The impact of DocosaHexaenoic Acid supplementation during pregnancy and lactation on Neurodevelopment of the offspring in India (DHANI): trial protocol.

BACKGROUND: Evidence suggests a strong association between nutrition during the first 1000 days (conception to 2 years of life) and cognitive development. Maternal docosahexaenoic acid (DHA) supplementation has been suggested to be linked with cognitive development of their offspring. DHA is a structural component of human brain and retina, and can be derived from marine algae, fatty fish and marine oils. Since Indian diets are largely devoid of such products, plasma DHA levels are low. We are testing the effect of pre- and post-natal DHA maternal supplementation in India on infant motor and mental development, anthropometry and morbidity patterns. METHODS: DHANI is a double-blinded, parallel group, randomized, placebo controlled trial supplementing 957 pregnant women aged 18-35 years from ≤20 weeks gestation through 6 months postpartum with 400 mg/d algal-derived DHA or placebo. Data on the participant's socio-demographic profile, anthropometric measurements and dietary intake are being recorded at baseline. The mother-infant dyads are followed through age 12 months. The primary outcome variable is infant motor and mental development quotient at 12 months of age evaluated by Development Assessment Scale in Indian Infants (DASII). Secondary outcomes are gestational age, APGAR scores, and infant anthropometry. Biochemical indices (blood and breast-milk) from mother-child dyads are being collected to estimate changes in DHA levels in response to supplementation. All analyses will follow the intent-to-treat principle. Two-sample t test will be used to test unadjusted difference in mean DASII score between placebo and DHA group. Adjusted analyses will be performed using multiple linear regression. DISCUSSION: Implications for maternal and child health and nutrition in India: DHANI is the first large pre- and post-natal maternal dietary supplementation trial in India. If the trial finds substantial benefit, it can serve as a learning to scale up the DHA intervention in the country. TRIAL REGISTRATION: The trial is retrospectively registered at clinicaltrials.gov ( NCT01580345 , NCT03072277 ) and ctri.nic.in ( CTRI/2013/04/003540 , CTRI/2017/08/009296 ).

An Intervention to Enhance Obstetric and Newborn Care in India: A Cluster Randomized-Trial.

OBJECTIVES: This study assessed whether community mobilization and interventions to improve emergency obstetric and newborn care reduced perinatal mortality (PMR) and neonatal mortality rates (NMR) in Belgaum, India. METHODS: The cluster-randomised controlled trial was conducted in Belgaum District, Karnataka State, India. Twenty geographic clusters were randomized to control or the intervention. The intervention engaged and mobilized community and health authorities to leverage support; strengthened community-based stabilization, referral, and transportation; and aimed to improve quality of care at facilities. RESULTS: 17,754 Intervention births and 15,954 control births weighing ≥1000 g, respectively, were enrolled and analysed. Comparing the baseline period to the last 6 months period, the NMR was lower in the intervention versus control clusters (OR 0.60, 95% CI 0.34-1.06, p = 0.076) as was the PMR (OR 0.74, 95% CI 0.46-1.19, p = 0.20) although neither reached statistical significance. Rates of facility birth and caesarean section increased among both groups. There was limited influence on quality of care measures. CONCLUSIONS FOR PRACTICE: The intervention had large but not statistically significant effects on neonatal and perinatal mortality. Community mobilization and increased facility care may ultimately improve neonatal and perinatal survival, and are important in the context of the global transition towards institutional delivery.

Postpartum contraceptive use and unmet need for family planning in five low-income countries.

BACKGROUND: During the post-partum period, most women wish to delay or prevent future pregnancies. Despite this, the unmet need for family planning up to a year after delivery is higher than at any other time. This study aims to assess fertility intention, contraceptive usage and unmet need for family planning amongst women who are six weeks postpartum, as well as to identify those at greatest risk of having an unmet need for family planning during this period. METHODS: Using the NICHD Global Network for Women's and Children's Health Research's multi-site, prospective, ongoing, active surveillance system to track pregnancies and births in 100 rural geographic clusters in 5 countries (India, Pakistan, Zambia, Kenya and Guatemala), we assessed fertility intention and contraceptive usage at day 42 post-partum. RESULTS: We gathered data on 36,687 women in the post-partum period. Less than 5% of these women wished to have another pregnancy within the year. Despite this, rates of modern contraceptive usage varied widely and unmet need ranged from 25% to 96%. Even amongst users of modern contraceptives, the uptake of the most effective long-acting reversible contraceptives (intrauterine devices) was low. Women of age less than 20 years, parity of two or less, limited education and those who deliver at home were at highest risk for having unmet need. CONCLUSIONS: Six weeks postpartum, almost all women wish to delay or prevent a future pregnancy. Even in sites where early contraceptive adoption is common, there is substantial unmet need for family planning. This is consistently highest amongst women below the age of 20 years. Interventions aimed at increasing the adoption of effective contraceptive methods are urgently needed in the majority of sites in order to reduce unmet need and to improve both maternal and infant outcomes, especially amongst young women. STUDY REGISTRATION: Clinicaltrials.gov (ID# NCT01073475).

