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BACKGROUND: Copper (Cu), an essential trace mineral regulating multiple actions of inflammation and oxidative stress, has been implicated in risk for preterm birth (PTB). OBJECTIVES: This study aimed to determine the association of maternal Cu concentration during pregnancy with PTB risk and gestational duration in a large multicohort study including diverse populations. METHODS: Maternal plasma or serum samples of 10,449 singleton live births were obtained from 18 geographically diverse study cohorts. Maternal Cu concentrations were determined using inductively coupled plasma mass spectrometry. The associations of maternal Cu with PTB and gestational duration were analyzed using logistic and linear regressions for each cohort. The estimates were then combined using meta-analysis. Associations between maternal Cu and acute-phase reactants (APRs) and infection status were analyzed in 1239 samples from the Malawi cohort. RESULTS: The maternal prenatal Cu concentration in our study samples followed normal distribution with mean of 1.92 μg/mL and standard deviation of 0.43 μg/mL, and Cu concentrations increased with gestational age up to 20 wk. The random-effect meta-analysis across 18 cohorts revealed that 1 μg/mL increase in maternal Cu concentration was associated with higher risk of PTB with odds ratio of 1.30 (95% confidence interval [CI]: 1.08, 1.57) and shorter gestational duration of 1.64 d (95% CI: 0.56, 2.73). In the Malawi cohort, higher maternal Cu concentration, concentrations of multiple APRs, and infections (malaria and HIV) were correlated and associated with greater risk of PTB and shorter gestational duration. CONCLUSIONS: Our study supports robust negative association between maternal Cu and gestational duration and positive association with risk for PTB. Cu concentration was strongly correlated with APRs and infection status suggesting its potential role in inflammation, a pathway implicated in the mechanisms of PTB. Therefore, maternal Cu could be used as potential marker of integrated inflammatory pathways during pregnancy and risk for PTB.

BackgroundAflatoxin (AF) exposure is associated with child growth faltering in cross-sectional studies, with limited findings from longitudinal studies.ObjectivesTo evaluate the relationship between maternal AF B1-lysine adduct concentration, child AF B1-lysine adduct concentration, and child growth in the first 30 mo of life.MethodsAF B1-lysine adduct was measured in mother-child dyad plasma samples using isotope dilution mass spectrometry. Using linear regression, we assessed the relationship between AF B1-lysine adduct concentration and child weight, height, and head and mid-upper arm circumferences at 1 wk, 6, 12, 18, 24, and 30 mo of age.ResultsIn adjusted models, maternal prenatal AF B1-lysine adduct (pg/μL) was positively associated with newborn anthropometric outcomes; largest beta coefficients for associations between standardized values were for newborn weight-for-age z-score [β = 0.13; 95% confidence interval (CI): 0.02, 0.24; P < 0.05 and β = 0.11; 95% CI: 0.00, 0.22; P < 0.05 for second and third trimester AF, respectively]. Child AF B1-lysine adduct (pg/μL) at 6 mo was negatively associated with head circumference-for-age z-score at 6, 18, 24, and 30 mo, with beta coefficients ranging from β = -0.15; 95% CI: -0.28, -0.02 to β = -0.17; 95% CI: -0.31, -0.03; P < 0.05); 18-mo AF was negatively associated with anthropometric outcomes at 18, 24, and 30 mo, most consistently with length-for-age z-score (β = -0.18; 95% CI: -0.32, -0.04, β = -0.21; 95% CI: -0.35, -0.07, β = -0.18; 95% CI: -0.32, -0.03 at 18, 24 and 30 mo, respectively).ConclusionsChild AF exposure was associated with impaired child growth, but maternal AF exposure was not. Exposure during infancy was linked to persistent deficit in head circumference, implying reduced brain size lasting beyond the age of 2 years. Exposure at 18 mo was linked to persistent linear growth deficit. Further research should elucidate mechanisms through which AF affects child growth.

Little is known about the impact of small-quantity lipid-based nutrient supplements (SQ-LNSs) on maternal morbidity. This secondary outcome analysis aimed to compare morbidity symptoms among women in two trials evaluating the efficacy of SQ-LNSs. From enrolment (≤20-week gestation) to 6 months postpartum, Ghanaian (n = 1320) and Malawian (n = 1391) women were assigned to consume daily: 60 mg iron and 400 µg folic acid until childbirth and placebo thereafter (iron and folic acid [IFA] group); or multiple micronutrients (MMN); or 20 g/day SQ-LNSs. Within country, we used repeated measures logistic regression and analysis of variance models to compare group differences in the period prevalence and percentage of days of monitoring when women had fever, gastrointestinal, reproductive, and respiratory symptoms during the second and third trimesters of pregnancy (n ~ 1243 in Ghana, 1200 in Malawi) and 0-3 and 3-6 months postpartum (n ~ 1212 in Ghana, 730 in Malawi). Most outcomes did not differ significantly among groups, with the following exceptions: in Ghana, overall, the prevalence of vomiting was lower in the LNS (21.5%) than MMN (25.6%) group, with the IFA group (23.2%) in-between (p = 0.046); mean ± SD percentage of days with nausea was greater in the LNS (3.5 ± 10.3) and MMN (3.3 ± 10.4) groups than the IFA (2.7 ± 8.3) group (p = 0.002). In Malawi, during 3-6 month postpartum, the prevalence of severe diarrhoea was greater in the LNS (8.1%) than the MMN (2.9%) group, with IFA (4.6%) in-between, p = 0.041). We conclude that the type of nutrient supplement received during pregnancy and lactation generally does not influence morbidity symptoms in these settings. Clinicaltrials.gov identifiers: NCT00970866; NCT01239693.

