or skin infections or sepsis is less clear because of conflicting reports.34 Thus, several neonatal skin care reviews have called for discontinuation of routine topical antiseptic care of the cord based on conflicting evidence regarding which topical agent most effectively decreases colonization and the lack of a clear relationship between colonization and infection.456,457 However, in many cases, when antiseptic treatments have been discontinued, increased rates of cord colonization and infection have been found.458,459 In general, wide variation in trial design, small sample sizes with insufficient power to assess impact on infections, and inconsistent comparisons between different regimens have contributed to the largely conflicting literature on the impact of cord-care regimens.
A Cochrane review on different methods of neonatal cord care, including the use of topical antimicrobials, suggested that the incidence of omphalitis and skin infections within 6 weeks of observation was not affected by use of antiseptics.460 There was a trend toward reduced microbial colonization with the use of antibiotics compared with no treatment. Antiseptics such as chlorhexidine, however, prolonged the time to cord separation. It was concluded that simply keeping the cord clean was probably as effective as topical antibiotic use. However, this review was based on 10 RCTs, all conducted in developed countries, none of which reported any systemic infections or neonatal deaths.
In addition to the aforementioned Cochrane review, the WHO461 also reviewed the evidence from a host of descriptive and physiologic studies and concluded that medical cord-care practice recommendations are overwhelmingly based on research from hospital nurseries in developed countries. It was concluded that, compared with no treatment, application of a topical antimicrobial to the cord stump reduced umbilical colonization by harmful bacteria in hospital nurseries. Chlorhexidine, tincture of iodine, povidone-iodine solutions, triple dye and silver sulfadiazine were all found to be effective in reducing microbial colonization, although caution was issued regarding the need to balance their use with the potential for emergence of antimicrobial resistance. In general, dry cord care was recommended along with the use of soap-and-water solution to clean the cord when visibly soiled.
There is a large body of literature outlining the increased risk of umbilical infection, mainly due to Clostridium tetani colonization, after application of unclean substances such as ash or mud to the cord of neonates in developing countries.462–464 Observational studies have shown that application of antimicrobial agents to the cord after cutting was protective against tetanus and resulted in reduced neonatal mortality and morbidity381,387,463 (Table 28). In a large CCS of tetanus deaths in Pakistan, Bennett et al388 showed that infants who received applications of antimicrobials (type unspecified), both at birth and subsequently, were at significantly less risk of death than those who received dry cord care alone (OR: 0.2; CI: 0.06–0.58), even after adjusting for use of unclean substances such as cow dung, ash, or ghee (clarified butter) (OR: 0.4; CI: 0.21–0.77). In Papua New Guinea, neonates who received daily application of 10% acriflavine in spirit to the umbilical cord were 9.4 (P < .02) and 6.7 (P < .01) times less likely to have sepsis or fever, respectively, than those who did not receive the antiseptic applications.463
There is no definitive answer to the question of what constitutes the best form of cord care after birth, particularly in domiciliary settings. More research is needed on this issue, especially in situations of limited resources and high potential for environmental contamination of the cord. Although there is evidence to suggest that cord antisepsis may be beneficial, there is insufficient evidence to recommend the widespread use of topical antimicrobials on the cord stump. Nevertheless, the decision to use them may depend on local circumstances.
Rooming-in and keeping the infant with the mother also significantly reduces the incidence of colonization with pathogenic bacteria and cord infections.465,466 Thus, early colonization of the newborn with commensal flora from the mother, facilitated by early and prolonged contact as with KMC, may be protective and may have contributed to the reduction in infections observed in cohorts who practiced KMC (see “KMC” and Table 35). Similarly, for home deliveries and for cord care after discharge from hospital in developed countries, clean cord care seems to be sufficient, and the application of antiseptics may not be required. However, for developing-country communities in which the majority of newborns are delivered at home and may face severe immunologic challenge from pathogenic bacteria in the environment, the benefits of topical antiseptics remain unknown. Provision of clean delivery kits may increase compliance with clean cord cutting and tying after birth, although this has not been demonstrated (see “TT Immunization and Clean Delivery” and Table 20). Topical antimicrobial applications may be a useful strategy for other instances in which potentially harmful practices such as cow dung application on the cord stump are widely prevalent, even if just for replacement of the harmful practices.388,461 If chosen, the antimicrobial should have a broad spectrum of activity against Gram-positive and Gram-negative pathogens and should be inexpensive, culturally acceptable, and widely available.
Additional research is needed to define best cord-care practices in developing-country communities. Meanwhile, efforts must focus also on providing culturally appropriate behavior-change communications to communities and caregivers on proven interventions such as clean cord-care practices, particularly hand-washing and use of a clean blade to cut the cord.
Hypothermia Prevention and Management
Hypothermia in the newborn period is widely regarded as a major contributory cause of morbidity in developing countries,467 although it has been poorly documented. Hypothermia has been associated with increased risk of infection, coagulation defects, acidosis, delayed fetal-to-newborn circulatory adjustment, hyaline membrane disease, and brain hemorrhage.468,469 At its extreme, hypothermia may manifest as neonatal cold injury470,471 and be associated with significant mortality.439 This risk is particularly marked among LBW infants in developing countries and is seen commonly even in countries with tropical climates. Studies in Nepal using continuous temperature monitoring have indicated that thermal stress may be extremely common among newborn infants; 80% of hospital-born infants became hypothermic soon after birth.472 In another maternity hospital study in Nepal, 85% of newborns had a temperature <36°C within 2 hours of birth.473 Similarly, in facility-based studies in Ethiopia,474 Zambia,475 and Zimbabwe,476 one half to two thirds of newborns had hypothermia.
Few studies have addressed practices during and after birth, which can put the newborn at risk for hypothermia. In a multicenter evaluation in Latin America, Asia, and Africa, 65% and 73% of health facility workers had adequate knowledge regarding causes and prevention, respectively, of hypothermia, yet interventions to prevent hypothermia were seldom provided (eg, 0% warmed the delivery room, 11% dried and wrapped the infant, and 50% and 61% provided special protection during transport or to LBW infants, respectively).477 In 1 village-based study in India, 11% of 189 neonates were found to be hypothermic based on a single temperature reading taken within the first 24 hours after birth. Only 58% of newborns were wiped soon after delivery, the head was covered in 59% in winter and 10.5% in summer, no newborns were kept in skin-to-skin contact, and the room temperature was <24°C in 41% of households.442 Early bathing and removal of vernix are also recognized but understudied risk factors for hypothermia. However, based on expert opinion, the WHO recommends that bathing be delayed for at least 6 hours after birth to minimize the risk of cold stress during the period of maximum physiologic transition of the newborn.469
Although it has been demonstrated that physicians and trained assistants in health facilities are capable of perceiving newborn body temperature by touch with reasonable accuracy,441,478,479 in a community-based study in India, mothers using touch alone had limited ability to detect hypothermia.480 Overall, only one fourth (24.6%) of hypothermic infants were correctly identified as such by the mothers. A temperature-indicator device (ThermoSpot) placed on the newborn's skin has been shown to provide an accurate indicator of the presence of hypothermia and is acceptable to mothers in hospital settings,476,481–484 but additional research on its utility and use in resource-poor communities, especially by mothers, is needed.
It is now well recognized that rapid rewarming of hypothermic newborns in developed-country settings may be entirely safe and result in lower mortality compared with slower methods of rewarming.485,486 The WHO has recognized the importance of thermal care of the newborn by including it as a priority behavior in the Mother-Infant Package of interventions in developing countries,14 and the Saving Newborn Lives initiative of Save the Children/USA considers it an essential newborn care practice.17 Accepted ways to achieve optimal thermal control of the newborn include warming of the room, immediate drying and wrapping after birth, immediate and frequent breastfeeding, delay in bathing until the infant is physiologically stable, close contact with the mother such as skin-to-skin contact, and appropriate swaddling and dressing, including the use of head cover. However, few studies have been conducted to evaluate feasible strategies for the prevention, recognition and management of hypothermia in developing countries. Recent emphasis has been on the use of skin-to-skin contact or KMC in the prevention of hypothermia, and this strategy will be considered separately (see “KMC”). Other potential interventions (eg, incubators, semipermeable plastic sheeting) commonly used to reduce transepidermal water loss (TEWL) and heat loss, particularly in preterm infants in developed countries,455 have not been adequately evaluated in developing-country settings, are largely impractical for community settings, and will not be considered further here.
Topical application of products such as paraffin-based ointments or oils aimed to modify skin-barrier function and reduce transepidermal loss of water and heat455,487–490 has been evaluated in 2 hospital-based studies in developing countries473,491 (Table 29). In India, topical therapy of preterm infants with corn oil every 4 hours resulted in a significant reduction (P < .001) in need for an external source of heat to maintain normal body temperature.491 Another study in Nepal found that traditional oil massage with mustard oil, swaddling with a plastic swaddler, or KMC was equally effective in preventing hypothermia during the first 24 hours after birth.473
During neonatal transport, a simple Styropor box showed promise for preventing hypothermia.492,493 Other trials have included elements of hypothermia prevention in a package of postnatal interventions,438,439,494,495 but the specific impact of the thermal control interventions could not be determined.
Despite the critical importance of maintaining warmth for the newborn, there is a remarkable paucity of studies evaluating and commenting on community-based prevention, recognition, and/or management of hypothermia. There is a clear need for additional research on appropriate and cost-effective strategies for prevention of hypothermia in health system settings, including transport and care of high-risk LBW infants. Approaches such as training TBAs, CHWs, and caregivers to recognize and respond appropriately to warning signs of hypothermia, for example, have not been reported. Although heated cots have been scientifically evaluated in institutional settings,485 these are too expensive for use in most developing countries.494 The Styropor box offers an excellent example of simple technology that could be used as an alternative to transport incubators in developing countries, but additional evaluation is warranted to compare it with other options. Preliminary studies suggest that topical applications of skin barrier–modifying products may be beneficial for preservation of body heat.473,491 Nevertheless, most cases of hypothermia likely could be prevented by a few simple behaviors such as immediate drying and wrapping of the infant, including the head; immediate breastfeeding; delay in the initiation of bathing; close contact with the mother; and keeping the room warm and the infant properly clothed and/or wrapped. In addition, KMC may be a highly cost-effective intervention for preventing hypothermia, especially of LBW infants (see “KMC”). Nevertheless, even when health workers possess knowledge of how to prevent hypothermia, this knowledge may not be translated into practice.477 Thus, there is a great need to develop and evaluate the impact of culturally appropriate behavior-change communications to promote these healthful domiciliary thermal control practices.
Hypoglycemia Prevention and Management
Hypoglycemia after birth is a major cause of morbidity, particularly among intrauterine growth-restricted and preterm infants. The risk of hypoglycemia is significantly greater among preterm infants because of their reduced energy and glycogen reserves and inability to mobilize alternative metabolic fuels.496 Hypoglycemia is also relatively common among LBW infants and macrosomic infants of diabetic mothers.497 Prevention and management of neonatal hypoglycemia have been the subjects of a major review by Williams.498
Little data on hypoglycemia incidence or impact on newborn health are available from developing countries, in part due to difficulties in detection, which requires proper processing in a well-functioning laboratory. Studies in Nepal indicated that 38% of term infants had hypoglycemic episodes after birth.499,500
The most cost-effective strategy for preventing hypoglycemia is early feeding (continued every 2 to 3 hours on demand day and night) with breast milk, which is superior to milk formula in that it can promote relatively greater ketogenesis501 and has a relatively lower insulinogenic effect.502 The benefits of breast milk feeding are comparatively more marked in preterm infants.503 Although nasogastric feeding may be difficult in primary care settings, there is evidence that cup and/or spoon feeding in larger preterm infants may be entirely feasible.504,505 Although the cornerstone of prevention and management of neonatal hypoglycemia is early colostrum and breast milk feeding, other options may be needed for circumstances in which breast milk is not available, insufficient, or contaminated with HIV.
We identified 2 studies from India for which alternative strategies for prevention of hypoglycemia were used506,507 (Table 30). Both studies, conducted in urban hospital settings, indicated that the addition of granulated sugar to formula feeds in a sterile fashion was satisfactory for prevention and treatment of hypoglycemia. The osmolality of the sugar-fortified formula, however, was significantly higher than standard feeds. Thus, in the absence of follow-up information on risk of enteric infections and diarrhea with such an approach, sugar fortification of formula cannot be recommended for widespread implementation in programs.
