An Egg Intervention Improves Dietary Intakes but Does Not Fill Intake Gaps for Multiple Micronutrients among Infants in Rural Bangladesh.

BACKGROUND: Eggs are nutrient-rich. Strengthening evidence of the impact of egg consumption on dietary quality can inform complementary feeding guidance. OBJECTIVES: We aimed to assess the effect of an egg intervention on dietary intakes among infants aged 6-12 mo in rural Bangladesh. METHODS: We conducted a cluster-randomized controlled trial allocating clusters (n = 566) to enteric pathogen control or placebo treatment, with daily provision of a protein-rich meal, isocaloric meal, egg, or control. Nutrition education was provided to all arms. Our focus here is on the egg and control arms. Infants were enrolled at 3 mo. From 6 mo, we visited households weekly to distribute eggs and measure compliance. A semistructured feeding questionnaire assessed 24-h intake at 6, 9, and 12 mo. Assessments were repeated in ∼10% of subjects 2-29 d later. Using NCI SAS macros, we estimated usual intake distributions for energy, protein, fat, and 18 micronutrients and the proportion meeting intake recommendations. We compared the outcomes between the arms using clustered bootstrapping. RESULTS: Data were available from 757 infants (137 clusters) and 943 infants (141 clusters) in the egg and control arms, respectively. In the egg arm compared with the control arm, the mean usual intakes were higher for energy (610 compared with 602 kcal/d, 9 mo; 669 compared with 658 kcal/d, 12 mo), crude protein (2.2 compared with 1.7 g/(kg·d), 9 mo; 2.4 compared with 1.9 g/(kg·d), 12 mo), available protein (2.0 compared with 1.6 g/(kg·d), 9 mo; 2.1 compared with 1.8 g/(kg·d), 12 mo), and for 13 and 14 micronutrients at 9 and 12 mo, respectively. The proportion meeting intake recommendations for most micronutrients was higher in the egg arm but remained <50% for 15 and 13 micronutrients at 9 and 12 mo, respectively. CONCLUSIONS: Daily egg consumption improved dietary intakes among Bangladeshi infants, but was insufficient to meet multiple micronutrient intake recommendations, demonstrating the need to be coupled with other strategies.

Preventive small-quantity lipid-based nutrient supplements reduce severe wasting and severe stunting among young children: an individual participant data meta-analysis of randomized controlled trials.

BACKGROUND: Meta-analyses show that small-quantity lipid-based nutrient supplements (SQ-LNSs) reduce child wasting and stunting. There is little information regarding effects on severe wasting or stunting. OBJECTIVES: We aimed to identify the effect of SQ-LNSs on prevalence of severe wasting (weight-for-length z score < -3) and severe stunting (length-for-age z score < -3). METHODS: We conducted a 2-stage meta-analysis of individual participant data from 14 randomized controlled trials of SQ-LNSs provided to children 6-24 mo of age. We generated study-specific and subgroup estimates of SQ-LNS compared with control and pooled the estimates using fixed-effects models. We used random-effects meta-regression to examine study-level effect modifiers. In sensitivity analyses, we examined whether results differed depending on study arm inclusion criteria and types of comparisons. RESULTS: SQ-LNS provision led to a relative reduction of 31% in severe wasting [prevalence ratio (PR): 0.69; 95% CI: 0.55, 0.86; n = 34,373] and 17% in severe stunting (PR: 0.83; 95% CI: 0.78, 0.90; n = 36,795) at endline. Results were similar in most of the sensitivity analyses but somewhat attenuated when comparisons using passive control arms were excluded (PR: 0.74; 95% CI: 0.57, 0.96; n = 26,327 for severe wasting and PR: 0.88; 95% CI: 0.81, 0.95; n = 28,742 for severe stunting). Study-level characteristics generally did not significantly modify the effects of SQ-LNSs, but results suggested greater effects of SQ-LNSs in sites with greater burdens of wasting or stunting, or with poorer water quality or sanitation. CONCLUSIONS: Including SQ-LNSs in preventive interventions to promote healthy child growth and development is likely to reduce rates of severe wasting and stunting. This meta-analysis was registered at www.crd.york.ac.uk/PROSPERO as CRD42019146592.

Birth anthropometry predicts neonatal and infant mortality in rural Bangladesh: a focus on circumferential measurements.

BACKGROUND: Low birth weight predicts risk of infant death. However, several birth measurements may be equally predictive, for which cutoffs and associated risks are less explored. OBJECTIVES: We assessed and optimized population cutoffs of birth length, weight, and midupper arm circumference (MUAC), head circumference (HC), and chest circumference (CC) for predicting neonatal (≤28 d) and infant (≤365 d) mortality in northwest Bangladesh. METHODS: Among 28,026 singletons born in an antenatal micronutrient supplement trial, 21,174 received anthropometry ≤72 h after birth, among whom 583 died in infancy. Optimization for predicting mortality for each measurement was guided by the Youden Index (sensitivity + specificity - 1). Relative risk ratios (RRRs) and positive predictive values (PPVs) were calculated across cutoff ranges for individual and any pair of measurements. RESULTS: Optimal cutoffs, harmonized to 100-g or 0.5-cm readings, for neonatal and infant mortality were 44.5 cm for length, 2200 g for weight, 9.0 cm for MUAC, 31.0 cm for HC, and 28.5 cm for CC, below which all predicted mortality. However, a CC <28.5 cm, alone and combined with HC <31.0 cm, yielded the highest RRR [9.68 (95% CI: 7.84, 11.94) and 15.74 (95% CI: 12.54, 19.75), respectively] and PPV (11.3% and 10.7%) for neonatal mortality and highest RRR [6.02 (95% CI: 5.15, 7.02) and 9.19 (95% CI: 7.72, 10.95)] and PPV (16.3% and 14.5%) for infant mortality. Pairs of measurements revealed a higher RRR for neonatal and infant mortality than individual measurements of any one pair, although the ranges of PPV remained comparable. CONCLUSIONS: In Bangladesh, multiple birth measurements alone or in combination, particularly chest circumference, predict neonatal and infant mortality.

