Impact of topical applications of sunflower seed oil on neonatal mortality and morbidity in southern Nepal: a community-based, cluster-randomised trial.

INTRODUCTION: Hospital-based studies have demonstrated topical applications of sunflower seed oil (SSO) to skin of preterm infants can reduce nosocomial infections and improve survival. In South Asia, replacing traditional mustard with SSO might have similar benefits. METHODS: 340 communities in Sarlahi, Nepal were randomised to use mustard oil (MO) or SSO for community practice of daily newborn massage. Women were provided oil in late pregnancy and the first month post partum, and visited daily through the first week of life to encourage massage practice. A separate data collection team visited on days 1, 3, 7, 10, 14, 21 and 28 to record vital status and assess serious bacterial infection. RESULTS: Between November 2010 and January 2017, we enrolled 39 479 pregnancies. 32 114 live births were analysed. Neonatal mortality rates (NMRs) were 31.8/1000 (520 deaths, 16 327 births) and 30.5/1000 (478 deaths, 15 676 births) in control and intervention, respectively (relative risk (RR)=0.95, 95% CI: 0.84, 1.08). Among preterm births, NMR was 90.4/1000 (229 deaths, 2533 births) and 79.2/1000 (188 deaths, 2373 births) in control and intervention, respectively (RR=0.88; 95% CI: 0.74, 1.05). Among preterm births <34 weeks, the RR was 0.83 (95% CI: 0.67, 1.02). No statistically significant differences were observed in incidence of serious bacterial infection. CONCLUSIONS: We did not find any neonatal mortality or morbidity benefit of using SSO instead of MO as emollient therapy in the early neonatal period. Further studies examining whether very preterm babies may benefit are warranted. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT01177111).

Neonatal mortality risk of vulnerable newborns by fine stratum of gestational age and birthweight for 230 679 live births in nine low- and middle-income countries, 2000-2017.

OBJECTIVE: To describe the mortality risks by fine strata of gestational age and birthweight among 230 679 live births in nine low- and middle-income countries (LMICs) from 2000 to 2017. DESIGN: Descriptive multi-country secondary data analysis. SETTING: Nine LMICs in sub-Saharan Africa, Southern and Eastern Asia, and Latin America. POPULATION: Liveborn infants from 15 population-based cohorts. METHODS: Subnational, population-based studies with high-quality birth outcome data were invited to join the Vulnerable Newborn Measurement Collaboration. All studies included birthweight, gestational age measured by ultrasound or last menstrual period, infant sex and neonatal survival. We defined adequate birthweight as 2500-3999 g (reference category), macrosomia as ≥4000 g, moderate low as 1500-2499 g and very low birthweight as <1500 g. We analysed fine strata classifications of preterm, term and post-term: ≥42+0 , 39+0 -41+6 (reference category), 37+0 -38+6 , 34+0 -36+6 ,34+0 -36+6 ,32+0 -33+6 , 30+0 -31+6 , 28+0 -29+6 and less than 28 weeks. MAIN OUTCOME MEASURES: Median and interquartile ranges by study for neonatal mortality rates (NMR) and relative risks (RR). We also performed meta-analysis for the relative mortality risks with 95% confidence intervals (CIs) by the fine categories, stratified by regional study setting (sub-Saharan Africa and Southern Asia) and study-level NMR (≤25 versus >25 neonatal deaths per 1000 live births). RESULTS: We found a dose-response relationship between lower gestational ages and birthweights with increasing neonatal mortality risks. The highest NMR and RR were among preterm babies born at <28 weeks (median NMR 359.2 per 1000 live births; RR 18.0, 95% CI 8.6-37.6) and very low birthweight (462.8 per 1000 live births; RR 43.4, 95% CI 29.5-63.9). We found no statistically significant neonatal mortality risk for macrosomia (RR 1.1, 95% CI 0.6-3.0) but a statistically significant risk for all preterm babies, post-term babies (RR 1.3, 95% CI 1.1-1.5) and babies born at 370 -386 weeks (RR 1.2, 95% CI 1.0-1.4). There were no statistically significant differences by region or underlying neonatal mortality. CONCLUSIONS: In addition to tracking vulnerable newborn types, monitoring finer categories of birthweight and gestational age will allow for better understanding of the predictors, interventions and health outcomes for vulnerable newborns. It is imperative that all newborns from live births and stillbirths have an accurate recorded weight and gestational age to track maternal and neonatal health and optimise prevention and care of vulnerable newborns.

Comparison of pregnancy and neonatal outcomes in a retrospective full pregnancy history survey versus population-based prospective records: a validation study in rural Sarlahi District, Nepal.

