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Abstract Background Ongoing high neonatal mortality rates (NMRs) represent a global challenge. In 2021, of the 5 million deaths reported worldwide for children under five years of age, 47% were newborns. Pakistan has one of the five highest national NMRs in the world, with an estimated 39 neonatal deaths per 1,000 live births. Reducing newborn deaths requires sustainable, evidence-based, and cost-effective interventions that can be integrated within existing community healthcare infrastructure across regions with high NMR. Methods This pragmatic, community-based, parallel-arm, open-label, cluster randomized controlled trial aims to estimate the effect of Lady Health Workers (LHWs) providing an integrated newborn care kit (iNCK) with educational instructions to pregnant women in their third trimester, compared to the local standard of care in Gilgit-Baltistan, Pakistan, on neonatal mortality and other newborn and maternal health outcomes. The iNCK contains a clean birth kit, 4% chlorhexidine topical gel, sunflower oil emollient, a ThermoSpot™ temperature monitoring sticker, a fleece blanket, a click-to-heat reusable warmer, three 200 μg misoprostol tablets, and a pictorial instruction guide and diary. LHWs are also provided with a handheld scale to weigh the newborn. The primary study outcome is neonatal mortality, defined as a newborn death in the first 28 days of life. Discussion This study will generate policy-relevant knowledge on the effectiveness of integrating evidence-based maternal and newborn interventions and delivering them directly to pregnant women via existing community health infrastructure, for reducing neonatal mortality and morbidity, in a remote, mountainous area with a high NMR. Trial registration NCT04798833, March 15, 2021.

Abstract Background Understanding the burden and determinants of suicide during adolescence is key to achieving global health goals. We examined the prevalence and determinants of self-reported suicidal ideation and attempts among younger (13–15 years) and older adolescents (16–17 years). Methods Pooled prevalence estimates with 95% confidence interval, were calculated for suicide ideation and attempts for 118 surveys from 90 countries that administered the Global School-based Student Health Survey (GSHS) to adolescents (13–17 years of age) from 2003 to 2017. Indicators (including individual and social factors) associated with suicidal ideation and attempts were determined from multivariable linear regressions on key outcomes. Results The prevalence of suicidal ideation representing 397,299 adolescents (51.3% female) was significantly higher among girls than boys whereas attempts did not differ by age or sex. Being bullied, or having no close friends was associated with suicidal ideation among girls 13–15 years and 16–17 years, respectively. Among all boys, being in a fight and having no close friends was associated with suicidal ideation with the addition of serious injury for boys 13–15 years. Common to all younger adolescents was an association of suicide attempt with being bullied and having had a serious injury. Among young boys, having no close friends was an additional indicator for suicide attempt. Having no close friends was associated with suicide attempt in older adolescents with the addition to being bullied in older girls and serious injury in older boys. Conclusions Building positive social relationships with peers and avoiding serious injury appear key to suicide prevention strategies for vulnerable adolescents. Targeted programs by age group and sex for such indicators could improve mental health during adolescence in low and middle-income countries, given the diverse risk profiles for suicidal ideation and attempts.

Abstract Background The Lives Saved Tool (LiST) is a widely used resource for evidence-based decision-making regarding health program scale-up in low- and middle-income countries. LiST estimates the impact of specified changes in intervention coverage on mortality and stunting among children under 5 years of age. We aimed to improve the estimates of the parameters in LiST that determine the rate at which the effects of interventions to prevent stunting attenuate as children get older. Methods We identified datasets with serial measurements of children’s lengths or heights and used random effects models and restricted cubic splines to model the growth trajectories of children with at least six serial length/height measurements. We applied WHO growth standards to both measured and modelled (smoothed) lengths/heights to determine children’s stunting status at multiple ages (1, 6, 12, 24 months). We then calculated the odds ratios for the association of stunting at one age point with stunting at the next (“stunting-to-stunting ORs”) using both measured and smoothed data points. We ran analyses in LiST to compare the impact on intervention effect attenuation of using smoothed rather than measured stunting-to-stunting ORs. Results A total of 21,786 children with 178,786 length/height measurements between them contributed to our analysis. The odds of stunting at a given age were strongly related to whether a child is stunted at an earlier age, using both measured and smoothed lengths/heights, although the relationship was stronger for smoothed than measured lengths/heights. Using smoothed lengths/heights, we estimated that children stunted at 1 month have 45 times the odds of being stunted at 6 months, with corresponding odds ratios of 362 for the period 6 to 12 months and 175 for the period 12 to 24 months. Using the odds ratios derived from the smoothed data in LiST resulted in a somewhat slower attenuation of intervention effects over time, but substantial attenuation was still observed in the LiST outputs. For example, in Mali the effect of effectively eliminating SGA births reduced prevalence of stunting at age 59 months from 44.4% to 43.7% when using odds ratios derived from measured lengths/heights and from 44.4% to 41.9% when using odds ratios derived from smoothed lengths/heights. Conclusions Smoothing of children’s measured lengths/heights increased the strength of the association between stunting at a given age and stunting at an earlier age. Using odds ratios based on smoothed lengths/heights in LiST resulted in a small reduction in the attenuation of intervention effects with age and thus some increase in the estimated benefits, and may better reflect the true benefits of early nutritional interventions.

Abstract Background In the Sustainable Development Goals (SDGs) era, there is growing recognition of the responsibilities of non-health sectors in improving the health of children. Interventions to improve access to clean water, sanitation facilities, and hygiene behaviours (WASH) represent key opportunities to improve child health and well-being by preventing the spread of infectious diseases and improving nutritional status. Methods We conducted a systematic review of studies evaluating the effects of WASH interventions on childhood diarrhea in children 0–5 years old. Searches were run up to September 2016. We screened the titles and abstracts of retrieved articles, followed by screening of the full-text reports of relevant studies. We abstracted study characteristics and quantitative data, and assessed study quality. Meta-analyses were performed for similar intervention and outcome pairs. Results Pooled analyses showed diarrhea risk reductions from the following interventions: point-of-use water filtration (pooled risk ratio (RR): 0.47, 95% confidence interval (CI): 0.36–0.62), point-of-use water disinfection (pooled RR: 0.69, 95% CI: 0.60–0.79), and hygiene education with soap provision (pooled RR: 0.73, 95% CI: 0.57–0.94). Quality ratings were low or very low for most studies, and heterogeneity was high in pooled analyses. Improvements to the water supply and water disinfection at source did not show significant effects on diarrhea risk, nor did the one eligible study examining the effect of latrine construction. Conclusions Various WASH interventions show diarrhea risk reductions between 27% and 53% in children 0–5 years old, depending on intervention type, providing ample evidence to support the scale-up of WASH in low and middle-income countries (LMICs). Due to the overall low quality of the evidence and high heterogeneity, further research is required to accurately estimate the magnitude of the effects of these interventions in different contexts.