Characteristics that modify the effect of small-quantity lipid-based nutrient supplementation on child growth: an individual participant data meta-analysis of randomized controlled trials.

BACKGROUND: Meta-analyses show that small-quantity lipid-based nutrient supplements (SQ-LNSs) reduce child stunting and wasting. Identification of subgroups who benefit most from SQ-LNSs may facilitate program design. OBJECTIVES: We aimed to identify study-level and individual-level modifiers of the effect of SQ-LNSs on child growth outcomes. METHODS: We conducted a 2-stage meta-analysis of individual participant data from 14 randomized controlled trials of SQ-LNSs provided to children 6-24 mo of age (n = 37,066). We generated study-specific and subgroup estimates of SQ-LNS compared with control and pooled the estimates using fixed-effects models. We used random-effects meta-regression to examine study-level effect modifiers. In sensitivity analyses, we examined whether results differed depending on study arm inclusion criteria and types of comparisons. RESULTS: SQ-LNS provision decreased stunting (length-for-age z score < -2) by 12% (relative reduction), wasting [weight-for-length (WLZ) z score < -2] by 14%, low midupper arm circumference (MUAC) (<125 mm or MUAC-for-age z score < -2) by 18%, acute malnutrition (WLZ < -2 or MUAC < 125 mm) by 14%, underweight (weight-for-age z score < -2) by 13%, and small head size (head circumference-for-age z score < -2) by 9%. Effects of SQ-LNSs generally did not differ by study-level characteristics including region, stunting burden, malaria prevalence, sanitation, water quality, duration of supplementation, frequency of contact, or average compliance with SQ-LNS. Effects of SQ-LNSs on stunting, wasting, low MUAC, and small head size were greater among girls than among boys; effects on stunting, underweight, and low MUAC were greater among later-born (than among firstborn) children; and effects on wasting and acute malnutrition were greater among children in households with improved (as opposed to unimproved) sanitation. CONCLUSIONS: The positive impact of SQ-LNSs on growth is apparent across a variety of study-level contexts. Policy-makers and program planners should consider including SQ-LNSs in packages of interventions to prevent both stunting and wasting.This trial was registered at www.crd.york.ac.uk/PROSPERO as CRD42019146592.

Newborn micronutrient status biomarkers in a cluster-randomized trial of antenatal multiple micronutrient compared with iron folic acid supplementation in rural Bangladesh.

BACKGROUND: Daily antenatal multiple micronutrient (MM) compared with iron folic acid (IFA) supplementation from early pregnancy improved birth outcomes and maternal micronutrient status in rural Bangladesh, but effects on newborn status are unknown. OBJECTIVE: We examined cord blood micronutrient biomarkers in relation to antenatal MM and IFA supplementation and maternal gestational micronutrient status in rural Bangladeshi newborns. DESIGN: In a double-blinded, cluster-randomized trial of antenatal IFA or MM (with the same IFA content), we analyzed cord blood plasma from 333 singleton births, and corresponding maternal plasma at 32.5 ± 2.6 wk of gestation, for ferritin (iron stores), folate, cobalamin (vitamin B-12), retinol (vitamin A), 25-hydroxyvitamin D [25(OH)D, vitamin D status], α-tocopherol (vitamin E), zinc, thyroglobulin, and free thyroxine (iodine status). Intervention effects and associations were determined using linear regression, exploring maternal status as a mediator of intervention effects on cord biomarkers. RESULTS: The MM intervention increased cord ferritin (mean: +12.4%; 95% CI: 1.3, 24.6%), 25(OH)D (mean: +14.7%; 95% CI: 4.8, 25.6%), and zinc (mean: +5.8%; 95% CI: 1.0, 10.8%). Cord folate (mean: +26.8%; 95% CI: 19.6, 34.5%), cobalamin (mean: +31.3%; 95% CI: 24.6, 38.3%), 25(OH)D (mean: +26.7%; 95% CI: 23.2, 30.3%), α-tocopherol (mean: +8.7%; 95% CI: 3.6, 13.7%), zinc (mean: +2.3%; 95% CI: 0.5, 4.2%), thyroglobulin (mean: +20.1%; 95% CI: 9.0, 32.2%) and thyroxine (mean: +1.5%; 95% CI: 0.0, 3.0%) increased per 1-SD increment in maternal status (all P < 0.05); ferritin and retinol changed by +2.0%; 95% CI: -8.9, 14.3%; P = 0.72; and +3.5%; 95% CI: -0.4, 7.3%; P = 0.07, respectively. Ferritin, folate, cobalamin, zinc, and thyroglobulin averaged 1.57-6.75 times higher and retinol, α-tocopherol, and 25(OH)D 0.30-0.84 times lower in cord than maternal plasma, suggesting preferential maternal-fetal transfer of iron, folate, cobalamin, and zinc; limited transfer of fat-soluble vitamins; and high fetal iodine demand. CONCLUSIONS: Antenatal MM supplementation increased newborn ferritin, 25(OH)D, and zinc, while maternal and newborn folate, vitamins B-12, D, and E, zinc, and iodine biomarkers were positively related. Despite limited effects of MM, better maternal micronutrient status was associated with improved micronutrient status of Bangladeshi newborns. This trial was registered at clinicaltrials.gov as NCT00860470.