INTRODUCTION: Countries without complete civil registration and vital statistics systems rely on retrospective full pregnancy history surveys (FPH) to estimate incidence of pregnancy and mortality outcomes, including stillbirth and neonatal death. Yet surveys are subject to biases that impact demographic estimates, and few studies have quantified these effects. We compare data from an FPH vs. prospective records from a population-based cohort to estimate validity for maternal recall of live births, stillbirths, and neonatal deaths in a rural population in Sarlahi District, Nepal. METHODS: We used prospective data, collected through frequent visits of women from early pregnancy through the neonatal period, from a population-based randomized trial spanning 2010-2017. We randomly selected 76 trial participants from three pregnancy outcome groups: live birth (n = 26), stillbirth (n = 25), or neonatal death (n = 25). Data collectors administered the Nepal 2016 Demographic and Health Surveys (DHS)-VII pregnancy history survey between October 22, 2021, and November 18, 2021. We compared total pregnancy outcomes and numbers of pregnancy and neonatal outcomes between the two data sources. We matched pregnancy outcomes dates in the two sources within ± 30 days and calculated measures of validity for adverse outcomes. RESULTS: Among 76 participants, we recorded 122 pregnancy outcomes in the prospective data and 104 outcomes in the FPH within ± 30 days of each woman's total observation period in the trial. Among 226 outcomes, we observed 65 live births that survived to 28 days, 25 stillbirths, and 32 live births followed by neonatal death in the prospective data and participants reported 63 live births that survived to 28 days, 15 stillbirths, and 26 live births followed by neonatal death in the pregnancy history survey. Sixty-two FPH outcomes were matched by date within ± 30 days to an outcome in prospective data. Stillbirth, neonatal death, higher parity, and delivery at a health facility were associated with likelihood of a non-matched pregnancy outcome. CONCLUSIONS: Stillbirth and neonatal deaths were underestimated overall by the FPH, potentially underestimating the burden of mortality in this population. There is a need to develop tools to reduce or adjust for biases and errors in retrospective surveys to improve reporting of pregnancy and mortality outcomes.

Validation of maternal recall of number of antenatal care visits attended in rural Southern Nepal: a longitudinal cohort study.

OBJECTIVES: This study aimed to examine the validity of maternal recall of total number of antenatal care (ANC) visits during pregnancy and factors associated with the accuracy of maternal recall. DESIGN: This was a longitudinal cohort study conducted from December 2018 through November 2020. SETTING: Five government health posts in the Sarlahi district of Southern Nepal. PARTICIPANTS: 402 pregnant women between ages 15 and 49 who presented for their first ANC visit at the study health posts. MAIN OUTCOMES: The observed number of ANC visits (gold standard) and the reported number of ANC visits at the postpartum interview (maternal recall). RESULTS: On average, women in the study who had a live birth attended 4.7 ANC visits. About 65% of them attended four or more ANC visits during pregnancy as recommended by the Nepal government, and 38.3% of maternal report matched the categorical ANC visits as observed by the gold standard. The individual validity was poor to moderate, with the highest area under the receiver operating characteristic curve (AUC) being 0.69 (95% CI: 0.65 to 0.74) in the 1-3 visits group. Population-level bias (as distinct from individual-level bias) was observed in the 1-3 visits and 4 visits groups, where 1-3 visits were under-reported (inflation factor (IF): 0.69) and 4 ANC visits were highly over-reported (IF: 2.12). The binary indicator ANC4+ (1-3 visits vs 4+ visits) showed better population-level validity (AUC: 0.69; IF: 1.17) compared with the categorical indicators (1-3 visits, 4 visits, 5-6 visits and more than 6 visits). Report accuracy was not associated with maternal characteristics but was related to ANC frequency. Women who attended more ANC visits were less likely to correctly report their total number of visits. CONCLUSION: Maternal report of number of ANC visits during pregnancy may not be a valid indicator for measuring ANC coverage. Improvements are needed to measure the frequency of ANC visits.

Supplementation with fortified balanced energy-protein during pregnancy and lactation and its effects on birth outcomes and infant growth in southern Nepal: protocol of a 2×2 factorial randomised trial.

INTRODUCTION: Many women in low and middle-income countries enter pregnancy with low nutritional reserves with increased risk of fetal growth restriction and poor birth outcomes, including small-for-gestational-age (SGA) and preterm birth. Balanced energy-protein (BEP) supplements have shown reductions in risk of stillbirth and SGA, yet variations in intervention format and composition and limited evidence on the impact of BEP during lactation on growth outcomes warrant further study. This paper describes the protocol of the Maternal Infant Nutrition Trial (MINT) Study, which aims to evaluate the impact of a fortified BEP supplement during pregnancy and lactation on birth outcomes and infant growth in rural Nepal. METHODS AND ANALYSIS: MINT is a 2×2 factorial, household randomised, unblinded, efficacy trial conducted in a subarea of Sarlahi District, Nepal. The study area covers six rural municipalities with about 27 000 households and a population of approximately 100 000. Married women (15-30 years) who become pregnant are eligible for participation in the trial and are randomly assigned at enrolment to supplementation with fortified BEP or not and at birth to fortified BEP supplementation or not until 6 months post partum. The primary pregnancy outcome is incidence of SGA, using the INTERGROWTH-21st standard, among live born infants with birth weight measured within 72 hours of delivery. The primary infant growth outcome is mean length-for-age z-score at 6 months using the WHO international growth reference. ETHICS AND DISSEMINATION: The study was approved by the Institutional Review Board (IRB) at Johns Hopkins Bloomberg School of Public Health, Baltimore, USA (IRB00009714), the Committee on Human Research IRB at The George Washington University, Washington, DC, USA (081739), and the Ethical Review Board of the Nepal Health Research Council, Kathmandu, Nepal (174/2018). TRIAL REGISTRATION NUMBER: NCT03668977.

