Improving infant Neurocognitive Development and Growth Outcomes with micronutrients (INDiGO): A protocol for an efficacy trial in rural Gambia.

Background: Undernutrition during the early years of life has a harmful and irreversible impact on child growth and cognitive development. Many of the interventions tested to improve outcomes across infancy have had disappointing or inconsistent impact, a common feature being the absence of any attempt to provide nutritional supplements to infants during the first six months. With increasing evidence of micronutrient deficiencies in this age group, alongside strong evidence that growth and developmental deficits begin before six months, a renewed focus on the micronutrient status of infants is required. Methods: This study is a five-arm, double-blind, placebo-controlled, randomised efficacy trial of micronutrient supplementation to mothers (during pregnancy or pregnancy and lactation) and infants (Day 8 to six months of age) in rural Gambia, where rates of micronutrient deficiencies are high. 600 pregnant women (<20 weeks gestation) will be enrolled into one of five trial arms and followed to 12 months post-partum. The primary outcome will be infant brain development at six months, with micronutrient status, growth and neurocognitive development to 12 months as secondary outcomes. Discussion: This novel research will identify the most efficacious way of improving micronutrient status in infancy, and assess impact on infant developmental outcomes, providing an evidence base for future effectiveness trials and policy recommendations. Trial registration: ISRCTN registry ( ISRCTN15063705, 09/07/2021); Pan African Clinical Trials Registry ( PACTR202201552774601, 21/01/2022).

Deficiencies of micronutrients in infants and young children can have a long-lasting impact on growth and development. This is especially relevant in populations with poor diets. However, little research has focused on interventions to improve micronutrient deficiencies in the first six-months of life, during the period when exclusive breastfeeding is recommended. Here we describe the protocol for a randomised trial among women and infants living in sub-Saharan Africa, to determine whether supplementation with micronutrients to mothers (in pregnancy, or pregnancy and lactation) or supplementation to infants directly (while promoting exclusive breastfeeding) will improve infant development across the first 12 months of life. This trial will test the effect of supplementation on infant brain development, micronutrient status and growth. This novel research will determine the best way to improve infant micronutrient status and developmental outcomes, providing important data for policy considerations.

Effect of heat stress in the first 1000 days of life on fetal and infant growth: a secondary analysis of the ENID randomised controlled trial.

BACKGROUND: The intersecting crises of climate change, food insecurity, and undernutrition disproportionately affect children. Understanding the effect of heat on growth from conception to 2 years of age is important because of mortality and morbidity implications in the near term and over the life course. METHODS: In this secondary analysis, we used longitudinal pregnancy cohort data from the Early Nutrition and Immunity Development (ENID) randomised controlled trial in West Kiang, The Gambia, which occurred between Jan 20, 2010, and Feb 10, 2015. The ENID trial assessed micronutrient supplementation in the first 1000 days of life starting from 20 weeks' gestation, during which anthropometric measurements were collected prospectively. We used multivariable linear regression to assess the effect of heat stress (defined by Universal Thermal Climate Index [UTCI]) on intrauterine growth restriction based on length-for-gestational age Z score (LGAZ), weight-for-gestational age Z score (WGAZ), and head circumference-for-gestational age Z score (HCGAZ) at birth, and assessed for effect modification of supplement intervention on the relationship between heat stress and infant anthropometry. We used multivariable, multilevel linear regression to evaluate the effect of heat stress on infant growth postnatally based on weight-for-height Z score (WHZ), weight-for-age Z score (WAZ), and height-for-age Z score (HAZ) from 0 to 2 years of age. FINDINGS: Complete data were available for 668 livebirth outcomes (329 [49%] female infants and 339 [51%] male infants). With each 1°C increase in mean daily maximum UTCI exposure, in the first trimester, we observed a reduction in WGAZ (-0·04 [95% CI -0·09 to 0·00]), whereas in the third trimester, we observed an increase in HCGAZ (0·06 [95% CI 0·00 to 0·12]), although 95% CIs included 0. Maternal protein-energy supplementation in the third trimester was associated with reduced WGAZ (-0·16 [-0·30 to -0·02]) with each 1°C increase in mean daily maximum UTCI exposure, while no effect of heat stress on WGAZ was found with either standard care (iron and folate) or multiple micronutrient supplementation. For the postnatal analysis, complete anthropometric data at 2 years were available for 645 infants (316 [49%] female infants and 329 [51%] male infants). Postnatally, heat stress effect varied by infant age, with infants aged 6-18 months being the most affected. In infants aged 12 months exposed to a mean daily UTCI of 30°C (preceding 90-day period) versus 25°C UTCI, we observed reductions in mean WHZ (-0·43 [95% CI -0·57 to -0·29]) and mean WAZ (-0·35 [95% CI -0·45 to -0·26]). We observed a marginal increase in HAZ with increasing heat stress exposure at age 6 months, but no effect at older ages. INTERPRETATION: Our results suggest that heat stress impacts prenatal and postnatal growth up to 2 years of age but sensitivity might vary by age. In the context of a rapidly warming planet, these findings could have short-term and long-term health effects for the individual, and immediate and future implications for public child health. FUNDING: Wellcome Trust.