Micronutrient and Inflammation Status Following One Year of Complementary Food Supplementation in 18-Month-Old Rural Bangladeshi Children: A Randomized Controlled Trial.

Background: Four fortified complementary food supplements (CFSs) in a randomized controlled trial (RCT) were found to improve childhood linear growth in rural Bangladesh. We hypothesized children receiving these supplements would have improved micronutrient status. Methods: In the RCT, we assessed hemoglobin and serum ferritin, retinol, zinc, C-reactive protein (CRP), and α-1-acid glycoprotein (AGP) at endline (18 mo) in a subsample of children (n = 752). The impact of supplementation on mean concentrations and the prevalence of nutrient deficiency and inflammation were evaluated using adjusted generalized estimating equation (GEE) linear and log-binomial regression models. Results: In the control arm at age 18 months, 13% of children were anemic (hemoglobin < 110 g/L), and 6% were iron (inflammation-adjusted ferritin < 12 µg/L), 8% vitamin A (inflammation-adjusted retinol < 0.70 µmol/L), and 5% zinc (zinc < 9.9 µmol/L) deficient. The prevalence of inflammation by CRP (>5 mg/L) and AGP (>1 g/L) was 23% and 66%, respectively, in the control group. AGP trended lower in CFS groups (p = 0.04), while CRP did not. Mean ferritin (p < 0.001) and retinol (p = 0.007) were higher in all supplemented groups relative to control, whereas hemoglobin improved with two of the four CFSs (p = 0.001), and zinc was equal or lower in supplemented groups relative to control (p = 0.017). Conclusions: CFSs improved iron status and vitamin A concentrations and lowered inflammation in a context of low underlying nutrient deficiency but high inflammation.

Supplementation with Fortified Lipid-Based and Blended Complementary Foods has Variable Impact on Body Composition Among Rural Bangladeshi Children: A Cluster-Randomized Controlled Trial.

BACKGROUND: Complementary food supplementation enhances linear growth and may affect body composition in children. OBJECTIVE: We aimed to determine the effect of complementary food supplements provided from the age of 6 to 18 mo on fat-free mass (FFM) and fat mass (FM) gain among children in rural Bangladesh. METHODS: In an unblinded, cluster-randomized, controlled trial we tested the effects of 4 complementary food supplements for 1 y [chickpea, rice lentil, Plumpy'doz, and wheat-soy-blend++ (WSB++)] compared with no supplements on linear growth. Body composition was estimated using weight-length-based, age- and sex-specific equations at 6, 9, 12, 15, and 18 mo and postintervention aged 24 mo. Generalized estimating equations (GEEs) were applied to estimate the effect of each complementary food on mean FFM and FM from 9 to 18 and 24 mo compared with the control, adjusting for baseline measures. Sex interactions were also explored. RESULTS: In total, 3592 (65.9% of enrolled) children completed all anthropometric assessments. Estimated FFM and FM (mean ± SD) were 5.3 ± 0.6 kg and 1.4 ± 0.4 kg, respectively, at the age of 6 mo. Mean ± SE FFM and FM from 9 to 18 mo were 75.4 ± 14.0 g and 32.9 ± 7.1 g, and 61.0 ± 16.6 g and 30.0 ± 8.4 g, higher with Plumpy'doz and chickpea foods, respectively, than the control (P < 0.001). Estimated FFM was 41.5 ± 16.6 g higher in rice-lentil-fed versus control (P < 0.05) children. WSB++ had no impact on FFM or FM. A group-sex interaction (P < 0.1) was apparent with Plumpy'doz and rice-lentil foods, with girls involved in the intervention having higher estimated FFM and FM than control girls compared with no significant effect in boys. At 24 mo, FFM and FM remained higher only in girls eating Plumpy'doz compared with the controls (P < 0.01). CONCLUSIONS: In this randomized trial, supplementation effected small shifts in apparent body composition in rural Bangladeshi children. Where seen, FFM increments were twice that of FM, in proportion to these compartments, and more pronounced in girls. FFM increased in line with reported improvements in length. This trial was registered at clinicaltrials.gov as NCT01562379.

Thinness and fecundability: Time to pregnancy after adolescent marriage in rural Bangladesh.

Undernutrition may affect fecundability, but few studies have quantified this relationship. In rural Bangladesh, where newlywed couples face strong pressures to become pregnant, we assessed fecundability, estimated by time to pregnancy (TTP), and its association with preconceptional thinness among nulligravid, newlywed female adolescents. During 2001-2002, 5,516 newlywed women aged 12-19 years participated in a home-based, 5-weekly surveillance system for 5-6 years to enrol pregnant women into an antenatal vitamin A or ß-carotene supplementation trial. Thinness was defined as a left mid-upper arm circumference (MUAC) ≤21.5 versus >21.5 cm. At each visit, staff obtained a monthly history of menstruation. Report of amenorrhea prompted a human chorionic gonadotropin urine test to confirm pregnancy. We derived hazard ratios (with 95% confidence intervals [CI]) for pregnancy and Kaplan-Meier curves for TTP. Ages of women at marriage and pregnancy detection (mean ± standard deviation) were 15.3 ± 1.9 and 17.0 ± 1.9 years, respectively. A total of 82.7% of thinner and 87.3% of better nourished women became pregnant. The unadjusted and multivariable relative hazard of ever becoming pregnant was 0.84 (95% CI [0.78, 0.89]) and 0.86 (95% CI [0.81, 0.92]), respectively, and TTP was 12 weeks longer (median [95% CI]: 63 [58-68] vs. 51 [49-54]) in women whose MUAC was ≤21.5 versus >21.5 cm. In rural Bangladesh, thin adolescent newlywed girls have a lower probability of becoming pregnant and experience a longer time to pregnancy.