The use of artificial formulas fortified with glucose polymers508 or lipids such as medium-chain triglycerides,509,510 has been shown to be effective in the prevention and management of hypoglycemia in developed-country studies. It is highly unlikely, however, that these strategies would find favor in developing countries with significantly higher risk of infection. Although the data on use of sugar-fortified milk supplements in India are interesting,506,507 these studies did not evaluate the efficacy of this intervention in comparison with colostrum and breast milk feeding, nor would it have been ethical to do so. These alternative strategies to breast milk feeding cannot be recommended presently but merit careful controlled evaluation with appropriate endpoints and outcomes as possible interventions in settings in which breast milk feeding is not possible or is inadvisable. Thus, consonant with the recommendations of the WHO,498 the mainstay of prevention and treatment of hypoglycemia in developing countries must clearly remain early and exclusive breastfeeding and the use of expressed breast milk in other circumstances.
Breastfeeding is a foundational practice for appropriate care and feeding of newborn infants. A wide variety of benefits of breastfeeding have been well documented, including reduced risk of hypothermia, hypoglycemia, necrotizing enterocolitis, omphalitis, acute respiratory infections (ARIs), diarrhea, and septicemia.511 Benefits of breastfeeding on infant and child health and development have also been extensively reviewed recently.60,512 Several studies have effectively demonstrated reduced rates of morbidity and mortality in early infancy with exclusive breastfeeding in community settings in developing countries.513–519 However, there are relatively few studies that have principally evaluated the impact of breastfeeding on neonatal outcomes. Huffman et al511 recently reviewed the evidence in this regard and concluded that early and exclusive breastfeeding played an important role in reducing neonatal mortality, particularly after the first week of life. There is also additional evidence linking lack of exclusive breastfeeding with increased risk of early-onset520 and late-onset neonatal sepsis.521
Our review identified several studies that addressed the issue of impact of breastfeeding practices on perinatal and neonatal outcomes in developing countries. These studies were mostly from developing-country hospital-born cohorts220,505,522–525 (Table 31), although 2 other reports principally provided community-based data.526,527 These studies consistently showed reduced rates of morbidity (eg, diarrhea, pneumonia) and mortality associated with breastfeeding. The largest systematic review available on the relationship of breastfeeding to infectious disease outcomes in developing countries is the WHO multicountry pooled analysis.528 This study clearly indicated that those infants <2 months old who were not breastfed had significantly higher mortality (OR: 5.8; CI: 3.4–9.8) due to infectious diseases than breastfed infants.
Although a number of barriers to effective breastfeeding in the neonatal period have been identified,529–532 including reduced tendency to breastfeed LBW infants,533 there is ample evidence that culturally appropriate behavior-change communications strategies can increase immediate and exclusive breastfeeding rates59,61,62,531,532,534–536 (Table 32). In particular, recent data from India convincingly demonstrate the benefit of community strategies for promotion of breastfeeding in terms of reducing diarrhea morbidity and preventing growth faltering.537
Despite the lack of RCTs evaluating the impact of breastfeeding on neonatal outcomes, there is overwhelming evidence in support of a variety of perinatal and neonatal health benefits from breastfeeding. All newborn infants in developing countries, especially in domiciliary settings, must receive colostrum and exclusive breastfeeding, and intervention programs must place substantial emphasis on this component. Several authors have demonstrated that it is possible to improve breastfeeding practices through culturally appropriate behavior-change communications. There is a need, however, for enhanced understanding of barriers to early, exclusive breastfeeding in many settings, leading to effective development and implementation of breastfeeding promotion programs.
Prevention and Treatment of Ophthalmia Neonatorum
Ophthalmia neonatorum is caused primarily by Neisseriagonorrhea or Chlamydia trachomatis. The prevalence of ophthalmia neonatorum in developing countries is uncertain. Before the introduction of preventive therapy, this condition was recognized to affect between 1% and 15% of newborn infants in Europe and 9% of newborn infants in the United States.538 Transmission rates from mothers with gonococcal cervicitis to their offspring range from 30% to 50% in the absence of prophylactic ocular treatment,14 whereas transmission ranges from 18% to 61% for chlamydia.539 In developing countries such as Kenya, where rates of maternal STDs are high, rates of gonococcal ophthalmia range from 15% to 34%.540,541
A variety of interventions have been evaluated for prevention of ophthalmia neonatorum in developed countries, mostly in hospital settings, and have largely focused on the prevention of gonococcal infections.542–545 These studies have suggested that silver-nitrate, tetracycline, or erythromycin ointments given prophylactically are equivalent in efficacy.546,547 The WHO recommends 1% silver-nitrate solution, 1% tetracycline ointment, or 2.5% povidone-iodine within 1 hour of delivery.14,16,548 The American Academy of Pediatrics also considers 0.5% erythromycin ointment as standard therapy, in addition to silver nitrate or tetracycline.549 In the presence of proper prophylactic treatment, gonococcal ophthalmia develops infrequently. However, silver nitrate is not effective if used after infection has been established, which may help to explain the higher risk of gonococcal eye infections observed in association with PROM. For infants born to mothers with confirmed gonorrhea, parenteral treatment with ceftriaxone is recommended as first-line therapy by the WHO548 and the American Academy of Pediatrics,549 although penicillin G can be considered if resistant strains are unlikely. Silver nitrate has been shown to be equivalent to tetracycline or erythromycin ointments for prevention of chlamydia conjunctivitis.539,545 Thus, systemic treatment with erythromycin is also needed to prevent progression to chlamydial pneumonia.
Our search identified 2 studies from developing countries (see Table 33) on prevention and treatment of ophthalmia neonatorum. Both were undertaken in urban hospital settings.541,550 In 1 study, povidone-iodine was superior to silver-nitrate drops and to costlier erythromycin ointment.550 In another study, tetracycline ointment was superior to silver-nitrate drops.541
Evidence for the benefit of prophylaxis with silver-nitrate drops, tetracycline ointment, or erythromycin ointment to prevent ophthalmia neonatorum is well established, based largely on developed-country studies. Scarce data from developing countries suggest that povidone-iodine is also effective, and this agent is recognized by the American Academy of Pediatrics as a first-line prophylactic therapy. Thus, choice of agent may be less important than wide-scale implementation of this intervention, which must form part of primary neonatal management packages, particularly in areas endemic for sexually transmitted diseases (STDs) due to gonorrhea. In areas with low rates of gonococcal infections in pregnancy, the benefits of routine prophylaxis relative to other newborn interventions may be questionable. Although local gonococcal resistance rates should be considered, local availability, acceptability, and cost of the various agents generally will be primary determinants in choice of agent. Overall, the evidence in support of prophylaxis for chlamydial infections is less clear.
Vitamin K Prophylaxis
Vitamin K prophylaxis in neonates for prevention of IVH is well established. Two Cochrane reviews have addressed the role of vitamin K prophylaxis in neonatal health. Puckett and Offringa,551 in a Cochrane review of prophylactic vitamin K for prevention of IVH, also concluded that a single dose (1.0 mg) of intramuscular (IM) vitamin K after birth is effective in the prevention of classic hemorrhagic disease of the newborn (HDN), and IM or oral (1.0 mg) vitamin K prophylaxis improves biochemical indices of coagulation status at 1 to 7 days. However, neither IM nor oral vitamin K has been tested in randomized trials with respect to the effect on late HDN, and oral vitamin K, in either single or multiple doses, has not been tested in randomized trials for its effect on either classic or late HDN. Crowther and Henderson-Smart,552 in a Cochrane review of vitamin K administration to pregnant women before preterm delivery, concluded that antenatal vitamin K was associated with a nonsignificant trend toward reducing all grades of periventricular hemorrhage (RR: 0.82; 95% CI: 0.67–1.00), particularly severe (grades 3–4) disease (RR: 0.75; CI: 0.45–1.25). This trend disappeared when poorer-quality trials were excluded. It was concluded that vitamin K administered to women before very preterm birth has not been shown to significantly prevent periventricular hemorrhage.
Although well established in developed countries, the incidence and implications of vitamin K deficiency in developing countries has received little attention. In a national hospital-based survey in Thailand, the incidence of vitamin K deficiency was found to be 35 cases per 100 000 births.553 In contrast, a community hospital–based study in rural Thailand found the incidence to be as high as 72 cases per 100 000 births.554 There are very few community-based data on vitamin K deficiency or HDN from either Africa or south Asia.
Our review could not identify any community-based vitamin K intervention trials.
Vitamin K prophylaxis is a well-established intervention for prevention of IVH and early HDN in newborns in developed countries. The preferred route is IM administration, whereas the efficacy of the oral route needs additional investigation. There is no definitive evidence that administering prenatal vitamin K to pregnant women entering preterm labor can prevent IVH in the neonate, but this intervention warrants additional investigation. Moreover, studies are needed in developing-country community settings to identify cost-effective methods of implementing vitamin K interventions.555
Hepatitis B Vaccination
Disease due to hepatitis B virus (HBV) infection is one of the most prevalent public health problems worldwide. An estimated 350 million people are HBV carriers, and >1 million deaths each year are attributed to the virus.556,557 The hepatitis B surface antigen (HBsAg) carrier rate in the general population in Taiwan was reported to be 15% to 20%,558 whereas the prevalence of HBsAg positivity in Bangladesh was highest in 5- to 9-year-olds (8.5%), and simultaneous infection with hepatitis D virus was common (24.4%), particularly in older age groups.559 Dusheiko et al560 reported a hepatitis B carrier rate of 5.5% to 14% in the southern African population.
Hepatitis B immunization prevents chronic HBV carrier states and, subsequently, chronic liver disease in adulthood. However, Wong et al561 found that the incidence of preterm birth, PPROM, SGA births, neonatal jaundice, fetal distress, perinatal asphyxia, congenital abnormalities, gastrointestinal tract abnormalities, and perinatal mortality were similar among pregnant women with and without serologic HBsAg positivity. Thus, the benefits of hepatitis B vaccination are long-term and most evident well after the neonatal period.
Seven studies were identified that discussed programs implementing hepatitis B vaccination in developing-country communities; the 2 main studies were conducted in Taiwan and The Gambia558,562–567 (Table 34). In general, incorporation of hepatitis B immunization into the EPI program of various countries was highly successful and effective. Hepatitis B vaccination programs were not only effective in preventing perinatal and early horizontal transmission of HBV but also resulted in decreasing mortality due to fulminant hepatitis and reduced development of childhood hepatocellular carcinoma. One study in South Africa,568 however, determined that the intervention was not effective. Some reasons for the lack of effectiveness were given, and the authors proposed that the problems they identified were likely to be faced by other programs in developing nations. Importantly, they found that program participants had difficulty in complying with WHO recommendations that the first dose of hepatitis B vaccine be given as soon as possible after birth. Administering all 3 doses within reasonable limits of the recommended vaccine schedule is often difficult in rural areas, where distances to clinics are great and mobile outreach clinics are impeded by poor road conditions. Moreover, the birth dose may be particularly difficult given various proscriptions against seeking care for newborns outside the home in the formal health sector, particularly for early postnatal care.439,569–571 Providing appropriate training to village health workers (VHWs) in The Gambia to deliver heat-stable vaccines in a Uniject device, however, was shown to be a cost-effective and reliable method for hepatitis B vaccination in rural settings.572 This alternative means of delivering the intervention may facilitate resolution of the above-mentioned problems with traditional hepatitis B vaccination and may be an effective way to improve coverage and seroconversion rates.
Hepatitis B vaccine is administered universally at birth in developed countries. Considering the high risk of hepatitis B infection in many developing countries and the efficacy of the hepatitis B vaccine, policies regarding routine immunization need to be developed and implemented urgently in developing countries endemic for HBV infection. It is important to recognize, however, that evaluating the success of integrating hepatitis B vaccination into the EPI is more complex than for many other diseases. Because many infected children do not have any recognizable signs of illness, serologic surveys, rather than disease surveillance, will be needed to monitor the success of immunization programs. The appropriate field methodology for such surveys must be developed and standardized. The true benefit of such programs also requires measurement of the reduction in long-term sequelae of infection.
The total financial burden derived from both the direct and indirect costs of HBV detection and vaccination must be weighed critically in light of multiple health problems and competing agendas in resource-poor countries. However, support from donor agencies such as the Bill & Melinda Gates Foundation and the Children's Vaccine Program, which has initiated aid for hepatitis B vaccination in a number of countries, could help to make immunization against HBV, a proven intervention for benefit later in life, a reality.