Human milk oligosaccharides are associated with maternal genetics and respiratory health of human milk-fed children.

Breastfeeding provides many health benefits, but its impact on respiratory health remains unclear. This study addresses the complex and dynamic nature of the mother-milk-infant triad by investigating maternal genomic factors regulating human milk oligosaccharides (HMOs), and their associations with respiratory health among human milk-fed infants. Nineteen HMOs are quantified from 980 mothers of the CHILD Cohort Study. Genome-wide association studies identify HMO-associated loci on chromosome 19p13.3 and 19q13.33 (lowest P = 2.4e-118), spanning several fucosyltransferase (FUT) genes. We identify novel associations on chromosome 3q27.3 for 6'-sialyllactose (P = 2.2e-9) in the sialyltransferase (ST6GAL1) gene. These, plus additional associations on chromosomes 7q21.32, 7q31.32 and 13q33.3, are replicated in the independent INSPIRE Cohort. Moreover, gene-environment interaction analyses suggest that fucosylated HMOs may modulate overall risk of recurrent wheeze among preschoolers with variable genetic risk scores (P < 0.01). Thus, we report novel genetic factors associated with HMOs, some of which may protect the respiratory health of children.

Effects of prenatal small-quantity lipid-based nutrient supplements on pregnancy, birth, and infant outcomes: a systematic review and meta-analysis of individual participant data from randomized controlled trials in low- and middle-income countries.

BACKGROUND: Undernutrition during pregnancy increases the risk of giving birth to a small vulnerable newborn. Small-quantity lipid-based nutrient supplements (SQ-LNSs) contain both macro- and micronutrients and can help prevent multiple nutritional deficiencies. OBJECTIVES: We examined the effects of SQ-LNSs provided during pregnancy compared with 1) iron and folic acid or standard of care (IFA/SOC) or 2) multiple micronutrient supplements (MMSs) and identified characteristics that modified the estimates of effects of SQ-LNSs on birth outcomes. METHODS: We conducted a 2-stage meta-analysis of individual participant data from 4 randomized controlled trials of SQ-LNSs provided during pregnancy (n = 5273). We generated study-specific and subgroup estimates of SQ-LNS compared with IFA/SOC or MMS and pooled the estimates. In sensitivity analyses, we examined whether the results differed depending on methods for gestational age dating, birth anthropometry, or study design. RESULTS: SQ-LNSs (compared with IFA/SOC) increased birth weight [mean difference: +49 g; 95% confidence interval (CI): 26, 71 g] and all birth anthropometric z-scores (+0.10-0.13 standard deviation); they reduced risk of low birth weight by 11%, newborn stunting by 17%, newborn wasting by 11%, and small head size by 15%. Only 2 trials compared SQ-LNSs and MMSs; P values for birth outcomes were >0.10 except for head circumference (e.g., z-score for gestational age: +0.11; 95% CI: -0.01, 0.23). Effect estimates for SQ-LNSs compared with IFA/SOC were greater among female infants and, for certain outcomes, among mothers with body mass index <20 kg/m2, inflammation, malaria, or household food insecurity. Effect estimates for SQ-LNSs compared with MMSs were greater for certain outcomes among female infants, first-born infants, and mothers <25 y. CONCLUSIONS: SQ-LNSs had positive impacts on multiple outcomes compared to IFA/SOC, but further research directly comparing SQ-LNSs and MMSs is needed. Targeting SQ-LNSs to vulnerable subgroups may be worth considering. CLINICAL TRIAL REGISTRY: This study was registered at PROSPERO as CRD42021283391.