A prospective observational description of frequency and timing of antenatal care attendance and coverage of selected interventions from sites in Argentina, Guatemala, India, Kenya, Pakistan and Zambia.

BACKGROUND: The Global Network for Women's and Children's Health Research is one of the largest international networks for testing and generating evidence-based recommendations for improvement of maternal-child health in resource-limited settings. Since 2009, Global Network sites in six low and middle-income countries have collected information on antenatal care practices, which are important as indicators of care and have implications for programs to improve maternal and child health. We sought to: (1) describe the quantity of antenatal care attendance over a four-year period; and (2) explore the quality of coverage for selected preventative, screening, and birth preparedness components. METHODS: The Maternal Newborn Health Registry (MNHR) is a prospective, population-based birth and pregnancy outcomes registry in Global Network sites, including: Argentina, Guatemala, India (Belgaum and Nagpur), Kenya, Pakistan, and Zambia. MNHR data from these sites were prospectively collected from January 1, 2010 - December 31, 2013 and analyzed for indicators related to quantity and patterns of ANC and coverage of key elements of recommended focused antenatal care. Descriptive statistics were generated overall by global region (Africa, Asia, and Latin America), and for each individual site. RESULTS: Overall, 96% of women reported at least one antenatal care visit. Indian sites demonstrated the highest percentage of women who initiated antenatal care during the first trimester. Women from the Latin American and Indian sites reported the highest number of at least 4 visits. Overall, 88% of women received tetanus toxoid. Only about half of all women reported having been screened for syphilis (49%) or anemia (50%). Rates of HIV testing were above 95% in the Argentina, African, and Indian sites. The Pakistan site demonstrated relatively high rates for birth preparation, but for most other preventative and screening interventions, posted lower coverage rates as compared to other Global Network sites. CONCLUSIONS: Results from our large, prospective, population-based observational study contribute important insight into regional and site-specific patterns for antenatal care access and coverage. Our findings indicate a quality and coverage gap in antenatal care services, particularly in regards to syphilis and hemoglobin screening. We have identified site-specific gaps in access to, and delivery of, antenatal care services that can be targeted for improvement in future research and implementation efforts. TRIAL REGISTRATION: Registration at Clinicaltrials.gov (ID# NCT01073475).

A color-coded tape for uterine height measurement: a tool to identify preterm pregnancies in low resource settings.

INTRODUCTION: Neonatal mortality associated with preterm birth can be reduced with antenatal corticosteroids (ACS), yet <10% of eligible pregnant women in low-middle income countries. The inability to accurately determine gestational age (GA) leads to under-identification of high-risk women who could receive ACS or other interventions. To facilitate better identification in low-resource settings, we developed a color-coded tape for uterine height (UH) measurement and estimated its accuracy identifying preterm pregnancies. METHODS: We designed a series of colored-coded tapes with segments corresponding to UH measurements for 20-23.6 weeks, 24.0-35.6 weeks, and >36.0 weeks GA. In phase 1, UH measurements were collected prospectively in the Democratic Republic of Congo, India and Pakistan, using distinct tapes to address variation across regions and ethnicities. In phase 2, we tested accuracy in 250 pregnant women with known GA from early ultrasound enrolled at prenatal clinics in Argentina, India, Pakistan and Zambia. Providers masked to the ultrasound GA measured UH. Receiver operating characteristics (ROC) analysis was conducted. RESULTS: 1,029 pregnant women were enrolled. In all countries the tapes were most effective identifying pregnancies between 20.0-35.6 weeks, compared to the other GAs. The ROC areas under the curves and 95% confidence intervals were: Argentina 0.69 (0.63, 0.74); Zambia 0.72 (0.66, 0.78), India 0.84 (0.80, 0.89), and Pakistan 0.83 (0.78, 0.87). The sensitivity and specificity (and 95% confidence intervals) for identifying pregnancies between 20.0-35.6 weeks, respectively, were: Argentina 87% (82%-92%) and 51% (42%-61%); Zambia 91% (86%-95%) and 50% (40%-60%); India 78% (71%-85%) and 89% (83%-94%); Pakistan 63% (55%-70%) and 94% (89%-99%). CONCLUSIONS: We observed moderate-good accuracy identifying pregnancies ≤ 35.6 weeks gestation, with potential usefulness at the community level in low-middle income countries to facilitate the preterm identification and interventions to reduce preterm neonatal mortality. Further research is needed to validate these findings on a population basis.