Risk factors for neonatal mortality: an observational cohort study in Sarlahi district of rural southern Nepal.

OBJECTIVES: To assess the association between maternal characteristics, adverse birth outcomes (small-for-gestational-age (SGA) and/or preterm) and neonatal mortality in rural Nepal. DESIGN: This is a secondary observational analysis to identify risk factors for neonatal mortality, using data from a randomised trial to assess the impact of newborn massage with different oils on neonatal mortality in Sarlahi district, Nepal. SETTING: Rural Sarlahi district, Nepal. PARTICIPANTS: 40 119 pregnant women enrolled from 9 September 2010 to 16 January 2017. MAIN OUTCOME: The outcome variable is neonatal death. Cox regression was used to estimate adjusted Hazard Ratios (aHRs) to assess the association between adverse birth outcomes and neonatal mortality. RESULTS: There were 32 004 live births and 998 neonatal deaths. SGA and/or preterm birth was strongly associated with increased neonatal mortality: SGA and preterm (aHR: 7.09, 95% CI: (4.44 to 11.31)), SGA and term/post-term (aHR: 2.12, 95% CI: (1.58 to 2.86)), appropriate-for-gestational-age/large-for-gestational-age and preterm (aHR: 3.23, 95% CI: (2.30 to 4.54)). Neonatal mortality was increased with a history of prior child deaths (aHR: 1.53, 95% CI: (1.24 to 1.87)), being a twin or triplet (aHR: 5.64, 95% CI: (4.25 to 7.48)), births at health posts/clinics or in hospital (aHR: 1.34, 95% CI: (1.13 to 1.58)) and on the way to facilities or outdoors (aHR: 2.26, 95% CI: (1.57 to 3.26)). Risk was lower with increasing maternal height from <145 cm to 145-150 cm (aHR: 0.78, 95% CI: (0.65 to 0.94)) to ≥150 cm (aHR: 0.57, 95% CI: (0.47 to 0.68)), four or more antenatal care (ANC) visits (aHR: 0.67, 95% CI: (0.53 to 0.86)) and education >5 years (aHR: 0.75, 95% CI: (0.62 to 0.92)). CONCLUSION: SGA and/or preterm birth are strongly associated with increased neonatal mortality. To reduce neonatal mortality, interventions that prevent SGA and preterm births by promoting ANC and facility delivery, and care of high-risk infants after birth should be tested. TRIAL REGISTRATION NUMBER: NCT01177111.

Quality of vital event data for infant mortality estimation in prospective, population-based studies: an analysis of secondary data from Asia, Africa, and Latin America.

INTRODUCTION: Infant and neonatal mortality estimates are typically derived from retrospective birth histories collected through surveys in countries with unreliable civil registration and vital statistics systems. Yet such data are subject to biases, including under-reporting of deaths and age misreporting, which impact mortality estimates. Prospective population-based cohort studies are an underutilized data source for mortality estimation that may offer strengths that avoid biases. METHODS: We conducted a secondary analysis of data from the Child Health Epidemiology Reference Group, including 11 population-based pregnancy or birth cohort studies, to evaluate the appropriateness of vital event data for mortality estimation. Analyses were descriptive, summarizing study designs, populations, protocols, and internal checks to assess their impact on data quality. We calculated infant and neonatal morality rates and compared patterns with Demographic and Health Survey (DHS) data. RESULTS: Studies yielded 71,760 pregnant women and 85,095 live births. Specific field protocols, especially pregnancy enrollment, limited exclusion criteria, and frequent follow-up visits after delivery, led to higher birth outcome ascertainment and fewer missing deaths. Most studies had low follow-up loss in pregnancy and the first month with little evidence of date heaping. Among studies in Asia and Latin America, neonatal mortality rates (NMR) were similar to DHS, while several studies in Sub-Saharan Africa had lower NMRs than DHS. Infant mortality varied by study and region between sources. CONCLUSIONS: Prospective, population-based cohort studies following rigorous protocols can yield high-quality vital event data to improve characterization of detailed mortality patterns of infants in low- and middle-income countries, especially in the early neonatal period where mortality risk is highest and changes rapidly.

