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Higher birth order is associated with altered risk of many disease states. Changes in placentation and exposures to in utero growth factors with successive pregnancies may impact later life disease risk via persistent DNA methylation alterations. We investigated birth order with Illumina DNA methylation array data in each of 16 birth cohorts (8164 newborns) with European, African, and Latino ancestries from the Pregnancy and Childhood Epigenetics Consortium. Meta-analyzed data demonstrated systematic DNA methylation variation in 341 CpGs (FDR adjusted P

Objective To investigate the effect of daily iron supplementation for 14 weeks on the serum iron concentration and other markers of iron status in exclusively breastfed infants in Gambia. Methods A placebo-controlled, randomized, double-blind trial was performed in rural Gambia between 3 August 2021 and 9 March 2022. Overall, 101 healthy, exclusively breastfed infants aged 6 to 10 weeks were recruited at vaccination clinics and through community health workers. Infants were randomized to receive iron supplementation (7.5 mg/day as ferrous sulfate in sorbitol solution) or placebo for 98 days. Venous blood samples were collected at baseline and on day 99 to assess the serum iron concentration and other markers of iron and haematological status. Findings At day 99, the serum iron concentration was significantly higher in the iron supplementation group than the placebo group (crude difference in means: 2.5 [micro]mol/L; 95% confidence interval: 0.6 to 4.3) and there were significant improvements in other iron and haematological markers. There were 10 serious adverse events (five in each group), 106 non- serious adverse events (54 with iron supplementation; 52 with placebo) and no deaths. There was no marked difference between the groups in maternally reported episodes of diarrhoea, fever, cough, skin infection, eye infection or nasal discharge. Conclusion In exclusively breastfed Gambian infants, iron supplementation from 6 weeks of age was associated with a significant improvement in markers of iron status at around 6 months of age. There was no indication of adverse effects on growth or infections. Objectif Etudier l'effet d'une administration quotidienne de supplements de fer pendant 14 semaines sur la concentration serique en fer et sur d'autres marqueurs relatifs au bilan en fer chez des nourrissons exclusivement allaites au sein en Gambie. Methodes Un essai randomise en double aveugle et controle contre placebo a ete mene en region rurale dans le pays entre le 3 aout 2021 et le 9 mars 2022. Au total, 101 nourrissons sains ages de six a dix semaines et exclusivement allaites au sein ont ete recrutes dans des centres de vaccination et par le biais d'agents de sante communautaires. Les nourrissons ont recu aleatoirement un supplement de fer (7,5 mg/jour de sulfate ferreux dans une solution de sorbitol) ou un placebo durant 98 jours. Des echantillons de sang veineux ont ete recoltes au debut de l'essai et au 99e jour afin de mesurer la concentration serique en fer et d'autres marqueurs relatifs au bilan en fer et au bilan hematologique. Resultats Au 99e jour, la concentration serique en fer etait considerablement plus elevee dans le groupe ayant recu un supplement de fer que dans celui ayant recu un placebo (difference brute moyenne: 2,5 [micro]mol/L; intervalle de confiance de 95%: 0,6 a 4,3), tandis que d'autres marqueurs relatifs au bilan en fer et au bilan hematologique affichaient de nettes ameliorations. Dix effets secondaires graves ont ete signales (cinq dans chaque groupe), 106 effets secondaires sans gravite (54 dans le groupe ayant recu un supplement de fer; 52 dans le groupe ayant recu un placebo) et aucun deces. Aucune difference majeure n'a ete constatee entre les groupes au niveau des episodes de diarrhee, fievre, toux, infection cutanee, infection oculaire ou ecoulement nasal signales par la mere. Conclusion Chez les nourrissons gambiens exclusivement allaites au sein, l'administration de supplements de fer des l'age de six semaines a entraine une nette amelioration des marqueurs relatifs au bilan en fer vers l'age de six mois. Rien n'indique que ces supplements aient eu des effets secondaires sur la croissance ou cause des infections. Objetivo Investigar el efecto de la administracion diaria de suplementos de hierro durante 14 semanas sobre la concentracion serica de hierro y otros marcadores del estado del hierro en lactantes alimentados exclusivamente con leche materna en Gambia. Metodos Entre el 3 de agosto de 2021 y el 9 de marzo de 2022, se llevo a cabo un ensayo con enmascaramiento doble, aleatorizado y controlado con placebo en areas rurales de Gambia. En total, se reclutaron 101 lactantes sanos, alimentados exclusivamente con leche materna y con edades comprendidas entre las 6 y las 10 semanas, en clinicas de vacunacion y a traves de trabajadores sanitarios comunitarios. Los lactantes se asignaron aleatoriamente para recibir suplementos de hierro (7,5 mg/dia como sulfato ferroso en solucion de sorbitol) o placebo durante 98 dias. Se recogieron muestras de sangre venosa al inicio del ensayo y el dia 99 para evaluar la concentracion serica de hierro y otros marcadores del hierro y el estado hematologico. Resultados En el dia 99, la concentracion serica de hierro era significativamente mayor en el grupo de suplementacion con hierro que en el grupo placebo (diferencia bruta de medias: 2,5 [micro]mol/L; intervalo de confianza del 95%: 0,6 a 4,3) y hubo mejoras significativas en otros marcadores hematologicos y de hierro. Ocurrieron 10 acontecimientos adversos graves (cinco en cada grupo), 106 acontecimientos adversos no graves (54 con suplementos de hierro; 52 con placebo) y ninguna muerte. No hubo diferencias notables entre los grupos respecto a los episodios de diarrea, fiebre, tos, infeccion cutanea, infeccion ocular o secrecion nasal notificados por las madres. Conclusion En los lactantes de Gambia alimentados exclusivamente con leche materna, la administracion de suplementos de hierro a partir de las 6 semanas de vida se asocio a una mejora significativa de los marcadores del estado del hierro en torno a los 6 meses de edad. No hubo indicios de efectos adversos sobre el crecimiento o las infecciones., Introduction Breastfeeding infants offers strong protection against infection and associated deaths, but there are increasing doubts about whether the iron supplied by exclusive breastfeeding in low-income countries is adequate for [...]