Antenatal care in rural Bangladesh: current state of costs, content and recommendations for effective service delivery.

BACKGROUND: Measurement of antenatal care (ANC) service coverage is often limited to the number of contacts or type of providers, reflecting a gap in the assessment of quality as well as cost estimations and health impact. The study aims to determine service subcomponents and provider and patient costs of ANC services and compares them between community (i.e. satellite clinics) and facility care (i.e. primary and secondary health centers) settings in rural Bangladesh. METHODS: Service contents and cost data were collected by one researcher and four interviewers in various community and facility health care settings in Gaibandha district between September and December 2016. We conducted structured interviews with organization managers, observational studies of ANC service provision (n = 70) for service contents and provider costs (service and drug costs) and exit interviews with pregnant women (n = 70) for patient costs (direct and indirect costs) in health clinics at community and facility levels. Fisher's exact tests were used to determine any different patient characteristics between community and facility settings. ANC service contents were assessed by 63 subitems categorized into 11 groups and compared within and across community and facility settings. Provider and patient costs were collected in Bangladesh taka and analyzed as 2016 US Dollars (0.013 exchange rate). RESULTS: We found generally similar provider and patient characteristics between the community and facility settings except in clients' gestational age. High compliance (> 50%) of service subcomponents were observed in blood pressure monitoring, weight measurement, iron and folate supplementation given, and tetanus vaccine, while lower compliance of service subcomponents (< 50%) were observed in some physical examinations such as edema and ultrasonogram and routine tests such as blood test and urine test. Average unit costs of ANC service provision were about double at the facility level ($2.75) compared with community-based care ($1.62). ANC patient costs at facilities ($2.66) were about three times higher than in the community ($0.78). CONCLUSION: The study reveals a delay in pregnant women's initial ANC care seeking, gaps in compliance of ANC subcomponents and difference of provider and patient costs between facility and community settings.

Antenatal Multiple Micronutrient Supplementation Compared to Iron-Folic Acid Affects Micronutrient Status but Does Not Eliminate Deficiencies in a Randomized Controlled Trial Among Pregnant Women of Rural Bangladesh.

BACKGROUND: Antenatal multiple micronutrient (MM) supplementation improves birth outcomes relative to iron-folic acid (IFA) in developing countries, but limited data exist on its impact on pregnancy micronutrient status. OBJECTIVE: We assessed the efficacy of a daily MM (15 nutrients) compared with IFA supplement, each providing approximately 1 RDA of nutrients and given beginning at pregnancy ascertainment, on late pregnancy micronutrient status of women in rural Bangladesh. Secondarily, we explored other contributors to pregnancy micronutrient status. METHODS: Within a double-masked trial (JiVitA-3) among 44,500 pregnant women, micronutrient status indicators were assessed in n = 1526 women, allocated by cluster to receive daily MM (n = 749) or IFA (n = 777), at 10 wk (baseline: before supplementation) and 32 wk (during supplementation) gestation. Efficacy of MM supplementation on micronutrient status indicators at 32 wk was assessed, controlling for baseline status and other covariates (e.g., inflammation and season), in regression models. RESULTS: Baseline status was comparable by intervention. Prevalence of deficiency among all participants was as follows: anemia, 20.6%; iron by ferritin, 4.0%; iron by transferrin receptor, 4.7%; folate, 2.5%; vitamin B-12, 35.4%; vitamin A, 6.7%; vitamin E, 57.7%; vitamin D, 64.0%; zinc, 13.4%; and iodine, 2.6%. At 32 wk gestation, vitamin B-12, A, and D and zinc status indicators were 3.7-13.7% higher, and ferritin, γ-tocopherol, and thyroglobulin indicators were 8.7-16.6% lower, for the MM group compared with the IFA group, with a 15-38% lower prevalence of deficiencies of vitamins B-12, A, and D and zinc (all P < 0.05). However, indicators typically suggested worsening status during pregnancy, even with supplementation, and baseline status or other covariates were more strongly associated with late pregnancy indicators than was MM supplementation. CONCLUSIONS: Rural Bangladeshi women commonly entered pregnancy deficient in micronutrients other than iron and folic acid. Supplementation with MM improved micronutrient status, although deficiencies persisted. Preconception supplementation or higher nutrient doses may be warranted to support nutritional demands of pregnancy in undernourished populations. This trial was registered at clinicaltrials.gov as NCT00860470.

Modifiers of the effect of maternal multiple micronutrient supplementation on stillbirth, birth outcomes, and infant mortality: a meta-analysis of individual patient data from 17 randomised trials in low-income and middle-income countries.