How does social desirability bias influence survey-based estimates of the use of antenatal care in rural Nepal? A validation study.

OBJECTIVES: Social desirability bias is often speculated to influence survey responses but seldom studied in healthcare. The objective was to explore whether social desirability scores (SDS) or the presence of interview observers is associated with inaccurate recall and overestimation of antenatal care (ANC) services. DESIGN: Longitudinal validation study comparing recalled receipt of ANC services and nutrition components of ANC against direct observations of care. An adapted short form Marlowe-Crowne questionnaire was used to generate an SDS, and the presence of interview observers was treated as a separate exposure. We assessed accuracy and overestimation of recalled receipt of ANC services against observed receipt using log-binomial regression, adjusting for age, education, first-pregnancy and socioeconomic status. SETTING: Rural Southern Nepal with recruitment from five government health posts. PARTICIPANTS: 401 pregnant women. RESULTS: Social desirability scores did not significantly predict accuracy or overestimation of most types of ANC care except counselling on nausea. Higher SDS was associated with more accurate recall (adjusted RR, aRR 1.08 (95% CI 1.03, 1.12)) and less overestimation (aRR 0.85 (0.80, 0.91)). The presence of mothers-in-law or husbands during interviews was associated with greater overestimation of the number of ANC visits received by more than three visits (aRR 2.07 (1.11, 3.84)) and (aRR 4.19 (2.17, 8.10)), respectively. Those interviewed with friends present tended to overestimate the receipt of counselling on nausea, avoiding alcohol and not smoking. CONCLUSION: The presence of observers can lead to overestimation of the receipt of ANC care and support the conduct of interviews in private settings despite challenges of doing so in village contexts. Findings that the SDS did not predict the accuracy of most types of ANC care might reflect a reality that such questions may not be sensitive from a social-norms perspective. Additional local adaptation of SDS is recommended.

Neonatal mortality risk of vulnerable newborns: A descriptive analysis of subnational, population-based birth cohorts for 238 203 live births in low- and middle-income settings from 2000 to 2017.

OBJECTIVE: We aimed to understand the mortality risks of vulnerable newborns (defined as preterm and/or born weighing smaller or larger compared to a standard population), in low- and middle-income countries (LMICs). DESIGN: Descriptive multi-country, secondary analysis of individual-level study data of babies born since 2000. SETTING: Sixteen subnational, population-based studies from nine LMICs in sub-Saharan Africa, Southern and Eastern Asia, and Latin America. POPULATION: Live birth neonates. METHODS: We categorically defined five vulnerable newborn types based on size (large- or appropriate- or small-for-gestational age [LGA, AGA, SGA]), and term (T) and preterm (PT): T + LGA, T + SGA, PT + LGA, PT + AGA, and PT + SGA, with T + AGA (reference). A 10-type definition included low birthweight (LBW) and non-LBW, and a four-type definition collapsed AGA/LGA into one category. We performed imputation for missing birthweights in 13 of the studies. MAIN OUTCOME MEASURES: Median and interquartile ranges by study for the prevalence, mortality rates and relative mortality risks for the four, six and ten type classification. RESULTS: There were 238 203 live births with known neonatal status. Four of the six types had higher mortality risk: T + SGA (median relative risk [RR] 2.6, interquartile range [IQR] 2.0-2.9), PT + LGA (median RR 7.3, IQR 2.3-10.4), PT + AGA (median RR 6.0, IQR 4.4-13.2) and PT + SGA (median RR 10.4, IQR 8.6-13.9). T + SGA, PT + LGA and PT + AGA babies who were LBW, had higher risk compared with non-LBW babies. CONCLUSIONS: Small and/or preterm babies in LIMCs have a considerably increased mortality risk compared with babies born at term and larger. This classification system may advance the understanding of the social determinants and biomedical risk factors along with improved treatment that is critical for newborn health.

Harmonization of maternal balanced energy-protein supplementation studies for individual participant data (IPD) meta-analyses - finding and creating similarities in variables and data collection.