BACKGROUND: Low birth weight (LBW) is associated with neonatal mortality and sequelae of lifelong health problems; prioritizing the most promising antenatal interventions may guide resource allocation and improve health outcomes. OBJECTIVE: We sought to identify the most promising interventions that are not yet included in the policy recommendations of the World Health Organization (WHO) but could complement antenatal care and reduce the prevalence of LBW and related adverse birth outcomes in low- and middle-income settings. METHODS: We utilized an adapted Child Health and Nutrition Research Initiative (CHNRI) prioritization method. RESULTS: In addition to procedures already recommended by WHO for the prevention of LBW, we identified six promising antenatal interventions that are not currently recommended by WHO with an indication for LBW prevention, namely: (1) provision of multiple micronutrients; (2) low-dose aspirin; (3) high-dose calcium; (4) prophylactic cervical cerclage; (5) psychosocial support for smoking cessation; and (6) other psychosocial support for targeted populations and settings. We also identified seven interventions for further implementation research and six interventions for efficacy research. CONCLUSION: These promising interventions, coupled with increasing coverage of currently recommended antenatal care, could accelerate progress toward the global target of a 30% reduction in the number of LBW infants born in 2025 compared to 2006-10.

Inadequate diet and frequent symptomatic infections are considered major causes of growth stunting in low-income countries, but interventions targeting these risk factors have achieved limited success. Asymptomatic infections can restrict growth, but little is known about their role in global stunting prevalence. We investigated factors related to length-for-age Z-score (LAZ) at 24 months by constructing an interconnected network of various infections, biomarkers of inflammation (as assessed by alpha-1-acid glycoprotein [AGP]), and growth (insulin-like growth factor 1 [IGF-1] and collagen X biomarker [CXM]) at 18 months, as well as other children, maternal, and household level factors. Among 604 children, there was a continuous decline in mean LAZ and increased mean length deficit from birth to 24 months. At 18 months of age, the percentage of asymptomatic children who carried each pathogen was: 84.5% enterovirus, 15.5% parechovirus, 7.7% norovirus, 4.6% rhinovirus, 0.6% rotavirus, 69.6% Campylobacter, 53.8% Giardia lamblia, 11.9% malaria parasites, 10.2% Shigella, and 2.7% Cryptosporidium. The mean plasma IGF-1 concentration was 12.5 ng/ml and 68% of the children had systemic inflammation (plasma AGP concentration >1 g/L). Shigella infection was associated with lower LAZ at 24 months through both direct and indirect pathways, whereas enterovirus, norovirus, Campylobacter, Cryptosporidium, and malaria infections were associated with lower LAZ at 24 months indirectly, predominantly through increased systemic inflammation and reduced plasma IGF-1 and CXM concentration at 18 months.

BackgroundMeta-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.ObjectivesWe 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).MethodsWe 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.ResultsSQ-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.ConclusionsIncluding 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.

In populations with a high prevalence of childhood and adolescent undernutrition, supplementation during pregnancy aiming at improving maternal nutritional status and preventing fetal growth restriction might theoretically lead to cephalopelvic disproportion and delivery complications. We investigated whether the prenatal provision of small-quantity lipid-based nutrient supplements (SQ-LNS) was associated with an increased risk of caesarean section (CS) or other delivery complications. Pregnant Malawian women were randomised to receive daily i) iron-folic acid (IFA) capsule (control), ii) multiple micronutrient (MMN) capsule of 18 micronutrients (second control), or iii) SQ-LNS with similar micronutrients as MMN, plus four minerals and macronutrients contributing 118 kcal. We analysed the associations of SQ-LNS, CS, and other delivery complications using log-binomial regressions. Among 1391 women enrolled, 1255 had delivery information available. The incidence of CS and delivery complications was 6.3% and 8.2%, respectively. The incidence of CS was 4.0%, 6.0%, and 8.9% (p = 0.017) in the IFA, MMN, and LNS groups, respectively. Compared to the IFA group, the relative risk (95% confidence interval) of CS was 2.2 (1.3-3.8) (p = 0.006) in the LNS group and 1.5 (0.8-2.7) (p = 0.200) in the MMN group. We found no significant differences for other delivery complications. Provision of SQ-LNS to pregnant women may have increased the incidence of CS. The baseline rate was, however, lower than recommended. It is unclear if the higher CS incidence in the SQ-LNS group resulted from increased obstetric needs or more active health seeking and a better supply of services. Trial registered at clinicaltrials.gov, NCT01239693.

Lipid-based nutrient supplements (LNS) have been found to improve child growth and reduce child mortality. However, the mechanistic pathways for these improvements warrant exploration. One potential pathway is linked to improvement in intestinal health. Our study aimed to test a hypothesis that small-quantity LNS (SQ-LNS) could reduce the levels of intestinal inflammation, repair and permeability of children. As intestinal health markers we measured fecal calprotectin, regenerating 1B protein (REG1B) and alpha-1-antitrypsin concentrations at 18 months of age (after 12 months of supplementation) and 1 year later (12 months after cessation of supplementation). In this analysis, we included data of 735 children who participated in a randomised dietary supplementation trial in rural Malawi; 243 children who received 20 g/day SQ-LNS from 6 to 18 months of age were in the SQ-LNS group, while the others who received no dietary supplementation during this period were in the control group. At 18 months of age, the mean concentrations of calprotectin, REG1B and alpha-1-antitrypsin were 241, 105 µg/g and 7.1 mg/dl, respectively, in the SQ-LNS group, and 224, 105 µg/g and 7.4 mg/dl, respectively, in the control group, and did not differ between the SQ-LNS and control groups. We conclude that SQ-LNS provision did not have an impact on children's intestinal health in rural Malawi.

BackgroundPregnant women in Malawi are at risk of selenium deficiency, which can have adverse effects on pregnancy outcomes. Interventions for improving selenium status are needed.ObjectivesTo assess the effect of provision of small-quantity lipid-based nutrient supplements (SQ-LNSs) to Malawian women during pregnancy on their plasma selenium concentrations at 36 wk of gestation.MethodsPregnant women (≤20 wk of gestation) were randomly assigned to receive daily either: 1) iron and folic acid (IFA); 2) multiple micronutrients (MMN; 130 µg selenium per capsule); or 3) SQ-LNS (130 µg selenium/20 g). Plasma selenium concentrations were measured by inductively coupled plasma mass spectrometry at baseline and after ≥16 wk of intervention (at 36 wk of gestation) and compared by intervention group.ResultsAt 36 wk of gestation, median (quartile 1, quartile 3) plasma selenium concentrations (micromoles per liter) were 0.96 (0.73, 1.23), 0.94 (0.78, 1.18), and 1.01 (0.85, 1.28) in the IFA, MMN, and SQ-LNS groups, respectively. Geometric mean (GM) plasma selenium concentration was 5.4% (95% CI: 1.8%, 9.0%) higher in the SQ-LNS group than in the MMN group and tended to be higher than in the IFA group (+4.2%; 95% CI: 1.0%, 7.8%). The prevalence of adjusted plasma selenium concentrations

