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Rapid changes in the global climate are deepening existing health disparities from resource scarcity and malnutrition. Rising ambient temperatures represent an imminent risk to pregnant women and infants. Both maternal malnutrition and heat stress during pregnancy contribute to poor fetal growth, the leading cause of diminished child development in low-resource settings. However, studies explicitly examining interactions between these two important environmental factors are lacking. We leveraged maternal and neonatal anthropometry data from a randomized controlled trial focused on improving preconception maternal nutrition (Women First Preconception Nutrition trial) conducted in Thatta, Pakistan, where both nutritional deficits and heat stress are prevalent. Multiple linear regression of ambient temperature and neonatal anthropometry at birth (n = 459) showed a negative association between daily maximal temperatures in the first trimester and Z-scores of birth length and head circumference. Placental mRNA-sequencing and protein analysis showed transcriptomic changes in protein translation, ribosomal proteins, and mTORC1 signaling components in term placenta exposed to excessive heat in the first trimester. Targeted metabolomic analysis indicated ambient temperature associated alterations in maternal circulation with decreases in choline concentrations. Notably, negative impacts of heat on birth length were in part mitigated in women randomized to comprehensive maternal nutritional supplementation before pregnancy suggesting potential interactions between heat stress and nutritional status of the mother. Collectively, the findings bridge critical gaps in our current understanding of how maternal nutrition may provide resilience against adverse effects of heat stress in pregnancy.

BackgroundMaternal nutrition in preconception and early pregnancy influences fetal growth. Evidence for effects of prenatal maternal nutrition on early child development (ECD) in low-income and middle-income countries is limited.ObjectivesTo examine impact of maternal nutrition supplementation initiated prior to or during pregnancy on ECD, and to examine potential association of postnatal growth with ECD domains.DesignSecondary analysis regarding the offspring of participants of a maternal multicountry, individually randomised trial.SettingRural Democratic Republic of the Congo, Guatemala, India and Pakistan.Participants667 offspring of Women First trial participants, aged 24 months.InterventionMaternal lipid-based nutrient supplement initiated preconceptionally (arm 1, n=217), 12 weeks gestation (arm 2, n=230) or not (arm 3, n=220); intervention stopped at delivery.Main outcome measuresThe INTERGROWTH-21st Neurodevelopment Assessment (INTER-NDA) cognitive, language, gross motor, fine motor, positive and negative behaviour scores; visual acuity and contrast sensitivity scores and auditory evoked response potentials (ERP). Anthropometric z-scores, family care indicators (FCI) and sociodemographic variables were examined as covariates.ResultsNo significant differences were detected among the intervention arms for any INTER-NDA scores across domains, vision scores or ERP potentials. After adjusting for covariates, length-for-age z-score at 24 months (LAZ24), socio-economic status, maternal education and FCI significantly predicted vision and INTER-NDA scores (R2=0.11–0.38, pConclusionsPrenatal maternal nutrition supplementation was not associated with any neurodevelopmental outcomes at age 2 years. Maternal education, family environment and LAZ24predicted ECD. Interventions addressing multiple components of the nurturing care model may offer greatest impact on children’s developmental potential.Trial registration numberNCT01883193.