Global network for women's and children's health research: a system for low-resource areas to determine probable causes of stillbirth, neonatal, and maternal death.

BACKGROUND: Determining cause of death is needed to develop strategies to reduce maternal death, stillbirth, and newborn death, especially for low-resource settings where 98% of deaths occur. Most existing classification systems are designed for high income settings where extensive testing is available. Verbal autopsy or audits, developed as an alternative, are time-intensive and not generally feasible for population-based evaluation. Furthermore, because most classification is user-dependent, reliability of classification varies over time and across settings. Thus, we sought to develop classification systems for maternal, fetal and newborn mortality based on minimal data to produce reliable cause-of-death estimates for low-resource settings. RESULTS: In six low-resource countries (India, Pakistan, Guatemala, DRC, Zambia and Kenya), we evaluated data which are collected routinely at antenatal care and delivery and could be obtained with interview, observation, or basic equipment from the mother, lay-health provider or family to inform causes of death. Using these basic data collected in a standard way, we then developed an algorithm to assign cause of death that could be computer-programmed. Causes of death for maternal (trauma, abortion, hemorrhage, infection and hypertensive disease of pregnancy), stillbirth (birth trauma, congenital anomaly, infection, asphyxia, complications of preterm birth) and neonatal death (congenital anomaly, infection, asphyxia, complications of preterm birth) are based on existing cause of death classifications, and compatible with the World Health Organization International Classification of Disease system. CONCLUSIONS: Our system to assign cause of maternal, fetal and neonatal death uses basic data from family or lay-health providers to assign cause of death by an algorithm to eliminate a source of inconsistency and bias. The major strengths are consistency, transparency, and comparability across time or regions with minimal burden on the healthcare system. This system will be an important contribution to determining cause of death in low-resource settings.

Biofortification of pearl millet with iron and zinc in a randomized controlled trial increases absorption of these minerals above physiologic requirements in young children.

Millet is unusually drought resistant and consequently there is a progressive increase in the use of these grains as a human food staple, especially in large areas of India and sub-Saharan Africa. The purpose of this study was to determine the absorption of iron and zinc from pearl millet biofortified with 2 micronutrients that are typically deficient in nonfortified, plant-based diets globally. The study was undertaken in 40 children aged 2 y in Karnataka, India (n = 21 test/19 controls). Three test meals providing ∼84 ± 17 g dry pearl millet flour were fed on a single day for zinc and 2 d for iron between 0900 and 1600 h. The quantities of zinc and iron absorbed were measured with established stable isotope extrinsic labeling techniques and analyses of duplicate diets. The mean (± SD) quantities of iron absorbed from test and control groups were 0.67 ± 0.48 and 0.23 ± 0.15 mg/d, respectively (P < 0.001). The quantities of zinc absorbed were 0.95 ± 0.47 and 0.67 ± 0.24 mg/d, respectively (P = 0.03). These data did not include absorption of the modest quantities of iron and zinc contained in snacks eaten before and after the 3 test meals. In conclusion, quantities of both iron and zinc absorbed when iron and zinc biofortified pearl millet is fed to children aged 2 y as the major food staple is more than adequate to meet the physiological requirements for these micronutrients.

Provider insights on barriers and opportunities for birth spacing utilization in Karnataka, India.

India is the second most populous country in the world, with half of its citizens being of reproductive age. Despite the availability of a long-standing national family planning program, India maintains an unmet contraceptive need and high rate of maternal morbidity and mortality. In order to develop strategies to improve the utilization of birth-spacing contraceptive methods, we conducted a qualitative study with providers of family planning services in Karnataka, India. We elicited facilitators and barriers associated with peripartum contraceptive counseling and provision and identified an important opportunity to increase the use of postpartum contraception and improve birth spacing.

Antenatal corticosteroids trial in preterm births to increase neonatal survival in developing countries: study protocol.