BackgroundEnvironmental enteric dysfunction (EED) is common in low- and middle-income countries and associated with childhood undernutrition. The composition of gut microbiota has been implicated in the pathogenesis of EED. Our aim was to assess the associations between gut microbiota and EED biomarkers in rural Malawian children. We hypothesized that there would be an inverse association between microbiota maturity and diversity and fecal concentrations of EED biomarkers.MethodsWe used data from fecal samples collected at 6, 18 and 30 months from 611 children who were followed up during a nutrition intervention trial. The primary time point for analysis was 18 months. Microbiota data were obtained through 16S rRNA sequencing and variables included microbiota maturity and diversity, phylogenetic dissimilarity and relative abundances of individual taxa. EED biomarkers included calprotectin (marker of inflammation), alpha-1 antitrypsin (intestinal permeability) and REG1B (intestinal damage).ResultsThere was an inverse association between microbiota maturity and diversity and fecal concentrations of all 3 EED biomarkers at 18 months (p≤0.001). The results were similar at 30 months, while at 6 months inverse associations were found only with calprotectin and alpha-1 antitrypsin concentrations. At 18 months, EED biomarkers were not associated with phylogenetic dissimilarity, but at 6 and 30 months several associations were observed. Individual taxa predicting EED biomarker concentrations at 18 months included several Bifidobacterium and Enterobacteriaceae taxa as well as potentially displaced oral taxa.ConclusionsOur findings support the hypothesis of an inverse association between microbiota maturity and diversity and EED in rural Malawian children.

BackgroundIn utero or early-life exposure to aflatoxin, which contaminates staple crops in disadvantaged settings, may compromise pregnancy and infant outcomes, but investigations into the extent, persistence, and determinants of aflatoxin exposure at these life stages have lacked longitudinal data collection and broad geographic representation.ObjectivesAflatoxin exposure and selected determinants thereof were characterized in mother-child dyads with serial plasma/serum samples in prenatal, perinatal, and early life in Malawi and Bangladesh.MethodsCirculating aflatoxin B1 (AFB1)-lysine albumin adducts were measured in dyads from Bangladesh (n = 573; maternal first and third trimester, 3 mo postpartum, cord blood, infant 24 mo) and Malawi (n = 255; maternal second and third trimester, 6 mo postpartum, infant 6 and 18 mo) with isotope dilution mass spectrometry. We examined AFB1-lysine adduct magnitude, persistence, seasonality, and associations with infant feeding, and estimated daily AFB1 intake.ResultsMaternal AFB1-lysine was higher in Malawi (98% detectable; median: 0.469, IQR: 0.225-1.027 pg/µL) than in Bangladesh (59%; 0.030, nondetectable [nd]-0.077 pg/µL). Although estimated dietary exposure in Malawi was temporally stable (648 ng AFB1/day), estimated intake in Bangladesh was reduced by 94% between rainy and winter seasons (98 to 6 ng/day). AFB1-lysine was low in cord blood from Bangladesh (15% detectable; 0.045, 0.031-0.088 pg/µL among detectable) and in Malawian infants at 6 mo of age (0.072, nd-0.236 pg/µL), but reached maternal concentrations by 18 or 24 mo (Bangladesh: 0.034, nd-0.063 pg/µL; Malawi: 0.370, 0.195-0.964 pg/µL). In Malawian infants, exclusive breastfeeding at 3 mo was associated with 58% lower AFB1-lysine concentrations at 6 mo compared with other feeding modes (P = 0.010).ConclusionsAmong pregnant women, aflatoxin exposure was persistently high in Malawi, while lower and seasonal in Bangladesh. Infants were partially protected from exposure in utero and with exclusive breastfeeding, but exposures reached adult levels by 18-24 mo of age. The Bangladesh and Malawi trials are registered at clinicaltrials.gov as NCT00860470 and NCT01239693.

BackgroundPrevious studies show an association between maternal plasma and salivary cortisol and preterm birth but have been primarily conducted in high-income countries. It is unknown whether salivary cortisol is a risk factor for preterm birth in Ghana. Our objective was to determine whether maternal salivary cortisol during pregnancy was associated with pregnancy duration and preterm delivery in Ghana.MethodsWe conducted a cohort study of 783 pregnant women in Ghana. We measured salivary cortisol at baseline (mean 16 wk), 28 wk., and 36 wk. gestation. Pregnancy duration was determined primarily by ultrasound. We used adjusted linear regression models to examine the association between cortisol and pregnancy duration and Poisson regression models to determine the risk of preterm delivery among women with high cortisol at baseline or 28 wk. gestation.ResultsMean pregnancy duration was 39.4 ± 1.8 wk. and 6.6% had a preterm delivery. Mean maternal cortisol increased throughout pregnancy, from 4.9 ± 2.7 nmol/L at baseline (16 wk) to 6.4 ± 3.2 nmol/L at 28 wk. and 7.9 ± 3.0 nmol/L at 36 wk. gestation. In adjusted analyses, higher cortisol concentrations at baseline (β = - 0.39, p = .002) and 28 wk. (β = - 0.49, p = .001), but not 36 wk. (β = - 0.23, p = .084) were associated with a shorter pregnancy duration. Women with high cortisol at baseline (> 6.3 nmol/L) had an increased relative risk of preterm delivery (RR (95% CI): 1.96 (1.13, 3.40)), but the association between high cortisol at 28 wk. and preterm delivery was not significant. There was a significant interaction with fetal sex (p-for-interaction = 0.037): among women carrying male fetuses, high cortisol at baseline increased the risk of preterm delivery threefold (3.18 (1.51, 6.71)) while there was no association (1.17 (0.50, 2.74)) among women carrying female fetuses.ConclusionHigher maternal cortisol is associated with a shorter pregnancy duration and an increased risk of preterm delivery. Subgroup analysis by fetal sex revealed that this association is evident primarily among women carrying male fetuses. Future studies of cortisol and preterm delivery should include consideration of fetal sex as a potential effect modifier.

