High proportion of overt diabetes mellitus in pregnancy and missed opportunity for early detection of diabetes at a tertiary care centre in Pakistan.

OBJECTIVES: To determine the frequency of diabetes in pregnancy (DIP), namely pre-gestational, gestational (GDM) and overt diabetes mellitus (DM) in women registered for delivery. METHODS: A retrospective chart review of antenatal women registered between January 01 to August 31, 2017 was performed. Gestational age, diagnosis of DIP, glucose levels at diagnosis and other relevant data was extracted. The effect of various fasting blood glucose (FBG) thresholds for diagnosis of DIP was assessed. RESULTS: DIP was diagnosed in 21.8% women (pre-gestational: 2%, GDM: 81.2%, overt: DM: 16.8%). In early registrants, 30.2% were detected through screening. However, 55.3% of women registered late. Women with pre-gestational DM were older, had more miscarriages, and greater personal and family history of diabetes versus GDM and overt DM. Raising the diagnostic threshold of FBG from 92 mg/dl to 95 mg/dl missed three women (0.1%) and to 105 mg/dl, missed six women (0.2%). CONCLUSION: We observed a high proportion of overt DM. In early registrants, almost one third of DIP was diagnosed in the first half of pregnancy, an opportunity missed in late registrants. Altering diagnostic thresholds of DIP affected only a small proportion of women.

Omega-3 Fatty Acids and Incident Ischemic Stroke and Its Atherothrombotic and Cardioembolic Subtypes in 3 US Cohorts.

BACKGROUND AND PURPOSE: The associations of individual long-chain n-3 polyunsaturated fatty acids with incident ischemic stroke and its main subtypes are not well established. We aimed to investigate prospectively the relationship of circulating eicosapentaenoic acid, docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA) with risk of total ischemic, atherothrombotic, and cardioembolic stroke. METHODS: We measured circulating phospholipid fatty acids at baseline in 3 separate US cohorts: CHS (Cardiovascular Health Study), NHS (Nurses' Health Study), and HPFS (Health Professionals Follow-Up Study). Ischemic strokes were prospectively adjudicated and classified into atherothrombotic (large- and small-vessel infarctions) or cardioembolic by imaging studies and medical records. Risk according to fatty acid levels was assessed using Cox proportional hazards (CHS) or conditional logistic regression (NHS, HPFS) according to study design. Cohort findings were pooled using fixed-effects meta-analysis. RESULTS: A total of 953 incident ischemic strokes were identified (408 atherothrombotic, 256 cardioembolic, and 289 undetermined subtypes) during median follow-up of 11.2 years (CHS) and 8.3 years (pooled, NHS and HPFS). After multivariable adjustment, lower risk of total ischemic stroke was seen with higher DPA (highest versus lowest quartiles; pooled hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.58-0.92) and DHA (HR, 0.80; 95% CI, 0.64-1.00) but not eicosapentaenoic acid (HR, 0.94; 95% CI, 0.77-1.19). DHA was associated with lower risk of atherothrombotic stroke (HR, 0.53; 95% CI, 0.34-0.83) and DPA with lower risk of cardioembolic stroke (HR, 0.58; 95% CI, 0.37-0.92). Findings in each individual cohort were consistent with pooled results. CONCLUSIONS: In 3 large US cohorts, higher circulating levels of DHA were inversely associated with incident atherothrombotic stroke and DPA with cardioembolic stroke. These novel findings suggest differential pathways of benefit for DHA, DPA, and eicosapentaenoic acid.

Stillbirths: what difference can we make and at what cost?

Worldwide, 2·65 million (uncertainty range 2·08 million to 3·79 million) stillbirths occur yearly, of which 98% occur in countries of low and middle income. Despite the fact that more than 45% of the global burden of stillbirths occur intrapartum, the perception is that little is known about effective interventions, especially those that can be implemented in low-resource settings. We undertook a systematic review of randomised trials and observational studies of interventions which could reduce the burden of stillbirths, particularly in low-income and middle-income countries. We identified several interventions with sufficient evidence to recommend implementation in health systems, including periconceptional folic acid supplementation or fortification, prevention of malaria, and improved detection and management of syphilis during pregnancy in endemic areas. Basic and comprehensive emergency obstetric care were identified as key effective interventions to reduce intrapartum stillbirths. Broad-scale implementation of intervention packages across 68 countries listed as priorities in the Countdown to 2015 report could avert up to 45% of stillbirths according to a model generated from the Lives Saved Tool. The overall costs for these interventions are within the general estimates of cost-effective interventions for maternal care, especially in view of the effects on outcomes across maternal, fetal, and neonatal health.

