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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., (© 2023. The Author(s).)

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., (© 2022 The Authors. Maternal & Child Nutrition published by John Wiley & Sons Ltd.)

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., (© 2021 The Authors. Maternal & Child Nutrition published by John Wiley & Sons Ltd.)

Unlabelled: Child eating behaviors play an important role in nutrient intake, ultimately affecting child growth and later outcomes in adulthood. The study assessed the effects of iron-folic acid and zinc supplementation on child temperament and child eating behaviors in rural Nepal. Children (N = 569) aged 4-17 months in Sarlahi district, southern Nepal were randomized to receive daily supplements of placebo, iron-folic acid, zinc, or zinc plus iron-folic acid and followed for approximately 1 year. At baseline and four follow-up visits mothers completed questionnaires including information on demographic characteristics and child temperament and eating behaviors. The main effects of zinc and iron-folic acid supplementation on temperament and eating behaviors were assessed through crude and adjusted differences in mean cumulative score changes between visits 1 and 5. The adjusted rate-of-change for these outcomes was modeled using generalized estimating equations. Mean changes in temperament scores and in eating behavior scores between visits 1 and 5 were not significant in either the zinc or non-zinc group. Children in the iron-folic acid group increased temperament scores by 0.37 points over 5 visits (95% CI 0.02, 0.7), which was not significant after adjustment. Neither the adjusted rate-of-change in temperament scores between zinc and non-zinc (β = -0.03, 95% CI -0.3, 0.2) or iron-folic acid and non-iron-folic acid (β = 0.08, 95% CI -0.2, 0.3) were significantly different. Adjusted rate of change analysis showed no significant difference between zinc and non-zinc (β = -0.14, 95% CI -0.3, 0.04) or between iron and non-iron eating behavior scores (β = -0.11, 95% CI -0.3, 0.1). Only among children with iron-deficiency anemia at baseline was there a significant decrease in eating behavior score, indicating better eating behaviors, when supplemented with zinc (β = -0.3, 95% CI -0.6, -0.01), Ultimately, this effect of zinc on eating behaviors was the only effect we observed after approximately one year of micronutrient supplementation., Trial Registration: ClinicalTrials.gov NCT00109551.

Background: Children's development is affected by the interplay of internal and external factors and changes in one factor can precipitate changes in multiple developmental domains., Aims: The aim of this study was to test a theoretical model of children's development using structural equation modeling., Study Design: This was designed as a substudy of a randomized, placebo-controlled, 2 × 2 factorial trial of the effects of daily supplementation with iron (12.5 mg) + folic acid (50 μg) (FeFA) with or without zinc (10 mg) (Zn) on child mortality., Subjects: Zanzibari children aged 5-9 mo (n = 106) and 10-14 mo (n = 141) at baseline were included in this sub study., Outcome Measures: Longitudinal data on children's hemoglobin, growth, malaria infection, motor development, motor activity, and language development and caregiver behavior were used to test the fit of the theoretical model for two age groups and to examine the direct and indirect relationships among the variables in the model., Results: The theoretical models were a good fit to the data for both age groups and revealed that FeFA with or without Zn had positive effects on motor development. FeFA alone had negative effects on language development in both age groups and Zn alone had negative effects on language development in children aged 10-14 mo. The incidence of malaria had negative effects on the majority of health and development outcomes in children aged 5-9 mo, and on motor development and hemoglobin in children aged 10-14 mo., Conclusions: These findings illustrate how nutrition and health factors can affect different domains of development and how these changes can precipitate changes in other domains. More work is needed to better understand the multiple impacts of internal and external factors on children's development and how changes in developmental domains interact with each other over time to determine children's overall developmental trajectory. The randomized, placebo-controlled study was registered as an International Standard Randomized Controlled Trial, number ISRCTN59549825., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background/objective: To assess the effects of micronutrient supplementation on head circumference of rural Nepali infants and children., Subjects/methods: We used a randomized controlled trial to assess the effects of micronutrient supplementation on head circumference in 569 rural Nepali infants and children aged 4-17 months. Children were randomized to: (1) zinc, (2) iron-folic acid, (3) zinc plus iron-folic acid or (4) a placebo group. Data on head circumference were collected during five visits at ∼3 month intervals over the course of a year. We calculated change in head circumference in treatment groups receiving zinc and iron comparing the first and fifth visits as well as used generalized estimating equations (GEE) to take advantage of data from all points in time. Models were adjusted for covariates unbalanced in the randomization and for baseline head circumference., Results: Estimating differences in head circumference between baseline and visit 5, children in the zinc treatment group showed smaller decreases in head circumference z-score compared with placebo (adjusted β=0.13, 95% confidence interval (CI): 0.03 to 0.23). Using GEE, zinc treatment was associated with 0.11 (95% CI: 0.05 to 0.17) decrease in the rate of decline in head circumference z-score across visits as compared with placebo. Iron-folic acid supplementation was not associated with head circumference z-scores when comparing visits 1 with 5 or including data across all visits in adjusted models., Conclusion: Our results suggest that zinc supplementation confers a beneficial effect on the rate of head growth in Nepali infants.