BackgroundMeta-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.ObjectivesWe aimed to identify study-level and individual-level modifiers of the effect of SQ-LNSs on child growth outcomes.MethodsWe 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.ResultsSQ-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) (

BackgroundSmall-quantity (SQ) lipid-based nutrient supplements (LNSs) provide many nutrients needed for brain development.ObjectivesWe aimed to generate pooled estimates of the effect of SQ-LNSs on developmental outcomes (language, social-emotional, motor, and executive function), and to identify study-level and individual-level modifiers of these effects.MethodsWe conducted a 2-stage meta-analysis of individual participant data from 14 intervention against control group comparisons in 13 randomized trials of SQ-LNSs provided to children age 6-24 mo (total n = 30,024).ResultsIn 11-13 intervention against control group comparisons (n = 23,588-24,561), SQ-LNSs increased mean language (mean difference: 0.07 SD; 95% CI: 0.04, 0.10 SD), social-emotional (0.08; 0.05, 0.11 SD), and motor scores (0.08; 95% CI: 0.05, 0.11 SD) and reduced the prevalence of children in the lowest decile of these scores by 16% (prevalence ratio: 0.84; 95% CI: 0.76, 0.92), 19% (0.81; 95% CI: 0.74, 0.89), and 16% (0.84; 95% CI: 0.76, 0.92), respectively. SQ-LNSs also increased the prevalence of children walking without support at 12 mo by 9% (1.09; 95% CI: 1.05, 1.14). Effects of SQ-LNSs on language, social-emotional, and motor outcomes were larger among study populations with a higher stunting burden (≥35%) (mean difference: 0.11-0.13 SD; 8-9 comparisons). At the individual level, greater effects of SQ-LNSs were found on language among children who were acutely malnourished (mean difference: 0.31) at baseline; on language (0.12), motor (0.11), and executive function (0.06) among children in households with lower socioeconomic status; and on motor development among later-born children (0.11), children of older mothers (0.10), and children of mothers with lower education (0.11).ConclusionsChild SQ-LNSs can be expected to result in modest developmental gains, which would be analogous to 1-1.5 IQ points on an IQ test, particularly in populations with a high child stunting burden. Certain groups of children who experience higher-risk environments have greater potential to benefit from SQ-LNSs in developmental outcomes.This trial was registered at www.crd.york.ac.uk/PROSPERO as CRD42020159971.

BackgroundSmall-quantity lipid-based nutrient supplements (SQ-LNSs) have been shown to reduce the prevalence of child anemia and iron deficiency, but effects on other micronutrients are less well known. Identifying subgroups who benefit most from SQ-LNSs could support improved program design.ObjectivesWe aimed to identify study-level and individual-level modifiers of the effect of SQ-LNSs on child hemoglobin (Hb), anemia, and inflammation-adjusted micronutrient status outcomes.MethodsWe conducted a 2-stage meta-analysis of individual participant data from 13 randomized controlled trials of SQ-LNSs provided to children 6-24 mo of age (n = 15,946). We generated study-specific and subgroup estimates of SQ-LNSs compared with control, and pooled the estimates using fixed-effects models. We used random-effects meta-regression to examine potential study-level effect modifiers.ResultsSQ-LNS provision decreased the prevalence of anemia (Hb < 110 g/L) by 16% (relative reduction), iron deficiency (plasma ferritin < 12 µg/L) by 56%, and iron deficiency anemia (IDA; Hb < 110 g/L and plasma ferritin 12 mo and provided 9 (as opposed to

BackgroundSelenium (Se), an essential trace mineral, has been implicated in preterm birth (PTB). We aimed to determine the association of maternal Se concentrations during pregnancy with PTB risk and gestational duration in a large number of samples collected from diverse populations.MethodsGestational duration data and maternal plasma or serum samples of 9946 singleton live births were obtained from 17 geographically diverse study cohorts. Maternal Se concentrations were determined by inductively coupled plasma mass spectrometry analysis. The associations between maternal Se with PTB and gestational duration were analysed using logistic and linear regressions. The results were then combined using fixed-effect and random-effect meta-analysis.FindingsIn all study samples, the Se concentrations followed a normal distribution with a mean of 93.8 ng/mL (SD: 28.5 ng/mL) but varied substantially across different sites. The fixed-effect meta-analysis across the 17 cohorts showed that Se was significantly associated with PTB and gestational duration with effect size estimates of an OR=0.95 (95% CI: 0.9 to 1.00) for PTB and 0.66 days (95% CI: 0.38 to 0.94) longer gestation per 15 ng/mL increase in Se concentration. However, there was a substantial heterogeneity among study cohorts and the random-effect meta-analysis did not achieve statistical significance. The largest effect sizes were observed in UK (Liverpool) cohort, and most significant associations were observed in samples from Malawi.InterpretationWhile our study observed statistically significant associations between maternal Se concentration and PTB at some sites, this did not generalise across the entire cohort. Whether population-specific factors explain the heterogeneity of our findings warrants further investigation. Further evidence is needed to understand the biologic pathways, clinical efficacy and safety, before changes to antenatal nutritional recommendations for Se supplementation are considered.

ObjectivesInadequate iodine intake during pregnancy increases the risk of neonatal morbidity and mortality. We aimed to evaluate whether prenatal supplements containing iodine affect urinary iodine concentrations (UIC) of pregnant women in Malawi.DesignA randomised controlled trial. Pregnant women (n 1391) were assigned to consume 60 mg/d Fe and 400 µg/d folic acid (IFA) or 18 vitamins and minerals including 250 µg/d iodine (MMN) or 20 g/d small-quantity lipid-based nutrient supplements (SQ-LNS) with similar nutrient contents as MMN group, plus macronutrients (LNS) until childbirth. In a sub-study (n 317), we evaluated group geometric mean urinary iodine concentration (UIC) (µg/L) at 36 weeks of gestation controlling for baseline UIC and compared median (baseline) and geometric mean (36 weeks) UIC with WHO cut-offs: UIC < 150, 150-249, 250-499 and ≥500 reflecting insufficient, adequate, above requirements and excessive iodine intakes, respectively.SettingMangochi District, Malawi.ParticipantsWomen ≤20 weeks pregnant.ResultsGroups had comparable background characteristics. At baseline, overall median (Q1, Q3) UIC (319 (167, 559)) suggested iodine intakes above requirements. At 36 weeks, the geometric mean (95 % CI) UIC of the IFA (197 (171, 226)), MMN (212 (185, 243)) and LNS (220 (192, 253)) groups did not differ (P = 0·53) and reflected adequate intakes.ConclusionsIn this setting, provision of supplements containing iodine at the recommended dose to pregnant women with relatively high iodine intakes at baseline, presumably from iodised salt, has no impact on the women's UIC. Regular monitoring of the iodine status of pregnant women in such settings is advisable. Clinicaltrials.gov identifier: NCT01239693.