Abstract Background The worldwide burden of stillbirths is large, with an estimated 2.6 million babies stillborn in 2015 including 1.3 million dying during labour. The Every Newborn Action Plan set a stillbirth target of ≤12 per 1000 in all countries by 2030. Planning tools will be essential as countries set policy and plan investment to scale up interventions to meet this target. This paper summarises the approach taken for modelling the impact of scaling-up health interventions on stillbirths in the Lives Saved tool (LiST), and potential future refinements. Methods The specific application to stillbirths of the general method for modelling the impact of interventions in LiST is described. The evidence for the effectiveness of potential interventions to reduce stillbirths are reviewed and the assumptions of the affected fraction of stillbirths who could potentially benefit from these interventions are presented. The current assumptions and their effects on stillbirth reduction are described and potential future improvements discussed. Results High quality evidence are not available for all parameters in the LiST stillbirth model. Cause-specific mortality data is not available for stillbirths, therefore stillbirths are modelled in LiST using an attributable fraction approach by timing of stillbirths (antepartum/ intrapartum). Of 35 potential interventions to reduce stillbirths identified, eight interventions are currently modelled in LiST. These include childbirth care, induction for prolonged pregnancy, multiple micronutrient and balanced energy supplementation, malaria prevention and detection and management of hypertensive disorders of pregnancy, diabetes and syphilis. For three of the interventions, childbirth care, detection and management of hypertensive disorders of pregnancy, and diabetes the estimate of effectiveness is based on expert opinion through a Delphi process. Only for malaria is coverage information available, with coverage estimated using expert opinion for all other interventions. Going forward, potential improvements identified include improving of effectiveness and coverage estimates for included interventions and addition of further interventions. Conclusions Known effective interventions have the potential to reduce stillbirths and can be modelled using the LiST tool. Data for stillbirths are improving. Going forward the LiST tool should seek, where possible, to incorporate these improving data, and to continually be refined to provide an increasingly reliable tool for policy and programming purposes.

Abstract Background Countdown to 2015 (Countdown) supported countries to produce case studies that examine how and why progress was made toward the Millennium Development Goals (MDGs) 4 and 5. Analysing how health-financing data explains improvements in RMNCH outcomes was one of the components to the case studies. Methods This paper presents a descriptive analysis on health financing from six Countdown case studies (Afghanistan, Ethiopia, Malawi, Pakistan, Peru, and Tanzania), supplemented by additional data from global databases and country reports on macroeconomic, health financing, demographic, and RMNCH outcome data as needed. It also examines the effect of other contextual factors presented in the case studies to help interpret health-financing data. Results Dramatic increases in health funding occurred since 2000, where the MDG agenda encouraged countries and donors to invest more resources on health. Most low-income countries relied on external support to increase health spending, with an average 20–64 % of total health spending from 2000 onwards. Middle-income countries relied more on government and household spending. RMNCH funding also increased since 2000, with an average increase of 119 % (2005–2010) for RMNH expenditures (2005–2010) and 165 % for CH expenditures (2005–2011). Progress was made, especially achieving MDG 4, even with low per capita spending; ranging from US$16 to US$44 per child under 5 years among low-income countries. Improvements in distal factors were noted during the time frame of the analysis, including rapid economic growth in Ethiopia, Peru, and Tanzania and improvements in female literacy as documented in Malawi, which are also likely to have contributed to MDG progress and achievements. Conclusions Increases in health and RMNCH funding accompanied improvements in outcomes, though low-income countries are still very reliant on external financing, and out-of-pocket comprising a growing share of funds in middle-income settings. Enhancements in tracking RMNCH expenditures across countries are still needed to better understand whether domestic and global health financing initiatives lead to improved outcomes as RMNCH continues to be a priority under the Sustainable Development Goals.

Abstract Background Afghanistan has made considerable gains in improving maternal and child health and survival since 2001. However, socioeconomic and regional inequities may pose a threat to reaching universal coverage of health interventions and further health progress. We explored coverage and socioeconomic inequalities in key life-saving reproductive, maternal, newborn and child health (RMNCH) interventions at the national level and by region in Afghanistan. We also assessed gains in child survival through scaling up effective community-based interventions across wealth groups. Methods Using data from the Afghanistan Multiple Indicator Cluster Survey (MICS) 2010/11, we explored 11 interventions that spanned all stages of the continuum of care, including indicators of composite coverage. Asset-based wealth quintiles were constructed using standardised methods, and absolute inequalities were explored using wealth quintile (Q) gaps (Q5-Q1) and the slope index of inequality (SII), while relative inequalities were assessed with ratios (Q5/Q1) and the concentration index (CIX). The lives saved tool (LiST) modeling used to estimate neonatal and post-neonatal deaths averted from scaling up essential community-based interventions by 90 % coverage by 2025. Analyses considered the survey design characteristics and were conducted via STATA version 12.0 and SAS version 9.4. Results Our results underscore significant pro-rich socioeconomic absolute and relative inequalities, and mass population deprivation across most all RMNCH interventions studied. The most inequitable are antenatal care with a skilled attendant (ANCS), skilled birth attendance (SBA), and 4 or more antenatal care visits (ANC4) where the richest have between 3.0 and 5.6 times higher coverage relative to the poor, and Q5-Q1 gaps range from 32 % - 65 %. Treatment of sick children and breastfeeding interventions are the most equitably distributed. Across regions, inequalities were highest in the more urbanised East, West and Central regions of the country, while they were lowest in the South and Southeast. About 7700 newborns and 26,000 post-neonates could be saved by scaling up coverage of community outreach interventions to 90 %, with the most gains in the poorest quintiles. Conclusions Afghanistan is a pervasively poor and conflict-prone nation that has only recently experienced a decade of relative stability. Though donor investments during this period have been plentiful and have contributed to rebuilding of health infrastructure in the country, glaring inequities remain. A resolution to scaling up health coverage in insecure and isolated regions, and improving accessibility for the poorest and marginalised populations, should be at the forefront of national policy and programming efforts.