Effect of routine iron supplementation with or without folic acid on anemia during pregnancy.

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.

Effect of breastfeeding promotion interventions on breastfeeding rates, with special focus on developing countries.

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.

Impact of maternal education about complementary feeding and provision of complementary foods on child growth in developing countries.

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 0.25 kg (± 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.

The effect of folic acid, protein energy and multiple micronutrient supplements in pregnancy on stillbirths.

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.

Screening and triage of intrauterine growth restriction (IUGR) in general population and high risk pregnancies: a systematic review with a focus on reduction of IUGR related stillbirths.

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%.

Effect of multiple micronutrient supplementation during pregnancy on maternal and birth outcomes.

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.

Effect of screening and management of diabetes during pregnancy on stillbirths.

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.

Elective induction for pregnancies at or beyond 41 weeks of gestation and its impact on stillbirths: a systematic review with meta-analysis.

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.

Impact of interventions to prevent and manage preeclampsia and eclampsia on stillbirths.

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.

Impact of vitamin A supplementation on infant and childhood mortality.

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.

Effectiveness of interventions to screen and manage infections during pregnancy on reducing stillbirths: a review.

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 randomized 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.

The effect of providing skilled birth attendance and emergency obstetric care in preventing stillbirths.

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.

Preventive zinc supplementation in developing countries: impact on mortality and morbidity due to diarrhea, pneumonia and malaria.

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.

Vitamin A supplementation for preventing morbidity and mortality in children from 6 months to 5 years of age.

BACKGROUND: Vitamin A deficiency (VAD) is a major public health problem in low and middle income countries affecting 190 million children under 5. VAD can lead to many adverse health consequences, including death. OBJECTIVES: To evaluate the effect of vitamin A supplementation (VAS) for preventing morbidity and mortality in children aged 6 months to 5 years. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2010 Issue 2),  MEDLINE (1950 to April Week 2 2010), EMBASE (1980 to 2010 Week 16), Global Health (1973 to March 2010), Latin American and Caribbean Health Sciences (LILACS), metaRegister of Controlled Trials and African Index Medicus (27 April 2010). SELECTION CRITERIA: Randomised controlled trials (RCTs) and cluster RCTs evaluating the effect of synthetic VAS in children aged 6 months to 5 years living in the community. We excluded studies concerned with children in hospital and children with disease or infection. We excluded studies evaluating the effects of food fortification, consumption of vitamin A rich foods or beta-carotene supplementation. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion. Data were double abstracted and discrepancies were resolved by discussion. Meta-analyses were performed for outcomes including all-cause and cause-specific mortality, disease, vision, and side-effects. MAIN RESULTS: 43 trials involving 215,633 children were included. A meta-analysis for all-cause mortality included 17 trials comprising 194,795 children with 3536 deaths in both groups. At follow-up, there was a 24% observed reduction in the risk of all-cause mortality for Vitamin A compared with Control (Relative risk (RR) = 0.76 [95% confidence interval (CI) 0.69, 0.83]). Seven trials reported diarrhoea mortality and a 28% overall reduction for VAS (RR = 0.72 [0.57, 0.91]). There was no significant effect of VAS on cause specific mortality of measles, respiratory disease and meningitis. VAS reduced incidence of diarrhoea (RR = 0.85 [0.82, 0.87]) and measles morbidity (RR = 0.50 [0.37, 0.67]); however, there was no significant effect on incidence of respiratory disease or hospitalisations due to diarrhoea or pneumonia. There was an increased risk of vomiting within the first 48 hours of VAS (RR = 2.75 [1.81, 4.19]). AUTHORS' CONCLUSIONS: VAS is effective in reducing all-cause mortality by about 24% compared to no treatment. In our opinion, given the evidence that VAS causes considerable reduction in child mortality, further placebo-controlled trials of VAS in children between 6 months and 5 years of age are not required. There is a need for further studies comparing different doses and delivery mechanisms (for example, fortification).