Neonatal Vitamin A Supplementation
The significant public health benefits of vitamin A supplementation on child mortality in developing countries210 are well established. There is much interest in the potential benefit of neonatal vitamin A supplementation on neonatal and infant outcomes, given the widespread subclinical vitamin A deficiency that exists among pregnant women and lactating mothers in many developing-country settings, the demonstrated positive impact of antenatal vitamin A supplementation on maternal mortality218 (see “Antenatal Vitamin A Supplementation”), and the demonstrated benefits of vitamin A supplementation during infancy and childhood.94
Vitamin A supplementation has been investigated in selected subsets of newborns in developed countries, such as in VLBW infants, to prevent chronic lung disease.573–575 However, the benefit and cost-effectiveness of such interventions in developing-country settings, in which survival rates of VLBW infants are low, remain unclear; few VLBW infants survive to develop chronic lung disease.419
We identified 3 studies that evaluated the impact of vitamin A supplementation during the neonatal period on neonatal and/or infant outcomes in developing countries in both rural and urban settings (Table 35). No study showed a reduction in mortality during the neonatal period,576,577 and the 3 studies showed a mixed impact on infant mortality.576–578 Results are forthcoming from an additional large-scale trial of neonatal vitamin A supplementation in Zimbabwe.
Neonatal supplementation with vitamin A holds some promise for reducing mortality during or shortly after the neonatal period, and there is some evidence of reduced mortality during infancy.576 These results, coupled with emerging evidence that antenatal vitamin A supplementation may reduce maternal mortality,218 indicate the need for additional research in this area. A critical factor may be the timing of vitamin A supplementation, with potentially increased impact with early administration.577 The role of supplementation in populations with relatively high rates of HIV infection also requires investigation.
KMC refers to the technique of positioning and skin-to-skin care of LBW infants after birth and was pioneered by Rey579 from Colombia. After initial skepticism,580 the technique has now found widespread acceptance and has been used extensively in both developed and developing countries. Despite numerous intervention studies evaluating the technique, however, very few have used rigorous (eg, RCT) designs. A recent Cochrane review of KMC581 identified 3 studies that met criteria for inclusion in their analysis, but the analysis was based largely on just 1 RCT.582 The review found that neonates who were given KMC versus standard care had lower risk of nosocomial infection (OR: 0.49; CI: 0.25–0.93), severe illness (OR: 0.3; CI: 0.14–0.67), and lower respiratory tract disease (OR: 0.37; CI: 0.15–0.89) at 6-month follow-up. In addition, the proportion of infants who were not exclusively breastfeeding at discharge was reduced (OR: 0.41; CI: 0.25–0.68), as was the rate of maternal dissatisfaction with method of care (OR: 0.41; CI: 0.22–0.75). Infants given KMC also had gained more weight per day by discharge (weighted mean difference: 3.6 g per day; CI: 0.8–6.4). Despite these interesting data, because the results were largely based on a solitary RCT, it was concluded that there were insufficient data to recommend its routine use in LBW infants.
Since the Cochrane review noted above, Charpak et al583 reported another RCT of KMC impact in a hospital setting. The intervention consisted of continuous skin-to-skin contact and nearly exclusive breastfeeding, and infants were followed until 12 months' corrected age. Risk of death tended to be lower in the infants given KMC (OR: 0.57; CI: 0.17–1.18) but was not significantly lower than the control infants given routine incubator care. Infection rates were similar, although severity was judged to be higher in the control infants, and there was no difference in disability rates. Total days in the hospital were decreased in infants who weighed ≤1500 g at birth and received KMC.
An earlier 2-cohort study by Charpak et al584 reported a higher RR of mortality in infants given KMC (RR: 1.9; CI: 0.6–5.8), although this risk reversed after adjusting for weight at birth and gestational age (RR: 0.5; CI: 0.2–1.2). Infants given KMC grew less in the first 3 months and had a higher proportion of developmental delay at 1 year. No significant differences were found in overall mortality rates between the 2 groups. The cohorts in the study, recruited from 2 different tertiary hospitals, showed many social and economic differences.
A nonrandomized, controlled study conducted in a remote Zimbabwe mission hospital without incubator care reported that survival of infants born weighing <1500 g improved from 10% to 50%, whereas that of infants 1500 to 1999 g improved from 70% to 90%.585 Similar results were shown by another nonrandomized study from a secondary hospital in Mozambique. Of 32 infants weighing <1800 g, survival was 73% in 22 infants given KMC and 20% in 10 infants not given KMC (P < .01). It also has been suggested that infants given KMC discharged during the cold season may be more vulnerable to severe illness, especially lower respiratory tract infections, than those discharged during the warm season.586 Another study on a small number of newborn infants with mild respiratory distress suggested that early introduction of KMC might have beneficial effects.587
Ramanathan et al588 reported from their RCT in Delhi, India, that KMC neonates demonstrated better weight gain after the first week of life (15.9 ± 4.5 vs 10.6 ± 4.5 g/day in KMC and control groups, respectively; P < .05) and earlier hospital discharge (27.2 ± 7 vs 34.6 ± 7 days in KMC and control groups, respectively; P < .05). The number of mothers exclusively breastfeeding at 6-week follow-up in the KMC group was double that of the control group (12 of 14 [86%] vs 6 of 14 [43%]; P < .05).
There are no data on the impact of KMC from community-based settings in developing countries. All studies reported from developing countries were conducted among medically stable LBW infants (typically <2000 g) in urban hospital settings (Table 36).
Two reports describe adaptation of the technique for use in the community.589 In a pilot study in Bangladesh, CHWs were trained in community-based application of KMC (CKMC) and subsequently taught expectant and new mothers how to give KMC. Women were interviewed 1 month postpartum to evaluate their experience with CKMC. In all, 77% of mothers initiated skin-to-skin care, and 85% with LBW infants did so (37% were LBW). CKMC was adopted quickly and popularly in this community. Similarly, in Uttar Pradesh, India, promotion of CKMC through a community mobilization and behavior change communication program resulted in adoption of skin-to-skin care of newborns by >70% of families.590
Studies to date have suggested that KMC had a variety of beneficial effects on the health of LBW infants, including increased weight gain and exclusive breastfeeding rates and lower risk of nosocomial infection and severe illness. The literature also suggests that KMC promotes mother-infant bonding, improves newborn thermal control, shortens duration of hospital stay, results in earlier stabilization of physiologic and behavioral functioning, and may improve survival. This last claim is unproven and may be unrealistic, given that studies have all included medically stable infants.
Limited experience with adaptation of skin-to-skin care for use in the community in developing countries has been encouraging. There is an urgent need, however, to adapt the approach for various cultural settings and to further evaluate its acceptability, safety, and efficacy in developing-country community settings.26,591 We feel that KMC must be viewed in its wider application to include even culturally appropriate variants such as co-bedding with the mother and skin-to-skin practice by caregivers other than the mother herself, particularly the father, because fathers, too, can provide effective thermal control in newborn infants to reduce the risk of hypothermia.592 Given the paucity of resources and risk of hypothermia in domiciliary settings in developing countries, this intervention (or mode of newborn care) may be suitable for essential care of all newborns in the community as well as for high-risk situations such as the care of preterm, VLBW infants, and transport of sick newborns.
Topical Emollient Therapy
The skin barrier of preterm infants is compromised for a variety of reasons including developmental immaturity455 and lack of vernix, which is produced near term during gestation and serves as a naturally protective cutaneous biofilm.593 In addition, the skin barrier of preterm infants is easily injured,594 and particularly in developing-country situations, the skin barrier of even term infants may be compromised as a result of intrauterine malnutrition.595 Thus, the skin may serve as an important portal of entry for serious bacterial infections.596 However, evidence from laboratory studies in animals and clinical trials in humans suggests that it may be possible to enhance skin-barrier function through application of topical emollients or oils, thereby improving health outcomes.
In experimental conditions, compromised epidermal barrier function and dermatitis in essential fatty acid (EFA)-deficient rodents was reversed by topical application of either purified EFAs or EFA-rich vegetable oils, particularly sunflower-seed oil.597,598 Cutaneous absorption and metabolism of linoleic acid seemed largely responsible for the beneficial effects of sunflower-seed oil.490,598–600 Topical therapy with sunflower-seed oil has also been found to correct cutaneous signs of EFA deficiency (ie, normalization of TEWL, resolution of dermatitis) in humans, including premature infants.598,601,602 It has been advanced that these beneficial effects may be due to increased metabolism of lipids in the epidermis, including active fatty-acid transport by keratinocytes, which makes it possible for even the immature epidermis of preterm infants to metabolize lipids derived from topically applied emollients and to utilize them as nutritional building blocks for the formation of a healthy, functional epidermal barrier.455,490,603,604
Darmstadt et al490 used a hairless-mouse model to demonstrate that the impact of topical therapy varies markedly with the product applied. A single application of sunflower-seed oil significantly improved skin-barrier function within 1 hour, and the effect was sustained 5 hours after application. In contrast, other vegetable oils tested (mustard, olive, and soybean oils) significantly worsened skin-barrier function (ie, increased TEWL) 1 and 5 hours after application and delayed recovery of a compromised skin barrier compared with control- or Aquaphor-treated skin. Moreover, a single application of mustard oil resulted in a variety of adverse ultrastructural changes in the epidermis under transmission electron microscopy, suggestive of toxicity.490,605 Thus, given the widespread use of mustard oil for massage of newborns, as documented in south Asia,488,606 it seems that millions of newborns each year are being treated with potentially toxic applications to the skin.488,490
In clinical trials in developed countries, topical applications of epidermal barrier-enhancing emollients have been shown to decrease TEWL, improve skin condition, and minimize skin injury in extremely preterm infants.490,594,607–609 However, topical therapy has had a variable impact on risk of infection. A pilot study at Stanford University (Stanford, CA) showed that twice-daily application of the ointment Aquaphor for the first 2 weeks of life to premature infants <33 weeks' gestational age resulted in improved skin condition and a reduction in episodes of culture-proven sepsis due to coagulase-negative staphylococci.608 In another trial, Aquaphor therapy in neonates weighing <1500 g decreased the nosocomial bloodstream infection rate to 5.4 per 1000 patient-days, compared with 12.7 per 1000 patient-days during the preceding 16 months.610 In contrast, a small CCS suggested that extremely preterm infants weighing <1000 g who were treated with topical petrolatum ointment were at increased risk for Candida infections,611 and another report suggested that topical applications of Aquaphor might serve as a source for nosocomial infections with coagulase-negative staphylococci and Gram-negative organisms.612 A recently completed multicenter US-based trial showed that Aquaphor therapy increased risk of sepsis with coagulase-negative staphylococci among neonates weighing 501 to 750 g (OR: 1.60; CI: 1.07–2.39); no effects were seen in neonates weighing 751 to 1000 g.613 A Cochrane review of studies in developed countries concluded that prophylactic topical-ointment therapy increases the risk of coagulase-negative staphylococcal infection and any nosocomial infection.614
Oil massage of neonates is a nearly universal practice in south Asia.488,606 The typical timing (from the first days of life), frequency (typically 1–3 times daily), pattern (total body), and duration (throughout infancy and early childhood) of use suggest that the practice is an important event in daily child care, that significant time and resources are devoted to it, and that exposure of the infant's skin to the oil is significant. The most commonly used oil for infant massage is mustard oil, which, as noted above, is potentially toxic490 and, when tainted with seeds of the weed Argemone mexicana, may cause the neurologic syndrome coined “epidemic dropsy.”615,616
In India, topical therapy with corn oil improved thermoregulation (see also “Hypothermia Prevention and Management”) of 5- to 7-week-old infants in the community,491 and growth of hospitalized preterm infants was improved with sesame-seed oil therapy.617 In Nepal, it was found that traditional oil massage with mustard oil, swaddling with a plastic swaddler, or KMC was equally effective in preventing hypothermia during the first 24 hours after birth (see Table 29).473
No community-based data are available on the effect of topical therapy on neonatal infections or mortality. Hospital-based studies have been concluded in Egypt and Bangladesh, and data have been reported from Egypt (Table 37). In Egypt, topical application of sunflower-seed oil 3 times daily to preterm infants <34 weeks gestational age (n = 51) at the Kasr El-Aini neonatal intensive care unit at Cairo University significantly improved skin condition (P = .037) and reduced the incidence of nosocomial infections (incidence rate ratio: 0.46; CI: 0.26–0.81; P = .007; adjusted for weight on admission, gestational age, and gender) compared with infants not receiving topical prophylaxis (n = 52) (see ref 732). In Bangladesh, preliminary data analysis suggested that emollient therapy of preterm infants <33 weeks gestational age 3 times daily with sunflower-seed oil or Aquaphor reduced the odds of neonatal mortality (OR: 0.75; C:I 0.57–0.98). Among infants weighing ≤1250 g, emollient therapy reduced the odds of mortality by 35% (OR: 0.63; CI: 0.46–0.87).618
Emollient therapy is a promising intervention, particularly for LBW infants in developing countries, although data to date are hospital-based. Data thus far are also restricted to LBW infants <33 to 34 weeks’ gestational age, in whom the skin barrier is likely to be most highly compromised. Additional research is needed on the impact of this therapy in the community and among all newborns (without restriction based on birth weight).