Abstract Background An important determinant of pregnancy outcome is the timely onset of labor and birth. Prolonged gestation complicates 5% to 10% of all pregnancies and confers increased risk to both the fetus and mother. The purpose of this review was to study the possible impact of induction of labour (IOL) for post-term pregnancies compared to expectant management on stillbirths. Methods A systematic review of the published studies including randomized controlled trials, quasi- randomized trials and observational studies was conducted. Search engines used were PubMed, the Cochrane Library, the WHO regional databases and hand search of bibliographies. A standardized data abstraction sheet was used. Recommendations have been made for input to the Lives Saved Tool (LiST) model by following standardized guidelines developed by the Child Health Epidemiology Reference Group (CHERG). Results A total of 25 studies were included in this review. Meta-analysis of 14 randomized controlled trials (RCTs) suggests that a policy of elective IOL for pregnancies at or beyond 41 weeks is associated with significantly fewer perinatal deaths (RR=0.31; 95% CI: 0.11-0.88) compared to expectant management, but no significant difference in the incidence of stillbirth (RR= 0.29; 95% CI: 0.06-1.38) was noted. The included trials evaluating this intervention were small, with few events in the intervention and control group. There was significant decrease in incidence of neonatal morbidity from meconium aspiration (RR = 0.43, 95% CI 0.23-0.79) and macrosomia (RR = 0.72; 95% CI: 0.54 – 0.98). Using CHERG rules, we recommended 69% reduction as a point estimate for the risk of stillbirth with IOL for prolonged gestation (> 41 weeks). Conclusions Induction of labour appears to be an effective way of reducing perinatal morbidity and mortality associated with post-term pregnancies. It should be offered to women with post-term pregnancies after discussing the benefits and risks of induction of labor.

Abstract Introduction Iron deficiency is the most prevalent nutrient deficiency in the world, particularly during pregnancy. According to the literature, anemia, particularly severe anemia, is associated with increased risk of maternal mortality. It also puts mothers at risk of multiple perinatal complications. Numerous studies in the past have evaluated the impact of supplementation with iron and iron-folate but data regarding the efficacy and quality of evidence of these interventions are lacking. This article aims to address the impact of iron with and without folate supplementation on maternal anemia and provides outcome specific quality according to the Child Health Epidemiology Reference Group (CHERG) guidelines. Methods We conducted a systematic review of published randomized and quasi-randomized trials on PubMed and the Cochrane Library as per the CHERG guidelines. The studies selected employed daily supplementation of iron with or without folate compared with no intervention/placebo, and also compared intermittent supplementation with the daily regimen. The studies were abstracted and graded according to study design, limitations, intervention specifics and outcome effects. CHERG rules were then applied to evaluate the impact of these interventions on iron deficiency anemia during pregnancy. Recommendations were made for the Lives Saved Tool (LiST). Results After screening 3550 titles, 31 studies were selected for assessment using CHERG criteria. Daily iron supplementation resulted in 73% reduction in the incidence of anemia at term (RR = 0.27; 95% CI: 0.17 – 0.42; random effects model) and 67% reduction in iron deficiency anemia at term (RR = 0.33; 95% CI: 0.16 – 0.69; random model) compared to no intervention/placebo. For this intervention, both these outcomes were graded as ‘moderate’ quality evidence. Daily supplementation with iron-folate was associated with 73% reduction in anemia at term (RR = 0.27; 95% CI: 0.12 – 0.56; random model) with a quality grade of ‘moderate’. The effect of the same intervention on iron deficiency anemia was non-significant (RR = 0.43; 95% CI: 0.17 – 1.09; random model) and was graded as ‘low’ quality evidence. There was no difference in rates of anemia at term with intermittent iron-folate vs. daily iron-folate supplementation (RR = 1.61; 95% CI: 0.82 –3.14; random model). Conclusion Applying the CHERG rules, we recommend a 73% reduction in anemia at term with daily iron (alone) supplementation or iron/folate (combined) vs. no intervention or placebo; for inclusion in the LiST model. Given the paucity of studies of intermittent iron or iron-folate supplementation, especially in developing countries, we recommend further evaluation of this intervention in comparison with daily supplementation regimen.

Abstract Background The nutritional status of the mother prior to and during pregnancy plays a vital role in fetal growth and development, and maternal undernourishment may lead to adverse perinatal outcomes including intrauterine growth restriction (IUGR). Several macronutrient interventions had been proposed for adequate protein and energy supplementation during pregnancy. The objective of this paper was to review the effect of balanced protein energy supplementation during pregnancy on birth outcomes. This paper is a part of a series of reviews undertaken for getting estimates of effectiveness of an intervention for input to Lives Saved Tool (LiST) model. Methods A literature search was conducted on PubMed, Cochrane Library and WHO regional data bases to identify randomized trials (RCTs) and quasi RCTs that evaluated the impact of balanced protein energy supplementation in pregnancy. Balanced protein energy supplementation was defined as nutritional supplementation during pregnancy in which proteins provided less than 25% of the total energy content. Those studies were excluded in which the main intervention was dietary advice to pregnant women for increase in protein energy intake, high protein supplementation (i.e. supplementation in which protein provides at least 25% of total energy content), isocaloric protein supplementation (where protein replaces an equal quantity of non-protein energy content), or low energy diet to pregnant women who are either overweight or who exhibit high weight gain earlier in gestation. The primary outcomes were incidence of small for gestational age (SGA) birth, mean birth weight and neonatal mortality. Quality of evidence was evaluated according to the Child Health Epidemiology Reference group (CHERG) adaptation of Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria. Results The final number of studies included in our review was eleven comprising of both RCTs and quasi-RCTs. Our meta-analysis indicates that providing pregnant females with balanced protein energy supplementation resulted in a significant reduction of 31 % in the risk of giving birth to small for gestational age infants (Relative risk (RR) =0.69, 95% Confidence interval (CI) 0.56 to 0.85). This estimate had been recommended for LiST as a proxy for reduction in IUGR. Pooled results for mean birth weight showed that balanced protein supplemented group gained more weight compared to control [Mean difference 59.89 g, 95 % CI 33.09-86.68]. This effect was more pronounced in malnourished women compared to adequately nourished women. There was no statistically significant effect of balanced protein energy supplementation on neonatal mortality (RR= 0.63, 95% CI 0.37 to 1.06). Conclusion Providing pregnant females with balanced protein energy supplementation leads to reduction in risk of small for gestational age infants, especially among undernourished pregnant women. Given these findings, we can recommend balanced protein energy supplementation as an intervention among undernourished women for inclusion in the LiST model with a point estimate of 31% [95% CI 15% to 44%] reduction in IUGR.