BACKGROUND: Micronutrient deficiencies are common among women in low-income and middle-income countries. Data from randomised trials suggest that maternal multiple micronutrient supplementation decreases the risk of low birthweight and potentially improves other infant health outcomes. However, heterogeneity across studies suggests influence from effect modifiers. We aimed to identify individual-level modifiers of the effect of multiple micronutrient supplements on stillbirth, birth outcomes, and infant mortality in low-income and middle-income countries. METHODS: This two-stage meta-analysis of individual patient included data from 17 randomised controlled trials done in 14 low-income and middle-income countries, which compared multiple micronutrient supplements containing iron-folic acid versus iron-folic acid alone in 112 953 pregnant women. We generated study-specific estimates and pooled subgroup estimates using fixed-effects models and assessed heterogeneity between subgroups with the χ2 test for heterogeneity. We did sensitivity analyses using random-effects models, stratifying by iron-folic acid dose, and exploring individual study effect. FINDINGS: Multiple micronutrient supplements containing iron-folic acid provided significantly greater reductions in neonatal mortality for female neonates compared with male neonates than did iron-folic acid supplementation alone (RR 0·85, 95% CI 0·75-0·96 vs 1·06, 0·95-1·17; p value for interaction 0·007). Multiple micronutrient supplements resulted in greater reductions in low birthweight (RR 0·81, 95% CI 0·74-0·89; p value for interaction 0·049), small-for-gestational-age births (0·92, 0·87-0·97; p=0·03), and 6-month mortality (0·71, 0·60-0·86; p=0·04) in anaemic pregnant women (haemoglobin <110g/L) as compared with non-anaemic pregnant women. Multiple micronutrient supplements also had a greater effect on preterm births among underweight pregnant women (BMI <18·5 kg/m2; RR 0·84, 95% CI 0·78-0·91; p=0·01). Initiation of multiple micronutrient supplements before 20 weeks gestation provided greater reductions in preterm birth (RR 0·89, 95% CI 0·85-0·93; p=0·03). Generally, the survival and birth outcome effects of multiple micronutrient supplementation were greater with high adherence (≥95%) to supplementation. Multiple micronutrient supplements did not significantly increase the risk of stillbirth or neonatal, 6-month, or infant mortality, neither overall or in any of the 26 examined subgroups. INTERPRETATION: Antenatal multiple micronutrient supplements improved survival for female neonates and provided greater birth-outcome benefits for infants born to undernourished and anaemic pregnant women. Early initiation in pregnancy and high adherence to multiple micronutrient supplements also provided greater overall benefits. Studies should now aim to elucidate the mechanisms accounting for differences in the effect of antenatal multiple micronutrient supplements on infant health by maternal nutrition status and sex. FUNDING: None.

Effect of maternal antenatal and newborn supplementation with vitamin A on cognitive development of school-aged children in rural Bangladesh: a follow-up of a placebo-controlled, randomized trial.

Background: The impact of early vitamin A supplementation on neurodevelopmental function has not been adequately studied. In rural Bangladesh we examined cognitive and motor function and scholastic achievement in a cohort of children who were exposed to vitamin A in utero or at birth.Objective: The aim of this study was to examine independent and combined effects of antenatal and newborn supplementation with vitamin A on the cognitive function of children at 8 y of age.Design: A cohort of rural Bangladeshi children from 2 previous double-blind, placebo-controlled cluster-randomized trials were revisited at age 8 y between February 2013 and June 2014. Data on sociodemographic, social, and physical conditions; schooling; child care behavior; anthropometric measures; and cognitive function were collected with the use of various psychometric assessment tools.Results: Among 11,950 children from the parent trial who were last known to be alive, a subset of 1803 children balanced by treatment group in a selected contiguous study area were re-enrolled and 1613 (89%) provided consent for assessments. Of these, 1577 (87%) children had a complete cognitive evaluation. All groups were highly comparable on baseline variables collected in the previous trials and factors measured at re-enrollment. Overall, there was no impact of either maternal or newborn supplementation with vitamin A on intelligence, memory, and motor function. Compared with placebo, children who received both interventions had significantly better performance in reading, spelling, and math computation, with increased mean (95% CI) scores of 8.0 (2.2, 13.8), 6.8 (1.9, 11.7), and 4.8 (0.6, 9.0), respectively.Conclusions: General intelligence or memory and motor functions were not affected by antenatal or newborn supplementation with vitamin A. Scholastic performance and aspects of executive function improved when both interventions were provided. These trials were registered at clinicaltrials.gov as NCT00198822 and NCT00128557.

Early newborn ritual foods correlate with delayed breastfeeding initiation in rural Bangladesh.