Background Preconceptional maternal small-quantity lipid-based nutrient supplementation (SQLNS) improved intrauterine linear growth in low-resource countries as demonstrated by the Women First Preconception Maternal Nutrition Trial (WF). Fetal growth is dependent on nutrient availability and regulated by insulin-like growth factor 1 (IGF-1) through changes in placental transfer capacity, mediated by the mechanistic target of rapamycin (mTOR) pathway. Objectives Our objective was to evaluate the role of placental mTOR and IGF-1 signaling on fetal growth in women from 2 low-resource countries with high rates of stunting after they received preconceptional SQLNS. Methods We studied 48 women from preconception through delivery who were from Guatemala and Pakistan and received SQLNS or not, as part of the WF study. Placental samples were obtained at delivery (control, n = 24; SQLNS, n = 24). Placental protein or mRNA expression of eukaryotic translation initiation factor binding protein-1 (4E-BP1), ribosomal protein S6 (rpS6), AMP-activated protein kinase α (AMPKA), IGF-1, insulin-like growth factor receptor (IGF-1R), and pregnancy associated plasma protein (PAPP)-A, and DNA methylation of the IGF1 promoter were determined. Maternal serum IGF-1, insulin-like growth factor binding protein (IGFBP)-3, IGFBP-4, IGFBP-5, PAPP-A, PAPP-A2, and zinc were measured. Results Mean ± SEM maternal prepregnancy BMI differed between participants in Guatemala (26.5 ± 1.3) and Pakistan (19.8 ± 0.7) (P

ObjectiveTo characterize the changes in gut microbiota during pregnancy and determine the effects of nutritional intervention on gut microbiota in women from sub-Saharan Africa (the Democratic Republic of the Congo, DRC), South Asia (India and Pakistan), and Central America (Guatemala).MethodsPregnant women in the Women First (WF) Preconception Maternal Nutrition Trial were included in this analysis. Participants were randomized to receive a lipid-based micronutrient supplement either ≥3 months before pregnancy (Arm 1); started the same intervention late in the first trimester (Arm 2); or received no nutrition supplements besides those self-administered or prescribed through local health services (Arm 3). Stool and blood samples were collected during the first and third trimesters. Findings presented here include fecal 16S rRNA gene-based profiling and systemic and intestinal inflammatory biomarkers, including alpha (1)-acid glycoprotein (AGP), C-reactive protein (CRP), fecal myeloperoxidase (MPO), and calprotectin.ResultsStool samples were collected from 640 women (DRC, n = 157; India, n = 102; Guatemala, n = 276; and Pakistan, n = 105). Gut microbial community structure did not differ by intervention arm but changed significantly during pregnancy. Richness, a measure of alpha-diversity, decreased over pregnancy. Community composition (beta-diversity) also showed a significant change from first to third trimester in all four sites. Of the top 10 most abundant genera, unclassified Lachnospiraceae significantly decreased in Guatemala and unclassified Ruminococcaceae significantly decreased in Guatemala and DRC. The change in the overall community structure at the genus level was associated with a decrease in the abundances of certain genera with low heterogeneity among the four sites. Intervention arms were not significantly associated with inflammatory biomarkers at 12 or 34 weeks. AGP significantly decreased from 12 to 34 weeks of pregnancy, whereas CRP, MPO, and calprotectin did not significantly change over time. None of these biomarkers were significantly associated with the gut microbiota diversity.ConclusionThe longitudinal reduction of individual genera (both commensals and potential pathogens) and alpha-diversity among all sites were consistent and suggested that the effect of pregnancy on the maternal microbiota overrides other influencing factors, such as nutrition intervention, geographical location, diet, race, and other demographical variables.

OBJECTIVES: Understanding the interactions between nutrition and climate-driven health outcomes is increasingly necessary. Employing data from the Women First trial conducted in Thatta, Pakistan, we examined the interactions between maternal nutritional deficits and heat stress (HS) on birth outcomes. METHODS: Women of child-bearing age either consumed a small quantity lipid-based nutrition supplement (sqLNS) prior to conception (Arm 1), from 12 wk of gestation until delivery (Arm 2); or were not supplemented with sqLNS (Arm 3). At the Pakistan site, samples sizes with birth outcomes obtained within 48 h of delivery for Arms 1, 2 and 3 were 157,150 and 138, respectively. Daily maximal air temperatures were used to were compute the average daily maximal temperatures (T(max)) for each infant over four 90-day windows representing each trimester of gestation and 3 mo preconception. The number of days in each period when the T(max) was > 39°C was computed to assess ‘heat stress days’. RESULTS: Linear regression models assessing the associations between heat exposure and outcome variables (gestational age adjusted Z-scores of birth length (LGAZ), birth weight (WGAZ) and head circumference (HCGAZ) revealed a striking negative association of both ambient temperature and HS days in the first trimester on birth length (LGAZ) and head circumference (HCGAZ) (p