Abstract Background Of 136 million babies born annually, around 10 million require assistance to breathe. Each year 814,000 neonatal deaths result from intrapartum-related events in term babies (previously “birth asphyxia”) and 1.03 million from complications of prematurity. No systematic assessment of mortality reduction from tactile stimulation or resuscitation has been published. Objective To estimate the mortality effect of immediate newborn assessment and stimulation, and basic resuscitation on neonatal deaths due to term intrapartum-related events or preterm birth, for facility and home births. Methods We conducted systematic reviews for studies reporting relevant mortality or morbidity outcomes. Evidence was assessed using GRADE criteria adapted to provide a systematic approach to mortality effect estimates for the Lives Saved Tool (LiST). Meta-analysis was performed if appropriate. For interventions with low quality evidence but strong recommendation for implementation, a Delphi panel was convened to estimate effect size. Results We identified 24 studies of neonatal resuscitation reporting mortality outcomes (20 observational, 2 quasi-experimental, 2 cluster randomized controlled trials), but none of immediate newborn assessment and stimulation alone. A meta-analysis of three facility-based studies examined the effect of resuscitation training on intrapartum-related neonatal deaths (RR= 0.70, 95%CI 0.59-0.84); this estimate was used for the effect of facility-based basic neonatal resuscitation (additional to stimulation). The evidence for preterm mortality effect was low quality and thus expert opinion was sought. In community-based studies, resuscitation training was part of packages with multiple concurrent interventions, and/or studies did not distinguish term intrapartum-related from preterm deaths, hence no meta-analysis was conducted. Our Delphi panel of 18 experts estimated that immediate newborn assessment and stimulation would reduce both intrapartum-related and preterm deaths by 10%, facility-based resuscitation would prevent a further 10% of preterm deaths, and community-based resuscitation would prevent further 20% of intrapartum-related and 5% of preterm deaths. Conclusion Neonatal resuscitation training in facilities reduces term intrapartum-related deaths by 30%. Yet, coverage of this intervention remains low in countries where most neonatal deaths occur and is a missed opportunity to save lives. Expert opinion supports smaller effects of neonatal resuscitation on preterm mortality in facilities and of basic resuscitation and newborn assessment and stimulation at community level. Further evaluation is required for impact, cost and implementation strategies in various contexts. Funding This work was supported by the Bill & Melinda Gates Foundation through a grant to the US Fund for UNICEF, and to the Saving Newborn Lives program of Save the Children, through Save the Children US.

Abstract Background Pre-eclampsia and Eclampsia are relatively common complications of pregnancy, leading to considerable maternal and fetal mortality and morbidity. We sought to review the effect of aspirin, calcium supplementation, antihypertensive agents and magnesium sulphate on risk stillbirths. Methods A systematic literature search was conducted to identify studies evaluating the above interventions. We used a standardized abstraction and grading format and performed meta-analyses where data were available from more than one studies. The estimated effect on stillbirths was determined by applying the standard Child Health Epidemiology Reference Group (CHERG) rules for multiple outcomes. For interventions with insufficient evidence for overall effect, a Delphi process was undertaken to estimate effectiveness. Results We identified 82 relevant studies. For aspirin, maganesium sulphate and use of antihypertensive we found an insignificant decrease in stillbirth and perinatal mortality. For calcium supplementation, there was a borderline significant reduction in stillbirths (RR 0.81, 95 % CI 0.63-1.03). We undertook a Delphi consultation among experts to assess the potential impact of a package of interventions for the management of pre-eclampsia and eclampsia (antihypertensive, magnesium sulphate and C-section if needed). The Delphi process suggested 20% reduction each in both antepartum and intrapartum stillbirths with the use of this package. Conclusions Despite promising benefits of calcium supplementation and aspirin use cases on maternal morbidity and eclampsia in high risk cases, further work is needed to ascertain their benefits in relation to stillbirths. The Delphi process undertaken for assessing potential impact of a package of interventions indicated that this could be associated with 20% reduction in stillbirths, for input into LiST.

Abstract Introduction Vitamin A is important for the integrity and regeneration of respiratory and gastrointestinal epithelia and is involved in regulating human immune function. It has been shown previously that vitamin A has a preventive effect on all-cause and disease specific mortality in children under five. The purpose of this paper was to get a point estimate of efficacy of vitamin A supplementation in reducing cause specific mortality by using Child Health Epidemiology Reference Group (CHERG) guidelines. Methods A literature search was done on PubMed, Cochrane Library and WHO regional data bases using various free and Mesh terms for vitamin A and mortality. Data were abstracted into standardized forms and quality of studies was assessed according to standardized guidelines. Pooled estimates were generated for preventive effect of vitamin A supplementation on all-cause and disease specific mortality of diarrhea, measles, pneumonia, meningitis and sepsis. We did a subgroup analysis for vitamin A supplementation in neonates, infants 1-6 months and children aged 6-59 months. In this paper we have focused on estimation of efficacy of vitamin A supplementation in children 6-59 months of age. Results for neonatal vitamin A supplementation have been presented, however no recommendations are made as more evidence on it would be available soon. Results There were 21 studies evaluating preventive effect of vitamin A supplementation in community settings which reported all-cause mortality. Twelve of these also reported cause specific mortality for diarrhea and pneumonia and six reported measles specific mortality. Combined results from six studies showed that neonatal vitamin A supplementation reduced all-cause mortality by 12 % [Relative risk (RR) 0.88; 95 % confidence interval (CI) 0.79-0.98]. There was no effect of vitamin A supplementation in reducing all-cause mortality in infants 1-6 months of age [RR 1.05; 95 % CI 0.88-1.26]. Pooled results for preventive vitamin A supplementation showed that it reduced all-cause mortality by 25% [RR 0.75; 95 % CI 0.64-0.88] in children 6-59 months of age. Vitamin A supplementation also reduced diarrhea specific mortality by 30% [RR 0.70; 95 % CI 0.58-0.86] in children 6-59 months. This effect has been recommended for inclusion in the Lives Saved Tool. Vitamin A supplementation had no effect on measles [RR 0.71, 95% CI: 0.43-1.16], meningitis [RR 0.73, 95% CI: 0.22-2.48] and pneumonia [RR 0.94, 95% CI: 0.67-1.30] specific mortality. Conclusion Preventive vitamin A supplementation reduces all-cause and diarrhea specific mortality in children 6-59 months of age in community settings in developing countries.