BACKGROUND: Early and exclusive breastfeeding may improve neonatal survival in low resource settings, but suboptimal breastfeeding still exists in areas with high infant mortality. Prelacteal feeding, the practice of giving a non-breastmilk food as a neonate's first food, has been associated with suboptimal breastfeeding practices. We examined the association of feeding a non-breastmilk food in the first three days of life (early neonatal food, or ENF) with time from birth to initiation of breastfeeding among 25,286 Bangladeshi mother-neonate pairs, in a secondary analysis of a randomized controlled trial in northwestern rural Bangladesh conducted from 2001-2007. METHODS: Trained interviewers assessed the demographic characteristics during pregnancy. At three months postpartum, the interviewers visited participants again and retrospectively assessed demographic and breastfeeding characteristics surrounding the birth. We assessed the relationship between ENF and time to initiation of breastfeeding in hours in both unadjusted and adjusted linear regression analyses. We also calculated reverse cumulative distribution curves for time to initiation of breastfeeding and analyses were stratified by an infant's ability to breastfeed normally at birth. RESULTS: The mean ± SD time from birth to initiation of breastfeeding was 30.6 ± 27.9 hours. Only 2,535 (10.0%) of women reported initiating breastfeeding in the first hour after birth and 10,207 (40.4%) reported initiating breastfeeding in the first 12 hours after birth. In adjusted linear regression analyses, feeding ENF was associated with a significant increase in time, in hours, to breastfeeding initiation both among children not able to breastfeed at birth (37.4; 95% CI 33.3, 41.5) and among children able to breastfeed at birth (13.3; 95% CI 12.7, 14.0). CONCLUSIONS: Feeding ENF was strongly associated with delayed initiation of breastfeeding, even after adjusting for other related factors and stratifying on the neonate's ability to suckle normally after birth. More research is needed to understand the impact of these findings on optimal breastfeeding in this setting. It is possible that ENF feeding and the ability to breastfeed immediately after birth are interrelated in their respective associations to suboptimal breastfeeding initiation. This study in a large population representative of other populations in rural South Asia, demonstrates significantly longer times to breastfeeding initiation than previously appreciated, with a possible important role of ENF feeding. TRIAL REGISTRATION: The randomized controlled trial on which this analysis is based, "Impact of Maternal Vitamin A or Beta-Carotene Supplementation on Maternal and Infant Mortality in Bangladesh", was registered with ClinicalTrials.gov as trial number ID GHS-A-00-03-00019-00 and identifier NCT00198822. The identifier was first received September 12, 2005 (retrospectively registered). The first participant was enrolled in August 2001.

Effects of prenatal multiple micronutrient supplementation on growth and cognition through 2 y of age in rural Bangladesh: the JiVitA-3 Trial.

BACKGROUND: Childhood undernutrition may have prenatal origins, and the impact of prenatal interventions on postnatal growth is not well known. OBJECTIVE: We assessed the effects of prenatal multiple micronutrient (MM) supplementation on child growth and cognitive development. DESIGN: In a cluster-randomized controlled trial in rural Bangladesh, prenatal MM supplementation compared with iron-folic acid (IFA) supplementation was examined for its impact on growth assessed longitudinally from birth up to 24 mo of age (n = 8529) and, in a subsample (n = 734), on cognitive function at 24 mo of age by use of the Bayley scales of infant and toddler development-third edition test. RESULTS: Prevalence of stunting at birth [length for age z score (LAZ): <-2] was 31.9% in the MM and 35.7% in the IFA groups (P < 0.001); however, LAZ increased during the first 3-4 mo in both groups. With the use of a linear random-effects model, prenatal MM-exposed children sustained a higher mean predicted LAZ of ∼0.10 at 1 and 3 mo and 0.06 at 6 mo of age compared with children in the IFA group. Supplementation reduced the prevalence of stunting at 1 (RR: 0.95; 95% CI: 0.92, 0.98) and 3 (RR: 0.91; 95% CI: 0.88, 0.94) mo of age. Differences between groups were absent by 6, 12, and 24 mo of age, when nearly 50% of children had stunted growth. Ponderal and linear growth velocities were somewhat slower from 3 to 12 mo of age in the MM group than in the IFA group, but not from 12 to 24 mo of age. There was no difference between groups on composite scores of cognition, language, and motor performance at 24 mo of age. CONCLUSIONS: In this Bangladeshi trial, maternal pre- and postnatal MM supplementation resulted in improvements in LAZ and reduction in stunting through 3 mo of age, but not thereafter and had no impact on cognitive and motor function at 2 y. This trial was registered at clinicaltrials.gov as NCT000860470.

Maternal Dietary Diversity Decreases with Household Food Insecurity in Rural Bangladesh: A Longitudinal Analysis.

BACKGROUND: Household food insecurity (HFI) can lead to a poor diet and malnutrition. Yet, little is known about the extent to which maternal diet covaries with food insecurity during pregnancy and lactation. OBJECTIVE: Longitudinal associations between HFI and maternal dietary diversity from early pregnancy to 3 mo postpartum were examined in rural Bangladesh. METHODS: We repeatedly assessed dietary intake by using a 7-d food-frequency questionnaire in the first and third trimesters of pregnancy and at 3 mo postpartum among 14,600 women enrolled into an antenatal micronutrient supplementation trial. Maternal dietary diversity score (DDS) was constructed as the sum of 10 food groups reportedly consumed at each assessment. Households were classified at 6 mo postpartum as being food secure or having mild, moderate, or severe HFI on the basis of a 9-item standard scale. Generalized estimating equations were used to estimate the longitudinal relation between HFI status and DDS and the likelihood of individual food-group consumption, adjusting for confounders at the maternal and household levels. RESULTS: The DDS decreased with progressively worse HFI, an association best explained by a derived household wealth index. Compared with women from food-secure households, women of mild, moderate, and severe HFI were less likely, in a dose-response fashion, to have consumed dairy products [adjusted ORs (95% CIs): 0.73 (0.69, 0.78), 0.62 (0.58, 0.66), and 0.52 (0.48, 0.55), respectively], eggs [0.81 (0.76, 0.85), 0.73 (0.68, 0.77), and 0.61 (0.57, 0.65)], meat [0.83 (0.79, 0.88), 0.73 (0.69, 0.78), and 0.60 (0.56, 0.64)], fish [0.87 (0.80, 0.94), 0.76 (0.70, 0.83), and 0.59 (0.54, 0.65)], legumes and nuts [0.88 (0.83, 0.93), 0.81 (0.76, 0.87), and 0.79 (0.74, 0.85)], and yellow and orange fruit and vegetables [0.85 (0.80, 0.91), 0.78 (0.73, 0.84), and 0.72 (0.67, 0.78)]. Neither intakes of dark-green leafy vegetables nor of vegetable oil were associated with HFI status. CONCLUSION: Antenatal and postnatal maternal dietary diversity, especially intakes of animal-source foods, fruit, and vegetables, declined with worsening food insecurity in rural Bangladesh.