Emollient therapy is inexpensive (∼ $0.20 [US dollars] for a course of therapy in a preterm infant weighing 1.5 kg)490 and technologically simple and can be delivered readily by health care workers and caregivers. Research suggests that the practice of oil massage is nearly universal in south Asia, and caregivers indicate a willingness to modify their behavior and apply an alternative oil that has skin barrier–enhancing properties.488,606 Behavior-change communications may be an effective way to introduce the intervention more broadly by modifying what is already a well-entrenched traditional practice. Furthermore, in many communities, cadres of workers such as the domin or naún in India (and similarly, in Nepal) are designated to apply oil massage in the community to newborns, and working with them could enhance the feasibility and scalability of the intervention.606
Choice of emollient is important. Emollients containing a physiologic balance of epidermal lipids (3:1:1:1 molar ratio of cholesterol/ceramide/palmitate/linoleate) are optimal for barrier repair,604,619 and tests of impact on neonatal outcomes are warranted using topical products with optimized effects on skin-barrier function. However, natural vegetable oils are readily available worldwide and may provide a simpler, inexpensive alternative that also warrants additional investigation as a more readily scalable and affordable intervention, particularly for use in the community.
Hyperbilirubinemia is widespread among newborns. Almost 97% of all healthy newborn infants have biochemical hyperbilirubinemia (ie, serum bilirubin >17.1 μmol/L), and almost 65% may be overtly jaundiced. Jaundice tends to occur in term infants with serum bilirubin levels above ∼85 μmol/L.620 Although hyperbilirubinemia may not be a major direct cause of mortality in developing countries, delayed detection and therapy may predispose infants to bilirubin encephalopathy and kernicterus,621,622 both of which are common causes of handicaps in developing countries.419,623
It is not the purpose of this review to discuss the numerous options for management of hyperbilirubinemia but rather to evaluate strategies for its early recognition in community settings. Management of this condition has been reviewed extensively, and interventions such as phototherapy and medical therapy (eg, phenobarbital, exchange transfusion, and management of underlying conditions such as sepsis, hemoglobinopathies, and blood-group incompatibilities) largely pertain to hospital settings.624 Nevertheless, of the known risk factors for jaundice and bilirubin encephalopathy, prematurity and past history of hemolytic disease of the newborn are important. Frequent and exclusive breastfeeding must be encouraged, because it has been shown to reduce the propensity for hyperbilirubinemia, due at least in part to improved hydration status.625,626
Early detection of jaundice in developing countries would be significantly facilitated if first-line health workers at peripheral health facilities were able to accurately identify young infants with clinically significant jaundice who needed care at a referral-level facility. Several studies, mostly from developed countries, have found that bilirubin levels determined with a simple hand-held icterometer correlated to varying degrees with measures made by using more expensive and sophisticated instruments and standard techniques (ie, serum bilirubin measurement).627–632 However, there has been considerable debate, even in developed countries, about whether the presence of jaundice can be determined reliably by using visual assessment and what cadres of individuals can perform visual assessments reliably. Although some investigators have found that clinical estimation of jaundice in newborns by neonatologists633 or physicians or nurses631,634,635 was highly correlated with serum bilirubin levels, others have questioned the ability of health care providers, including physicians and nurses, to diagnose clinical jaundice by visual estimation.628,636
Our review identified 5 studies from developing countries that evaluated strategies for the early detection of neonatal hyperbilirubinemia (Table 38); however, none of these studies were in a rural setting (all were conducted in urban hospitals). Only 1 of these studies tested the accuracy of visual estimation of jaundice; Riskin et al633 reported that neonatologists' visual estimates were highly correlated to measurements using a spectrophotometer (r: 0.682; P < .001).
All the other studies tested the accuracy of noninvasive techniques (eg, use of a hand-held icterometer or bilirubinometer) relative to laboratory serum bilirubin measurement. Bilgen et al632 and Kumar et al627 compared transcutaneous bilirubin readings by using a bilirubinometer to serum bilirubin, and both reported strong evidence of a linear correlation (r = 0.83 and 0.91, respectively). Two studies, 1 in Turkey and 1 in India, also found a significant positive correlation between icterometer measurement and serum bilirubin levels.630,632 However, in Pakistan, Bhutta and Yusuf629 found that transcutaneous bilirubinometry was much less effective than standard biochemical testing in accurately identifying hyperbilirubinemia, particularly among dark-skinned infants.
Simple methods including visual assessment of degree of jaundice by health workers and use of simple, hand-held icterometers hold promise for use at the community and primary care levels in developing countries, but additional studies are warranted. The role of visual inspection in the home by caregivers, particularly in areas with a relatively high prevalence of hyperbilirubinemia, has never been evaluated.
Although there is consensus that increased access to skilled health care, including a skilled birth attendant during delivery, is widely desired and likely to improve pregnancy outcomes,16,24 approximately half of women and newborns lack access to skilled care.18 Moreover, nearly two thirds of births worldwide take place in the home, and a large percentage of births in developing countries take place in the hands of untrained or trained TBAs. Given the projected absence of adequate cadres of skilled birth attendants in many countries for years to come and a potential role for TBAs and/or CHWs in health service delivery for newborn care, we evaluated the available evidence for the impact of TBA and CHW training on perinatal outcomes. CHWs typically differ from TBAs in education (higher) and age (younger) and are perceived by many as being more amenable to training.24 However, we considered them together for the purposes of this review.
A number of studies have assessed changes in knowledge and attitudes after the training of TBAs.440,637–642 An observational study showed that trained TBAs were more likely than untrained TBAs to give advice on breastfeeding as well as on immunizations and oral rehydration therapy.643 Trained TBAs also had better skills in neonatal resuscitation relative to untrained TBAs but did not have any impact on maternal behaviors. Kumar et al640 stressed that continued training of TBAs was important in sustaining improved maternal and newborn care practices.
Table 39 (see also Tables 26, 41, and 42) summarizes the evidence from studies that examined the effect of TBA and CHW training on perinatal and neonatal health status outcomes in community settings. The CHWs were community based in all settings and had varying levels of training and linkage to the health system. Their relationship to the health system ranged from close association that facilitated referral of high-risk infants and/or those with complications to settings in which care was entirely home based.439
The 1 randomized trial in The Gambia644 showed a reduction in neonatal mortality of 61% in the villages to which primary health care was introduced and TBAs were trained. However, neonatal mortality also fell by 35% in the control villages, rendering the 26% comparative fall in neonatal mortality nonsignificant. There was a significant increase in the number of women receiving antenatal visits and tetanus immunization during pregnancy, although the number of women whose births were conducted by a trained midwife fell by 7% during the trial, confounding precise interpretation of the effect of TBA training. In another study, perinatal mortality decreased by 19% among offspring of women delivered by TBAs who had been trained in essential newborn care and advanced resuscitation, including use of the mucus extractor and bag-and-mask ventilation.639
In an uncontrolled study in India,438 CHWs identified and managed high-risk neonates in the home, including preterm and LBW infants and those with feeding problems, illness, or a history of prolonged and difficult labor. Interventions included resuscitation of asphyxiated newborns, including cleaning of the mouth and pharynx and mouth-to-mouth respiration; antiseptic cord care, including cutting; promotion of breastfeeding; minimal handling to reduce the risk of infection; postnatal home visitation and provision of anticipatory guidance about routine newborn care; and referral of sick newborns and those with feeding problems to a hospital. Home care of preterm and LBW infants also included keeping the room warm and feeding with a dropper if necessary. In the absence of management of sepsis, newborn mortality declined by 25% during the intervention year compared with the year before implementation of the program.
Similar but less stringently evaluated success has been reported by Daga et al441,449 from the Rural Neonatal Care Project in Dahanu, India, where NMR and PMR fell 41% and 62%, respectively, over a 3-year period. The project used TBAs as the means for delivery of neonatal care. Maintenance of the “warm chain,” resuscitation of asphyxiated newborns, and appropriate, early referral of high-risk mothers and newborns (eg, LBW) were recognized as the most important interventions.441 Anganwadi workers also played an important role in bridging the gap between TBAs and formal health workers.449 Overall, the IMR in the block to which these services were introduced declined 70% over a 4-year period, from 148 to 45 per 1000.449
As part of the Narangwal Nutrition Study, a controlled trial in a rural area of Punjab, India, the Rural Health Research Centre trained a cadre of villagers as family health workers (FHWs) (lady health visitors) to provide health services in the villages in which they lived. All were given special training in comprehensive primary care and surveillance techniques and provided prevention, early diagnosis, management of illnesses (including penicillin injections for suspected pneumonia in infants), and referral services in village clinics and homes.645 FHWs were the principal providers of nutrition and medical care in the study and were data collectors for longitudinal fertility and dietary surveys. They had detailed, written standing orders and were given weekly supervision by a doctor and a public health nurse to provide support, facilitate referrals, and ensure quality data collection. FHWs spent at least half their time performing home visits, which helped them identify pregnancies early and provide basic prenatal care to all women in service villages.244,645 The interventions significantly reduced perinatal mortality. Analysis of service records revealed that 90% of patient contacts were handled capably by FHWs, and the remainder were safely referred to physicians.244
In another study in India, Society for Education, Action and Research in Community Health (SEARCH) trained TBAs in elements of clean delivery and CHWs in a variety of antenatal and postnatal interventions including provision of health education to caregivers in the home, promotion of breastfeeding, management of birth asphyxia, identification of premature and LBW (ie, high-risk) infants, prevention and management of hypothermia, treatment of skin and cord infections, identification of sick newborns, and administration of oral and injectable antibiotics for cases of suspected sepsis.646 Although the precise impact of the TBAs versus the CHWs cannot be determined, there was little to no input from the formal health sector; thus, the impact apparently was largely facilitated by these trained village-level workers alone. The NMR fell by 62%, the PMR fell by 71%, and stillbirths were reduced by 18%.
A community-based trial conducted in Tanzania and Kenya demonstrated that, for areas in which maternal immunization was not a feasible method of decreasing tetanus morbidity and mortality, measures such as TBA training for safe and clean delivery and cord care were effective in decreasing perinatal, neonatal, and infant mortality389 (Table 20).
Janowitz reported that trained TBAs in rural Brazil identified and appropriately referred most high-risk women.647 In another study evaluating the impact of TBA training in Ghana, Smith et al648 found reductions in intrapartum fever, labor >18 hours, and retained placenta, but the number of perinatal deaths and tetanus cases were too low to evaluate. Clients of trained TBAs were more likely than those of untrained TBAs to be referred for tetanus immunization (58% vs 28%, respectively), and immunization rates in both groups were high (87% vs 77%, respectively). In this setting, in which health providers other than TBAs were the primary antenatal care contacts, the value of training TBAs in clean cord care was questioned.648
O'Rourke642 reported a twofold increase over a nearly 3-year period in referrals of women with pregnancy complications after introduction of a TBA training program in Guatemala. A 27% nonsignificant reduction in PMR was reported using a before-after comparison.
A recent meta-analysis of TBA training showed that there were statistically significant decreases of 11% in neonatal complications and 6% in perinatal deaths in areas served by trained TBAs compared with areas without trained TBAs.3
The overall effects of TBA training on perinatal and neonatal outcomes were generally beneficial. Little evidence was found to support the widely held notion that TBA training is futile. On the contrary, training was associated with improved behaviors (ie, advice, skills) among birth attendants, although it did not necessarily translate into improved maternal behaviors regarding newborn care. In some cases, caregiver behaviors did improve: the meta-analysis by Sibley and Sipe3 showed improvements in overall TBA and caregiver knowledge as well as behaviors. Although there has been little evaluation of the impact of TBA training on perinatal and neonatal health outcomes, the weight of evidence suggests that TBAs may make positive contributions to newborn care, and further definition of TBA and CHW roles and evaluation of the impact of TBA training on perinatal and neonatal outcomes are merited.
TBA training need not be seen in isolation from other interventions, particularly interventions that improve the skills of other caregivers. The Gadchiroli trial successfully used both TBAs and CHWs working as a team along with the mother and other caregivers, particularly the mother-in-law, to improve domiciliary care for the mothers and newborn infants.439 These interventions, therefore, may be considered for settings in which TBAs and CHWs will remain an important group of care providers for the foreseeable future. However, additional research is needed to define the interventions that TBAs and/or CHWs can be trained to provide most effectively in programs at scale, to delineate criteria for selection of TBAs to be trained, to develop appropriate preservice and in-service training programs, and to evaluate the cost-effectiveness of such training programs.