Background: Estimated physiologic requirements (PRs) for zinc increase in late pregnancy and early lactation, but the effect on dietary zinc requirements is uncertain.Objective: The aim of this study was to determine changes in daily fractional absorbed zinc and total absorbed zinc (TAZ) from ad libitum diets of differing phytate contents in relation to physiologic zinc requirements during pregnancy and lactation.Methods: This was a prospective observational study of zinc absorption at 8 (phase 1) and 34 (phase 2) wk of gestation and 2 (phase 3) and 6 (phase 4) mo of lactation. Participants were indigenous Guatemalan women of childbearing age whose major food staple was maize and who had been randomly assigned in a larger study to either of 2 ad libitum feeding groups: low-phytate maize (LP; 1.6 mg/g; n = 14) or control maize (C; 7.1 mg/g; n = 8). Total dietary zinc (milligrams per day, TDZ) and phytate (milligrams per day) were determined from duplicate diets and fractional absorption (FAZ) by dual isotope ratio technique (TAZ = TDZ × FAZ). All variables were examined longitudinally and by group and compared with PRs. TAZ values at later phases were compared with phase 1. Measured TAZ was compared with predicted TAZ for nonpregnant, nonlactating (NPNL) women.Results: TAZ was greater in the LP group than in the C group at all phases. All variables increased from phase 1 to phases 2 and 3 and declined at phase 4. TAZ increased by 1.25 mg/d (P = 0.045) in the C group and by 0.81 mg/d (P = 0.058) in the LP group at phase 2. At phase 3, the increases were 2.66 mg/d (P = 0.002) in the C group and 2.28 mg/d (P = 0.0004) in the LP group, compared with a 1.37-mg/d increase in PR. Measured TAZ was greater than predicted values in phases 2-4.Conclusions: Upregulation of zinc absorption in late pregnancy and early lactation matches increases in PRs of pregnant and lactating women, regardless of dietary phytate, which has implications for dietary zinc requirements of pregnant and lactating women.

Background To compare and characterize the gut microbiota in women of childbearing age from sub-Saharan Africa (the Democratic Republic of the Congo, DRC) and South Asia (India), in relation to dietary intakes. Methods Women of childbearing age were recruited from rural DRC and India as part of the Women First (WF) preconception maternal nutrition trial. Findings presented include fecal 16S rRNA gene-based profiling of women in the WF trial from samples obtained at the time of randomization, prior to initiation of nutrition intervention and to conception. Results Stool samples were collected from 217 women (DRC n = 117; India n = 100). Alpha diversity of the gut microbiota was higher in DRC than in India (Chao1: 91 ± 11 vs. 82 ± 12, P = 6.58E-07). The gut microbial community structure was not significantly affected by any demographical or environmental variables, such as maternal BMI, education, and water source. Prevotella, Succinivibrio, and Roseburia were at relatively high abundance without differences between sites. Bifidobacterium was higher in India (4.95 ± 1.0%) than DRC (0.3 ± 0.1%; P = 2.71E-27), as was Lactobacillus (DRC: 0.2 ± 0.0%; India: 1.2 ± 0.1%; P = 2.39E-13) and Faecalibacterium (DRC: 6.0 ± 1.7%; India: 8.4 ± 2.9%; P = 6.51E-7). Ruminococcus was higher in DRC (2.3 ± 0.7%) than in India (1.8 ± 0.4%; P = 3.24E-5) and was positively associated with consumption of flesh foods. Succinivibrio was positively associated with dairy intake in India and fish/insects in DRC. Faecalibacterium was positively associated with vitamin A-rich fruits and vegetables. Overall, these observations were consistent with India being primarily vegetarian with regular fermented dairy consumption and DRC regularly consuming animal-flesh foods. Conclusion Consumption of animal-flesh foods and fermented dairy foods were independently associated with the gut microbiota while demographic variables were not, suggesting that diet may have a stronger association with microbiota than demographic characteristics.

