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).

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.

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.

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.

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.

Impact of sunflower seed oil versus mustard seed oil on skin barrier function in newborns: a community-based, cluster-randomized trial.

BACKGROUND: Natural vegetable oils are widely used for newborn massage in many low resource settings. Animal models indicated that sunflower seed oil (SSO) can accelerate skin barrier recovery following damage, while other oils, including mustard oil (MO), may cause further skin barrier damage. The objective was to compare the effects of two SSO and MO used for routine massage on skin integrity in premature and full-term neonates. METHODS: This community-based cluster randomized controlled trial included 995 neonates assigned to full body massage with sunflower seed oil (SSO, intervention) or mustard seed oil (MO, standard practice) from July 2012-May 2014 in Sarlahi, Nepal. Skin integrity measures were evaluated over 28 days, including skin condition (erythema, rash, dryness), skin surface pH, stratum corneum (SC) cohesion/protein concentration, and transepidermal water loss (TEWL). Overall means and rates of change in these skin measures were compared between oil groups using bivariate random-effects models. RESULTS: 500 and 495 live born neonates received repeated massage with MO and SSO, respectively. Skin pH decreased more quickly for SSO than MO in the first week of life, with a difference in mean daily reductions of 0.02 (95% CI: 0.002-0.040). Erythema, rash and dryness increased (worsened) over days 1-14 then decreased by day 28, with no significant oil group differences. TEWL increased over time, with no significant oil group differences. Gestational age did not modify the effect; the slightly faster decrease in skin pH among SSO infants was similar in magnitude between term and preterm infants. CONCLUSIONS: Oil type may contribute to differences in skin integrity when neonates are massaged regularly. The more rapid acid mantle development observed for SSO may be protective for neonates in lower resource settings. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01177111); registered August 6th, 2010.

Plasma Concentrations of Hepcidin in Anemic Zimbabwean Infants.

OBJECTIVE: Anemia in infancy is a global public health problem. We evaluated the relative contributions of iron deficiency and inflammation to infant anemia. METHODS: We measured plasma hepcidin, ferritin, soluble transferrin receptor (sTfR), alpha-1-acid glycoprotein and C-reactive protein (CRP) by ELISA on archived plasma from 289 HIV-unexposed anemic or non-anemic Zimbabwean infants at ages 3 mo, 6 mo and 12 mo. Among anemic infants, we determined the proportion with iron-deficiency anemia (IDA) and anemia of inflammation (AI). We undertook regression analyses of plasma hepcidin and anemia status, adjusting for sex, age and birthweight. RESULTS: Anemic infants at 3 mo were more stunted and had higher CRP (median 0.45 vs 0.21 mg/L; P = 0.037) and hepcidin (median 14.7 vs 9.7 ng/mL; P = 0.022) than non-anemic infants, but similar levels of ferritin and sTfR; 11% infants had IDA and 15% had AI. Anemic infants at 6 mo had higher hepcidin (median 7.9 vs 4.5 ng/mL; P = 0.016) and CRP (median 2.33 vs 0.32 mg/L; P<0.001), but lower ferritin (median 13.2 vs 25.1 µg/L; P<0.001) than non-anemic infants; 56% infants had IDA and 12% had AI. Anemic infants at 12 mo had lower ferritin (median 3.2 vs 22.2 µg/L; P<0.001) and hepcidin (median 0.9 vs 1.9 ng/mL; P = 0.019), but similar CRP levels; 48% infants had IDA and 8% had AI. Comparing anemic with non-anemic infants, plasma hepcidin was 568% higher, 405% higher and 64% lower at 3 mo, 6 mo and 12 mo, respectively, after adjusting for sex and birthweight (all p<0.01). Plasma hepcidin declined significantly with age among anemic but not non-anemic infants. Girls had 61% higher hepcidin than boys, after adjusting for age, anemia and birthweight (p<0.001). CONCLUSION: Anemia is driven partly by inflammation early in infancy, and by iron deficiency later in infancy, with plasma hepcidin concentrations reflecting the relative contribution of each. However, there is need to better characterize the drivers of hepcidin during infancy in developing countries.