Pneumonia Case Management
The true incidence of neonatal pneumonia or ARI at the community level is not known; however, a significant proportion of newborn infants diagnosed with sepsis or serious infections may have associated pneumonia, and the clinical presentations of these conditions have significant overlap in the newborn. Recommended treatment of serious systemic bacterial infections, including pneumonia, in neonates in developed countries includes parenteral administration of antibiotics in a health care facility. Similarly, in developing countries, the WHO recommends parenteral antibiotic therapy (eg, benzylpenicillin or ampicillin plus an aminoglycoside such as gentamicin) in a health facility for treatment of serious neonatal infections.16,25,649,650 In resource-poor countries, however, the majority of births and neonatal deaths take place in the home, and families are often reluctant to seek care outside the home for neonatal illness.439,569–571 In these settings, facility-based care with use of parenteral antibiotics is currently infeasible for many neonates, and alternative management strategies are needed. Insight into the role of oral antibiotic therapy as a potentially simpler and more feasible regimen for treatment of serious neonatal infections for situations in which referral to a health facility for quality care and parenteral therapy is not possible may be gained by reviewing pneumonia case management trials that included treatment of neonates.
We identified 6 reports654 and 2 meta-analyses of community-based trials of pneumonia case management that included neonates (Table 40). Sazawal and Black651,652 conducted a meta-analysis of community-based intervention trials on case management of pneumonia in unselected preschool-aged children in developing countries. The impact of pneumonia case management on total neonatal mortality and pneumonia-specific neonatal mortality was determined. The 5 studies comprising the neonatal mortality analysis compared concurrent control and treatment groups.653–660 In 4 of the studies, neonates with suspected pneumonia were treated with oral co-trimoxazole,653–656,659,661 and another used both injectable penicillin and oral ampicillin.660 Uncorrected analysis showed a 27% reduction in all-cause neonatal mortality (CI: 18–35).652 After correction for perceived biases that may have affected the study results, the estimated reduction in total and pneumonia-specific neonatal mortality was 30% (CI: 15–42%; OR: 0.70, 0.59–0.84) and 42% (CI: 20% to 64%; OR: 0.56, 0.37–0.83), respectively.
In an additional study in Indonesia, use of ampicillin plus supportive care (eg, continued breastfeeding, clearing of the nose, fever control) in children with pneumonia had no measurable impact on cure rates of mild disease at 1-week follow-up, and did not halt progression to moderate disease at 1 week compared with the use of supportive care alone in the control group.662
Several studies have shown that it is possible to train CHWs to recognize and successfully treat pneumonia in newborn infants in community-based settings.653–660,663 The impact of such training on reducing neonatal mortality and morbidity in community settings in developing countries is significant. Available data clearly indicate that a case management approach emphasizing essential newborn care along with prompt recognition of serious bacterial infections and treatment with oral antibiotics is superior to no case management. In fact, the reduction in neonatal mortality found in the meta-analysis was comparable to estimates of the proportion of neonatal deaths due to infections (ie, 32%18), suggesting that a substantial proportion of these deaths were averted through case management that primarily included oral antibiotic therapy in the home. However, the impact has its limits, given that it is impossible in many cases to distinguish pneumonia from sepsis on clinical grounds, and these conditions frequently coexist during the neonatal period. Thus, pneumonia case management alone, including use of oral antibiotics, will lead to undertreatment of many infants with more widespread infections (ie, sepsis) that require parenteral therapy. It was this realization that led the group at SEARCH to provide more comprehensive detection and management of serious neonatal infections with a combination of oral and parenteral antibiotics (see “Neonatal Care Packages”). A host of factors, including feasibility and cost-effectiveness of implementation, as well as ethical standards, must be considered when weighing the relative merits of neonatal pneumonia versus more comprehensive sepsis case management.
Neonatal Care Packages
Given that the majority of births take place at home in developing countries, frequently in the hands of relatively untrained birth attendants, there is considerable interest in the potential of developing locally adapted packages of newborn care in community-based settings. Whereas the previous sections reviewed trials that focused on use of trained TBAs/CHWs and on pneumonia case management, this section discusses more comprehensive packages of care that may or may not have included management of sick newborns.
We identified 9 studies that were undertaken in community settings and included a comprehensive neonatal care plan rather than solitary interventions (Table 41). Several of these studies used TBAs and/or CHWs to provide care and thus were discussed in detail in “TBA/CHW Training” (Table 39).
In India, Pratinidhi et al438 used VHWs to identify and manage high-risk neonates in the home. Interventions addressed birth asphyxia, hypothermia prevention, clean cord care, breastfeeding promotion, postnatal visitation, and identification and referral of sick newborns and those with feeding problems to health facilities. Newborn mortality declined by 25% during the intervention year, compared with the year before implementation of the program (Tables 26 and 39).
In Narangwal, a town in Rural Punjab, India, 3 service groups received nutrition care (nutrition education, surveillance, and food supplementation of 1674 J and 11 g/day of protein through special feeding centers), medical care (immunization, health education, and early diagnosis and treatment of illness through frequent surveillance), or both nutrition care and medical care.118,244,645 A fourth group served as the control group. Results showed significant improvements in growth (weight and height) and Hb levels of children. Medical care significantly reduced postneonatal morbidity and mortality in the 1- to 3-year-old age groups and decreased illness duration of all 6 conditions examined in this study. Prenatal nutrition care to pregnant women was most effective in preventing perinatal deaths, followed by medical care for infants (Table 41).
Two decades ago in a rural area of The Gambia, a package of primary health care interventions was introduced by the Gambian government to improve maternal and neonatal birth outcomes.644 A VHW and a TBA from each village were trained to provide antenatal care (especially malarial prophylaxis), risk assessment and subsequent referral, intrapartum care (especially safe and clean delivery), and neonatal care. Alongside significant declines in maternal mortality over the 3 years after the program was introduced (from 2716 to 1051 of 100 000; χ2: 5.9; P < .05), the program documented statistically significantly lower rates of neonatal deaths in intervention villages relative to nonintervention villages (46.6 vs 69.6 of 1000, respectively; χ2: 4.3; P < .05), primarily due to a reduction in late neonatal deaths due to infections.
In Guatemala, pregnant women were taught routine infant care and care seeking for illness, and when symptoms of severe illnesses were detected, immediate empiric treatment was begun in the community with accompanied referral to an area hospital.664 The mortality rate among infants enrolled in the study was reduced by 85% compared with historical controls.
In rural India, Daga et al441,449,492 emphasized resuscitation of asphyxiated newborns, prevention of hypothermia, and referral of sick newborns and achieved 41% and 62% reductions in NMR and PMR, respectively, compared with baseline data over a 3-year period. The administration cost of the program was considered “affordable,” because it was based on inexpensive domiciliary neonatal care by TBAs supported by relatively low-cost facilities for neonatal care. This intervention was acceptable to the community and the TBAs because it was simple to carry out and did not involve technology that causes “culture shock”441 (Tables 26, 39, and 41).
An uncontrolled trial (the “Warmi” Project) to improve maternal and child health in the rural province of Inquisivi, Bolivia, included training TBAs, offering tetanus immunizations to women of reproductive age, ensuring a clean birthing surface and hygienic cord care, providing antibiotic eye drops, encouraging immediate breastfeeding, and ensuring thermal control.642 Family-planning services and community funds and mechanisms for transport of women in need of care to secondary health facilities were established also. The program emphasized community participation in identifying and solving problems. This approach led to a 67% reduction in perinatal mortality over a 3-year period, an increased proportion of women receiving prenatal care, and an increased number of women initiating breastfeeding on the first day after birth compared with baseline (from 25% to 50%).
In rural India, SEARCH trained VHWs in intervention areas to provide a package of home-based neonatal care, including health education to pregnant women, diagnosis and management of birth asphyxia, identification of high-risk (premature and LBW) neonates for more intensive surveillance, temperature maintenance, promotion of breastfeeding, administration of vitamin K, treatment of skin infections, and identification of sick newborns suspected of having septicemia, meningitis, and/or pneumonia and administration of antibiotics (oral co-trimoxazole and IM gentamicin) in the home.439 Neonatal mortality due to sepsis was reduced 76% and overall neonatal mortality declined by 62%, compared with the control, nonintervention area.
More recently, in the rural district of Makwanpur, Nepal, Osrin et al69 conducted a cluster-randomized trial to evaluate a community-based participatory intervention to improve essential newborn care. The intervention, which covered a population of 28 000 married women of reproductive age, trained local female facilitators in intervention villages to lead discussions within village-development committees about perinatal health issues. These facilitators also helped the groups develop participatory action plans in an iterative process. Mothers' groups within each village-development committee met monthly to identify perinatal health problems, design and implement solutions, monitor birth outcomes, and share results with others. Common goals of the action plans included community surveillance of births and birth outcomes, improved caregiver recognition of danger signs, proper care seeking, improved knowledge and skills of health workers, clean delivery practices, increased rates of early breastfeeding, and improved referral patterns. Infant mortality was reduced by 30% (OR: 0.70; CI: 0.53–0.44) and maternal mortality was reduced by 78% (OR: 0.22; CI: 0.05–0.90).665
These data strongly support implementation of packages of essential newborn care. For settings in which health facility capacity is limited and referral is not possible, the data also support the utilization of trained community-based workers in the screening and preventive and curative care of newborn infants. These interventions have not been evaluated in effectiveness trials using available staff and infrastructure. Thus, there are legitimate concerns regarding the replicability and sustainability of these comprehensive programs of care. Additional cost-effectiveness evaluations of this approach must be undertaken in larger trials in diverse geographic locations.
Creation of linkages to referral facilities and facilitation of referral pathways and improvement in quality of care at referral facilities were essential aspects of most community-based newborn care programs reporting improved survival. Nevertheless, some programs118,244,439,642,665 reduced neonatal mortality with little health systems, capacity, primarily through provision of improved antenatal and neonatal care in a context of community empowerment.
Care in Peripheral Health Facilities
In many settings, a primary strategy to improve neonatal outcomes will be to increase healthful essential newborn care practices in the home, while also seeking to improve care seeking for newborn illness, and stabilization and referral of sick infants to health care facilities as close to the community as possible, where better-quality care may be available.
We identified 9 studies that described and evaluated various postnatal interventions in primary or secondary health facilities in community settings (Table 42). Most of the facilities described were community-based and had limited resources. Also included was a study that evaluated postdischarge follow-up of neonates in a community setting.666
Various approaches to improving neonatal care and outcomes were evaluated in these studies, which focused primarily on training caregivers and health providers in essential newborn care. Although no study used a randomized, controlled design, improvements were reported in survival441,494,667–669 and immunization rates,669 and reductions were noted in length of hospitalization and number of readmissions after discharge.666
Strengthening health facilities and health systems is an essential aspect of community-based programs to improve neonatal health. However, given the barriers that exist to care seeking for neonatal illness,439,569–571 it is unlikely that utilization of facility-based services for newborn care in many communities will increase in the absence of demand creation, improved referral pathways, and quality of care. Although it is unlikely that interventions based in facility settings alone will make a major difference in situations in which the bulk of deliveries take place in domiciliary settings, they are nevertheless an essential adjunct to such care.
There are few existing guidelines for the care of sick newborn infants in health care institutions with limited facilities and manpower.548,670 Thus, there is an urgent need to improve and strengthen referral pathways and linkages between domiciliary-based interventions and facility-based care for sick neonates. There are considerable opportunities to reduce cost of care and improve efficiency by such an approach. Despite the limited information, we would strongly endorse incorporation of basic guidelines for improved secondary care of newborns in health facilities as an essential adjunct to community-based and domiciliary interventions.
COST-EFFECTIVENESS OF COMMUNITY-BASED INTERVENTIONS
During the last few decades, significant reductions in perinatal and neonatal mortality have been achieved in the context of studies evaluating a variety of interventions in developing-country communities, as reviewed above. For some interventions or packages of care, promising results in efficacy trials have included, or subsequently led to, evaluations of their cost-effectiveness.671,672 In general, however, attempts at costing interventions have included posthoc data collection or extrapolation, which are not optimal for this kind of analysis.673
Studies in developed countries have shown that early initiation of antenatal care is among the most cost-effective strategies for reducing neonatal mortality. In contrast, neonatal intensive care, despite its impact on mortality of the sickest patients, has been found to be one of the least cost-effective and feasible approaches.81,674 Several interventions in pregnancy such as the preterm birth–prevention program in urban Los Angeles675 and management of gestational diabetes mellitus676 have also been shown to be cost-effective. Well-defined efforts in developed countries to estimate the cost-effectiveness of various other interventions have been reported, such as prevention of preterm births,675 reorganization of perinatal services,677 and establishment of perinatal databases.678 In addition, certain specific postnatal interventions such as neonatal resuscitation,679 indomethacin therapy for premature infants,680 surfactant replacement therapy,681 prevention of respiratory syncytial virus infections,682 or therapy for apnea of prematurity683 have been shown to be cost-effective interventions in the context of developed countries. Most available information on cost-effectiveness of interventions refers to hospital or facility-based interventions, and these cost-effectiveness evaluations have used variable methods; only rarely have maternal and infant benefits together been evaluated.