Effects of maternal calcium supplementation on offspring blood pressure and growth in childhood and adolescence in a population with a low-calcium intake: follow-up study of a randomized controlled trial.

BACKGROUND: The World Health Organization recommends calcium supplementation (1500-2000 mg/d) during pregnancy for women with a low-calcium intake. OBJECTIVES: The purpose of this study was to investigate whether pregnancy calcium supplementation affects offspring blood pressure and growth in The Gambia where calcium intakes are low (300-400 mg/d). METHODS: Follow-up of offspring born during a randomized controlled trial of pregnancy calcium supplementation (ISRCTN96502494, 1996-2000) in which mothers were randomly assigned to 1500 mg Ca/d (Ca) or placebo (P) from 20 wk pregnancy to delivery. Offspring were enrolled at age 3 y in studies where blood pressure and anthropometry were measured under standardized conditions at approximately 2-yearly intervals. Mean blood pressure and growth curves were fitted for females and males separately, using the longitudinal SuperImposition by Translation and Rotation (SITAR) mixed effects model. This generates 3 individual-specific random effects: size, timing, and intensity, reflecting differences in size, age at peak velocity, and peak velocity through puberty relative to the mean curve, respectively. RESULTS: Five hundred twenty-three singleton infants were born during the trial (maternal group assignment: Ca/P = 259/264). Four hundred ninety-one were enrolled as children (females: F-Ca/F-P = 122/129 and males: M-Ca/M-P = 119/121) and measured regularly from 3.0 y to mean age 18.4 y; 90% were measured on ≥8 occasions. SITAR revealed differences in the systolic blood pressure and height curves between pregnancy supplement groups in females, but not in males. F-Ca had lower systolic blood pressure than F-P at all ages (size = -2.1 ± SE 0.8 mmHg; P = 0.005) and lower peak height velocity (intensity = -2.9 ± SE 1.1%, P = 0.009). No significant pregnancy supplement effects were seen for other measures. CONCLUSIONS: This study showed, in female offspring, that pregnancy calcium supplementation may lower systolic blood pressure and slow linear growth in childhood and adolescence, adding to evidence of offspring sexual dimorphism in responses to maternal supplementation. Further research is warranted on the long-term and intergenerational effects of antenatal supplementations. This trial was registered at ISRCTN Registry as ISRCTN96502494.

Cognitive control in infancy: Attentional predictors using a tablet-based measure.

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.

Early iron supplementation in exclusively breastfed Gambian infants: a randomized controlled trial.

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 µmol/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.

Sex differences in growth and neurocognitive development in infancy and early childhood.

Undernutrition in early life remains a significant public health challenge affecting millions of infants and young children globally. Children who are wasted, stunted or underweight are at increased risk of morbidity and mortality. Undernutrition at critical periods also impacts on aspects of neurodevelopment, with longer-term consequences to educational performance and mental health outcomes. Despite consistent evidence highlighting an increased risk of neonatal and infant mortality among boys, a common assumption held across many disciplines is that girls are more vulnerable with respect to early-life exposures. In relation to undernutrition, however, recent evidence indicates the reverse, and in contexts of food insecurity, boys are at increased risk of undernutrition in early life compared to girls, with sex-specific risks for neurodevelopmental deficits. These effects appear independent of social factors that may favour boys, such as gender disparities in infant feeding practices and health-seeking behaviours. The observed vulnerability among boys may therefore be underpinned by biological processes such as differential energy requirements during periods of rapid growth. As boys have greater needs for growth and maintenance, then, in times of nutritional hardship, these needs may not be met resulting in risk of undernutrition and subsequent health consequences. In view of this emerging evidence, a greater understanding of the mechanisms behind this vulnerability among boys is needed and policy considerations to protect boys should be considered. This review will explore sex differences in risk of undernutrition and consider these in the context of existing programmes and policies.