The role of zinc and iron-folic acid supplementation on early child temperament and eating behaviors in rural Nepal: a randomized controlled trial.

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 (ß = -0.03, 95% CI -0.3, 0.2) or iron-folic acid and non-iron-folic acid (ß = 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 (ß = -0.14, 95% CI -0.3, 0.04) or between iron and non-iron eating behavior scores (ß = -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 (ß = -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.

Incidence of and risk factors for neonatal jaundice among newborns in southern Nepal.

OBJECTIVE: To quantify the incidence of and risk factors for neonatal jaundice among infants referred for care from a rural, low-resource, population-based cohort in southern Nepal. METHODS: Study participants were 18,985 newborn infants born in Sarlahi District in southern Nepal from May 2003 through January 2006 who participated in a cluster-randomised, placebo-controlled, community-based trial to evaluate the effect of newborn chlorhexidine cleansing on neonatal mortality and morbidity. Jaundice was assessed based on visual assessment of the infant by a study worker and referral for care. Adjusted relative risks (RR) were estimated to identify risk factors for referral for neonatal jaundice using Poisson regression. RESULTS: The incidence of referral for neonatal jaundice was 29.3 per 1000 live births (95% confidence interval: 26.9, 31.7). Male sex, high birth weight, breastfeeding patterns, warm air temperature, primiparity, skilled birth attendance, place of delivery, prolonged labour, oil massage, paternal education and ethnicity were significant risk factors (P-values < 0.01). After multivariable adjustment, sex, birth weight, difficulty feeding, prolonged labour, primiparity, oil massage, ambient air temperature and ethnicity remained important factors. Among infants with difficulty feeding, exclusive breastfeeding was a risk factor for neonatal jaundice, whereas exclusive breastfeeding was protective among infants with no report of difficulty feeding. CONCLUSIONS: Several known risk factors for neonatal jaundice in a low-resource setting were confirmed in this study. Unique observed associations of jaundice with ambient air temperature and oil massage may be explained by the opportunity for phototherapy based on the cultural practices of this study population. Future research should investigate the role of an infant's difficulty in feeding as a potential modifier in the association between exclusive breastfeeding and jaundice.

Developmental effects of micronutrient supplementation and malaria in Zanzibari children.

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.

Effects of zinc and iron supplementation fail to improve motor and language milestone scores of infants and toddlers.

OBJECTIVE: To assess the effects of zinc and iron-folic acid supplementation on motor and language milestones in Nepali children. METHODS: Five hundred forty-four children 4 to 17 mo old residing in Ishwarpur, Nepal were randomized to receive placebo, iron-folic acid, zinc, or zinc plus iron-folic acid daily. Data were collected at baseline and at 3-mo intervals for 1 y. The main effects of zinc and iron folic-acid supplementation were estimated for motor and language milestones. Crude and adjusted mean cumulative changes in scores from visits 1 to 5 and adjusted rates of change were modeled. RESULTS: Adjusted differences in motor milestone scores from visits 1 to 5 and rates of change were not significantly different for the zinc and non-zinc groups (adjusted ß = -0.7, 95% confidence interval [CI] -1.4 to 0.01; adjusted ß = -0.1, 95% CI -0.5 to 0.3, respectively). Motor milestones in children receiving and not receiving iron supplements were not significantly different (adjusted ß = 0.1, 95% CI -0.7 to 0.8, from visits 1 to 5; adjusted ß = 0.1, 95% CI -0.3 to 0.5, for rate of change). Children receiving zinc had a 0.8 lower mean crude change in language score from visits 1 to 5 compared with children not receiving zinc (95% CI -1.3 to -0.3), but the significance was lost after adjustment (adjusted ß = -0.2, 95% CI -0.6 to 0.2, for visits 1 to 5; ß = -0.1, 95% CI -0.3 to 0.2, for rate of change). No significant difference in motor or language milestone scores from iron supplementation was observed. CONCLUSION: After 1 y, neither zinc nor iron-folic acid supplementation in Nepali children improved the attainment of motor or language milestones.

Preschool micronutrient supplementation effects on intellectual and motor function in school-aged Nepalese children.