OBJECTIVES: To characterize and compare the gut microbial structures in women of childbearing age from Africa (the Democratic Republic of the Congo, DRC) and South Asia (India) METHODS: Women of childbearing age were recruited from rural DRC and India as part of the WF preconception maternal nutrition trial. Findings presented include the gut microbiota (16S rRNA sequencing) of women at the time of randomization prior to conception in the WF trial and represented participants from two of the WF sites, with distinctive ethnicity, diet, culture and geographical locations. Women were recruited from 12 villages in rural DRC and 9 villages from rural India. 24-h dietary recalls were conducted on half of the participants during the first trimester of pregnancy. RESULTS: Stool samples were collected from n = 217 women (DRC n = 117; India n = 100). Alpha diversity of the gut microbiota was higher in DRC than in India using Chao1 (91 ± 11 vs. 82 ± 12, P

Background Maternal dietary restriction and supplementation of one-carbon (1C) metabolites can impact offspring growth and DNA methylation. However, longitudinal research of 1C metabolite and amino acid (AA) concentrations over the reproductive cycle of human pregnancy is limited. Objective To investigate longitudinal 1C metabolite and AA concentrations prior to and during pregnancy and the effects of a small-quantity lipid-based nutrition supplement (LNS) containing >20 micronutrients and prepregnancy BMI (ppBMI). Methods This study was an ancillary study of the Women First Trial (NCT01883193, clinicaltrials.gov) focused on a subset of Guatemalan women (n = 134), 49% of whom entered pregnancy with a BMI ≥25 kg/m2. Ninety-five women received LNS during pregnancy (+LNS group), while the remainder did not (−LNS group). A subset of women from the Pakistan study site (n = 179) were used as a replication cohort, 124 of whom received LNS. Maternal blood was longitudinally collected on dried blood spot (DBS) cards at preconception, and at 12 and 34 wk gestation. A targeted metabolomics assay was performed on DBS samples at each time point using LC-MS/MS. Longitudinal analyses were performed using linear mixed modeling to investigate the influence of time, LNS, and ppBMI. Results Concentrations of 23 of 27 metabolites, including betaine, choline, and serine, changed from preconception across gestation after application of a Bonferroni multiple testing correction (P

OBJECTIVES: Studies in both animals and humans have shown that maternal dietary restriction and supplementation of one carbon (1C) metabolites (methyl donors), such as methionine and choline, can impact offspring growth, insulin resistance, and DNA methylation. However, there has been limited longitudinal research of 1C metabolite concentrations over the reproduction cycle of human pregnancy. The purpose of this study was to investigate if 1C metabolite concentrations change prior to and during pregnancy and if a preconception lipid-based nutrition supplement (LNS) influences such changes. METHODS: This study was a secondary analysis as part of the Women First study (clinicaltrials.gov, NCT01883193), a large, randomized controlled trial investigating whether the timing of maternal LNS initiation would impact fetal growth and development. The study arms were supplementation at least 3 months prior to conception (Arm 1), supplementation at ∼12 weeks of gestation (Arm 2), or no supplementation (Arm 3). Dried blood spot (DBS) cards were collected at study enrollment prior to conception, and at 12 and 34 weeks gestation. A targeted 1C metabolite assay (27 metabolites) was performed on a subset of DBS samples from Guatemalan women (n = 134) at each time point using liquid chromatography/tandem mass spectrometry. Longitudinal analyses were performed using linear mixed modeling to investigate the influence of time and LNS on these metabolites. RESULTS: The concentrations of two metabolites were changed by intervention status: asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA). Twenty-one of 27 metabolites significantly changed from preconception and across gestation after correcting for multiple testing using the Bonferroni correction (P