BackgroundIt is unknown whether prenatal lipid-based nutrient supplements (LNSs) affect blood pressure (BP). Associations between hypertension and birth outcomes using recently updated BP cutoffs are undetermined.ObjectivesWe aimed to assess the impact of LNSs on maternal hypertension and associations between hypertension and birth outcomes.MethodsPregnant Ghanaian women at ≤20 weeks of gestation (n = 1320) were randomly assigned to receive daily 1) iron and folic acid (IFA), 2) multiple micronutrients (MMN), or 3) LNSs until delivery. BP was measured at enrollment and 36 weeks of gestation. We analyzed the effect of LNSs on BP using ANOVA and associations between hypertension [systolic BP (SBP) ≥130 mm Hg or diastolic BP (DBP) ≥80 mm Hg] and birth outcomes by linear and logistic regressions.ResultsMean ± SD SBP and DBP were 110 ± 11 and 63 ± 8 mm Hg at 36 weeks of gestation and did not differ by supplementation group (SBP, P > 0.05; DBP, P > 0.05). At enrollment, higher DBP was associated with lower birth weight and shorter gestation; women with high DBP had greater risk of low birth weight (LBW) [risk ratio (RR): 2.58; 95% CI: 1.09, 6.08] and preterm birth (PTB) (RR: 3.30; 95% CI: 1.47, 7.40). At 36 weeks of gestation, higher SBP was associated with lower birth weight, length, and head circumference and shorter gestation; higher DBP was associated with lower birth weight and length; and women with high DBP had greater risk of LBW (RR: 3.39; 95% CI: 1.32, 8.69). Neither high SBP nor hypertension were associated with birth outcomes at either time point.ConclusionsDaily provision of LNSs does not affect maternal hypertension, compared with IFA and MMN. Higher SBP and DBP are associated with a shorter gestation and smaller birth size; however, only high DBP is associated with LBW and PTB. The new BP cutoffs may help identify pregnancies at risk of adverse birth outcomes.This trial was registered at clinicaltrials.gov as NCT00970866.

BackgroundHuman milk oligosaccharides (HMOs) and bioactive proteins likely benefit infant health, but information on these relations is sparse.ObjectivesWe aimed to examine associations of milk content of HMOs and bioactive proteins with incidence and longitudinal prevalence of infant morbidity (any illness, fever, diarrhea, acute respiratory infection, and loss of appetite) and markers of inflammation [C-reactive protein (CRP) and α-1-acid glycoprotein (AGP)]. These are secondary analyses of a randomized controlled trial.MethodsBreast milk samples at 6 mo postpartum (n  = 659) were analyzed to quantify absolute abundance of HMOs, relative abundance of fucosylated HMOs, sialylated HMOs, and 51 individual HMOs, and concentrations of 6 bioactive proteins (lactalbumin, lactoferrin, lysozyme, antitrypsin, IgA, and osteopontin). We examined associations of these constituents with infant morbidity from 6 to 7 and 6 to 12 mo, and CRP and AGP at 6 and 18 mo, considering maternal secretor status [presence or absence of the functional enzyme encoded by the fucosyltransferase 2 gene (FUT2) ] and adjusting for covariates and multiple hypothesis testing.ResultsIn secretors there were positive associations between total HMOs and longitudinal prevalence of fever (P = 0.032), between fucosylated HMOs and incidence of diarrhea (P = 0.026), and between lactoferrin and elevated CRP at 18 mo (P = 0.011). In nonsecretors, there were inverse associations between lactoferrin and incidence of fever (P  = 0.007), between osteopontin and longitudinal prevalence of lost appetite (P  = 0.038), and between fucosylated HMOs and incidence of diarrhea (P = 0.025), lost appetite (P = 0.019), and concentrations of AGP and CRP at 6 mo (P = 0.001 and 0.010); and positive associations between total HMOs and incidence of lost appetite (P = 0.024) and elevated CRP at 18 mo (P  = 0.026), between lactalbumin and incidence of diarrhea (P = 0.006), and between lactoferrin and elevated CRP at 18 mo (P = 0.015).ConclusionsCertain HMOs and bioactive proteins were associated with infant morbidity and inflammation, particularly in nonsecretors. Further research is needed to elucidate the causality of these relations.This trial was registered at clinicaltrials.gov as NCT01239693.

BackgroundVitamin A (VA) deficiency is prevalent in preschool-aged children in sub-Saharan Africa.ObjectivesWe assessed the effect of small-quantity lipid-based nutrient supplements (SQ-LNS) given to women during pregnancy and lactation and their children from 6 to 18 mo of age on women's plasma and milk retinol concentrations in Malawi, and children's plasma retinol concentration in Malawi and Ghana.MethodsPregnant women (≤20 wk of gestation) were randomized to receive daily: 1) iron and folic acid (IFA) during pregnancy only; 2) multiple micronutrients (MMN; 800 μg retinol equivalent (RE)/capsule), or 3) SQ-LNS (800 μg RE/20g) during pregnancy and the first 6 mo postpartum. Children of mothers in the SQ-LNS group received SQ-LNS (400 μg RE/20 g) from 6 to 18 mo of age; children of mothers in the IFA and MMN groups received no supplement. Plasma retinol was measured in mothers at ≤20 and 36 wk of gestation and 6 mo postpartum, and in children at 6 and 18 mo of age. Milk retinol was measured at 6 mo postpartum. VA status indicators were compared by group.ResultsAmong Malawian mothers, geometric mean (95% CI) plasma retinol concentrations at 36 wk of gestation and 6 mo postpartum were 0.97 μmol/L (0.94, 1.01 μmol/L) and 1.35 μmol/L (1.31, 1.39 μmol/L), respectively; geometric mean (95% CI) milk retinol concentration at 6 mo postpartum was 1.04 μmol/L (0.97, 1.13 μmol/L); results did not differ by intervention group. Geometric mean (95% CI) plasma retinol concentrations for Malawian children at 6 and 18 mo of age were 0.78 μmol/L (0.75, 0.81 μmol/L) and 0.81 μmol/L (0.78, 0.85 μmol/L), respectively, and for Ghanaian children they were 0.85 μmol/L (0.82, 0.88 μmol/L) and 0.88 μmol/L (0.85, 0.91 μmol/L), respectively; results did not differ by intervention group in either setting.ConclusionsSQ-LNS had no effect on VA status of mothers or children, possibly because of low responsiveness of the VA status indicators.