Growth in early infancy drives optimal brain functional connectivity which predicts cognitive flexibility in later childhood.

Functional brain network organization, measured by functional connectivity (FC), reflects key neurodevelopmental processes for healthy development. Early exposure to adversity, e.g. undernutrition, affects neurodevelopment, observable via disrupted FC, and leads to poorer outcomes from preschool age onward. We assessed longitudinally the impact of early growth trajectories on developmental FC in a rural Gambian population from age 5 to 24 months. To investigate how these early trajectories relate to later childhood outcomes, we assessed cognitive flexibility at 3-5 years. We observed that early physical growth before the fifth month of life drove optimal developmental trajectories of FC that in turn predicted cognitive flexibility at pre-school age. In contrast to previously studied developmental populations, this Gambian sample exhibited long-range interhemispheric FC that decreased with age. Our results highlight the measurable effects that poor growth in early infancy has on brain development and the subsequent impact on pre-school age cognitive development, underscoring the need for early life interventions throughout global settings of adversity.

It takes a village: Caregiver diversity and language contingency in the UK and rural Gambia.

INTRODUCTION: There is substantial diversity within and between contexts globally in caregiving practices and family composition, which may have implications for the early interaction's infants engage in. We draw on data from the Brain Imaging for Global Health (BRIGHT, www.globalfnirs.org/the-bright-project) project, which longitudinally examined infants in the UK and in rural Gambia, West Africa. In The Gambia, households are commonly characterized by multigenerational, frequently polygamous family structures, which, in part, is reflected in the diversity of caregivers a child spends time with. In this paper, we aim to 1) evaluate and validate the Language Environment Analysis (LENA) for use in the Mandinka speaking families in The Gambia, 2) examine the nature (i.e., prevalence of turn taking) and amount (i.e., adult and child vocalizations) of conversation that infants are exposed to from 12 to 24 months of age and 3) investigate the link between caregiver diversity and child language outcomes, examining the mediating role of contingent turn taking. METHOD: We obtained naturalistic seven-hour-long LENA recordings at 12, 18 and 24 months of age from a cohort of N = 204 infants from Mandinka speaking households in The Gambia and N = 61 infants in the UK. We examined developmental changes and site differences in LENA counts of adult word counts (AWC), contingent turn taking (CTT) and child vocalizations (CVC). In the larger and more heterogenous Gambian sample, we also investigated caregiver predictors of turn taking frequency. We hereby examined the number of caregivers present over the recording day and the consistency of caregivers across two subsequent days per age point. We controlled for children's cognitive development via the Mullen Scales of Early Learning (MSEL). RESULTS: Our LENA validation showed high internal consistency between the human coders and automated LENA outputs (Cronbach's alpha's all >.8). All LENA counts were higher in the UK compared to the Gambian cohort. In The Gambia, controlling for overall neurodevelopment via the MSEL, CTT at 12 and 18 months predicted CVC at 18 and 24 months. Caregiver consistency was associated with CTT counts at 18 and 24 months. The number of caregivers and CTT counts showed an inverted u-shape relationship at 18 and 24 months, with an intermediate number of caregivers being associated with the highest CTT frequencies. Mediation analyses showed a partial mediation by number of caregivers and CTT and 24-month CVC. DISCUSSION: The LENA provided reliable estimates for the Mandinka language in the home recording context. We showed that turn taking is associated with subsequent child vocalizations and explored contextual caregiving factors contributing to turn taking in the Gambian cohort.

Iron status in early infancy is associated with trajectories of cognitive development up to pre-school age in rural Gambia.