Cost-effectiveness models and analyses of interventions to improve perinatal and neonatal outcomes have been infrequently applied in emerging economies684 and are rarer still in developing countries. Examples of cost-effectiveness assessment of intervention strategies in developing countries have largely included hospital-based interventions such as routine ultrasonography,685 surfactant replacement therapy,686 prevention of respiratory syncytial virus infections,687 and (more recently) the successful WHO-modified antenatal care package.84,688 In other instances, organization of basic neonatal care services in referral hospitals has been shown to be cost-effective.689
Cost-effectiveness data are also available from developing-country communities for selected interventions focusing on antenatal interventions to prevent infectious complications of pregnancy and their impact on neonatal outcomes. These interventions include antenatal screening and treatment for syphilis,324 syphilis prevention,690 toxoplasmosis treatment,691,692 TT-immunization administration,693 malaria-prevention programs,694 and screening and treatment for asymptomatic bacteriuria.695 These evaluations reported a wide range of cost-benefit ratios, with estimates ranging from $14 to $115 per neonatal death or adverse outcome averted (Table 43).
There has been much interest in recent years in the cost-effectiveness of community-based strategies for perinatal care. Such data, however, are almost exclusively available from developed countries and include the institution of community-based nurse-midwifery services, culturally adapted perinatal care,696 and earlier discharge and community care for premature infants.697,698 The strongest body of evidence for the impact and cost-effectiveness of community-based interventions in developed countries pertains to smoking-cessation699–701 and other LBW-prevention programs (for example, nutrition-related interventions such as the WIC program),702–704 indicating substantial benefits.
In contrast, there are almost no systematic studies of the cost-effectiveness of community-based interventions to improve perinatal and neonatal outcomes in developing countries, with the exception of studies in Nepal and rural India439,665 and several evaluations of malaria prophylaxis and therapy.283,694,705 Studies to evaluate even well-established strategies for the improvement of perinatal and neonatal health outcomes, such as breastfeeding promotion in large effectiveness trials, are only now being commissioned.706
Critical steps in the development of effective community-based health interventions include the demonstration of efficacy and effectiveness. To convince policy makers to support the programmatic implementation of promising interventions, however, cost-effectiveness data are needed to inform the feasibility of the intervention at scale and its expected benefits relative to other services. Even for interventions considered to be of proven benefit for perinatal and/or neonatal health, little such data are available and are primarily from facility-based evaluations and, moreover, from developed countries. Cost-effectiveness data for community-based perinatal/neonatal health interventions in developing countries are almost nonexistent. However, with the recent development of guidelines for costing of maternal and newborn interventions by the WHO709 and the Saving Newborn Lives Initiative (Saving Newborn Lives, Saving Newborn Lives Initiative: Project Costing Guidelines, Washington, DC, Save the Children/USA, unpublished data) and with the establishment of Marginal Budgeting for Bottlenecks and CHOICE activities to inform public health resource allocation, more such data are expected.707,708 For example, several trials of the impact of antenatal, intrapartum, and postnatal interventions on perinatal and neonatal health that are currently underway have included evaluation of cost-effectiveness as a key objective. Moreover, data are beginning to emerge from Marginal Budgeting for Bottlenecks on the marginal costs of introducing certain interventions relevant to perinatal and neonatal health to existing programs.
Implications for Programs
This review of evidence from developing-country community-based trials for the impact of antenatal, intrapartum, and postnatal interventions on perinatal and neonatal health outcomes has highlighted the paucity of available information, particularly from RCTs. Only 31 studies were RCTs that reported primary perinatal/neonatal health status outcomes (eg, stillbirth rate, PMR, NMR), and only 40 were RCTs that reported secondary perinatal/neonatal health outcomes (eg, LBW, preterm births, morbidities, or breastfeeding rates) (Table 1). Still fewer (only 10) were interventions conducted in health system settings or were effectiveness trials.
To broaden the relevance of the conclusions that can be drawn from the available data, we placed 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. Recommendations based on this review are broadly applicable to developing-country communities but are particularly germane to the most impoverished populations with high NMRs (eg, >40 per 1000 live births).
It is clear that the level of 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 identified through a strategic planning process at the international and multiple-country levels and outlined in a conceptual framework for community-based maternal and newborn care recently advanced by Save the Children/USA.17 Moreover, these elements of essential newborn care are highlighted in recent recommendations for routine and sick newborn care by the WHO.14–16 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 in developing countries. 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 not covered in this review have been added to Fig 1 (marked with an asterisk). These interventions include birth preparedness and recognition of and appropriate response to danger signs in the antenatal and intrapartum periods; skilled health care at delivery (evidence reviewed elsewhere); early postnatal visitation for provision of anticipatory guidance and recognition and management of maternal and newborn illness; and birth spacing. Many of these interventions have been included in comprehensive packages of maternal and newborn interventions but have not been rigorously evaluated per se for their specific contribution to the total impact of the package of care.
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 Moreover, although not emphasized here, many of the interventions of proven benefit for neonates also lead to improved maternal health (detailed in Tables 4–42),45,710 which serves to illustrate the importance of integrating maternal and neonatal care while avoiding vertical programs for either the mother or the newborn. Although data on cost-effectiveness are particularly lacking, an approach that integrates maternal and neonatal health into Safe Motherhood and Child Survival programs and bridges the gap between these programs will not only establish continuity of care across the life cycle but will also enhance the cost-effectiveness of intervention packages.
Although a number of interventions have been shown to reduce perinatal and/or neonatal mortality and to have the potential to reduce global neonatal mortality by approximately half through wide-scale implementation of evidence-based interventions,10 there are fundamental gaps in our knowledge of how to most effectively improve perinatal and neonatal outcomes in developing-country communities.711 Although we know that implementation of comprehensive neonatal care programs can reduce perinatal and/or neonatal mortality substantially, failure to empower and mobilize communities to accept interventions712 and lack of understanding of community practices and culture are major barriers. Thus, there is an urgent need to adapt and evaluate culturally and regionally appropriate packages of interventions in a variety of settings. 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 mothers and newborns at the community level? 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, particularly to address birth asphyxia?
The conceptual framework for newborn care at the community level advanced by Save the Children/USA17 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 case management of newborn illness by health workers, 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 in developing countries still occur at home during the early neonatal period, due to birth asphyxia and/or infections and primarily 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 the capacity of health systems 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 deliver services most effectively to newborns in an integrated way within existing programs for maternal and child health.20–22 Although difficult, answering 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 delivery and links with referral facilities.16
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 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, reduce the incidence of IUGR, or a combination of both. 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 are important adjuncts 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 rapid situational analysis, prioritization of program activities, and accurate monitoring and documentation of 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 This review further highlights the need, as recommended at the 2001 meeting, for dialogue among researchers, policy makers, program managers, and donors regarding the selection of research priorities; the use of common (and, whenever possible, rigorous) study designs; and for sharing of data-collection instruments and research results. Reporting of indicators of neonatal health at global and national levels is essential for monitoring large-scale success.
A paucity of community-based data are available from developing countries on health status impact, principally perinatal and/or neonatal mortality, for many interventions that are currently being considered for inclusion in neonatal health programs. 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 with which the intervention could be included now in programs. 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 the state-of-the-art in community-based neonatal care. It also may facilitate dialogue with policy makers about the importance of investing in neonatal health.
Clearly there is ample evidence for benefit of a number of antenatal, intrapartum, and postnatal interventions. Operational questions of how to implement the intervention(s) in an affordable and acceptable manner at scale were an overriding concern for many interventions. Thus, although there is great need for continued research on the cost-effectiveness of a number of interventions, particularly for prevention and care of LBW infants, prevention of fresh stillbirths, and prevention and management of birth asphyxia, it must not hamper implementation now of many interventions of known impact at a wider scale. For many of these proven interventions, however, critical questions remain regarding how to implement them in a cost-effective manner at scale. Close monitoring of the impact of these programs is imperative. Finally, close communication between program managers who document experience with intervention implementation; the researchers who generate answers to operational questions and devise new, innovative interventions and approaches; and the donors who promote the research will be critical to advancing maternal and neonatal health care at the community level.
This review was supported by the Saving Newborn Lives Initiative of Save the Children/USA through a grant from the Bill & Melinda Gates Foundation and the Department of Child and Adolescent Health and Development, World Health Organization.
We thank Dr Jose Martines of the World Health Organization and Anne Tinker of Save the Children/USA for technical input and encouragement during the review process; Chitra Krishnan for assistance in locating relevant articles for review; Fauzia Aman Malik for technical and editorial assistance; and Sarah Holland and Charlotte Storti for editorial expertise. We also thank the following individuals who reviewed the manuscript and provided technical and editorial review on behalf of the World Health Organization: Dr Martin Weber, Dr Jelka Zupan, and Dr Bernadette Daelmans (World Health Organization, Geneva, Switzerland); Professor Robert Black (Department of International Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD); Dr Douglas McMillan (University of Calgary/Calgary Health Region, Calgary, Alberta, Canada); and Dr Steven Wall and Dr Vinod Paul (Save the Children/USA, Washington, DC).
- Accepted August 10, 2004.
- Reprint requests to (Z.A.B.) Department of Pediatrics and Child Health, Aga Khan University, Stadium Road, Karachi 74800, Pakistan. E-mail: ; or Gary L. Darmstadt, MD, Department of International Health, E8153, Bloomberg School of Public Health, Johns Hopkins University, 615 N Wolfe St, Baltimore, MD, 21205. E-mail:
No conflict of interest declared.