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.

Pneumococcal carriage at age 2 months is associated with growth deficits at age 6 months among infants in South India.

Nasopharyngeal colonization is the first step in the pathway to Streptococcus pneumoniae (Spn) infection, a leading cause of childhood morbidity and mortality. We investigated the effect of Spn colonization at ages 2 and 4 mo on growth at age 6 mo among 389 infants living in rural South India by using data from an Spn carriage study nested within a randomized, double-blind, placebo-controlled community trial designed to evaluate the impact of newborn vitamin A supplementation on Spn carriage in the first 6 mo of life. Primary outcomes were weight, length, and anthropometric indices of nutritional status. Growth data at age 6 mo were available for 84% (389 of 464) of infants in the Spn carriage study. Carriage at age 2 mo was associated with increased odds of stunting [OR: 3.07 (95% CI: 1.29, 7.36) P = 0.012] and lower weight [ß: -266 g (95% CI: -527, -5) P = 0.045], length [ß: -1.31 cm (95% CI: -2.32, -0.31) P = 0.010], and length-for-age Z scores [ß: -0.59; (95% CI: -1.05, -0.13) P = 0.012] at age 6 mo. Spn carriage at age 4 mo did not affect growth. Carriage of invasive serotypes at age 2 mo was associated with decreases in mean weight [ß: -289 g; (95% CI: -491, -106) P = 0.002] and length [ß:-0.38 cm (95% CI: -1.49, -0.01) P = 0.047] at age 6 mo. Newborn vitamin A supplementation did not modify the association between Spn carriage and growth. Results suggest that pneumococcal carriage at age 2 mo is an independent risk factor for poor growth in young infants. Future studies need to clarify the role of Spn carriage on growth retardation in low-income countries.

Evidence for multiple micronutrient effects based on randomized controlled trials and meta-analyses in developing countries.

Providing multiple micronutrients via supplements, powders, or fortified ready-to-use foods is increasingly becoming a strategy for simultaneously addressing multiple nutrient deficiencies in developing countries. The pros and cons of the "gold standard" randomized controlled trial (RCT) design and meta-analyses of trials for establishing efficacy of nutritional interventions are discussed. Over the past decade, numerous RCT have been undertaken to test the efficacy of multiple micronutrient supplementation in both pregnant women and young children. Outcomes of interest have ranged from birth weight to child growth, and infant morbidity and mortality to nutrient status and cognitive function. These RCT have also been submitted to meta-analyses for estimating pooled effect sizes for various outcomes. Meta-analyses of antenatal multiple micronutrient supplementation reveal a modest but significant increase in birth weight of 22.4 g (95% CI: 8.3, 36.4 g) and an 11% (95% CI: 3, 19) reduction in low birth weight but no impact on preterm birth or perinatal mortality. In children, small effect sizes of 0.13 (95% CI: 0.06, 0.21) for length/height and 0.14 (95% CI: 0.03, 0.25) for weight have been shown with 3 or more micronutrients compared to fewer micronutrients, but there is limited evidence for an impact on outcomes such as morbidity and cognitive function. Gaps in research and future challenges for programmatic application of this strategy for both pregnant women and young children are discussed.

Preschool iron-folic acid and zinc supplementation in children exposed to iron-folic acid in utero confers no added cognitive benefit in early school-age.

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.

Inconsistent effects of iron-folic acid and/or zinc supplementation on the cognitive development of infants.

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.

Prenatal micronutrient supplementation and intellectual and motor function in early school-aged children in Nepal.