Little valid information is available on human milk nutrient concentrations, especially for micronutrients (MNs), and there are no valid reference values (RVs) across lactation. In this multi-center collaborative study, RVs will be established for human milk nutrients across the first 8.5 mo postpartum. Well-nourished, unsupplemented women in Bangladesh, Brazil, Denmark, and The Gambia (n = 250/site) were recruited during the third trimester of pregnancy. Milk, blood, saliva, urine, and stool samples from mothers and their infants are collected identically at 3 visits (1-3.49, 3.5-5.99, 6.0-8.49 mo postpartum). Milk analyses include macronutrients, selected vitamins, trace elements and minerals, iodine, metabolomics, amino acids, human milk oligosaccharides, and bioactive peptides. We measure milk volume; maternal and infant diets, anthropometry, and morbidity; infant development, maternal genome, and the infant and maternal microbiome. RVs will be constructed based on methods for the WHO Child Growth Standards and the Intergrowth-21st Project. This trial was registered at clinical trials.gov as NCT03254329.

Micronutrient (MN) deficiencies can produce a broad array of adverse health and functional outcomes. Young, preschool children and women of reproductive age in low- and middle-income countries are most affected by these deficiencies, but the true magnitude of the problems and their related disease burdens remain uncertain because of the dearth of reliable biomarker information on population MN status. The reasons for this lack of information include a limited understanding by policy makers of the importance of MNs for human health and the usefulness of information on MN status for program planning and management; insufficient professional capacity to advocate for this information and design and implement related MN status surveys; high costs and logistical constraints involved in specimen collection, transport, storage, and laboratory analyses; poor access to adequately equipped and staffed laboratories to complete the analyses reliably; and inadequate capacity to interpret and apply this information for public health program design and evaluation. This report describes the current situation with regard to data availability, the reasons for the lack of relevant information, and the steps needed to correct this situation, including implementation of a multi-component MN Data Generation Initiative to advocate for critical data collection and provide related technical assistance, laboratory services, professional training, and financial support.