INTRODUCTION: Iron deficiency is among the leading risk factors for poor cognitive development. However, interventions targeting iron deficiency have had mixed results on cognitive outcomes. This may be due to previous interventions focusing on the correction of iron deficiency anaemia in late infancy and early childhood, at which point long lasting neural impacts may already be established. We hypothesise that the relationship between iron status and cognitive development will be observable in the first months of life and will not be recovered by 5 years of age. METHODS: Using data from the Brain Imaging for Global Health (BRIGHT) Study in Gambia (n = 179), we conducted mixed effects modelling to assess the relationship between iron status at 5 months of age and trajectories of cognitive development from 5 months- 5 years using (i) a standardised measure of cognitive development (Mullen Scales of Early Learning) and (ii) an eye-tracking assessment of attention processing (visual disengagement time). RESULTS: All infants were iron sufficient at 1 month of age. At 5 and 12 months of age 30% and 55% of infants were iron deficient respectively. In fully adjusted analyses, infants in the lowest tercile of soluble transferrin receptor (sTfR) (best iron status) achieved MSEL Cognitive Scores on average 1.9 points higher than infants in the highest sTfR tercile (p = 0.009, effect size = 0.48). There was no evidence that this group difference was recovered by 5 years of age. Infants in the lowest sTfR tercile had visual disengagement time 57ms faster than the highest tercile (p = 0.001, effect size = 0.59). However, this difference diminished by early childhood (p = 0.024). CONCLUSION: Infants are at risk of iron deficiency in early infancy. A relationship between iron status and cognitive development is apparent from 5 months of age and remains observable at 5 years of age. One mechanism by which iron availability in early infancy impacts brain development may be through effects on early attentional processing, which is rapidly developing and has substantial nutritional requirements during this period. To support neurocognitive development, prevention of iron deficiency in pre- and early postnatal life may be more effective than correcting iron deficiency once already established.

DNA methylation at the suppressor of cytokine signaling 3 (SOCS3) gene influences height in childhood.

Human height is strongly influenced by genetics but the contribution of modifiable epigenetic factors is under-explored, particularly in low and middle-income countries (LMIC). We investigate links between blood DNA methylation and child height in four LMIC cohorts (n = 1927) and identify a robust association at three CpGs in the suppressor of cytokine signaling 3 (SOCS3) gene which replicates in a high-income country cohort (n = 879). SOCS3 methylation (SOCS3m)-height associations are independent of genetic effects. Mendelian randomization analysis confirms a causal effect of SOCS3m on height. In longitudinal analysis, SOCS3m explains a maximum 9.5% of height variance in mid-childhood while the variance explained by height polygenic risk score increases from birth to 21 years. Children's SOCS3m is associated with prenatal maternal folate and socio-economic status. In-vitro characterization confirms a regulatory effect of SOCS3m on gene expression. Our findings suggest epigenetic modifications may play an important role in driving child height in LMIC.

Human milk immune factors, maternal nutritional status, and infant sex: The INSPIRE study.

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, TGFß2, 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.

Caregiver perceptions of nutrition interventions in infants and children under 24 months of age: a systematic review.

OBJECTIVE: Efficacy studies show early nutrition interventions improving infant nutrition status, but understanding caregiver acceptability is required for implementation of such interventions. This systematic review examines caregivers' perceptions of nutrition interventions in young children. DESIGN: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, CINAHL and PsychINFO from date of online journal inception through December 2020. Interventions included oral (powder/liquid/tablet) and/or intravenous supplementation, food fortification and nutrition counselling. Inclusion criteria included primary research, data presented on caregiver perception and studies published in English. Quality assessment was performed using the Critical Appraisal Skills Programme tool. Studies underwent narrative synthesis using inductive thematic analysis. SETTING: No restriction. PARTICIPANTS: Caregivers of children under 24 months of age. RESULTS: Of 11 798 records identified, thirty-seven publications were included. Interventions included oral supplementation, food fortification and nutrition counselling. Caregivers included mothers (83 %), fathers, grandparents and aunts. Perceptions were gathered through individual interviews, focus group discussions, questionnaires, surveys and ratings. Totally, 89 % of studies noted high acceptability (n 33 most notably increased appetite (n 17). In total, 57 % of studies (n 21) cited low acceptability, commonly from side effects (n 13) such as gastrointestinal issues, appetite loss and stained teeth. CONCLUSIONS: Positive perceptions and enthusiasm for interventions were frequently reported. Key to implementation was the increased appetite noted by caregivers. A substantial proportion of studies reported negative perceptions, mainly due to side effects. In future interventions, mitigation and education around common side effects are crucial for acceptability. Understanding both positive and negative caregiver perceptions is important for informing future nutrition interventions and strengthening sustainability and implementation.