BACKGROUND: Public health and clinical recommendations are established from systematic reviews and retrospective meta-analyses combining effect sizes, traditionally, from aggregate data and more recently, using individual participant data (IPD) of published studies. However, trials often have outcomes and other meta-data that are not defined and collected in a standardized way, making meta-analysis problematic. IPD meta-analysis can only partially fix the limitations of traditional, retrospective, aggregate meta-analysis; prospective meta-analysis further reduces the problems. METHODS: We developed an initiative including seven clinical intervention studies of balanced energy-protein (BEP) supplementation during pregnancy and/or lactation that are being conducted (or recently concluded) in Burkina Faso, Ethiopia, India, Nepal, and Pakistan to test the effect of BEP on infant and maternal outcomes. These studies were commissioned after an expert consultation that designed recommendations for a BEP product for use among pregnant and lactating women in low- and middle-income countries. The initiative goal is to harmonize variables across studies to facilitate IPD meta-analyses on closely aligned data, commonly called prospective meta-analysis. Our objective here is to describe the process of harmonizing variable definitions and prioritizing research questions. A two-day workshop of investigators, content experts, and advisors was held in February 2020 and harmonization activities continued thereafter. Efforts included a range of activities from examining protocols and data collection plans to discussing best practices within field constraints. Prior to harmonization, there were many similar outcomes and variables across studies, such as newborn anthropometry, gestational age, and stillbirth, however, definitions and protocols differed. As well, some measurements were being conducted in several but not all studies, such as food insecurity. Through the harmonization process, we came to consensus on important shared variables, particularly outcomes, added new measurements, and improved protocols across studies. DISCUSSION: We have fostered extensive communication between investigators from different studies, and importantly, created a large set of harmonized variable definitions within a prospective meta-analysis framework. We expect this initiative will improve reporting within each study in addition to providing opportunities for a series of IPD meta-analyses.

Prevalence and predictors of spontaneous preterm births in Nepal: findings from a prospective, population-based pregnancy cohort in rural Nepal-a secondary data analysis.

OBJECTIVE: Preterm birth can have short-term and long-term complications for a child. Socioeconomic factors and pregnancy-related morbidities may be important to predict and prevent preterm births in low-resource settings. The objective of our study was to find prevalence and predictors of spontaneous preterm birth in rural Nepal. DESIGN: This is a secondary observational analysis of trial data (registration number NCT01177111). SETTING: Rural Sarlahi district, Nepal. PARTICIPANTS: 40 119 pregnant women enrolled from 9 September 2010 to 16 January 2017. OUTCOME MEASURES: The outcome variable is spontaneous preterm birth. Generalized Estimating Equations Poisson regression with robust variance was fitted to present effect estimates as risk ratios. RESULT: The prevalence of spontaneous preterm birth was 14.5% (0.5% non-spontaneous). Characteristics not varying in pregnancy associated with increased risk of preterm birth were maternal age less than 18 years (adjusted risk ratio=1.13, 95% CI: 1.02 to 1.26); being Muslim (1.53, 1.16 to 2.01); first pregnancy (1.15, 1.04 to 1.28); multiple births (4.91, 4.20 to 5.75) and male child (1.10, 1.02 to 1.17). Those associated with decreased risk were maternal education >5 years (0.81, 0.73 to 0.90); maternal height ≥150 cm (0.89, 0.81 to 0.98) and being from wealthier families (0.83, 0.74 to 0.93). Pregnancy-related morbidities associated with increased risk of preterm birth were vaginal bleeding (1.53, 1.08 to 2.18); swelling (1.37, 1.17 to 1.60); high systolic blood pressure (BP) (1.47, 1.08 to 2.01) and high diastolic BP (1.41, 1.17 to 1.70) in the third trimester. Those associated with decreased risk were respiratory problem in the third trimester (0.86, 0.79 to 0.94); having poor appetite, nausea and vomiting in the second trimester (0.86, 0.80 to 0.92) and third trimester (0.86, 0.79 to 0.94); and higher weight gain from second to third trimester (0.89, 0.87 to 0.90). CONCLUSION: The prevalence of preterm birth is high in rural Nepal. Interventions that increase maternal education may play a role. Monitoring morbidities during antenatal care to intervene to reduce them through an effective health system may help reduce preterm birth.

Cognitive testing of questions about antenatal care and nutrition interventions in southern Nepal.

Large scale surveys such as the Demographic and Health Surveys (DHS) are used to measure the coverage and quality of antenatal care (ANC)-related services. Studies have increasingly validated questions from these surveys, though few have explored respondent comprehension or associated thought processes. This study aimed to use cognitive testing and validation approaches to understand how survey respondents understand questions related to ANC-related nutrition services. The study was nested within a larger validation study in southern Nepal. Pregnant women's receipt of ANC related services was directly observed at five health posts followed by a recall interview at 6 months postpartum. A week later, a survey module was re-administered to 30 women containing 15 questions about receipt of ANC care and specifically nutrition-related services. Detailed probing was used to identify cognitive challenges related to comprehension, retrieval, judgement, and response. Respondents accurately recalled the four specific ANC visits recommended by the government of Nepal but those with more visits struggled to estimate the total number of ANC visits they had made. A number of terms including "antenatal care, "nutrition" and "breastfeeding" were challenging for many respondents to understand. Visits to private providers including for ultrasounds were inconsistently included in ANC visit counts suggesting that question wording could better specify the type of care. Many respondents over-estimated the number of iron folic acid (IFA) supplements taken during pregnancy, and recall was challenging. Calculations were based on estimating the number of months between first ANC visit to delivery, and only sometimes factored in missed tablets. Opportunities exist to improve questions to facilitate better comprehension by respondents through a combination of using local terms and explanations, reordering some questions, and adapting questions to better match respondents' approaches to estimating numeric responses.