Effects of Prenatal Multiple Micronutrient Supplementation on Fetal Growth Factors: A Cluster-Randomized, Controlled Trial in Rural Bangladesh.

UNLABELLED: Prenatal multiple micronutrient (MM) supplementation improves birth weight through increased fetal growth and gestational age, but whether maternal or fetal growth factors are involved is unclear. Our objective was to examine the effect of prenatal MM supplementation on intrauterine growth factors and the associations between growth factors and birth outcomes in a rural setting in Bangladesh. In a double-blind, cluster-randomized, controlled trial of MM vs. iron and folic acid (IFA) supplementation, we measured placental growth hormone (PGH) at 10 weeks and PGH and human placental lactogen (hPL) at 32 weeks gestation in maternal plasma (n = 396) and insulin, insulin-like growth factor-1 (IGF-1), and IGF binding protein-1 (IGFBP-1) in cord plasma (n = 325). Birth size and gestational age were also assessed. Early pregnancy mean (SD) BMI was 19.5 (2.4) kg/m2 and birth weight was 2.68 (0.41) kg. There was no effect of MM on concentrations of maternal hPL or PGH, or cord insulin, IGF-1, or IGFBP-1. However, among pregnancies of female offspring, hPL concentration was higher by 1.1 mg/L in the third trimester (95% CI: 0.2, 2.0 mg/L; p = 0.09 for interaction); and among women with height <145 cm, insulin was higher by 59% (95% CI: 3, 115%; p = 0.05 for interaction) in the MM vs. IFA group. Maternal hPL and cord blood insulin and IGF-1 were positively, and IGFBP-1 was negatively, associated with birth weight z score and other measures of birth size (all p<0.05). IGF-1 was inversely associated with gestational age (p<0.05), but other growth factors were not associated with gestational age or preterm birth. Prenatal MM supplementation had no overall impact on intrauterine growth factors. MM supplementation altered some growth factors differentially by maternal early pregnancy nutritional status and sex of the offspring, but this should be examined in other studies. TRIAL REGISTRATION: ClinicalTrials.gov NCT00860470.

Effect of fortified complementary food supplementation on child growth in rural Bangladesh: a cluster-randomized trial.

BACKGROUND: Growth faltering in the first 2 years of life is high in South Asia where prevalence of stunting is estimated at 40-50%. Although nutrition counselling has shown modest benefits, few intervention trials of food supplementation exist showing improvements in growth and prevention of stunting. METHODS: A cluster-randomized controlled trial was conducted in rural Bangladesh to test the effect of two local, ready-to-use foods (chickpea and rice-lentil based) and a fortified blended food (wheat-soy-blend++, WSB++) compared with Plumpy'doz, all with nutrition counselling vs nutrition counselling alone (control) on outcomes of linear growth (length and length-for-age z-score, LAZ), stunting (LAZ < -2), weight-for-length z-score (WLZ) and wasting (WLZ < -2) in children 6-18 months of age. Children (n = 5536) were enrolled at 6 months of age and, in the food groups, provided with one of the allocated supplements daily for a year. RESULTS: Growth deceleration occurred from 6 to 18 months of age but deceleration in LAZ was lower (by 0.02-0.04/month) in the Plumpy'doz (P = 0.02), rice-lentil (< 0.01), and chickpea (< 0.01) groups relative to control, whereas WLZ decline was lower only in Plumpy'doz and chickpea groups. WSB++ did not impact on these outcomes. The prevalence of stunting was 44% at 18 months in the control group, but lower by 5-6% (P ≤ 0.01) in those receiving Plumpy'doz and chickpea. Mean length and LAZ at 18 months were higher by 0.27-0.30 cm and 0.07-0.10 (all P < 0.05), respectively, in all four food groups relative to the control. CONCLUSIONS: In rural Bangladesh, small amounts of daily fortified complementary foods, provided for a year in addition to nutrition counselling, modestly increased linear growth and reduced stunting at 18 months of age.

Arsenic exposure and hepatitis E virus infection during pregnancy.

BACKGROUND: Arsenic has immunomodulatory properties and may have the potential to alter susceptibility to infection in humans. OBJECTIVES: We aimed to assess the relation of arsenic exposure during pregnancy with immune function and hepatitis E virus (HEV) infection, defined as seroconversion during pregnancy and postpartum. METHODS: We assessed IgG seroconversion to HEV between 1st and 3rd trimester (TM) and 3 months postpartum (PP) among 1100 pregnancies in a multiple micronutrient supplementation trial in rural Bangladesh. Forty women seroconverted to HEV and were matched with 40 non-seroconverting women (controls) by age, parity and intervention. We assessed urinary inorganic arsenic plus methylated species (∑As) (µg/L) at 1st and 3rd TM and plasma cytokines (pg/mL) at 1st and 3rd TM and 3 months PP. RESULTS: HEV seroconverters' urinary ∑As was elevated throughout pregnancy. Non-seroconverters' urinary ∑As was similar to HEV seroconverters at 1st TM but declined at 3rd TM. The adjusted odds ratio (95% confidence interval) of HEV seroconversion was 2.17 (1.07, 4.39) per interquartile range (IQR) increase in average-pregnancy urinary ∑As. Increased urinary ∑As was associated with increased concentrations of IL-2 during the 1st and 3rd TM and 3 months PP among HEV seroconverters but not non-seroconverters. CONCLUSIONS: The relation of urinary arsenic during pregnancy with incident HEV seroconversion and with IL-2 levels among HEV-seroconverting pregnant women suggests arsenic exposure during pregnancy may enhance susceptibility to HEV infection.