Abstract Background Given the recognized benefits of breastfeeding for the health of the mother and infants, the World Health Organization (WHO) recommends exclusive breastfeeding (EBF) for the first six months of life. However, the prevalence of EBF is low globally in many of the developing and developed countries around the world. There is much interest in the effectiveness of breastfeeding promotion interventions on breastfeeding rates in early infancy. Methods A systematic literature was conducted to identify all studies that evaluated the impact of breastfeeding promotional strategies on any breastfeeding and EBF rates at 4-6 weeks and at 6 months. Data were abstracted into a standard excel sheet by two authors. Meta-analyses were performed with different sub-group analyses. The overall evidence were graded according to the Child Health Epidemiology Reference Group (CHERG) rules using the adapted Grading of Recommendations, Assessment, Development and Evaluation (GRADE) criteria and recommendations made from developing country studies for inclusion into the Live Saved Tool (LiST) model. Results After reviewing 968 abstracts, 268 studies were selected for potential inclusion, of which 53 randomized and quasi-randomized controlled trials were selected for full abstraction. Thirty two studies gave the outcome of EBF at 4-6 weeks postpartum. There was a statistically significant 43% increase in this outcome, with 89% and 20% significant increases in developing and developed countries respectively. Fifteen studies reported EBF outcomes at 6 months. There was an overall 137% increase, with a significant 6 times increase in EBF in developing countries, compared to 1.3 folds increase in developed country studies. Further sub-group analyses proved that prenatal counseling had a significant impact on breastfeeding outcomes at 4-6 weeks, while both prenatal and postnatal counseling were important for EBF at 6 months. Conclusion Breastfeeding promotion interventions increased exclusive and any breastfeeding rates at 4-6 weeks and at 6 months. A relatively greater impact of these interventions was seen in developing countries with 1.89 and 6 folds increase in EBF rates at 4-6 weeks and at 6 months respectively.

Abstract Background Childhood undernutrition is prevalent in low and middle income countries. It is an important indirect cause of child mortality in these countries. According to an estimate, stunting (height for age Z score < -2) and wasting (weight for height Z score < -2) along with intrauterine growth restriction are responsible for about 2.1 million deaths worldwide in children < 5 years of age. This comprises 21 % of all deaths in this age group worldwide. The incidence of stunting is the highest in the first two years of life especially after six months of life when exclusive breastfeeding alone cannot fulfill the energy needs of a rapidly growing child. Complementary feeding for an infant refers to timely introduction of safe and nutritional foods in addition to breast-feeding (BF) i.e. clean and nutritionally rich additional foods introduced at about six months of infant age. Complementary feeding strategies encompass a wide variety of interventions designed to improve not only the quality and quantity of these foods but also improve the feeding behaviors. In this review, we evaluated the effectiveness of two most commonly applied strategies of complementary feeding i.e. timely provision of appropriate complementary foods (± nutritional counseling) and education to mothers about practices of complementary feeding on growth. Recommendations have been made for input to the Lives Saved Tool (LiST) model by following standardized guidelines developed by Child Health Epidemiology Reference Group (CHERG). Methods We conducted a systematic review of published randomized and quasi-randomized trials on PubMed, Cochrane Library and WHO regional databases. The included studies were abstracted and graded according to study design, limitations, intervention details and outcome effects. The primary outcomes were change in weight and height during the study period among children 6-24 months of age. We hypothesized that provision of complementary food and education of mother about complementary food would significantly improve the nutritional status of the children in the intervention group compared to control. Meta-analyses were generated for change in weight and height by two methods. In the first instance, we pooled the results to get weighted mean difference (WMD) which helps to pool studies with different units of measurement and that of different duration. A second meta-analysis was conducted to get a pooled estimate in terms of actual increase in weight (kg) and length (cm) in relation to the intervention, for input into the LiST model. Results After screening 3795 titles, we selected 17 studies for inclusion in the review. The included studies evaluated the impact of provision of complementary foods (±nutritional counseling) and of nutritional counseling alone. Both these interventions were found to result in a significant increase in weight [WMD 0.34 SD, 95% CI 0.11 – 0.56 and 0.30 SD, 95 % CI 0.05-0.54 respectively) and linear growth [WMD 0.26 SD, 95 % CI 0.08-0.43 and 0.21 SD, 95 % CI 0.01-0.41 respectively]. Pooled results for actual increase in weight in kilograms and length in centimeters showed that provision of appropriate complementary foods (±nutritional counseling) resulted in an extra gain of 0.25kg (±0.18) in weight and 0.54 cm (±0.38) in height in children aged 6-24 months. The overall quality grades for these estimates were that of ‘moderate’ level. These estimates have been recommended for inclusion in the Lives Saved Tool (LiST) model. Education of mother about complementary feeding led to an extra weight gain of 0.30 kg (±0.26) and a gain of 0.49 cm (±0.50) in height in the intervention group compared to control. These estimates had been recommended for inclusion in the LiST model with an overall quality grade assessment of ‘moderate’ level. Conclusion Provision of appropriate complementary food, with or without nutritional education, and maternal nutritional counseling alone lead to significant increase in weight and height in children 6-24 months of age. These interventions can significantly reduce the risk of stunting in developing countries and are recommended for inclusion in the LiST tool.

Abstract Background Hypertension in pregnancy stand alone or with proteinuria is one of the leading causes of maternal mortality and morbidity in the world. Epidemiological and clinical studies have shown that an inverse relationship exists between calcium intake and development of hypertension in pregnancy though the effect varies based on baseline calcium intake and pre-existing risk factors. The purpose of this review was to evaluate preventive effect of calcium supplementation during pregnancy on gestational hypertensive disorders and related maternal and neonatal mortality in developing countries. Methods A literature search was carried out on PubMed, Cochrane Library and WHO regional databases. Data were extracted into a standardized excel sheet. Identified studies were graded based on strengths and limitations of studies. All the included studies were from developing countries. Meta-analyses were generated where data were available from more than one study for an outcome. Primary outcomes were maternal mortality, eclampsia, pre-eclampsia, and severe preeclampsia. Neonatal outcomes like neonatal mortality, preterm birth, small for gestational age and low birth weight were also evaluated. We followed standardized guidelines of Child Health Epidemiology Reference Group (CHERG) to generate estimates of effectiveness of calcium supplementation during pregnancy in reducing maternal and neonatal mortality in developing countries, for inclusion in the Lives Saved Tool (LiST). Results Data from 10 randomized controlled trials were included in this review. Pooled analysis showed that calcium supplementation during pregnancy was associated with a significant reduction of 45% in risk of gestational hypertension [Relative risk (RR) 0.55; 95 % confidence interval (CI) 0.36-0.85] and 59% in the risk of pre-eclampsia [RR 0.41; 95 % CI 0.24-0.69] in developing countries. Calcium supplementation during pregnancy was also associated with a significant reduction in neonatal mortality [RR 0.70; 95 % CI 0.56-0.88] and risk of pre-term birth [RR 0.88, 95 % CI 0.78-0.99]. Recommendations for LiST for reduction in maternal mortality were based on risk reduction in gestational hypertensive related severe morbidity/mortality [RR 0.80; 95% CI 0.70-0.91] and that for neonatal mortality were based on risk reduction in all-cause neonatal mortality [RR 0.70; 95% CI 0.56-0.88]. Conclusion Calcium supplementation during pregnancy is associated with a reduction in risk of gestational hypertension, pre-eclampsia neonatal mortality and pre-term birth in developing countries.