Objective: To examine intellectual and motor functioning of children who received micronutrient supplementation from 12 to 35 months of age., Design: Cohort follow-up of children 7 to 9 years of age who participated in a 2 × 2 factorial, placebo-controlled, randomized trial from October 2001 through January 2006., Setting: Rural Nepal., Participants: A total of 734 children 12 to 35 months of age at supplementation and 7 to 9 years of age at testing., Interventions: Children received iron plus folic acid (12.5 mg of iron and 50 μg of folic acid); zinc (10 mg); iron plus folic acid and zinc; or placebo., Main Outcome Measures: Intellectual, motor, and executive function., Results: In both the unadjusted and adjusted analyses, iron plus folic acid supplementation had no effect overall or on any individual outcome measures being tested. In the unadjusted analysis, zinc supplementation had an overall effect, although none of the individual test score differences were significant. In the adjusted analysis, the overall difference was not significant., Conclusion: In rural Nepal, we found that iron plus folic acid or zinc supplementation during the preschool years had no effect on aspects of intellectual, executive, and motor function at 7 to 9 years of age, suggesting no long-term developmental benefit of iron or zinc supplementation during 12 to 35 months of age.

Despite concerns over the neurocognitive effects of micronutrient deficiencies in infancy, few studies have examined the effects of micronutrient supplementation on specific cognitive indicators. This study investigated, in 2002, the effects of iron-folic acid and/or zinc supplementation on the results of Fagan Test of Infant Intelligence (FTII) and the A-not-B Task of executive functioning among 367 Nepali infants living in Sarlahi district. Infants were enrolled in a cluster-randomized, placebo-controlled clinical trial of daily supplementation with 5 mg of zinc, 6.25 mg of iron with 25 microg of folic acid, or zinc-iron-folic acid, or placebo. These were tested on both the tasks using five indicators of information processing: preference for novelty (FTII), fixation duration (FTII), accelerated performance (> or = 85% correct; A-not-B), deteriorated performance (< 75% correct and > 1 error on repeat-following-correct trails; A-not-B), and the A-not-B error (A-not-B). At 39 and 52 weeks, 247 and 333 infants respectively attempted the cognitive tests; 213 made an attempt to solve both the tests. The likelihood of females completing the A-not-B Task was lower compared to males when cluster randomization was controlled [odds ratio = 0.67; 95% confidence interval 0.46-0.97; p < 0.05]. All of the five cognitive outcomes were modelled in linear and logistic regression. The results were not consistent across either the testing sessions or the information-processing indicators. Neither the combined nor the individual micronutrient supplements improved the performance on the FTII or the A-not-B Task (p > 0.05). These findings suggest that broader interventions (both in terms of scope and duration) are needed for infants who face many biological and social stressors.

Animal models suggest that vitamin A deficiency affects lung development adversely and promotes airway hyperresponsiveness, and may predispose to an increased risk of asthma. We examined the long-term effects of vitamin A supplementation early in life on later asthma risk. In 2006-2008, we revisited participants from two cohorts in rural Nepal who were enrolled in randomised trials of vitamin A supplementation. The first cohort received vitamin A or placebo for <16 months during their pre-school years (1989-1991). The second cohort was born to mothers who received vitamin A, β-carotene or placebo before, during and after pregnancy (1994-1997). At follow-up, we asked about asthma symptoms and performed spirometry. Out of 6,421 subjects eligible to participate, 5,430 (85%) responded to our respiratory survey. Wheezing prevalence during the previous year was 4.8% in participants aged 9-13 yrs and 6.6% in participants aged 14-23 yrs. We found no differences between the vitamin A supplemented and placebo groups from either trial in the prevalence of lifetime or current asthma and wheeze or in spirometric indices of obstruction (p ≥ 0.12 for all comparisons). Vitamin A supplementation early in life was not associated with a decreased risk of asthma in an area with chronic vitamin A deficiency.