BACKGROUND: Preterm birth is a major cause of neonatal mortality, responsible for 28% of neonatal deaths overall. The administration of antenatal corticosteroids to women at high risk of preterm birth is a powerful perinatal intervention to reduce neonatal mortality in resource rich environments. The effect of antenatal steroids to reduce mortality and morbidity among preterm infants in hospital settings in developed countries with high utilization is well established, yet they are not routinely used in developing countries. The impact of increasing antenatal steroid use in hospital or community settings with low utilization rates and high infant mortality among premature infants due to lack of specialized services has not been well researched. There is currently no clear evidence about the safety of antenatal corticosteroid use for community-level births. METHODS: We hypothesize that a multi country, two-arm, parallel cluster randomized controlled trial to evaluate whether a multifaceted intervention to increase the use of antenatal corticosteroids, including components to improve the identification of pregnancies at high risk of preterm birth and providing and facilitating the appropriate use of steroids, will reduce neonatal mortality at 28 days of life in preterm newborns, compared with the standard delivery of care in selected populations of six countries. 102 clusters in Argentina, Guatemala, Kenya, India, Pakistan, and Zambia will be randomized, and around 60,000 women and newborns will be enrolled. Kits containing vials of dexamethasone, syringes, gloves, and instructions for administration will be distributed. Improving the identification of women at high risk of preterm birth will be done by (1) diffusing recommendations for antenatal corticosteroids use to health providers, (2) training health providers on identification of women at high risk of preterm birth, (3) providing reminders to health providers on the use of the kits, and (4) using a color-coded tape to measure uterine height to estimate gestational age in women with unknown gestational age. In both intervention and control clusters, health providers will be trained in essential newborn care for low birth weight babies. The primary outcome is neonatal mortality at 28 days of life in preterm infants.

Epidemiology of stillbirth in low-middle income countries: a Global Network Study.

OBJECTIVE: To determine population-based stillbirth rates and to determine whether the timing and maturity of the stillbirths suggest a high proportion of potentially preventable deaths. DESIGN: Prospective observational study. SETTING: Communities in six low-income countries (Democratic Republic of Congo, Kenya, Zambia, Guatemala, India, and Pakistan) and one site in a mid-income country (Argentina). POPULATION: Pregnant women residing in the study communities. METHODS: Over a five-year period, in selected catchment areas, using multiple methodologies, trained study staff obtained pregnancy outcomes on each delivery in their area. MAIN OUTCOME MEASURES: Pregnancy outcome, stillbirth characteristics. RESULTS: Outcomes of 195,400 deliveries were included. Stillbirth rates ranged from 32 per 1,000 in Pakistan to 8 per 1,000 births in Argentina. Three-fourths (76%) of stillbirth offspring were not macerated, 63% were ≥ 37 weeks and 48% weighed 2,500 g or more. Across all sites, women with no education, of high and low parity, of older age, and without access to antenatal care were at significantly greater risk for stillbirth (p<0.001). Compared to those delivered by a physician, women delivered by nurses and traditional birth attendants had a lower risk of stillbirth. CONCLUSIONS: In these low-middle income countries, most stillbirth offspring were not macerated, were reported as ≥ 37 weeks' gestation, and almost half weighed at least 2,500 g. With access to better medical care, especially in the intrapartum period, many of these stillbirths could likely be prevented.

Side effects of oral misoprostol for the prevention of postpartum hemorrhage: results of a community-based randomised controlled trial in rural India.

OBJECTIVE: To investigate the side effects of 600 microg oral misoprostol given for the mother and the newborn to prevent postpartum hemorrhage (PPH). METHODS: One thousand six hundred twenty women delivering at home or subcentres in rural India were randomised to receive misoprostol or placebo in the third stage of labour. Women were evaluated for shivering, fever, nausea, vomiting and diarrhea at 2 and 24 h postpartum. Newborns were evaluated within 24 h for diarrhea, vomiting and fever. Symptoms were graded as absent, mild-to-moderate or severe. RESULTS: Women who received misoprostol had a significantly greater incidence of shivering (52%vs. 17%, p < 0.001) and fever (4.2%vs. 1.1%, p < 0.001) at 2 h postpartum compared with women who received placebo. At 24 h, women in the misoprostol group experienced significantly more shivering (4.6%vs. 1.4%, p < 0.001) and fever (1.4%vs. 0.4%, p < 0.03). There were no differences in nausea, vomiting or diarrhea between the two groups. There were no differences in the incidence of vomiting, diarrhea or fever for newborns. CONCLUSIONS: Misoprostol is associated with a significant increase in postpartum maternal shivering and fever with no side effects for the newborn. Given its proven efficacy for the prevention of PPH, the benefits of misoprostol are greater than the associated risks.

Variation in the postpartum hemorrhage rate in a clinical trial of oral misoprostol.