Executive functioning skills and their environmental predictors among pre-school aged children in South Africa and The Gambia.

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.

Longitudinal fNIRS and EEG metrics of habituation and novelty detection are correlated in 1-18-month-old infants.

INTRODUCTION: Habituation and novelty detection are two fundamental and widely studied neurocognitive processes. Whilst neural responses to repetitive and novel sensory input have been well-documented across a range of neuroimaging modalities, it is not yet fully understood how well these different modalities are able to describe consistent neural response patterns. This is particularly true for infants and young children, as different assessment modalities might show differential sensitivity to underlying neural processes across age. Thus far, many neurodevelopmental studies are limited in either sample size, longitudinal scope or breadth of measures employed, impeding investigations of how well common developmental trends can be captured via different methods. METHOD: This study assessed habituation and novelty detection in N = 204 infants using EEG and fNIRS measured in two separate paradigms, but within the same study visit, at 1, 5 and 18 months of age in an infant cohort in rural Gambia. EEG was acquired during an auditory oddball paradigm during which infants were presented with Frequent, Infrequent and Trial Unique sounds. In the fNIRS paradigm, infants were familiarised to a sentence of infant-directed speech, novelty detection was assessed via a change in speaker. Indices for habituation and novelty detection were extracted for both EEG and NIRS RESULTS: We found evidence for weak to medium positive correlations between responses on the fNIRS and the EEG paradigms for indices of both habituation and novelty detection at most age points. Habituation indices correlated across modalities at 1 month and 5 months but not 18 months of age, and novelty responses were significantly correlated at 5 months and 18 months, but not at 1 month. Infants who showed robust habituation responses also showed robust novelty responses across both assessment modalities. DISCUSSION: This study is the first to examine concurrent correlations across two neuroimaging modalities across several longitudinal age points. Examining habituation and novelty detection, we show that despite the use of two different testing modalities, stimuli and timescale, it is possible to extract common neural metrics across a wide age range in infants. We suggest that these positive correlations might be strongest at times of greatest developmental change.

Lipoprotein subfraction patterns throughout gestation in The Gambia: changes in subfraction composition and their relationships with infant birth weights.

BACKGROUND: Lipoprotein subfraction concentrations have been shown to change as gestation progresses in resource-rich settings. The objective of the current study was to evaluate the impact of pregnancy on different-sized lipoprotein particle concentrations and compositions in a resource-poor setting. METHOD: Samples were collected from pregnant women in rural Gambia at enrollment (8-20 weeks), 20 weeks, and 30 weeks of gestation. Concentrations of different-sized high-density, low-density, and triglyceride-rich lipoprotein particles (HDL, LDL, and TRL, respectively) were measured by nuclear magnetic resonance in 126 pooled plasma samples from a subset of women. HDL was isolated and the HDL proteome evaluated using mass spectroscopy. Subfraction concentrations from women in The Gambia were also compared to concentrations in women in the U.S. in mid gestation. RESULTS: Total lipoprotein particles and all-sized TRL, LDL, and HDL particle concentrations increased during gestation, with the exception of medium-sized LDL and HDL particles which decreased. Subfraction concentrations were not associated with infant birth weights, though relationships were found between some lipoprotein subfraction concentrations in women with normal versus low birth weight infants (< 2500 kg). HDL's proteome also changed during gestation, showing enrichment in proteins associated with metal ion binding, hemostasis, lipid metabolism, protease inhibitors, proteolysis, and complement activation. Compared to women in the U.S., Gambian women had lower large- and small-sized LDL and HDL concentrations, but similar medium-sized LDL and HDL concentrations. CONCLUSIONS: Most lipoprotein subfraction concentrations increase throughout pregnancy in Gambian women and are lower in Gambian vs U.S. women, the exception being medium-sized LDL and HDL particle concentrations which decrease during gestation and are similar in both cohorts of women. The proteomes of HDL also change in ways to support gestation. These changes warrant further study to determine how a lack of change or different changes could impact negative pregnancy outcomes.