In Nepal, antenatal iron-folic acid supplementation improved aspects of intellectual, executive, and fine motor function among school-age children. We examined the impact of added zinc to the maternal antenatal supplement (M-IFAZn) and preschool supplementation from 12 to 36 mo with iron-folic acid (C-IFA) ± zinc (C-IFAZn) on cognitive outcomes compared to maternal iron-folic acid (M-IFA) alone. Children 7-9 y old (n = 780) who participated in early childhood micronutrient supplementation trial during 2001-2004 and whose mothers participated in an antenatal micronutrient supplementation between 1999 and 2001 were followed for cognitive assessments in 2007-2009. Using multivariate analysis of variance and adjusting for confounders, M-IFA with child supplementation (either C-IFA or C-IFAZn) did not impact scores on the tests of general intelligence (Universal Nonverbal Intelligence Test), and executive function (Stroop and go/no go tests) relative to the M-IFA alone. However, children in the C-IFAZn group had slightly lower scores on the backward digit span (-0.29, 95% CI: -0.55, -0.04) and Movement Assessment Battery for Children (1.33, 95% CI: 0.26, 2.40) relative to the referent group, whereas both C-IFA (-1.92, 95% CI: -3.12, -0.71) and C-IFAZn (-1.78, 95% CI: -2.63, -0.92) produced somewhat lower finger tapping test scores (fine motor skills). The combination of M-IFAZn and C-IFA or C-IFAZn did not lead to any outcome differences relative to M-IFA alone. Preschool iron-folic acid ± zinc to children exposed to iron-folic acid in utero or addition of zinc to maternal iron-folic acid conferred no additional benefit to cognitive outcomes assessed in early school age. The late timing of supplementation during preschool may explain the lack of impact of iron and/or zinc.

A community-based, cluster-randomized, placebo-controlled trial of daily zinc and/or iron+folic acid supplementation was conducted in rural southern Nepal to examine motor milestone attainment among 3264 children 1-36 mo of age between 2001 and 2006. Treatment groups included placebo, zinc (10 mg), iron+folic acid (12.5 mg iron + 50 microg folic acid), and zinc+iron+folic acid (10 mg zinc + 12.5 mg iron + 50 microg folic acid). Infants received half of these doses. The iron arms were stopped November 2003 by recommendation of the Data Safety and Monitoring Board; zinc and placebo continued until January 2006. A total of 2457 children had not walked at the time of entry into the trial and 1775 were followed through 36 mo. Mean age at first walking unassisted did not differ among groups and was 444 +/- 81 d (mean +/- SD) in the placebo group, 444 +/- 81 d in the zinc group, 464 +/- 85 d in the iron+folic acid group, and 446 +/- 87 d in the iron+folic acid+zinc group. Results were similar after adjustment for age at enrollment, asset ownership, maternal literacy, and prior child deaths in the household and in children who consumed at least 60 tablets. Compared with placebo, iron+folic acid was associated with an adjusted mean delay of 28.0 d (95% CI: 11.3, 44.7) in time to walking among infants and the delay was more pronounced with mid-upper arm circumference (MUAC) < 9.5 cm [60.6 d, (95% CI: 28.5, 92.6)]. Risks and benefits of universal iron+folic acid supplementation of infants beyond improved hematologic status deserve further consideration.

Background: Vitamin A is important in regulating early lung development and alveolar formation. Maternal vitamin A status may be an important determinant of embryonic alveolar formation, and vitamin A deficiency in a mother during pregnancy could have lasting adverse effects on the lung health of her offspring. We tested this hypothesis by examining the long-term effects of supplementation with vitamin A or beta carotene in women before, during, and after pregnancy on the lung function of their offspring, in a population with chronic vitamin A deficiency., Methods: We examined a cohort of rural Nepali children 9 to 13 years of age whose mothers had participated in a placebo-controlled, double-blind, cluster-randomized trial of vitamin A or beta-carotene supplementation between 1994 and 1997., Results: Of 1894 children who were alive at the end of the original trial, 1658 (88%) were eligible to participate in the follow-up trial. We performed spirometry in 1371 of the children (83% of those eligible) between October 2006 and March 2008. Children whose mothers had received vitamin A had a forced expiratory volume in 1 second (FEV(1)) and a forced vital capacity (FVC) that were significantly higher than those of children whose mothers had received placebo (FEV(1), 46 ml higher with vitamin A; 95% confidence interval [CI], 6 to 86; FVC, 46 ml higher with vitamin A; 95% CI, 8 to 84), after adjustment for height, age, sex, body-mass index, calendar month, caste, and individual spirometer used. Children whose mothers had received beta carotene had adjusted FEV(1) and FVC values that were similar to those of children whose mothers had received placebo (FEV(1), 14 ml higher with beta carotene; 95% CI, -24 to 54; FVC, 17 ml higher with beta carotene, 95% CI, -21 to 55)., Conclusions: In a chronically undernourished population, maternal repletion with vitamin A at recommended dietary levels before, during, and after pregnancy improved lung function in offspring. This public health benefit was apparent in the preadolescent years., (2010 Massachusetts Medical Society)