Demographic, socio-economic, obstetric, and behavioral factors associated with small-and large-for-gestational-age from a prospective, population-based pregnancy cohort in rural Nepal: a secondary data analysis.

BACKGROUND: In South Asia, a third of babies are born small-for-gestational age (SGA). The risk factors are well described in the literature, but many studies are in high-and-middle income countries or measure SGA on facility births only. There are fewer studies that describe the prevalence of risk factors for large-for-gestational age (LGA) in low-income countries. We aim to describe the factors associated with SGA and LGA in a population-based cohort of pregnant women in rural Nepal. METHODS: This is a secondary data analysis of community-based trial on neonatal oil massage (22,545 women contributing 39,479 pregnancies). Demographic, socio-economic status (SES), medical/obstetric history, and timing of last menstruation were collected at enrollment. Vital signs, illness symptoms, and antenatal care (ANC) attendance were collected throughout the pregnancy and neonatal weight was measured for live births. We conducted multivariate analysis using multinomial, multilevel logistic regression, reporting the odds ratio (OR) with 95% confidence intervals (CIs). Outcomes were SGA, LGA compared to appropriate-for-gestational age (AGA) and were multiply imputed using birthweight recalibrated to time at delivery. RESULTS: SGA was associated with nulligravida (OR: 2.12 95% CI: 1.93-2.34), gravida/nulliparous (OR: 1.86, 95% CI: 1.26-2.74), interpregnancy intervals less than 18 months (OR: 1.16, 95% CI: 1.07-1.27), and poor appetite/vomiting in the second trimester, (OR: 1.27, 95% CI: 1.19-1.35). Greater wealth (OR: 0.78, 95% CI: 0.69-0.88), swelling of hands/face in the third trimester (OR: 0.81, 95% CI: 0.69-0.94) parity greater than five (OR: 0.77, 95% CI: 0.65-0.92), male fetal sex (OR: 0.91, 95% CI: 0.86-0.98), and increased weight gain (OR: 0.93 per weight kilogram difference between 2nd and 3rd trimester, 95% CI: 0.92-0.95) were protective for SGA. Four or more ANC visits (OR: 0.53, 95% CI: 0.41-0.68) and respiratory symptoms in the third trimester (OR: 0.67, 95% CI: 0.54-0.84) were negatively associated with LGA, and maternal age < 18 years (OR: 1.39, 95% CI: 1.03-1.87) and respiratory symptoms in the second trimester (OR: 1.27, 95% CI: 1.07-1.51) were positively associated with LGA. CONCLUSIONS: Our findings are in line with known risk factors for SGA. Because the prevalence and mortality risk of LGA babies is low in this population, it is likely LGA status does not indicate underlaying illness. Improved and equitable access to high quality antenatal care, monitoring for appropriate gestational weight gain and increased monitoring of women with high-risk pregnancies may reduce prevalence and improve outcomes of SGA babies. TRIAL REGISTRATION: The study used in this secondary data analysis was registered at Clinicaltrials.gov NCT01177111.

Development of an imputation model to recalibrate birth weights measured in the early neonatal period to time at delivery and assessment of its impact on size-for-gestational age and low birthweight prevalence estimates: a secondary analysis of a pregnancy cohort in rural Nepal.

OBJECTIVES: In low-income countries, birth weights for home deliveries are often measured at the nadir when babies may lose up of 10% of their birth weight, biasing estimates of small-for-gestational age (SGA) and low birth weight (LBW). We aimed to develop an imputation model that predicts the 'true' birth weight at time of delivery. DESIGN: We developed and applied a model that recalibrates weights measured in the early neonatal period to time=0 at delivery and uses those recalibrated birth weights to impute missing birth weights. SETTING: This is a secondary analysis of pregnancy cohort data from two studies in Sarlahi district, Nepal. PARTICIPANTS: The participants are 457 babies with daily weights measured in the first 10 days of life from a subsample of a larger clinical trial on chlorhexidine (CHX) neonatal skin cleansing and 31 116 babies followed through the neonatal period to test the impact of neonatal massage oil type (Nepal Oil Massage Study (NOMS)). OUTCOME MEASURES: We developed an empirical Bayes model of early neonatal weight change using CHX trial longitudinal data and applied it to the NOMS dataset to recalibrate and then impute birth weight at delivery. The outcomes are size-for-gestational age and LBW. RESULTS: When using the imputed birth weights, the proportion of SGA is reduced from 49% (95% CI: 48% to 49%) to 44% (95% CI: 43% to 44%). Low birth weight is reduced from 30% (95% CI: 30% to 31%) to 27% (95% CI: 26% to 27%). The proportion of babies born large-for-gestational age increased from 4% (95% CI: 4% to 4%) to 5% (95% CI: 5% to 5%). CONCLUSIONS: Using weights measured around the nadir overestimates the prevalence of SGA and LBW. Studies in low-income settings with high levels of home births should consider a similar recalibration and imputation model to generate more accurate population estimates of small and vulnerable newborns.