BackgroundInsulin-like growth factor I (IGF-I) is the most important hormonal promoter of linear growth in infants and young children.ObjectivesThe objectives of this study were to compare plasma IGF-I concentration in a low- compared with a high-income country and characterize biological pathways leading to reduced IGF-I concentration in children in a low-income setting.MethodsWe analyzed plasma IGF-I concentration from 716 Malawian and 80 Finnish children at 6-36 mo of age. In the Malawian children, we studied the association between IGF-I concentration and their environmental exposures; nutritional status; systemic and intestinal inflammation; malaria parasitemia and viral, bacterial, and parasitic enteric infections; as well as growth at 18 mo of age. We then conducted a pathway analysis to identify direct and indirect associations between these predictors and IGF-I concentration.ResultsThe mean IGF-I concentrations were similar in Malawi and Finland among 6-mo-old infants. At age 18 mo, the mean ± SD concentration was almost double among the Finns compared with the Malawians [24.2 ± 11.3 compared with 12.5 ± 7.7 ng/mL, age- and sex-adjusted difference in mean (95% CI): 11.8 (9.9, 13.7) ng/mL; P

BackgroundHuman milk oligosaccharides (HMOs) and bioactive breast milk proteins have many beneficial properties. Information is sparse regarding associations between these milk constituents and infant growth and development in lower-income countries.ObjectivesWe aimed to examine associations of milk content of HMOs and bioactive proteins at 6 mo postpartum with infant growth and motor and cognitive development. These are secondary analyses of a randomized controlled trial in rural Malawi.MethodsBreast milk samples were analyzed at 6 mo (n = 659) for general categories of HMOs (total HMOs, fucosylated HMOs, and sialylated HMOs), 51 individual HMOs, and 6 bioactive proteins (lactalbumin, lactoferrin, lysozyme, antitrypsin, IgA, and osteopontin). We examined associations of the relative abundances of HMOs and concentrations of bioactive proteins with infant growth from 6 to 12 mo [change in length-for-age (ΔLAZ), weight-for-age, weight-for-length, and head circumference z-scores] as well as ability to stand or walk alone at 12 mo, and motor and language skills, socioemotional development, executive function, and working memory at 18 mo. Analyses were adjusted for covariates and multiple hypothesis testing.ResultsAmong all participants, there were inverse associations of IgA and lactoferrin concentrations with motor skills (P = 0.018 and P = 0.044), and a positive association of lactalbumin concentration with motor skills (P = 0.038). Among secretors only [fucosyltransferase 2 gene (FUT2) positive], there were positive associations of absolute abundance of HMOs with ΔLAZ (P = 0.035), and relative abundance of fucosylated and sialylated HMOs with language at 18 mo (P

ABSTRACT Background Meta-analyses have demonstrated that small-quantity lipid-based nutrient supplements (SQ-LNS) reduce stunting and wasting prevalence among infants and young children. Identification of subgroups who benefit most from SQ-LNS may facilitate program design. Objective Our objective was to identify study-level and individual-level modifiers of the effect of SQ-LNS on child growth outcomes. Methods We conducted a two-stage meta-analysis of individual participant data from 14 randomized controlled trials of SQ-LNS provided to children 6 to 24 months of age in low- and middle-income countries (n=37,066). We generated study-specific and subgroup estimates of SQ-LNS vs. control and pooled the estimates using fixed-effects models, with random-effects models as sensitivity analyses. We used random effects meta-regression to examine study-level effect modifiers. Heterogeneity was assessed using I 2 and Tau 2 statistics. Sensitivity analyses were conducted to examine whether results differed depending on inclusion criteria for arms within trials 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 mid-upper arm circumference (MUAC < 125 mm or MUACZ < −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 z-score < −2) by 9%. Effects of SQ-LNS on growth outcomes 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 reported compliance with SQ-LNS. Effects of SQ-LNS 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 (vs. first-born) children; and effects on wasting and acute malnutrition were greater among children in households with improved (vs. unimproved) sanitation. Results were similar across sensitivity analyses. Conclusions The positive impact of SQ-LNS on growth is apparent across a wide variety of study-level contexts. Policy-makers and program planners should consider including SQ-LNS in the mix of interventions to prevent both stunting and wasting. This study was registered at www.crd.york.ac.uk/PROSPERO as CRD42019146592.