Background: There is some evidence that sleep patterns may be affected by iron deficiency anemia but the role of iron in sleep has not been tested in a randomized iron supplementation trial., Objective: We investigated the effect of iron supplementation on maternal reports of sleep in infants in 2 randomized, placebo-controlled trials from Pemba Island, Zanzibar, and Nepal., Design: In both studies, which had parallel designs and were carried out in years 2002 to 2003, infants received iron-folic acid with or without zinc daily for 12 months, and assessments of development were made every 3 months for the duration of the study. Eight hundred seventy-seven Pemban (12.5 +/- 4.0 months old) and 567 Nepali (10.8 +/- 4.0 months) infants participated. Maternal reports of sleep patterns (napping frequency and duration, nighttime sleep duration, frequency of night waking) were collected., Results: Mean Hb concentration was 9.2 +/- 1.1 for Pemban and 10.1 +/- 1.2 g/dL for Nepali infants. Approximately, one-third of the children were stunted. Supplemental iron was consistently associated with longer night and total sleep duration. The effects of zinc supplementation also included longer sleep duration., Conclusions: Micronutrient supplementation in infants at high risk for iron deficiency and iron deficiency anemia was related to increased night sleep duration and less night waking.

Vitamin A supplementation reduces mortality in young children in areas of endemic vitamin A deficiency. However, it has no impact on the incidence of common morbidities. This discrepancy has been explained by an impact on case fatality, although with the exception of hospitalized measles cases, there is little direct evidence to support this hypothesis. We assessed the impact of newborn dosing with vitamin A on the incidence and case fatality of common childhood morbidities in early infancy in a community-based, randomized trial in South India. Morbidity for each day in the previous 2 wk was assessed for the first 6 mo of life. A total of 11,619 live-born infants were enrolled and randomized to receive either 48,000 IU (50.4 micromol retinol) of oral vitamin A or placebo following delivery. There was no difference between treatment groups in the incidence of acute or chronic diarrhea, dysentery, or fever but a small increased incidence of acute respiratory illness (ARI). Case fatality for diarrhea and fever were significantly reduced in the vitamin A group compared with placebo (relative case fatality [95% CI] of 0.50 [0.27, 0.90] and 0.60 [0.40, 0.88], respectively). There was a trend in reduction of case fatality for various definitions of ARI, but the evidence for this effect was modest. Survival analysis among those with morbid episodes confirmed the case fatality analysis. This trial demonstrated that the reduction in overall mortality due to newborn vitamin A dosing was driven primarily by a reduction in case fatality among infants.

Objective: To assess the impact of supplementing newborn infants with vitamin A on mortality at age 6 months., Design: Community based, randomised, double blind, placebo controlled trial., Setting: Two rural districts of Tamil Nadu, southern India., Participants: 11 619 newborn infants allocated 24 000 IU oral vitamin A or placebo on days 1 and 2 after delivery., Main Outcome Measure: Primary outcome measure was mortality at age 6 months., Results: Infants in the vitamin A group had a 22% reduction in total mortality (95% confidence interval 4% to 37%) compared with those in the placebo group. Vitamin A had an impact on mortality between two weeks and three months after treatment, with no additional impact after three months., Conclusion: Supplementing newborn infants with vitamin A can significantly reduce early infant mortality.

Zinc is crucial for normal immune function and can reduce morbidity from multiple infectious diseases. To determine the influence of zinc on malaria morbidity we conducted a randomized placebo-controlled trial of daily zinc supplementation in children residing in a malaria endemic region of Papua New Guinea. A total of 274 preschool children aged 6 to 60 months were given 10 mg elemental zinc (n = 136) or placebo (n = 138) for 6 days a week for 46 weeks. Slide-confirmed malaria episodes were detected by surveillance of cases self-reporting to a local health center. Cross-sectional surveys were conducted at the beginning, middle, and end of the study to assess infection rates, parasite density, spleen enlargement, and hemoglobin levels. Zinc supplementation resulted in a 38% (95% CI 3-60, P = 0.037) reduction in Plasmodium falciparum health center-based episodes, defined as parasitemia > or = 9200 parasites/microl with axial temperature > or = 37.5 degreesC or reported fever. Episodes accompanied by any parasitemia were also reduced by 38% (95% CI 5-60, P = 0.028), and episodes with parasitemia > or = 100,000/microl were reduced by 69% (95% CI 25-87, P = 0.009). There was no evidence of the effects of zinc on Plasmodium vivax morbidity or on health center attendance for causes other than P. falciparum. Zinc had no consistent effect on cross-sectional malariometric indices. Although P. falciparum prevalence tended to be lower at the end of the study in children given the placebo, such changes were absent at the mid-study survey. These results suggest that improved dietary zinc intake may reduce morbidity due to P. falciparum.