An evidence review and nutritional conceptual framework for pre-eclampsia prevention.

Pre-eclampsia is a serious complication of pregnancy, and maternal nutritional factors may play protective roles or exacerbate risk. The tendency to focus on single nutrients as a risk factor obscures the complexity of possible interactions, which may be important given the complex nature of pre-eclampsia. An evidence review was conducted to compile definite, probable, possible and indirect nutritional determinants of pre-eclampsia to map a nutritional conceptual framework for pre-eclampsia prevention. Determinants of pre-eclampsia were first compiled through an initial consultation with experts. Second, an expanded literature review was conducted to confirm associations, elicit additional indicators and evaluate evidence. The strength of association was evaluated as definite relative risk (RR) < 0·40 or ≥3·00, probable RR 0·40-0·69 or 1·50-2·99, possible RR 0·70-0·89 or 1·10-1·49 or not discernible RR 0·90-1·09. The quality of evidence was evaluated using Grading of Recommendations, Assessment, Development and Evaluation. Twenty-five nutritional factors were reported in two umbrella reviews and twenty-two meta-analyses. Of these, fourteen were significantly associated with pre-eclampsia incidence. Higher serum Fe emerged as a definite nutritional risk factors for pre-eclampsia incidence across populations, while low serum Zn was a risk factor in Asia and Africa. Maternal vitamin D deficiency was a probable risk factor and Ca and/or vitamin D supplementation were probable protective nutritional factors. Healthy maternal dietary patterns were possibly associated with lower risk of developing pre-eclampsia. Potential indirect pathways of maternal nutritional factors and pre-eclampsia may exist through obesity, maternal anaemia and gestational diabetes mellitus. Research gaps remain on the influence of household capacities and socio-cultural, economic and political contexts, as well as interactions with medical conditions.

Human milk: From complex tailored nutrition to bioactive impact on child cognition and behavior.

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.

The Brain Imaging for Global Health (BRIGHT) Project: Longitudinal cohort study protocol.

There is a scarcity of prospective longitudinal research targeted at early postnatal life which maps developmental pathways of early-stage processing and brain specialisation in the context of early adversity. Follow up from infancy into the one-five year age range is key, as it constitutes a critical gap between infant and early childhood studies. Availability of portable neuroimaging (functional near infrared spectroscopy (fNIRS) and electroencephalography (EEG)) has enabled access to rural settings increasing the diversity of our sampling and broadening developmental research to include previously underrepresented ethnic-racial and geographical groups in low- and middle- income countries (LMICs). The primary objective of the Brain Imaging for Global Health (BRIGHT) project was to establish brain function - using longitudinal data from mother - for-age reference curves infant dyads living in the UK and rural Gambia and investigate the association between context-associated moderators and developmental trajectories across the first two years of life in The Gambia. In total, 265 participating families were seen during pregnancy, at 7-14 days, 1-, 5-, 8-, 12-, 18- and 24-months post-partum. An additional visit is now underway at 3-5 years to assess pre-school outcomes. The majority of our Gambian cohort live in poverty, but while resource-poor in many factors they commonly experience a rich and beneficial family and caregiving context with multigenerational care and a close-knit supportive community. Understanding the impact of different factors at play in such an environment ( i.e., detrimental undernutrition versus beneficial multigenerational family support) will (i) improve the representativeness of models of general cognitive developmental pathways from birth, (ii) identify causal pathways of altered trajectories associated with early adversity at both individual and group level, and (iii) identify the context-associated moderators ( i.e. social context) that protect development despite the presence of poverty-associated challenges. This will in turn contribute to the development of targeted interventions.