Prenatal micronutrient deficiencies are associated with negative maternal and birth outcomes. Multiple micronutrient supplementation (MMS) during pregnancy is a cost-effective intervention to reduce these adverse outcomes. However, important knowledge gaps remain in the implementation of MMS interventions. The Child Health and Nutrition Research Initiative (CHNRI) methodology was applied to inform the direction of research and investments needed to support the implementation of MMS interventions for pregnant women in low- and middle-income countries (LMIC). Following CHNRI methodology guidelines, a group of international experts in nutrition and maternal health provided and ranked the research questions that most urgently need to be resolved for prenatal MMS interventions to be successfully implemented. Seventy-three research questions were received, analyzed, and reorganized, resulting in 35 consolidated research questions. These were scored against four criteria, yielding a priority ranking where the top 10 research options focused on strategies to increase antenatal care attendance and MMS adherence, methods needed to identify populations more likely to benefit from MMS interventions and some discovery issues (e.g., potential benefit of extending MMS through lactation). This exercise prioritized 35 discrete research questions that merit serious consideration for the potential of MMS during pregnancy to be optimized in LMIC.

Inadequate micronutrient intakes are relatively common in low- and middle-income countries (LMICs), especially among pregnant women, who have increased micronutrient requirements. This can lead to an increase in adverse pregnancy and birth outcomes. This review presents the conclusions of a task force that set out to assess the prevalence of inadequate micronutrient intakes and adverse birth outcomes in LMICs; the data from trials comparing multiple micronutrient supplements (MMS) that contain iron and folic acid (IFA) with IFA supplements alone; the risks of reaching the upper intake levels with MMS; and the cost-effectiveness of MMS compared with IFA. Recent meta-analyses demonstrate that MMS can reduce the risks of preterm birth, low birth weight, and small for gestational age in comparison with IFA alone. An individual-participant data meta-analysis also revealed even greater benefits for anemic and underweight women and female infants. Importantly, there was no increased risk of harm for the pregnant women or their infants with MMS. These data suggest that countries with inadequate micronutrient intakes should consider supplementing pregnant women with MMS as a cost-effective method to reduce the risk of adverse birth outcomes.

Birthweight is associated with health outcomes across the life course, DNA methylation may be an underlying mechanism. In this meta-analysis of epigenome-wide association studies of 8,825 neonates from 24 birth cohorts in the Pregnancy And Childhood Epigenetics Consortium, we find that DNA methylation in neonatal blood is associated with birthweight at 914 sites, with a difference in birthweight ranging from -183 to 178 grams per 10% increase in methylation (PBonferroni

Executive functions (EFs) in early childhood are predictors of later developmental outcomes and school readiness. Much of the research on EFs and their psychosocial correlates has been conducted in high‐income, minority world countries, which represent a small and biased portion of children globally. The aim of this study is to examine EFs among children aged 3–5 years in two African countries, South Africa (SA) and The Gambia (GM), and to explore shared and distinct predictors of EFs in these settings. The SA sample (N = 243, 51.9% female) was recruited from low‐income communities within the Cape Town Metropolitan area. In GM, participants (N = 171, 49.7% female) were recruited from the rural West Kiang region. EFs, working memory (WM), inhibitory control (IC) and cognitive flexibility (CF), were measured using tablet‐based tasks. Associations between EF task performance and indicators of socioeconomic status (household assets, caregiver education) and family enrichment factors (enrichment activities, diversity of caregivers) were assessed. Participants in SA scored higher on all EF tasks, but children in both sites predominantly scored within the expected range for their age. There were no associations between EFs and household or familial variables in SA, except for a trend‐level association between caregiver education and CF. Patterns were similar in GM, where there was a trend‐level association between WM and enrichment activities but no other relationships. We challenge the postulation that children in low‐income settings have poorer EFs, simply due to lower socioeconomic status, but highlight the need to identify predictors of EFs in diverse, global settings. Research Highlights: Assessed Executive Functioning (EF) skills and their psychosocial predictors among pre‐school aged children (aged 3–5 years) in two African settings (The Gambia and South Africa).On average, children within each setting performed within the expected range for their age, although children in South Africa had higher scores across tasks.There was little evidence of any association between socioeconomic variables and EFs in either site.Enrichment activities were marginally associated with better working memory in The Gambia, and caregiver education with cognitive flexibility in South Africa, both associations were trend‐level significance. [ABSTRACT FROM AUTHOR]