CONTEXT: Iron and zinc are important for the development of both intellectual and motor skills. Few studies have examined whether iron and zinc supplementation during gestation, a critical period of central nervous system development, affects children's later functioning. OBJECTIVE: To examine intellectual and motor functioning of children whose mothers received micronutrient supplementation during pregnancy. DESIGN, SETTING, AND PARTICIPANTS: Cohort follow-up of 676 children aged 7 to 9 years in June 2007-April 2009 who had been born to women in 4 of 5 groups of a community-based, double-blind, randomized controlled trial of prenatal micronutrient supplementation between 1999 and 2001 in rural Nepal. Study children were also in the placebo group of a subsequent preschool iron and zinc supplementation trial. INTERVENTIONS: Women whose children were followed up had been randomly assigned to receive daily iron/folic acid, iron/folic acid/zinc, or multiple micronutrients containing these plus 11 other micronutrients, all with vitamin A, vs a control group of vitamin A alone from early pregnancy through 3 months postpartum. These children did not receive additional micronutrient supplementation other than biannual vitamin A supplementation. MAIN OUTCOME MEASURES: Children's intellectual functioning, assessed using the Universal Nonverbal Intelligence Test (UNIT); tests of executive function, including go/no-go, the Stroop test, and backward digit span; and motor function, assessed using the Movement Assessment Battery for Children (MABC) and finger-tapping test. RESULTS: The difference across outcomes was significant (Bonferroni-adjusted P < .001) for iron/folic acid vs control but not for other supplement groups. The mean UNIT T score in the iron/folic acid group was 51.7 (SD, 8.5) and in the control group was 48.2 (SD, 10.2), with an adjusted mean difference of 2.38 (95% confidence interval [CI], 0.06-4.70; P = .04). Differences were not significant between the control group and either the iron/folic acid/zinc (0.73; 95% CI, -0.95 to 2.42) or multiple micronutrient (1.00; 95% CI, -0.55 to 2.56) groups. In tests of executive function, scores were better in the iron/folic acid group relative to the control group for the Stroop test (adjusted mean difference in proportion who failed, -0.14; 95% CI, -0.23 to -0.04) and backward digit span (adjusted mean difference, 0.36; 95% CI, 0.01-0.71) but not for the go/no-go test. The MABC score was lower (better) in the iron/folic acid group compared with the control group but not after adjustment for confounders (mean difference, -1.47; 95% CI, -3.06 to 0.12; P = .07). Finger-tapping test scores were higher (mean difference, 2.05; 95% CI, 0.87-3.24; P = .001) in the iron/folic acid group. CONCLUSION: Aspects of intellectual functioning including working memory, inhibitory control, and fine motor functioning among offspring were positively associated with prenatal iron/folic acid supplementation in an area where iron deficiency is prevalent. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00115271.

Daily supplementation with iron plus folic acid, zinc, and their combination is not associated with younger age at first walking unassisted in malnourished preschool children from a deficient population in rural Nepal.

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.

Maternal vitamin A supplementation and lung function in offspring.

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.

Risk factors for maternal night blindness in rural South India.

PURPOSE: This study aimed to identify risk factors associated with maternal night blindness in rural South India. METHODS: At delivery, women enrolled in a population-based trial of newborn vitamin A supplementation were asked whether they were night blind at any time during the pregnancy. Multivariate logistic regression was used to identify socioeconomic, demographic, and pregnancy-related factors associated with maternal night blindness. RESULTS: Women reported night blindness in 687 (5.2%) of 13,171 pregnancies. In a multivariate model, having a concrete roof (Odds Ratio (OR): 0.60, 95% Confidence Interval (CI): 0.47, 0.78), religion other than Hindu (OR: 0.46, 95% CI: 0.27, 0.76), maternal literacy (OR: 0.58, 95% CI: 0.49, 0.69), and maternal age from 25 to 29 years (OR: 0.68, 95% CI: 0.50, 0.93) were associated with a lower risk of night blindness in pregnancy. The odds of night blindness were higher for those leasing rather than owning land (OR: 1.78, 95%CI: 1.08, 2.93), parity 6 or more compared to 0 (OR: 2.11, 95% CI: 1.09, 4.08), and with twin pregnancies (OR: 3.23, 95% CI: 1.93, 5.41). Factors not associated with night blindness in the multivariate model were other markers of socioeconomic status such as electricity in the house, radio and television ownership, type of cooking fuel and household transportation, and number of children under 5 years of age in the household. CONCLUSIONS: Maternal night blindness was prevalent in this population. Being pregnant with twins and of higher parity put women at higher risk. Maternal literacy and higher socioeconomic status lowered the risk.