ABSTRACT Background Small-quantity lipid-based nutrient supplements (SQ-LNS) have been shown to reduce the prevalence of anemia and iron deficiency among infants and young children, but effects on other micronutrients are less well known. Identifying subgroups who may experience greater benefits from SQ-LNS, or who are more likely to respond to the intervention, may facilitate the development of public health policies and programs. Objective Our objective was to identify study-level and individual-level modifiers of the effect of SQ-LNS on child hematological and micronutrient status outcomes. Methods We conducted a two-stage meta-analysis of individual participant data from 13 randomized controlled trials of SQ-LNS provided to children 6 to 24 months of age in low- and middle-income countries (n = 15,946). Outcomes were hemoglobin (Hb), inflammation-adjusted plasma ferritin, soluble transferrin receptor, zinc, retinol and retinol binding protein (RBP), and erythrocyte zinc protoporphyrin, and respective dichotomous outcomes indicative of anemia and micronutrient deficiency. We generated study-specific estimates of SQ-LNS vs. control, including main effects and subgroup estimates for individual-level effect modifiers, and pooled the estimates using fixed-effects models. We used random effects meta-regression to examine potential study-level effect modifiers. Results Provision of SQ-LNS decreased the prevalence of anemia (Hb < 110 g/L) by 16% (relative reduction), iron deficiency (plasma ferritin < 12 µg/L) by 56% and iron deficiency anemia (IDA; Hb < 110 g/L and plasma ferritin < 12 µg/L) by 64%. We observed positive effects of SQ-LNS on hematological and iron status outcomes within all subgroups of the study-level and individual-level effect modifiers, but effects were larger in certain subgroups. For example, effects of SQ-LNS on anemia and iron status were greater in trials that provided SQ-LNS for > 12 months and provided 9 mg/d vs. < 9 mg iron/d, and among later-born (vs. first-born) children. There was no effect of SQ-LNS on plasma zinc or retinol, but there was a 7% increase in plasma RBP and a 56% reduction in vitamin A deficiency (RBP < 0.70 µmol/L), with little evidence of effect modification by individual-level characteristics. Conclusions SQ-LNS provided to infants and young children 6-24 months of age can substantially reduce the prevalence of anemia, iron deficiency, and IDA across a range of individual, population and study design characteristics. Policy-makers and program planners should consider SQ-LNS within intervention packages to prevent anemia and iron deficiency. This study was registered at www.crd.york.ac.uk/PROSPERO as CRD42020156663.

Background Small-quantity lipid-based nutrient supplements (SQ-LNS) reduce child stunting and provide many of the fatty acids and micronutrients that are necessary for rapid brain development that occurs during infancy and early childhood. Positive effects of SQ-LNS on developmental outcomes have been found in some trials, but not others. Objectives Our objectives were to generate pooled estimates of the effect of SQ-LNS, compared to control groups that received no intervention or an intervention without any nutritional supplement, on developmental outcomes (language, social-emotional, motor, and executive function), and to identify study-level and individual-level modifiers of these effects. Methods We conducted a two-stage meta-analysis of individual participant data from 14 intervention versus control group comparisons in 13 randomized trials of SQ-LNS provided to infants and young children age 6 to 24 months in 9 low- or middle-income countries (total n=30,024). We generated study-specific estimates of SQ-LNS vs. control groups (including main effects and subgroup estimates for individual-level effect modifiers) and pooled the estimates using fixed-effects models. We used random effects meta-regression to examine potential study-level effect modifiers. Results In 11-13 intervention versus control group comparisons (n=23,588-24,561), SQ-LNS increased mean language (mean difference: 0.07 standard deviations; 95% CI: 0.04, 0.10), social-emotional (0.08; 0.05, 0.11), and motor scores (0.08; 0.05, 0.11) and reduced the prevalence of children in the lowest decile of these scores by 17% (prevalence ratio: 0.83, 95% CI 0.76, 0.91), 19% (0.81; 0.74, 0.90), and 16% (0.84; 0.77, 0.92), respectively. SQ-LNS also increased the prevalence of children walking without support at 12 months by 9% (1.09; 1.05, 1.14). Effects of SQ-LNS on language, social-emotional, and motor outcomes were larger among study populations with a higher burden (≥ 35%) of child stunting at 18 months (mean difference 0.11-0.13 SD; 8-9 comparisons) than in populations with lower stunting burden (estimates near zero). At the individual level, greater effects of SQ-LNS were found on language among children who were acutely malnourished (mean difference: 0.31) at baseline; on language (0.12), motor (0.11), and executive function (0.06) among children in households with lower socio-economic status; and on motor development among later-born children (0.11), children of older mothers (0.10), and children of mothers with lower education (0.11). Conclusions SQ-LNS provided daily to children in the range of 6-24 months of age can be expected to result in modest, but potentially important, developmental gains, particularly in populations with high child stunting burden. Certain groups of children who experience higher risk environments, such as those from poor households or with poor baseline nutritional status, have greater potential to benefit from SQ-LNS in developmental outcomes. This study was registered at www.crd.york.ac.uk/PROSPERO as CRD42020159971.

BackgroundHuman milk oligosaccharides (HMOs) and bioactive breast milk proteins have many beneficial properties. Information is sparse regarding associations between these milk constituents and infant growth and development in lower-income countries.ObjectivesWe aimed to examine associations of milk content of HMOs and bioactive proteins at 6 mo postpartum with infant growth and motor and cognitive development. These are secondary analyses of a randomized controlled trial in rural Malawi.MethodsBreast milk samples were analyzed at 6 mo (n = 659) for general categories of HMOs (total HMOs, fucosylated HMOs, and sialylated HMOs), 51 individual HMOs, and 6 bioactive proteins (lactalbumin, lactoferrin, lysozyme, antitrypsin, IgA, and osteopontin). We examined associations of the relative abundances of HMOs and concentrations of bioactive proteins with infant growth from 6 to 12 mo [change in length-for-age (ΔLAZ), weight-for-age, weight-for-length, and head circumference z-scores] as well as ability to stand or walk alone at 12 mo, and motor and language skills, socioemotional development, executive function, and working memory at 18 mo. Analyses were adjusted for covariates and multiple hypothesis testing.ResultsAmong all participants, there were inverse associations of IgA and lactoferrin concentrations with motor skills (P = 0.018 and P = 0.044), and a positive association of lactalbumin concentration with motor skills (P = 0.038). Among secretors only [fucosyltransferase 2 gene (FUT2) positive], there were positive associations of absolute abundance of HMOs with ΔLAZ (P = 0.035), and relative abundance of fucosylated and sialylated HMOs with language at 18 mo (P

An unhealthy gut microbial community may act as a barrier to improvement in growth and health outcomes in response to nutritional interventions. The objective of this analysis was to determine whether the infant microbiota modified the effects of a randomized controlled trial of lipid-based nutrient supplements (LNS) in Malawi on growth and inflammation at 12 and 18 months, respectively. We characterized baseline microbiota composition of fecal samples at 6 months of age (n = 506, prior to infant supplementation, which extended to 18 months) using 16S rRNA gene sequencing of the V4 region. Features of the gut microbiota previously identified as being involved in fatty acid or micronutrient metabolism or in outcomes relating to growth and inflammation, especially in children, were investigated. Prior to correction for multiple hypothesis testing, the effects of LNS on growth appeared to be modified by Clostridium (p-for-interaction = 0.02), Ruminococcus (p-for-interaction = 0.007), and Firmicutes (p-for-interaction = 0.04) and effects on inflammation appeared to be modified by Faecalibacterium (p-for-interaction = 0.03) and Streptococcus (p-for-interaction = 0.004). However, after correction for multiple hypothesis testing these findings were not statistically significant, suggesting that the gut microbiota did not alter the effect of LNS on infant growth and inflammation in this cohort.