- Graham W, Bell J, Bullough C. Can skilled attendance at delivery reduce maternal mortality in developing countries? In: Studies in Health Services, Organisation, and Policy. Antwerp, Belgium: Prince Leopold Institute of Tropical Medicine; 2001:97–129
- ↵Sibley L, Sipe T. Traditional Birth Attendant Training Effectiveness: A Meta-analysis. Final Technical Report. Washington, DC: Academy for Educational Development/Sara Project; 2002
- ↵Bale J, Stoll B, Lucas A, eds. Improving Birth Outcomes: Meeting the Challenge in the Developing World. Committee on Improving Birth Outcomes, Board on Global Health. Washington, DC: The National Academies Press; 2003
- ↵Victora C, Habicht J-P, Bryce J, Black R. Beyond randomized controlled trials (Cochrane Review). Oxford, United Kingdom: Update Software; 2004
- ↵International Nutritional Anemia Consultative Group. Efficacy and effectiveness interventions to control iron deficiency and iron deficiency anemia. Washington, DC: ILSI Human Nutrition Institute; 2004
- ↵Kramer M. Intrauterine growth and gestational duration determinants. Pediatrics.1987;80 :502– 522
- ↵Rutstein S. Birth spacing and newborn health. In: American Public Health Association, 130th Annual Meeting and Exposition, Program and Abstracts. 2002; Washington, DC: American Public Health Association; 2002
- ↵World Health Organization. Mother-Baby Package: Implementing Safe Motherhood in Countries: A Practical Guide. Maternal Health and Safe Motherhood Programme. Geneva, Switzerland: World Health Organization; 1994
- World Health Organization. Pregnancy, Childbirth, Postpartum and Newborn Care: A Guide for Essential Practice. Geneva, Switzerland: World Health Organization; 2003
- ↵Integrated Management of Pregnancy and Childbirth. Managing Complications in Pregnancy and Childbirth: A Guide for Midwives and Doctors. Geneva, Switzerland: World Health Organization; 2000
- ↵Saving Newborn Lives. State of the World's Newborns. Washington, DC: Save the Children/USA; 2001
- ↵Bhutta Z, Darmstadt G, Ransom E. Using Evidence to Save Newborn Lives. Policy brief. Washington, DC: Population Reference Bureau; 2003
- ↵Bhutta Z, Ali N, Hyder A, Wajid A. Perinatal and newborn care in Pakistan: seeing the unseen. In: Bhutta Z, ed. Maternal and Child Health in Pakistan: Challenges and Opportunities. Karachi, Pakistan: Oxford University Press; 2004:19–46
- ↵Bhutta Z, De Silva H, Awasthi S, et al. Maternal and child health: is South Asia ready for change? BMJ.2004;328 :816– 819
- ↵Parlato R, Darmstadt G, Tinker A. Planning and Using Qualitative Research to Improve Newborn Care Practices: A Guide for Program Managers. Washington, DC: Saving Newborn Lives, Save the Children/USA; 2004
- ↵Lawn J, Darmstadt G. To breathe or not to breathe: research and program priorities to improve management of birth asphyxia at community level in developing countries. J Perinatol.2005; In press
- ↵Zaidi A, Ali S, Darmstadt G, Bhutta Z. Serious bacterial infections among neonates and young infants in developing countries: evaluation of etiology, antimicrobial resistance and therapeutic management strategies in community settings. Pediatr Infect Dis J.2005; In press
- ↵Coco G, Darmstadt G, Kelley L, Martines J, Paul V, eds. Perinatal and neonatal health interventions research. Report of a meeting, April 29–May 3, 2001, Kathmandu, Nepal. J Perinatol.2002;22(suppl 2) :S1– S41
- ↵Hyder A, Morrow R, Wali S, McGuckin J. Burden of Disease for Neonatal Mortality in South Asia and Sub-Saharan Africa. Washington, DC: Save the Children Federation–USA; 2001
- ↵World Health Organization. Estimates. In: State of the World's Newborns. Washington, DC: Saving Newborn Lives, Save the Children/USA; 2001:1–49
- ↵Hill K. Approaches to the Measurement of Childhood Mortality: A Comparative Review. Baltimore, MD: Johns Hopkins University School of Hygiene and Public Health; 1992
- ↵Child Health Research Project. Reducing Perinatal and Neonatal Mortality. Baltimore, MD: Johns Hopkins School of Public Health; 1999
- ↵Kramer M, Liu S, Luo Z, et al. Analysis of perinatal mortality and its components: time for a change? Am J Epidemiol.2002;156 :493– 497
- ↵Frey-Hobcraft J, McDonald J, Rutstein S. Socio-economic factors in infant and child mortality: a cross-national comparison. Popul Stud (Camb).1984;38 :192– 223
- Harrison KA. Child-bearing, health and social priorities: a survey of 22 774 consecutive hospital births in Zaria, Northern Nigeria. Br J Obstet Gynaecol.1985;92(suppl 5) :1– 119
- ↵Ross S. Promoting Quality Maternal and Newborn Care: A Reference Manual for Program Managers. Washington, DC: CARE; 1999
- ↵Bhutta Z, Darmstadt G, Ransom E, Starrs A, Tinker A. Basing newborn and maternal health policies on evidence. In: Shaping Policy for Maternal and Newborn Health. Baltimore, MD: JHPIEGO; 2003:5–12
- ↵World Health Organization. Perinatal Mortality–A Listing of Available Information. Maternal Health and Safe Motherhood Programme. Geneva, Switzerland: World Health Organization; 1996
- ↵Ware H. Effects of maternal education, women's roles and child care on child mortality. In: Mosley W, Chen L, eds. Child Survival: Strategies for Research. Cambridge, United Kingdom: Cambridge UP; 1984:191–214
- Lindenbaum S, Chakraborty M, Elisa M. The Influence of Maternal Education on Infant and Child Mortality in Bangladesh. Dhaka, Bangladesh: Eastern Commercial Service; 1985
- Cleland J. Maternal education and child survival: further evidence and explanations. In: Caldwell J, Findley S, Caldwell P, et al, eds. What We Know About Health Transition: The Cultural, Social and Behavioural Determinants of Health. Canberra, Australia: Health Transition Center, Australian National University; 1990:400–419
- ↵Office of Population Research. World fertility surveys. Princeton, NJ: Office of Population Research, Princeton University; 1973–1977. Available at: http://opr.princeton.edu/archive/wfs. Accessed December 28, 2004
- ↵Bicego G, Boerma I. Maternal education and child survival: a comparative analysis of DHS data. In: Demographic and Health Surveys World Conference Proceedings. Vol 1. Columbia, MD: IRD/Macro International; 1991:177–204
- ↵Kramer M. Nutritional advice in pregnancy (Cochrane Review). Oxford, United Kingdom: Update Software; 2002a
- ↵Kafatos A, Vlachonikolis I, Codrington C. Nutrition during pregnancy: the effects of an educational intervention program in Greece. Am J Clin Nutr.1989;50 :970– 979
- ↵Leon-Cava N, Lutter C, Ross J, Martin L. Quantifying the Benefits of Breastfeeding: A Summary of the Evidence. Washington, DC: Pan American Health Organization and LINKAGES; 2002
- ↵Siegel E, Gillings D, Campbell S, Guild P. Controlled evaluation of rural regional perinatal care: developmental and neurologic outcomes at 1 year. Pediatrics.1986;77 :187– 195
- ↵Bolam A, Manandhar D, Shrestha P, Ellis M, Costello A. The effects of postnatal health education for mothers on infant care and family planning practices in Nepal: a randomized controlled trial. BMJ.1998;316 :805– 811
- ↵Osrin D, Mesko N, Shrestha B, et al. Implementing a community-based participatory intervention to improve essential newborn care in rural Nepal. Trans R Soc Trop Med Hyg.2003;97 :18– 21
- ↵Osrin D, Tumbahangphe K, Shrestha D, et al. Cross sectional, community based study of care of newborn infants in Nepal. BMJ.2002;325 :1063
- ↵Hill Z, Kirkwood B, Edmond K. Family and Community Practices That Promote Child Survival, Growth and Development: A Review of the Evidence. Geneva, Switzerland: World Health Organization; 2004
- ↵Amoa A, Kluffo C, Moro M, Kariwiga G, Mola G. A case-control study of stillbirths at the Port Moresby General Hospital. P N G Med J.1998;4 :126– 136
- ↵McDonagh M. Is antenatal care effective in reducing maternal morbidity and mortality? Health Policy Plan.1996;11 :1– 15
- ↵de Onis M, Villar J, Gulmezoglu M. Nutritional interventions to prevent intrauterine growth retardation: evidence from randomised controlled trials. Eur J Clin Nutr.1998;52(suppl 1) :S83– S93
- ↵Jackson A, Bhutta Z, Lumbiganon P. Nutrition as a preventive strategy against adverse pregnancy outcomes. J Nutr.2003;133 :1589S– 1591S
- ↵United Nations Administrative Committee on Coordination, Sub-Committee on Nutrition. Low Birthweight: Report of a Meeting in Dhaka, Bangladesh, on 14–17 June 1999. Pojda J, Kelly L, eds. Geneva, Switzerland: ACC/SCN. Nutrition Policy Paper No. 18.
- ↵Villar J, Merialdi M, Gulmezoglu A, et al. Nutritional interventions during pregnancy for the prevention or treatment of maternal morbidity and preterm delivery: an overview of randomized controlled trials. J Nutr.2003;133(5 suppl 2) :1606S– 1625S
- ↵Merialdi M, Carroli G, Villar J, et al. Nutritional interventions during pregnancy for the prevention or treatment of impaired fetal growth: an overview of randomized controlled trials. J Nutr.2003;133(5 suppl 2) :1626S– 1631S
- ↵De Brouwere V, Van Lerberghe W. Safe Motherhood Strategies: A Review of the Evidence. Antwerp, Belgium: ITG Press; 2001
- ↵Allen L, Gillespie S. Preventing and Treating Vitamin A Deficiency. What Works? A Review of the Efficacy and Effectiveness of Nutrition Interventions. Geneva, Switzerland: ACC/SCN; 2001. ACC/SCN Nutrition Policy Paper No. 19, ADB Nutrition and Development Series No. 5
- ↵Kramer M. Balanced protein/energy supplementation in pregnancy (Cochrane Review 1999). Oxford, United Kingdom: Update Software; 2001b
- ↵Elwood P, Haley T, Hughes S, Seetnam P, Gray O, Davies D. Child growth (0–5 years), and the effect of entitlement to a milk supplement. Arch Dis Child.1981;56 :831– 835
- ↵Viegas O, Scott P, Cole T, Eaton P, Needham P, Wharton B. Dietary protein energy supplementation of pregnant Asian mothers at Sorrento, Birmingham. II: Selective during third trimester only. BMJ.1982;285 :592– 595
- Viegas O, Scott P, Cole T, Mansfield H, Wharton P, Wharton B. Dietary protein energy supplementation of pregnant Asian mothers at Sorrento, Birmingham. I: Unselective during second and third trimesters. BMJ.1982;285 :589– 592
- ↵Mardones-Santander F, Rosso P, Stekel A, et al. Effect of a milk-based food supplement on maternal nutritional status and fetal growth in underweight Chilean women. Am J Clin Nutr.1988;47 :413– 419
- ↵Rush D, Stein D, Susser M. A randomized controlled trial of prenatal nutrition supplementation in New York City. Pediatrics.1980;65 :683– 697
- ↵Rush D. Effects of changes in protein and calorie intake during pregnancy on the growth of the human fetus. In: Chalmers I, Enkin M, Keirse M, eds. Effective Care in Pregnancy and Childbirth. Oxford, United Kingdom: Oxford UP; 1989:92–101
- ↵Ceesay S, Prentice A, Cole T, et al. Effects on birth weight and perinatal mortality of maternal dietary supplements in rural Gambia: 5 year randomised controlled trial. BMJ.1997;315 :786– 790
- ↵Mora J, Clement J, Christiansen N, Suescun J, Wagner M, Herrera M. Nutritional supplementation and the outcome of pregnancy. III. Perinatal and neonatal mortality. Nutr Rep Int.1978;18 :167– 175
- Campbell-Brown M. Protein energy supplements in primigravid women at risk of low birth weight. In: Campbell D, Gillmer M, eds. Nutrition in Pregnancy. Proceedings of the 10th Study Group of the Royal College of Obstetrics and Gynaecology, London, 1982; London, United Kingdom: Royal College of Obstetrics and Gynaecology; 1983:85–98
- ↵Adair L, Pollitt E. Outcome of maternal nutritional supplementation: a comprehensive review of the Bacon Chow study. Am J Clin Nutr.1985;41 :948– 978
- ↵McDonald E, Pollitt E, Mueller W, Hsueh A, Sherwin R. The Bacon Chow study: maternal nutritional supplementation and birth weight of offspring. Am J Clin Nutr.1981;34 :2133– 2144
- ↵Tontisirin K, Booranasubkajorn U, Hongsumarn A, Thewtong D. Formulation and evaluation of supplementary foods for Thai pregnant women. Am J Clin Nutr.1986;43 :931– 939
- ↵Villar J, Rivera J. Nutritional supplementation during two consecutive pregnancies and the interim lactation period: effect on birth weight. Pediatrics.1988;81 :51– 57
- ↵Prentice A, Whitehead R, Watkinson M, Lamb W, Cole T. Prenatal dietary supplementation of African women and birth weight. Lancet.1983;8323(1) :489– 492
- Prentice A, Cole T, Foord F, Lamb W, Whitehead R. Increased birth weight after prenatal dietary supplementation of rural African women. Am J Clin Nutr.1987;46 :912– 925