Cognitive control is a predictor of later‐life outcomes and may underpin higher order executive processes. The present study examines the development of early cognitive control during the first 24‐month. We evaluated a tablet‐based assessment of cognitive control among infants aged 18‐ and 24‐month. We also examined concurrent and longitudinal associations between attentional disengagement, general cognitive skills and cognitive control. Participants (N = 60, 30 female) completed the tablet‐task at 18‐ and 24‐month of age. Attentional disengagement and general cognitive development were assessed at 5‐, 8‐, 12‐, 18‐ and 24‐month using an eye‐tracking measure and the Mullen Scales of Early Learning (MSEL), respectively. The cognitive control task demonstrated good internal consistency, sensitivity to age‐related change in performance and stable individual differences. No associations were found between infant cognitive control and MSEL scores longitudinally or concurrently. The eye‐tracking task revealed that slower attentional disengagement at 8‐month, but faster disengagement at 18‐month, predicted higher cognitive control scores at 24‐month. This task may represent a useful tool for measuring emergent cognitive control. The multifaceted relationship between attention and infant cognitive control suggests that the rapid development of the attentional system in infancy results in distinct attentional skills, at different ages, being relevant for cognitive control development. [ABSTRACT FROM AUTHOR]

Background: Human milk is a complex fluid comprised of myriad substances, with one of the most abundant substances being a group of complex carbohydrates referred to as human milk oligosaccharides (HMOs). There has been some evidence that HMO profiles differ in populations, but few studies have rigorously explored this variability.Objectives: We tested the hypothesis that HMO profiles differ in diverse populations of healthy women. Next, we examined relations between HMO and maternal anthropometric and reproductive indexes and indirectly examined whether differences were likely related to genetic or environmental variations.Design: In this cross-sectional, observational study, milk was collected from a total of 410 healthy, breastfeeding women in 11 international cohorts and analyzed for HMOs by using high-performance liquid chromatography.Results: There was an effect of the cohort (P < 0.05) on concentrations of almost all HMOs. For instance, the mean 3-fucosyllactose concentration was >4 times higher in milk collected in Sweden than in milk collected in rural Gambia (mean ± SEM: 473 ± 55 compared with 103 ± 16 nmol/mL, respectively; P < 0.05), and disialyllacto-N-tetraose (DSLNT) concentrations ranged from 216 ± 14 nmol/mL (in Sweden) to 870 ± 68 nmol/mL (in rural Gambia) (P < 0.05). Maternal age, time postpartum, weight, and body mass index were all correlated with several HMOs, and multiple differences in HMOs [e.g., lacto-N-neotetrose and DSLNT] were shown between ethnically similar (and likely genetically similar) populations who were living in different locations, which suggests that the environment may play a role in regulating the synthesis of HMOs.Conclusions: The results of this study support our hypothesis that normal HMO concentrations and profiles vary geographically, even in healthy women. Targeted genomic analyses are required to determine whether these differences are due at least in part to genetic variation. A careful examination of sociocultural, behavioral, and environmental factors is needed to determine their roles in this regard. This study was registered at clinicaltrials.gov as NCT02670278.

Human milk oligosaccharides (HMOs) play an important role in the health of an infant as substrate for beneficial gut bacteria. Little is known about the effects of HMO composition and its changes on the morbidity and growth outcomes of infants living in areas with high infection rates. Mother's HMO composition and infant gut microbiota from 33 Gambian mother/infant pairs at 4, 16, and 20 weeks postpartum were analyzed for relationships between HMOs, microbiota, and infant morbidity and growth. The data indicate that lacto-N-fucopentaose I was associated with decreased infant morbidity, and 3'-sialyllactose was found to be a good indicator of infant weight-for-age. Because HMOs, gut microbiota, and infant health are interrelated, the relationship between infant health and their microbiome were analyzed. While bifidobacteria were the dominant genus in the infant gut overall, Dialister and Prevotella were negatively correlated with morbidity, and Bacteroides was increased in infants with abnormal calprotectin. Mothers nursing in the wet season (July to October) produced significantly less oligosaccharides compared to those nursing in the dry season (November to June). These results suggest that specific types and structures of HMOs are sensitive to environmental conditions, protective of morbidity, predictive of growth, and correlated with specific microbiota.