OBJECTIVE: The main objective of this study was to identify factors associated with variation in the rate of acute postpartum hemorrhage (PPH), defined as blood loss >or= 500 mL within 2 hours of delivery, observed in a randomized clinical trial of misoprostol for the prevention of PPH, conducted in rural India. Although the women in the misoprostol group had a significantly lower probability of having a PPH, we also noted a reduction in the rate of PPH in the placebo group over the course of the study. We hypothesized that this was due to the changing skills of the auxiliary nurse midwives (ANMs) over the course of the study. METHODS: We conducted a post-hoc analysis examining variation in PPH rates over the duration of the trial among the women randomized to the placebo arm (n = 808). Descriptive, correlation analysis and generalized estimating equations (GEE) were used to predict PPH rates. With no direct measure of ANM skills, we used proxy measures, including: (1) the ANM's point of entry into the study (original ANMs at the initiation of the trial were less skilled than replacement ANMs); (2) the study duration, representing exposure of the ANM to ongoing training and monitoring; and (3) duration of the second stage of labor as a measure of improved delivery practices. RESULTS: As the study duration increased, the duration of the second stage of labor decreased (-0.12, p = 0.001) and as the duration of the second stage of labor decreased, the rate of PPH decreased (0.0282; 95% CI 0.0201-0.0363). For each 10-minute increase in the duration of second stage labor increased PPH odds by 7.1% and each 30-day duration of the trial decreased PPH odds by 3.4%. Additionally, a patient delivered by an original ANM was 3.14 times more likely to have a PPH compared to a patient delivered by a replacement ANM. CONCLUSIONS: Declining PPH rates were associated with improved skills and delivery practices that decreased duration of the second stage of labor. These improvements appeared to be consistent with the introduction of the more skilled replacement ANMs as well as ongoing training and monitoring for all ANMs over the duration of the trial.

Factors associated with acute postpartum hemorrhage in low-risk women delivering in rural India.

OBJECTIVE: Postpartum hemorrhage (PPH), a major cause of maternal mortality and morbidity in low-income countries, can occur unpredictably. This study examined the sociodemographic, clinical, and perinatal characteristics of low-risk women who experienced PPH. METHODS: This analysis was conducted using data on 1620 women from a randomized trial testing oral misoprostol for prevention of PPH in rural India. RESULTS: Of the women, 9.2% experienced PPH. No maternal or sociodemographic factors and few perinatal factors differed between women with PPH and those without, other than treatment with misoprostol. Having fewer than 4 prenatal visits and lack of iron supplementation increased the risk for PPH (P<0.001 and P=0.037, respectively). Several factors unknown until the second stage of labor (perineal tear and birth weight) were also associated (P=0.003). CONCLUSIONS: Among women at low risk for PPH, there were few factors associated with further risk. Given that PPH can occur without warning, rural communities should consider ways to increase both primary prevention (iron supplementation, AMTSL) and secondary prevention of PPH (availability of obstetric first aid, availability of transport, and availability of emergency obstetric care).

Oral misoprostol in preventing postpartum haemorrhage in resource-poor communities: a randomised controlled trial.

BACKGROUND: Postpartum haemorrhage is a major cause of maternal mortality in the developing world. Although effective methods for prevention and treatment of such haemorrhage exist--such as the uterotonic drug oxytocin--most are not feasible in resource-poor settings where many births occur at home. We aimed to investigate whether oral misoprostol, a potential alternative to oxytocin, could prevent postpartum haemorrhage in a community home-birth setting. METHODS: In a placebo-controlled trial undertaken between September, 2002, and December, 2005, 1620 women in rural India were randomised to receive oral misoprostol (n=812) or placebo (n=808) after delivery. 25 auxiliary nurse midwives undertook the deliveries, administered the study drug, and measured blood loss. The primary outcome was the incidence of acute postpartum haemorrhage (defined as > or =500 mL bleeding) within 2 h of delivery. Analysis was by intention-to-treat. The trial was registered with the US clinical trials database (http://www. clinicaltrials.gov) as number NCT00097123. FINDINGS: Oral misoprostol was associated with a significant reduction in the rate of acute postpartum haemorrhage (12.0% to 6.4%, p<0.0001; relative risk 0.53 [95% CI 0.39-0.74]) and acute severe postpartum haemorrhage (1.2% to 0.2%, p<0.0001; 0.20 [0.04-0.91]. One case of postpartum haemorrhage was prevented for every 18 women treated. Misoprostol was also associated with a decrease in mean postpartum blood loss (262.3 mL to 214.3 mL, p<0.0001). Postpartum haemorrhage rates fell over time in both groups but remained significantly higher in the placebo group. Women taking misoprostol had a higher rate of transitory symptoms of chills and fever than the control. INTERPRETATION: Oral misoprostol was associated with significant decreases in the rate of acute postpartum haemorrhage and mean blood loss. The drug's low cost, ease of administration, stability, and a positive safety profile make it a good option in resource-poor settings.