- ↵Lechtig A, Habicht J, Delgado H, Klein R, Yarbrough C, Martorell R. Effect of food supplementation during pregnancy on birthweight. Pediatrics.1975;56 :508– 520
- ↵Girija A, Geervani P, Rao N. Influence of dietary supplementation during pregnancy on lactation performance. J Trop Pediatr.1984;30 :79– 83
- ↵Kielmann A, Taylor C, DeSweemer C, et al. The Narangwal experiment on interactions of nutrition and infections: II. Morbidity and mortality effects. Indian J Med Res.1978;68(suppl) :21– 41
- ↵World Health Organization, Maternal Health and Safe Motherhood Programme, Nutrition Programme. The Prevalence of Anemia in Women. 2nd ed. Geneva, Switzerland: World Health Organization; 1992
- ↵Rush D. Nutrition and maternal mortality in the developing world. Am J Clin Nutr.2000;72(suppl) :212S– 240S
- ↵AbouZahr C, Royston E. Maternal Mortality: A Global Factbook. Geneva, Switzerland: World Health Organization; 1991
- ↵Allen L. Anemia and iron deficiency: effects on pregnancy outcome. Am J Clin Nutr.2000;71(suppl 5) :S1280– S1284
- ↵World Health Organization/Food and Agriculture Organization, International Conference on Nutrition. Nutrition and Development: A Global Assessment. Rome, Italy: World Health Organization/Food and Agriculture Organization; 1992
- ↵Stolzfus R, Dreyfuss M. Guidelines for the Use of Iron Supplements to Prevent and Treat Iron Deficiency Anemia. Washington, DC: ILSI Press; 1998
- ↵Kolsteren P, de Souza S. Micronutrients and pregnancy outcome. In: De Brouwere V, Van Lerbeghe W, eds. Safe Motherhood Strategies: A Review of the Evidence. Antwerp, Belgium: ITG Press; 2001:55–76
- ↵Gallego EB. Severe Anemia in Pregnancy. Report of a workshop held at the Institute of Child and Mother Health in Dhaka, Bangladesh. Gallego EB, ed. Micronutrient Initiative 2000. Ottawa, ON, Canada: International Development Research Centre; 2000
- ↵Steer P. Maternal hemoglobin concentration and birth weight. Am J Clin Nutr.2000;71(suppl) :1285S– 1287S
- ↵Rasmussen K. Is there a causal relationship between iron deficiency or iron deficiency anemia and weight at birth, length of gestation and perinatal mortality? J Nutr.2001;131(suppl) :590S– 603S
- ↵Mahomed K. Iron supplementation in pregnancy (Cochrane Review). Oxford, United Kingdom: Update Software; 2000a
- ↵Brabin B, Hakimi M, Pelletier D. An analysis of anemia and pregnancy-related maternal mortality. J Nutr.2001;131 :604S– 614S
- ↵Scholl T, Hediger M. Anemia and iron deficiency anemia: compilation of data on pregnancy outcome. Am J Clin Nutr.1994;59(suppl) :492S– 510S
- Scholl T, Hediger M, Fischer R, Shearer J. Anemia versus iron deficiency: increased risk of preterm delivery in a prospective study. Am J Clin Nutr.1992;55 :985– 988
- ↵Zhou L, Yang W, Hua J, Deng C, Tao X, Stoltzfus R. Relation of hemoglobin measured at different times in pregnancy to preterm birth and low birth weight in Shanghai, China. Am J Epidemiol.1998;148 :998– 1006
- ↵Cuervo L, Mahomed K. Treatments for iron deficiency anaemia in pregnancy (Cochrane Review). Oxford, United Kingdom: Update Software; 2001
- ↵Mahomed K. Folate supplementation in pregnancy (Cochrane Review). Oxford, United Kingdom: Update Software; 2001a
- ↵Mahomed K. Iron and folate supplementation in pregnancy (Cochrane Review). Oxford, United Kingdom: Update Software; 2001b
- ↵Sood S, Ramachandran K, Mathur M, et al. W. H. O. sponsored collaborative studies on nutritional anaemia in India. 1. The effects of supplemental oral iron administration to pregnant women. Q J Med.1975;44 :241– 258
- ↵Menendez C, Todd J, Alonso P, et al. The effect of iron supplementation during pregnancy, given by traditional birth attendants, on the prevalence of anemia and malaria. Trans R Soc Trop Med Hyg.1994;88 :590– 593
- ↵Preziosi P, Prual A, Galan P, Daouda H, Boureima H. Hercberg Effect of iron supplementation on the iron status of pregnant women: consequences for newborns. Am J Clin Nutr.1997;66 :1178– 1182
- ↵Thane-Toe, Thein-Than. The effect of oral iron supplementation on ferritin levels in pregnant Burmese women. Am J Clin Nutr.1982;35 :95– 99
- Afifi A. Plexafer-F in the treatment of latent iron deficiency in pregnancy. J Int Med Res.1978;6 :34– 40
- Ridwan E, Schultink W, Dillon D, Gross R. Effects of weekly iron supplementation on pregnant Indonesian women are similar to those of daily supplementation. Am J Clin Nutr.1996;63 :884– 890
- Tan C, Ng K. The effect of oral iron on the haemoglobin concentration during the second half of pregnancy. In: 27th British Congress of Obstetrics and Gynaecology; 1995 July 4–7. Dublin, Ireland: Royal College of Obstetricians and Gynaecologists; 1995:A101
- ↵Ekstrom E, Kavishe F, Habicht J, Frongillo E, Rasmussen K, Hemed L. Adherence to iron supplementation during pregnancy in Tanzania: determinants and hematologic consequences. Am J Clin Nutr.1996;64 :368– 374
- ↵Sloan N, Jordan E, Winikoff B. Does Iron Supplementation Make a Difference? Mothercare Working Paper No. 15. Arlington, VA: John Snow, Inc; 1992
- ↵Yip R. Iron supplementation during pregnancy: is it effective? Am J Clin Nutr.1996;63 :853– 855
- ↵Atukorala S, de Silva L, Dechering W, Dassanaeike T, Perera R. Evaluation of effectiveness of iron-folate supplementation and antihelminthic therapy against anemia in pregnancy—a study in the plantation sector of Sri Lanka. Am J Clin Nutr.1994;60 :286– 292
- ↵Christian P, Shrestha I, LeClerq C, et al. Supplementation with micronutrients in addition to iron and folic acid does not further improve the hematologic status of pregnant women in rural Nepal. J Nutr.2003;133 :3492– 3498
- ↵Byles A, D'Sa A. Reduction of reaction to iron-dextran infusion using chloroquine. Br Med J.1970;3(723) :625– 627
- ↵Oppenheimer S, Macfarlane S, Moody J, Harrison C. Total dose iron infusion, malaria and pregnancy in Papua New Guinea. Trans R Soc Trop Med Hyg.1986;80 :818– 822
- ↵World Health Organization/United Nations Children's Fund, Integrated Management of the Sick Child Initiative. Integrated Management of Childhood Illness Guidelines. Geneva, Switzerland: World Health Organization; 2001
- ↵Scholl T, Hediger M, Schall J, Khoo C, Fischer R. Dietary and serum folate: their influence on the outcome of pregnancy. Am J Clin Nutr.1996;63 :520– 525
- ↵Rao S, Yajnik C, Kanade A, et al. Maternal fat intakes and micronutrient status are related to fetal size at birth in rural India; the Pune Maternal Nutrition Study. J Nutr.2001;131 :1217– 1224
- ↵Iyengar L, Apte S. Prophylaxis of anemia in pregnancy. Am J Clin Nutr.1970;23 :725– 730
- ↵Baumslag N, Edelstein T, Metz J. Reduction of incidence of prematurity by folic acid supplementation in pregnancy. Br Med J.1970;1(687) :16– 17
- ↵Suarez L, Hendricks K, Cooper S, Sweeney A, Hardy R, Larsen R. Neural tube defects among Mexican Americans living on the US-Mexico border: effects of folic acid and dietary folate. Am J Epidemiol.2000;152 :1017– 1023
- ↵Department of Health. Folic Acid and the Prevention of Disease: Report of the Committee on Medical Aspects of Food and Nutrition Policy. London, United Kingdom: The Stationery Office; 2000
- ↵Lumley J, Watson L, Watson MC. Periconceptional supplementation with folate and/or multivitamins for preventing neural tube defects (Cochrane Review). Oxford, United Kingdom: Update Software; 2001a
- ↵Indian Council of Medical Research Collaborating Centres and Central Technical Co-ordinating Unit. Multicentric study of efficacy of periconceptional folic acid containing vitamin supplementation in prevention of open neural tube defects from India. Indian J Med Res.2000;112 :206– 211
- ↵Laurence K, James N, Miller M, Tennant G, Campbell H. Double-blind randomised controlled trial of folate treatment before conception to prevent recurrence of neural-tube defects. Br Med J (Clin Res Ed).1981;282 :1509– 1511
- ↵Czeizel A. Prevention of congenital abnormalities by periconceptional multivitamin supplementation. BMJ.1993;306 :1645– 1648
- ↵El-Khairy L, Vollset S, Refsum H, Ueland P. Plasma total cysteine, pregnancy complications, and adverse pregnancy outcomes: the Hordaland Homocysteine Study. Am J Clin Nutr.2003;77 :467– 472
- ↵Hasan B, Bhutta Z. Periconceptional use of folic acid in pregnancy [commentary]. WHO Reprod Health Libr.2002:5
- ↵Recommendations of the International Task Force for Disease Eradication. MMWR Recomm Rep.1992;42(RR16) :1– 25
- ↵Mahomed K, Gulmezoglu A. Maternal iodine supplements in areas of deficiency. In: Cochrane Database Syst Rev. 2000:CD000135
- Pharoah P, Connolly K. A controlled trial of iodinated oil for the prevention of endemic cretinism: a long-term follow-up. Int J Epidemiol.1987;16 :68– 73
- ↵Pharoah P, Connolly K. Effects of maternal iodine supplementation during pregnancy. Arch Dis Child.1991;66 :145– 147
- ↵Thilly C, Swennen B, Moreno-Reyes R, Hindlet J, Bourdoux P, Vanderoas J. Maternal, fetal and juvenile hypothyroidism, birthweight and infant mortality in the etiopathogenesis of the IDD spectrum in Zaire and Malawi. In: Stanbury J, ed. The Damaged Brain of Iodine Deficiency. New York, NY: Cognizant Communication; 1994:241–250
- ↵Thilly C, Lagasse R, Roger G, Bourdoux P, Ermans A. Impaired fetal and postnatal development and high perinatal death rate in a severe iodine deficient area. In: Stockigt J, ed. Thyroid Research VIII. Proceedings of the 8th International Thyroid Congress. Canberra, Australia: Australian Academy of Sciences; 1980:20–23
- ↵Beaton G, Martorell R, Aronson K, et al. Effectiveness of vitamin A supplementation in the control of young child morbidity and mortality in developing countries. ACC/SCN Nutrition Policy Discussion Paper No. 13. Geneva, Switzerland: World Health Organization; 1993
- ↵Christian P, West KJ, Khatry S, et al. Night blindness of pregnancy in rural Nepal-nutritional and health risks. Int J Epidemiol.1998;27 :231– 237
- ↵Christian P, West KJ, Khatry S, et al. Maternal night blindness increases risk of mortality in the first 6 months of life among infants in Nepal. J Nutr.2001;131 :1510– 1512
- ↵Metcoff J, Costiloe J, Crosby W, et al. Maternal nutrition and fetal outcome. Am J Clin Nutr.1981;34 :708– 721
- ↵West KJ, Katz J, Khatry K, et al. Double blind, cluster randomized trial of low dose supplementation with vitamin A or B carotene on mortality related to pregnancy in Nepal. BMJ.1999;318 :570– 575
- ↵Katz J, West KJ, Khatry S, et al. Maternal low-dose vitamin A or beta-carotene supplementation has no effect on fetal loss and early infant mortality: a randomized cluster trial in Nepal. Am J Clin Nutr.2000;71 :1570– 1576
- ↵Coutsoudis A, Pillay K, Spooner E, Kuhn L, Coovadia H. Randomized trial testing the effect of vitamin A supplementation on pregnancy outcomes and early mother-to-child HIV-1 transmission in Durban, South Africa. South African Vitamin A Study Group. AIDS.1999;13 :1517– 1524
- ↵Kumwenda N, Miotti P, Taha T, et al. Antenatal vitamin A supplementation increases birth weight and decreases anemia among infants born to human immunodeficiency virus-infected women in Malawi. Clin Infect Dis.2002;35 :618– 624
- ↵King J. Determinants of maternal zinc status during pregnancy. Am J Clin Nutr.2000;71(suppl 5) :1334S– 1343S
- ↵Keen C, Clegg M, Hanna L, et al. The plausibility of micronutrient deficiencies being a significant contributing factor to the occurrence of pregnancy complications. J Nutr.2003;133 :1597S– 1605S
- ↵Mahomed K. Zinc supplementation in pregnancy. Cochrane Database Syst Rev.2000:CD000230
- ↵Osendarp S, West C, Black R. The need for maternal zinc supplementation in developing countries: an unresolved issue. J Nutr.2003;133 :817S– 827S
- ↵Nurdiati D. Nutrition and reproductive health in central Java, Indonesia [medical dissertations]. Umea, Sweden: University of Umea; 2001
- ↵Osendarp S, van Raaij J, Arifeen S, Wahed M, Baqui A, Fuchs G. A randomized, placebo-controlled trial of the effect of zinc supplementation during pregnancy on pregnancy outcome in Bangladeshi urban poor. Am J Clin Nutr.2000;71 :114– 119
- ↵Sazawal S, Black R, Menon V, et al. Zinc supplementation in infants born small for gestational age reduces mortality: a prospective, randomized, controlled trial. Pediatrics.2001;108 :1280– 1286
- ↵Hamadani J, Fuchs G, Osendarp S, Huda S, Grantha