Does higher early neonatal mortality in boys reverse over the neonatal period? A pooled analysis from three trials of Nepal.

OBJECTIVES: Neonatal mortality is generally 20% higher in boys than girls due to biological phenomena. Only a few studies have examined more finely categorised age patterns of neonatal mortality by sex, especially in the first few days of life. The objective of this study is to examine sex differentials in neonatal mortality by detailed ages in a low-income setting. DESIGN: This is a secondary observational analysis of data. SETTING: Rural Sarlahi district, Nepal. PARTICIPANTS: Neonates born between 1999 and 2017 in three randomised controlled trials. OUTCOME MEASURES: We calculated study-specific and pooled mortality rates for boys and girls by ages (0-1, 1-3, 3-7, 7-14, 14-21 and 21-28 days) and estimated HR using Cox proportional hazards models for male versus female mortality for treatment and control groups together (n=59 729). RESULTS: Neonatal mortality was higher in boys than girls in individual studies: 44.2 vs 39.7 in boys and girls in 1999-2000; 30.0 vs 29.6 in 2002-2006; 33.4 vs 29.4 in 2010-2017; and 33.0 vs 30.2 in the pooled data analysis. Pooled data found that early neonatal mortality (HR=1.17; 95% CI: 1.06 to 1.30) was significantly higher in boys than girls. All individual datasets showed a reversal in mortality by sex after the third week of life. In the fourth week, a reversal was observed, with mortality in girls 2.43 times higher than boys (HR=0.41; 95% CI: 0.31 to 0.79). CONCLUSIONS: Boys had higher mortality in the first week followed by no sex difference in weeks 2 and 3 and a reversal in risk in week 4, with girls dying at more than twice the rate of boys. This may be a result of gender discrimination and social norms in this setting. Interventions to reduce gender discrimination at the household level may reduce female neonatal mortality. TRIAL REGISTRATION NUMBER: NCT00115271, NCT00109616, NCT01177111.

Acceptability of 11 fortified balanced energy-protein supplements for pregnant women in Nepal.

Evidence suggests that multiple micronutrient and balanced energy protein (BEP) supplementation during pregnancy can decrease the risk of stillbirth and small-for-gestational-age births and increase birth weight. We conducted a mixed-methods formative research study to identify the most acceptable among a range of 11 candidates fortified BEP supplements for use in pregnancy and lactation in a rural district in Nepal. Forty pregnant women aged 15-40 years participated in a test meal tasting of 11 different sweet and savoury candidate BEP supplements. Each participant rated the products on organoleptic properties using a 7-point hedonic scale (1 = Dislike it very much to 7 = Like it very much), ranked her 'top 3' most liked supplements, and subsequently discussed each product with peers in focus group discussions (FGDs). Five supplements (sweet lipid-based nutrient supplement (LNS), savoury LNS, sweet vanilla biscuits, vanilla instant drinks and seasoned pillows) achieved the maximum overall median hedonic score of 7, with sweet LNS and seasoned pillows ranking as the top 2. This was consistent with the assessments in FGDs. Women in the FGDs expressed dislike of the smell and taste of the cocoa drink, savoury masala bar, sweet mango bar and savoury curry biscuit, which was consistent with the hedonic scale scores. This study provides valuable insights into our understanding of women's acceptance of different BEP supplements during pregnancy in rural Nepal and has helped identify the two most accepted BEP supplements to be used in a two-month home trial to assess utilisation and compliance in this setting.

Dissecting Fc signatures of protection in neonates following maternal influenza vaccination in a placebo-controlled trial.

Influenza is an important cause of illness and morbidity for infants. Seasonal influenza vaccination during pregnancy aims to provide protection to mothers, but it can also provide immunity to infants. The precise influence of maternal vaccination on immunity in infants and how vaccine-elicited antibodies provide protection in some but not all infants is incompletely understood. We comprehensively profiled the transfer of functional antibodies and defined humoral factors contributing to immunity against influenza in a clinical trial of maternal influenza vaccination. Influenza-specific antibody subclass levels, Fc ɣ receptor (FCGR) binding levels, and antibody-dependent innate immune functions were all profiled in the mothers during pregnancy and at birth, as well as in cord blood. Vaccination increased influenza-specific antibody levels, antibody binding to FCGR, and specific antibody-dependent innate immune functions in both maternal and cord blood, with FCGR binding most enhanced via vaccination. Influenza-specific FCGR binding levels were lower in cord blood of infants who subsequently developed influenza infection. Collectively these data suggest that in addition to increased antibody amounts, the selective transfer of FCGR-binding antibodies contributes to the protective immune response in infants against influenza.