Abstract Background Pregnancy is a state of increased requirement of macro- and micronutrients, and malnourishment or inadequate dietary intake before and during pregnancy, can lead to adverse perinatal outcomes including stillbirths. Many nutritional interventions have been proposed during pregnancy according to the nutritional status of the mother and baseline risk factors for different gestational disorders. In this paper, we have reviewed three nutritional interventions including peri-conceptional folic acid supplementation, balanced protein energy supplementation and multiple micronutrients supplementation during pregnancy. This paper is a part of a series to estimate the effect of interventions on stillbirths for input to Live Saved Tool (LiST) model. Methods We systematically reviewed all published literature to identify studies evaluating effectiveness of peri-conceptional folic acid supplementation in reducing neural tube defects (NTD), related stillbirths and balanced protein energy and multiple micronutrients supplementation during pregnancy in reducing all-cause stillbirths. The primary outcome was stillbirths. Meta-analyses were generated where data were available from more than one study. Recommendations were made for the Lives Saved Tool (LiST) model based on rules developed by the Child Health Epidemiology Reference Group (CHERG). Results There were 18 studies that addressed peri-conceptional folic acid supplementation for prevention of neural tube defects (NTDs). Out of these, 7 studies addressed folic acid supplementation while 11 studies evaluated effect of folic acid fortification. Pooled results from 11 fortification studies showed that it reduces primary incidence of NTDs by 41 % [Relative risk (RR) 0.59; 95 % confidence interval (CI) 0.52-0.68]. This estimate has been recommended for inclusion in the LiST as proxy for reduction in stillbirths. Pooled results from three studies considered to be of low quality and suggest that balanced protein energy supplementation during pregnancy could lead to a reduction of 45% in stillbirths [RR 0.55, 95 % CI 0.31-0.97]. While promising, the intervention needs more effectiveness studies before inclusion in any programs. Pooled results from 13 studies evaluating role of multiple micronutrients supplementation during pregnancy showed no significant effect in reducing stillbirths [RR = 0.98; 95% CI: 0.88 – 1.10] or perinatal mortality [RR = 1.07; 95% CI: 0.92 – 1.25; random model]. No recommendations have been made for this intervention for inclusion in the LiST model. Conclusions Peri-conceptional folic acid supplementation reduces stillbirths due to NTDs by approximately 41%, a point estimate recommended for inclusion in LiST.

Abstract Objectives/background Given the widespread prevalence of micronutrient deficiencies in developing countries, supplementation with multiple micronutrients rather than iron-folate alone, could be of potential benefit to the mother and the fetus. These benefits could relate to prevention of maternal complications and reduction in other adverse pregnancy outcomes such as small-for-gestational age (SGA) births, low birth weight, stillbirths, perinatal and neonatal mortality. This review evaluates the evidence of the impact of multiple micronutrient supplements during pregnancy, in comparison with standard iron-folate supplements, on specific maternal and pregnancy outcomes of relevance to the Lives Saved Tool (LiST). Data sources/review methods A systematic review of randomized controlled trials was conducted. Search engines used were PubMed, the Cochrane Library, the WHO regional databases and hand search of bibliographies. A standardized data abstraction and Child Health Epidemiology Reference (CHERG) adaptation of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) technique were used for data abstraction and overall quality of evidence. Meta-analyses were performed to calculate summary estimates of utility to the LiST model for the specified outcome of incidence of SGA births. We also evaluated the potential impact of multiple micronutrients on neonatal mortality according to the proportion of deliveries occurring in facilities (using a threshold of 60% to indicate functionality of health systems for skilled births). Results We included 17 studies for detailed data abstraction. There was no significant benefit of multiple micronutrients as compared to iron folate on maternal anemia in third trimester [Relative risk (RR) = 1.03; 95% confidence interval (CI): 0.87 – 1.22 (random model)]. Our analysis, however, showed a significant reduction in SGA by 9% [RR = 0.91; 95% CI: 0.86 – 0.96 (fixed model)]. In the fixed model, the SGA outcome remained significant only in women with mean body mass index (BMI) ≥ 22 kg/m2. There was an increased risk of neonatal mortality in studies with majority of births at home [RR = 1.47, 95% CI: 1.13-1.92]; such an effect was not evident where ≥ 60% of births occurred in facility settings [RR = 0.94, 95% CI: 0.81-1.09]. Overall there was no increase in the risk of neonatal mortality [RR = 1.05, 95% CI: 0.92 – 1.19 (fixed model)]. Conclusion This review provides evidence of a significant benefit of MMN supplementation during pregnancy on reducing SGA births as compared to iron-folate, with no significant increase in the risk of neonatal mortality in populations where skilled birth care is available and majority of births take place in facilities. Given comparability of impacts on maternal anemia, the decision to replace iron-folate with multiple micronutrients during pregnancy may be taken in the context of available services in health systems and birth outcomes monitored.

Abstract Introduction Zinc plays an important role in cellular growth, cellular differentiation and metabolism. The results of previous meta-analyses evaluating effect of zinc supplementation on linear growth are inconsistent. We have updated and evaluated the available evidence according to Grading of Recommendations, Assessment, Development and Evaluation (GRADE) criteria and tried to explain the difference in results of the previous reviews. Methods A literature search was done on PubMed, Cochrane Library, IZiNCG database and WHO regional data bases using different terms for zinc and linear growth (height). Data were abstracted in a standardized form. Data were analyzed in two ways i.e. weighted mean difference (effect size) and pooled mean difference for absolute increment in length in centimeters. Random effect models were used for these pooled estimates. We have given our recommendations for effectiveness of zinc supplementation in the form of absolute increment in length (cm) in zinc supplemented group compared to control for input to Live Saves Tool (LiST). Results There were thirty six studies assessing the effect of zinc supplementation on linear growth in children < 5 years from developing countries. In eleven of these studies, zinc was given in combination with other micronutrients (iron, vitamin A, etc). The final effect size after pooling all the data sets (zinc ± iron etc) showed a significant positive effect of zinc supplementation on linear growth [Effect size: 0.13 (95% CI 0.04, 0.21), random model] in the developing countries. A subgroup analysis by excluding those data sets where zinc was supplemented in combination with iron showed a more pronounced effect of zinc supplementation on linear growth [Weighed mean difference 0.19 (95 % CI 0.08, 0.30), random model]. A subgroup analysis from studies that reported actual increase in length (cm) showed that a dose of 10 mg zinc/day for duration of 24 weeks led to a net a gain of 0.37 (±0.25) cm in zinc supplemented group compared to placebo. This estimate is recommended for inclusion in Lives Saved Tool (LiST) model. Conclusions Zinc supplementation has a significant positive effect on linear growth, especially when administered alone, and should be included in national strategies to reduce stunting in children < 5 years of age in developing countries.