First-trimester plasma tocopherols are associated with risk of miscarriage in rural Bangladesh.

BACKGROUND: Tocopherols were discovered for their role in animal reproduction, but little is known about the contribution of deficiencies of vitamin E to human pregnancy loss. OBJECTIVE: We sought to determine whether higher first-trimester concentrations of α-tocopherol and γ-tocopherol were associated with reduced odds of miscarriage (pregnancy losses <24 wk of gestation) in women in rural Bangladesh. DESIGN: A case-cohort study in 1605 pregnant Bangladeshi women [median (IQR) gestational age: 10 wk (8-13 wk)] who participated in a placebo-controlled vitamin A- or ß-carotene-supplementation trial was done to assess ORs of miscarriage in women with low α-tocopherol (<12.0 µmol/L) and γ-tocopherol (<0.81 µmol/L; upper tertile cutoff of the γ-tocopherol distribution in women who did not miscarry). RESULTS: In all women, plasma α- and γ-tocopherol concentrations were low [median (IQR): 10.04 µmol/L (8.07-12.35 µmol/L) and 0.66 µmol/L (0.50-0.95 µmol/L), respectively]. In a logistic regression analysis that was adjusted for cholesterol and the other tocopherol, low α-tocopherol was associated with an OR of 1.83 (95% CI: 1.04, 3.20), whereas a low γ-tocopherol concentration was associated with an OR of 0.62 (95% CI: 0.41, 0.93) for miscarriage. Subgroup analyses revealed that opposing ORs were evident only in women with BMI (in kg/m(2)) ≥18.5 and serum ferritin concentration ≤150 µg/L, although low BMI and elevated ferritin conferred stronger risk of miscarriage. CONCLUSIONS: In pregnant women in rural Bangladesh, low plasma α-tocopherol was associated with increased risk of miscarriage, and low γ-tocopherol was associated with decreased risk of miscarriage. Maternal vitamin E status in the first trimester may influence risk of early pregnancy loss. The JiVitA-1 study, from which data for this report were derived, was registered at clinicaltrials.gov as NCT00198822.

Effect of maternal multiple micronutrient vs iron-folic acid supplementation on infant mortality and adverse birth outcomes in rural Bangladesh: the JiVitA-3 randomized trial.

IMPORTANCE: Maternal micronutrient deficiencies may adversely affect fetal and infant health, yet there is insufficient evidence of effects on these outcomes to guide antenatal micronutrient supplementation in South Asia. OBJECTIVE: To assess effects of antenatal multiple micronutrient vs iron-folic acid supplementation on 6-month infant mortality and adverse birth outcomes. DESIGN, SETTING, AND PARTICIPANTS: Cluster randomized, double-masked trial in Bangladesh, with pregnancy surveillance starting December 4, 2007, and recruitment on January 11, 2008. Six-month infant follow-up ended August 30, 2012. Surveillance included 127,282 women; 44,567 became pregnant and were included in the analysis and delivered 28,516 live-born infants. Median gestation at enrollment was 9 weeks (interquartile range, 7-12). INTERVENTIONS: Women were provided supplements containing 15 micronutrients or iron-folic acid alone, taken daily from early pregnancy to 12 weeks postpartum. MAIN OUTCOMES AND MEASURES: The primary outcome was all-cause infant mortality through 6 months (180 days). Prespecified secondary outcomes in this analysis included stillbirth, preterm birth (<37 weeks), and low birth weight (<2500 g). To maintain overall significance of α = .05, a Bonferroni-corrected α = .01 was calculated to evaluate statistical significance of primary and 4 secondary risk outcomes (.05/5). RESULTS: Among the 22,405 pregnancies in the multiple micronutrient group and the 22,162 pregnancies in the iron-folic acid group, there were 14,374 and 14,142 live-born infants, respectively, included in the analysis. At 6 months, multiple micronutrients did not significantly reduce infant mortality; there were 764 deaths (54.0 per 1000 live births) in the iron-folic acid group and 741 deaths (51.6 per 1000 live births) in the multiple micronutrient group (relative risk [RR], 0.95; 95% CI, 0.86-1.06). Multiple micronutrient supplementation resulted in a non-statistically significant reduction in stillbirths (43.1 vs 48.2 per 1000 births; RR, 0.89; 95% CI, 0.81-0.99; P = .02) and significant reductions in preterm births (18.6 vs 21.8 per 100 live births; RR, 0.85; 95% CI, 0.80-0.91; P < .001) and low birth weight (40.2 vs 45.7 per 100 live births; RR, 0.88; 95% CI, 0.85-0.91; P < .001). CONCLUSIONS AND RELEVANCE: In Bangladesh, antenatal multiple micronutrient compared with iron-folic acid supplementation did not reduce all-cause infant mortality to age 6 months but resulted in a non-statistically significant reduction in stillbirths and significant reductions in preterm births and low birth weight. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00860470.