Validation of Maternal Report of Receipt of Iron-Folic Acid Supplementation during Antenatal Care in Rural Southern Nepal.

BACKGROUND: Coverage of iron-folic acid (IFA) supplementation is a key indicator for tracking programmatic progress within and across countries. However, the validity of maternal report of this information during household surveys has yet to be determined. OBJECTIVES: This study aimed to examine the validity of maternal recall of receipt of IFA supplementation during antenatal care (ANC) and factors associated with accuracy of maternal recall. METHODS: A longitudinal cohort design was employed. The direct observation of the IFA received during all ANC visits at the 5 study health posts served as the "gold standard" to the maternal report of IFA received during the postpartum interview. Individual-level validity was assessed by calculating indicator sensitivity, specificity, and AUC. The inflation factor (IF) measured population-level bias. A multivariable log-binomial model was used to assess factors associated with accurate recall. RESULTS: The majority (95.8%) of women were observed receiving IFA during pregnancy. Women overreported the number of IFA tablets received compared with what was observed during ANC visits (mean difference: 45 tablets). Maternal report of any IFA receipt was moderate (AUC = 0.60; 95% CI: 0.50, 0.71), and population bias was low (IF = 1.01). However, the individual-level validity was poor across the 7 IFA tablet count categories; the AUC for categories ranged from misleading to moderate. Driven by the trend of maternal overreport, the IF indicated that maternal report drastically underestimated the coverage of lower tablet categories and overestimated the coverage of higher tablet counts. Accuracy of maternal report was not associated with months since last ANC observation nor any maternal characteristics. CONCLUSIONS: Maternal report of the amount of IFA supplementation received during pregnancy produced extremely biased population coverage and performed poorly to moderately for individual-level validity. It is imperative to improve this indicator because it is used in global frameworks and national program planning.

Compliance with and acceptability of two fortified balanced energy protein supplements among pregnant women in rural Nepal.

Some evidence suggests that balanced energy protein (BEP) supplements taken during pregnancy and lactation can have positive effects on birth outcomes such as small-for-gestational age and birthweight, but more evidence is needed on the long-term use and acceptability of such supplements. We conducted a mixed-methods formative research study to assess and compare compliance with and acceptability of two BEP supplements, a lipid-based peanut paste and a biscuit, to identify BEP supplements for subsequent inclusion in an efficacy trial. We conducted an 8-week feeding trial of daily supplementation among two groups of 40 pregnant women each in rural Nepal. Compliance data were collected and supplements distributed at the weekly visits. Sensory properties of the supplements were assessed using a 7-point Likert scale. In addition, in-depth interviews with women (n = 16), family members (n = 6) and health workers (n = 6) and focus group discussions (FGDs) (n = 4) were conducted to explore themes related to general use and intention of future use of the supplement. Overall self-reported compliance was high: medians of 91.1% in the lipid-based peanut paste group and 96.4% in the biscuit group. Both supplements were rated highly on overall likability (median score 6/7) and sensory properties. Qualitative findings showed that sustained use of the supplements was attributed to expected health benefits, favourable sensory attributes, and family support. The FGDs suggested providing the option to choose between more than one type/flavour of supplements to improve compliance. Sharing was mostly evident in the first week with higher sharing reported in the biscuit group.

Validation of maternal report of nutrition-related interventions and counselling during antenatal care in southern Nepal.

The delivery of nutrition-related interventions and counselling during antenatal care is critical for a healthy pregnancy for both mother and child. However, the accuracy of maternal reports of many of these services during household surveys has not yet been examined. Our objectives were to assess the validity of the maternal reports of 10 antenatal nutrition interventions, including counselling, and examine associates between maternal characteristics and accuracy. Maternal report of services received collected during a post-partum survey was compared to the gold standard, the direct observation of all women's antenatal care visits. Individual-level validity was assessed by calculating indicator sensitivity, specificity and area under the operating curve (AUC). The inflation factor (IF) measured population-level bias. For five indicators, the high true coverage limited our ability to assess the validity of the maternal reports. There were no indicators that had both high individual-level validity (AUC > 0.70) and low population bias (0.75 < IF < 1.25). Indicators with greater true coverage estimates had higher sensitivity and lower specificity estimates compared to those indicators with lower true coverage. There were no maternal characteristics associated with the accuracy of the report. Maternal report of antenatal nutrition-related interventions and counselling during household surveys was found to have variable validity across indicators. Additional research in settings with varying coverage levels should be considered to best inform antenatal care coverage measurement in household surveys.