Abstract Background Diabetes during pregnancy is associated with significant risk of complications to the mother, fetus and newborn. We reviewed the potential impact of early detection and control of diabetes mellitus during pregnancy on stillbirths for possible inclusion in the Lives Saved Tool (LiST). Methods A systematic literature search up to July 2010 was done to identify all published randomized controlled trials and observational studies. A standardized data abstraction sheet was employed and data were abstracted by two independent authors. Meta-analyses were performed with different sub-group analyses. The analyses were graded according to the CHERG rules using the adapted GRADE criteria and recommendations made after assessing the overall quality of the studies included in the meta-analyses. Results A total of 70 studies were selected for data extraction including fourteen intervention studies and fifty six observational studies. No randomized controlled trials were identified evaluating early detection of diabetes mellitus in pregnancy versus standard screening (glucose challenge test between 24th to 28th week of gestation) in pregnancy. Intensive management of gestational diabetes (including specialized dietary advice, increased monitoring and tailored dietary therapy) during pregnancy (3 studies: 3791 participants) versus conventional management (dietary advice and insulin as required) was associated with a non-significant reduction in the risk of stillbirths (RR 0.20; 95% CI: 0.03-1.10) (‘moderate’ quality evidence). Optimal control of serum blood glucose versus sub-optimal control was associated with a significant reduction in the risk of perinatal mortality (2 studies, 5286 participants: RR=0.40, 95% CI 0.25- 0.63), but not stillbirths (3 studies, 2469 participants: RR=0.51, 95% CI 0.14-1.88). Preconception care of diabetes (information about need for optimization of glycemic control before pregnancy, assessment of diabetes complications, review of dietary habits, intensification of capillary blood glucose self-monitoring and optimization of insulin therapy) versus none (3 studies: 910 participants) was associated with a reduction in perinatal mortality (RR=0.29, 95% CI 0.14 -0.60). Using the Delphi process for estimating effect size of optimal diabetes recognition and management yielded a median effect size of 10% reduction in stillbirths. Conclusions Diabetes, especially pre-gestational diabetes with its attendant vascular complications, is a significant risk factor for stillbirth and perinatal death. Our review highlights the fact that very few studies of adequate quality are available that can provide estimates of the effect of screening for aid management of diabetes in pregnancy on stillbirth risk. Using the Delphi process we recommend a conservative 10% reduction in the risk of stillbirths, as a point estimate for inclusion in the LiST.

Abstract Background There is a strong association between stillbirth and fetal growth restriction. Early detection and management of IUGR can lead to reduce related morbidity and mortality. In this paper we have reviewed effectiveness of fetal movement monitoring and Doppler velocimetry for the detection and surveillance of high risk pregnancies and the effect of this on prevention of stillbirths. We have also reviewed effect of maternal body mass index (BMI) screening, symphysial-fundal height measurement and targeted ultrasound in detection and triage of IUGR in the community. Methods We systematically reviewed all published literature to identify studies related to our interventions. We searched PubMed, Cochrane Library, and all World Health Organization Regional Databases and included publications in any language. Quality of available evidence was assessed using GRADE criteria. Recommendations were made for the Lives Saved Tool (LiST) based on rules developed by the Child Health Epidemiology Group. Given the paucity of evidence related to the effect of detection and management of IUGR on stillbirths, we undertook Delphi based evaluation from experts in the field. Results There was insufficient evidence to recommend against or in favor of routine use of fetal movement monitoring for fetal well being. (1) Detection and triage of IUGR with the help of (1a) maternal BMI screening, (1b) symphysial-fundal height measurement and (1c) targeted ultrasound can be an effective method of reducing IUGR related perinatal morbidity and mortality. Pooled results from sixteen studies shows that Doppler velocimetry of umbilical and fetal arteries in ‘high risk’ pregnancies, coupled with the appropriate intervention, can reduce perinatal mortality by 29 % [RR 0.71, 95 % CI 0.52-0.98]. Pooled results for impact on stillbirth showed a reduction of 35 % [RR 0.65, 95 % CI 0.41-1.04]; however, the results did not reach the conventional limits of statistical significance. This intervention could be potentially recommended for high income settings or middle income countries with improving rates and standards of facility based care. Based on the Delphi, a combination of screening with maternal BMI, Symphysis fundal height and targeted ultrasound followed by the appropriate management could potentially reduce antepartum and intrapartum stillbirth by 20% respectively. This estimate is presently being recommended for inclusion in the LiST. Conclusion There is insufficient evidence to recommend in favor or against fetal movement counting for routine use for testing fetal well being. Doppler velocimetry of umbilical and fetal arteries and appropriate intervention is associated with 29 % (95 % CI 2% to 48 %) reduction in perinatal mortality. Expert opinion suggests that detection and management of IUGR with the help of maternal BMI, symphysial-fundal height measurement and targeted ultrasound could be effective in reducing IUGR related stillbirths by 20%.

Abstract Background Infection is a well acknowledged cause of stillbirths and may account for about half of all perinatal deaths today, especially in developing countries. This review presents the impact of interventions targeting various important infections during pregnancy on stillbirth or perinatal mortality. Methods We undertook a systematic review including all relevant literature on interventions dealing with infections during pregnancy for assessment of effects on stillbirths or perinatal mortality. The quality of the evidence was assessed using the adapted Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach by Child Health Epidemiology Reference Group (CHERG). For the outcome of interest, namely stillbirth, we applied the rules developed by CHERG to recommend a final estimate for reduction in stillbirth for input to the Lives Saved Tool (LiST) model. Results A total of 25 studies were included in the review. A random-effects meta-analysis of observational studies of detection and treatment of syphilis during pregnancy showed a significant 80% reduction in stillbirths [Relative risk (RR) = 0.20; 95% confidence interval (CI): 0.12 - 0.34) that is recommended for inclusion in the LiST model. Our meta-analysis showed the malaria prevention interventions i.e. intermittent preventive treatment (IPTp) and insecticide-treated mosquito nets (ITNs) can reduce stillbirths by 22%, however results were not statistically significant (RR = 0.78; 95% CI: 0.59 – 1.03). For human immunodeficiency virus infection, a pooled analysis of 6 radomized controlled trials (RCTs) failed to show a statistically significant reduction in stillbirth with the use of antiretroviral in pregnancy compared to placebo (RR = 0.93; 95% CI: 0.45 – 1.92). Similarly, pooled analysis combining four studies for the treatment of bacterial vaginosis (3 for oral and 1 for vaginal antibiotic) failed to yield a significant impact on perinatal mortality (OR = 0.88; 95% CI: 0.50 – 1.55). Conclusions The clearest evidence of impact in stillbirth reduction was found for adequate prevention and treatment of syphilis infection and possibly malaria. At present, large gaps exist in the growing list of stillbirth risk factors, especially those that are infection related. Potential causes of stillbirths including HIV and TORCH infections need to be investigated further to help establish the role of prevention/treatment and its subsequent impact on stillbirth reduction.