Infants in low-resource settings are at heightened risk for compromised cognitive development due to a multitude of environmental insults in their surroundings. However, the onset of adverse outcomes and trajectory of cognitive development in these settings is not well understood. The aims of the present study were to adapt the Mullen Scales of Early Learning (MSEL) for use with infants in a rural area of The Gambia, to examine cognitive development in the first 24-months of life and to assess the association between cognitive performance and physical growth. In Phase 1 of this study, the adapted MSEL was tested on 52 infants aged 9- to 24-months (some of whom were tested longitudinally at two time points). Further optimization and training were undertaken and Phase 2 of the study was conducted, where the original measures were administered to 119 newly recruited infants aged 5- to 24-months. Infant length, weight and head circumference were measured concurrently in both phases. Participants from both phases were split into age categories of 5-9 m (N = 32), 10-14 m (N = 92), 15-19 m (N = 53) and 20--24 m (N = 43) and performance was compared across age groups. From the ages of 10-14 m, Gambian infants obtained lower MSEL scores than US norms. Performance decreased with age and was lowest in the 20-24 m old group. Differential onsets of reduced performance were observed in the individual MSEL domains, with declines in visual perception and motor performance detected as early as at 10-14 months, while reduced language scores became evident after 15-19 months of age. Performance on the MSEL was significantly associated with measures of growth.

The first 1,000 days of life are a critical window of vulnerability to exposure to socioeconomic and health challenges (i.e. poverty/undernutrition). The Brain Imaging for Global Health (BRIGHT) project has been established to deliver longitudinal measures of brain development from 0 to 24 months in UK and Gambian infants and to assess the impact of early adversity. Here results from the Habituation-Novelty Detection (HaND) functional near-infrared spectroscopy (fNIRS) task at 5 and 8 months are presented (N = 62 UK; N = 115 Gambia). In the UK cohort distinct patterns of habituation and recovery of response to novelty are seen, becoming more robust from 5 to 8 months of age. In The Gambia, an attenuated habituation response is evident: a larger number of trials are required before the response sufficiently suppresses relative to the response during the first presented trials. Furthermore, recovery of response to novelty is not evident at 5 or 8 months of age. As this longitudinal study continues in The Gambia, the parallel collection of socioeconomic, caregiving, health and nutrition data will allow us to stratify how individual trajectories of habituation and recovery of response to novelty associate with different risk factors and adaptive mechanisms in greater depth. Given the increasing interest in the use of neuroimaging methods within global neurocognitive developmental studies, this study provides a novel cross-culturally appropriate paradigm for the study of brain responses associated with attention and learning mechanisms across early development. [Co-written with The BRIGHT project team.]

Objectives: Breastfeeding is an energetically costly and intense form of human parental investment, providing sole‐source nutrition in early infancy and bioactive components, including immune factors. Given the energetic cost of lactation, milk factors may be subject to tradeoffs, and variation in concentrations have been explored utilizing the Trivers‐Willard hypothesis. As human milk immune factors are critical to developing immune system and protect infants against pathogens, we tested whether concentrations of milk immune factors (IgA, IgM, IgG, EGF, TGFβ2, and IL‐10) vary in response to infant sex and maternal condition (proxied by maternal diet diversity [DD] and body mass index [BMI]) as posited in the Trivers‐Willard hypothesis and consider the application of the hypothesis to milk composition. Methods: We analyzed concentrations of immune factors in 358 milk samples collected from women residing in 10 international sites using linear mixed‐effects models to test for an interaction between maternal condition, including population as a random effect and infant age and maternal age as fixed effects. Results: IgG concentrations were significantly lower in milk produced by women consuming diets with low diversity with male infants than those with female infants. No other significant associations were identified. Conclusions: IgG concentrations were related to infant sex and maternal diet diversity, providing minimal support for the hypothesis. Given the lack of associations across other select immune factors, results suggest that the Trivers‐Willard hypothesis may not be broadly applied to human milk immune factors as a measure of maternal investment, which are likely buffered against perturbations in maternal condition. [ABSTRACT FROM AUTHOR]

Human milk is a highly complex liquid food tailor-made to match an infant's needs. Beyond documented positive effects of breastfeeding on infant and maternal health, there is increasing evidence that milk constituents also impact child neurodevelopment. Non-nutrient milk bioactives would contribute to the (long-term) development of child cognition and behavior, a process termed 'Lactocrine Programming'. In this review we discuss the current state of the field on human milk composition and its links with child cognitive and behavioral development. To promote state-of-the-art methodologies and designs that facilitate data pooling and meta-analytic endeavors, we present detailed recommendations and best practices for future studies. Finally, we determine important scientific gaps that need to be filled to advance the field, and discuss innovative directions for future research. Unveiling the mechanisms underlying the links between human milk and child cognition and behavior will deepen our understanding of the broad functions of this complex liquid food, as well as provide necessary information for designing future interventions. [ABSTRACT FROM AUTHOR]