BackgroundDiet may alter the configuration of gut microbiota, but the impact of prenatal and postnatal nutritional interventions on infant gut microbiota has not been investigated.ObjectiveWe evaluated whether providing lipid-based nutrient supplements (LNSs) to mother-infant dyads promotes a more diverse and mature infant gut microbiota, compared to maternal supplementation with multiple micronutrients (MMN) or iron and folic acid (IFA).MethodsWe enrolled 869 pregnant women in a randomized trial in Malawi. There were 3 study groups, with women receiving 1 MMN capsule daily during pregnancy and 6 mo postpartum, or 1 LNS sachet (20 g) daily during pregnancy and 6 mo postpartum, or 1 IFA capsule daily (during pregnancy) then a placebo daily (postpartum). Infants in the LNS group received LNS from 6 to 18 mo; infants in the other groups did not receive supplements. The infants' fecal microbiota were characterized by PCR amplification and sequencing of the bacterial 16S rRNA gene (variable region 4). The primary outcomes were microbiota α diversity and maturation [as microbiota-for-age z score (MAZ)]. Specific associations of taxa with intervention were established with indicator species analysis (ISA).ResultsPrimary outcomes did not differ between IFA and MMN groups, so these groups were combined (IFA + MMN). Mean ± SD α diversity was higher in the LNS group at 18 mo for Shannon index [3.01 ± 0.57 (LNS) compared with 2.91 ± 0.60 (IFA + MMN), P = 0.032] and Pielou's evenness index [0.61 ± 0.08 (LNS) compared with 0.60 ± 0.09 (IFA + MMN), P = 0.043]; no significant differences were observed at 1, 6, 12, or 30 mo. MAZ and β diversity did not differ at any age. We found 10 and 3 operational taxonomic units (OTUs) positively associated with LNS and IFA + MMN, respectively; however, these associations became nonsignificant following false discovery rate correction at 10%.ConclusionsPrenatal and postnatal LNS intake promoted infant gut microbiota diversity at 18 mo, after 12 mo of child supplementation, but did not alter microbiota maturation. This trial was registered at clinicaltrials.gov as NCT01239693.

BackgroundGut microbiota composition is associated with child health, but the effect of the environment on microbiota composition is not well understood. Few studies have been conducted in low-income settings where childhood malnutrition is common and possibly related to microbiota composition.ObjectivesTo investigate whether gut microbiota composition in young children and their mothers is associated with different environmental exposures in rural Malawi. We hypothesized that more adverse environmental exposures would be associated with lower levels of microbiota maturity and diversity.MethodsFaecal samples from up to 631 children and mothers participating in a nutrition intervention trial were collected at 1, 6, 12, 18, and 30 months (children) and at 1 month (mothers) after birth and analysed for microbiota composition with 16S rRNA sequencing. Bacterial OTU and genus abundances, measures of microbiota maturity and diversity, and UniFrac distances were compared between participants with different environmental exposures. The exposure variables included socio-economic status, water source, sanitary facility, domestic animals, maternal characteristics, season, antibiotic use, and delivery mode.ResultsMeasures of microbiota maturity and diversity in children were inversely associated with maternal education at 6, 18, and 30 months and did not otherwise differ consistently between participants with different environmental exposures. Phylogenetic distance was related to season of stool sample collection at all time points. At the level of individual OTUs and genera, season of stool sample collection, type of water source, and maternal education showed most associations with child gut microbiota, while HIV status was the most important predictor of relative OTU and genus abundances in mothers.ConclusionThe results do not support the hypothesis that adverse environmental exposures are broadly associated with lower microbiota maturity and diversity but suggest that environmental exposures influence the abundance of several bacterial OTUs and genera and that low maternal education is associated with higher microbiota maturity and diversity.

BackgroundAdequate knowledge about the safety of consumption of small-quantity lipid-based nutrient supplements (SQ-LNSs) is needed.ObjectiveWe aimed to test the hypothesis that SQ-LNS consumption is noninferior to control with respect to child morbidity.MethodsWomen (n = 1320) ≤20 wk pregnant were assigned to iron and folic acid until delivery with no supplementation for offspring; or multiple micronutrient supplements until 6 mo postpartum with no supplementation for offspring; or SQ-LNSs until 6 mo postpartum, and SQ-LNSs for offspring (6 mg Fe/d) from 6 to 18 mo of age [the lipid-based nutrient supplement (LNS) group]. We assessed noninferiority (margin ≤20%) between any 2 groups during 0-6 mo of age, and between the non-LNS and LNS groups during 6-18 mo of age for caregiver-reported acute respiratory infection, diarrhea, gastroenteritis, fever/suspected malaria, poor appetite, and "other illnesses."ResultsDuring 0-6 mo of age, 1197 infants contributed 190,503 infant-days. For all morbidity combined, overall mean incidence (per 100 infant-days) was 3.3 episodes, overall mean prevalence (percentage of infant-days) was 19.3%, and the 95% CIs of the incidence rate ratio (IRR) and longitudinal prevalence rate ratio (LPRR) between any 2 groups were ≤1.20. During 6-18 mo, there were 240,097 infant-days for the non-LNS group and 118,698 for the LNS group. For all morbidity combined, group mean incidences were 4.3 and 4.3, respectively (IRR: 1.0; 95% CI: 1.0, 1.1), and mean prevalences were 28.2% and 29.3%, respectively (LPRR: 1.0; 95% CI: 1.0, 1.1). Noninferiority was inconclusive for diarrhea, fever/suspected malaria, and poor appetite.ConclusionsSQ-LNS consumption does not increase reported overall child morbidity in this population compared with the 2 other treatments.This trial was registered at clinicaltrials.gov as NCT00970866.