Abstract Background Of the global burden of 2.6 million stillbirths, around 1.2 million occur during labour i.e. are intrapartum deaths. In low-/middle-income countries, a significant proportion of women give birth at home, usually in the absence of a skilled birth attendant. This review discusses the impact of skilled birth attendance (SBA) and the provision of Emergency Obstetric Care (EOC) on stillbirths and perinatal mortality. Methods A systematic literature search was performed on PubMed/MEDLINE, Cochrane Database and the WHO regional libraries. Data of all eligible studies were extracted into a standardized Excel sheet containing variables such as participants’ characteristics, sample size, location, setting, blinding, allocation concealment, intervention and control details and limitations. We undertook a meta-analysis of the impact of SBA on stillbirths. Given the paucity of data from randomized trials or robust quasi-experimental designs, we undertook an expert Delphi consultation to determine impact estimates of provision of Basic and Comprehensive EOC on reducing stillbirths if there would be universal coverage (99%). Results The literature search yielded 871 hits. A total of 21 studies were selected for data abstraction. Our meta-analysis on community-based skilled birth attendance based on two before-after studies showed a 23% significant reduction in stillbirths (RR = 0.77; 95% CI: 0.69 – 0.85). The overall quality grade of available evidence for this intervention on stillbirths was ‘moderate’. The Delphi process supported the estimated reduction in stillbirths by skilled attendance and experts further suggested that the provision of Basic EOC had the potential to avert intrapartum stillbirths by 45% and with provision of Comprehensive EOC this could be reduced by 75%. These estimates are conservative, consistent with historical trends in maternal and perinatal mortality from both developed and developing countries, and are recommended for inclusion in the Lives Saved Tool (LiST) model. Conclusions Both Skilled Birth Attendance and Emergency/or Essential Obstetric Care have the potential to reduce the number of stillbirths seen globally. Further evidence is needed to be able to calculate an effect size.

Abstract Background Each year almost one million newborns die from infections, mostly in low-income countries. Timely case management would save many lives but the relative mortality effect of varying strategies is unknown. We have estimated the effect of providing oral, or injectable antibiotics at home or in first-level facilities, and of in-patient hospital care on neonatal mortality from pneumonia and sepsis for use in the Lives Saved Tool (LiST). Methods We conducted systematic searches of multiple databases to identify relevant studies with mortality data. Standardized abstraction tables were used and study quality assessed by adapted GRADE criteria. Meta-analyses were undertaken where appropriate. For interventions with biological plausibility but low quality evidence, a Delphi process was undertaken to estimate effectiveness. Results Searches of 2876 titles identified 7 studies. Among these, 4 evaluated oral antibiotics for neonatal pneumonia in non-randomised, concurrently controlled designs. Meta-analysis suggested reductions in all-cause neonatal mortality (RR 0.75 95% CI 0.64- 0.89; 4 studies) and neonatal pneumonia-specific mortality (RR 0.58 95% CI 0.41- 0.82; 3 studies). Two studies (1 RCT, 1 observational study), evaluated community-based neonatal care packages including injectable antibiotics and reported mortality reductions of 44% (RR= 0.56, 95% CI 0.41-0.77) and 34% (RR =0.66, 95% CI 0.47-0.93), but the interpretation of these results is complicated by co-interventions. A third, clinic-based, study reported a case-fatality ratio of 3.3% among neonates treated with injectable antibiotics as outpatients. No studies were identified evaluating injectable antibiotics alone for neonatal pneumonia. Delphi consensus (median from 20 respondents) effects on sepsis-specific mortality were 30% reduction for oral antibiotics, 65% for injectable antibiotics and 75% for injectable antibiotics on pneumonia-specific mortality. No trials were identified assessing effect of hospital management for neonatal infections and Delphi consensus suggested 80%, and 90% reductions for sepsis and pneumonia-specific mortality respectively. Conclusion Oral antibiotics administered in the community are effective for neonatal pneumonia mortality reduction based on a meta-analysis, but expert opinion suggests much higher impact from injectable antibiotics in the community or primary care level and even higher for facility-based care. Despite feasibility and low cost, these interventions are not widely available in many low income countries. Funding This work was supported by the Bill & Melinda Gates Foundation through a grant to the US Fund for UNICEF, and to Saving Newborn Lives Save the Children, through Save the Children US.

Abstract Background Zinc deficiency is commonly prevalent in children in developing countries and plays a role in decreased immunity and increased risk of infection. Preventive zinc supplementation in healthy children can reduce mortality due to common causes like diarrhea, pneumonia and malaria. The main objective was to determine all-cause mortality and cause-specific mortality and morbidity in children under five in developing countries for preventive zinc supplementation. Data sources/ review methods A literature search was carried out on PubMed, the Cochrane Library and the WHO regional databases to identify RCTs on zinc supplementation for greater than 3 months in children less than 5 years of age in developing countries and its effect on mortality was analyzed. Results The effect of preventive zinc supplementation on mortality was given in eight trials, while cause specific mortality data was given in five of these eight trials. Zinc supplementation alone was associated with a statistically insignificant 9% (RR = 0.91; 95% CI: 0.82, 1.01) reduction in all cause mortality in the intervention group as compared to controls using a random effect model. The impact on diarrhea-specific mortality of zinc alone was a non-significant 18% reduction (RR = 0.82; 95% CI: 0.64, 1.05) and 15% for pneumonia-specific mortality (RR = 0.85; 95% CI: 0.65, 1.11). The incidence of diarrhea showed a 13% reduction with preventive zinc supplementation (RR = 0.87; 95% CI: 0.81, 0.94) and a 19% reduction in pneumonia morbidity (RR = 0.81; 95% CI: 0.73, 0.90). Keeping in mind the direction of effect of zinc supplementation in reducing diarrhea and pneumonia related morbidity and mortality; we considered all the outcomes for selection of effectiveness estimate for inclusion in the LiST model. After application of the CHERG rules with consideration to quality of evidence and rule # 6, we used the most conservative estimates as a surrogate for mortality. We, therefore, conclude that zinc supplementation in children is associated with a reduction in diarrhea mortality of 13% and pneumonia mortality of 15% for inclusion in the LiST tool. Preventive zinc supplementation had no effect on malaria specific mortality (RR = 0.90; 95% CI: 0.77, 1.06) or incidence of malaria (RR=0.92; 95 % CI 0.82-1.04) Conclusion Zinc supplementation results in reductions in diarrhea and pneumonia mortality.