OBJECTIVES: Human metastable epialleles (MEs) are specific regions that are systemically methylated (lack tissue specificity), stable over time, and variably expressed between individuals. DNA methylation (DNAme) of MEs have been previously reported to be altered by maternal nutritional status at the time of conception. Here, we examined DNAme of MEs from a subset of Guatemalan mother/infant dyads as part of the Women First study, an international RCT that tested whether timing of a daily lipid-based nutrition supplement (LNS) improved birth length. The 3 study arms are: women consumed LNS ≥ 3 months prior to conception until delivery (Arm 1, N = 45); women consumed the same LNS commencing at 12 weeks gestation until delivery (Arm 2, N = 45); or no LNS (Arm 3, N = 44). The purpose of this study was to test if the timing of maternal LNS and pre-pregnancy BMI (ppBMI, BMI range = 20.1 – 38.4 kg/m(2)) led to differential DNAme of MEs in infants at birth. METHODS: Bisulfite-converted DNAme libraries were constructed using NimbleGen SeqCap Epi CpGiant probes from amnion tissue collected at birth. Individuals were sequenced via 2 × 150 paired end reads using the Illumina NovaSeq sequencer. Subjects that passed quality control (131/142 subjects) were used in subsequent statistical analyses. A linear model was used to test for the interaction between maternal LNS and ppBMI on infant DNAme for each base pair site within 296 previously identified candidate ME regions. The number of methylated base pairs per region ranged from 1 – 737. A significance level adjusting for the 296 regions was set at P ≤ 0.000169. RESULTS: We identified 6 ME regions with significant interactions, demonstrating differential ME DNAme due to intervention arm was dependent on ppBMI values. Our analyses also identified 3 CpGs associated with ppBMI regardless of LNS status and 1 CpG associated with LNS regardless of ppBMI suggesting a role for independent effects of maternal LNS and ppBMI on ME DNAme. CONCLUSIONS: Our findings indicate that timing of maternal LNS and ppBMI contribute to DNAme of candidate MEs in infants at birth, suggesting epigenetic influences due to in utero exposures. Future analyses will identify genes associated with changes in ME DNAme and the role of DNAme on infant growth. FUNDING SOURCES: Bill & Melinda Gates Foundation and National Institutes of Health.

Millet is unusually drought resistant and consequently there is a progressive increase in the use of these grains as a human food staple, especially in large areas of India and sub-Saharan Africa. The purpose of this study was to determine the absorption of iron and zinc from pearl millet biofortified with 2 micronutrients that are typically deficient in nonfortified, plant-based diets globally. The study was undertaken in 40 children aged 2 y in Karnataka, India (n = 21 test/19 controls). Three test meals providing ∼84 ± 17 g dry pearl millet flour were fed on a single day for zinc and 2 d for iron between 0900 and 1600 h. The quantities of zinc and iron absorbed were measured with established stable isotope extrinsic labeling techniques and analyses of duplicate diets. The mean (± SD) quantities of iron absorbed from test and control groups were 0.67 ± 0.48 and 0.23 ± 0.15 mg/d, respectively (P < 0.001). The quantities of zinc absorbed were 0.95 ± 0.47 and 0.67 ± 0.24 mg/d, respectively (P = 0.03). These data did not include absorption of the modest quantities of iron and zinc contained in snacks eaten before and after the 3 test meals. In conclusion, quantities of both iron and zinc absorbed when iron and zinc biofortified pearl millet is fed to children aged 2 y as the major food staple is more than adequate to meet the physiological requirements for these micronutrients.

Interference with Zn absorption is one proposed explanation for adverse effect of Fe supplements in Fe-replete subjects in malaria endemic areas. We determined the effect of Fe on Zn absorption and...