Longitudinal effects of prenatal alcohol exposure on visual neurodevelopment over infancy

Prenatal alcohol exposure (PAE) affects neurodevelopment in over 59 million individuals globally. Prior studies using dichotomous categorization of alcohol use and comorbid substance exposures provide limited knowledge of how prenatal alcohol specifically impacts early human neurodevelopment. In this longitudinal cohort study from Cape Town, South Africa, PAE is measured continuously-characterizing timing, dose, and drinking patterns (i.e., binge drinking). High-density electroencephalography (EEG) during a visual-evoked potential (VEP) task was collected from infants aged 8 to 52 weeks with prenatal exposure exclusively to alcohol and matched on sociodemographic factors to infants with no substance exposure in utero. First trimester alcohol exposure related to altered timing of the P1 VEP component over the first 6 months postnatally, and first trimester binge drinking exposure altered timing of the P1 VEP components such that increased exposure was associated with longer VEP latencies while increasing age was related to shorter VEP latencies (n = 108). These results suggest alcohol exposure in the first trimester may alter visual neurodevelopmental timing in early infancy. Exploratory individual-difference analysis across infants with and without PAE tested the relation between VEP latencies and myelination for a subsample of infants with usable magnetic resonance imaging (MRI) T1w and T2w scans collected at the same time point as EEG (n = 47). Decreased MRI T1w/T2w ratios (an indicator of myelin) in the primary visual cortex (n = 47) were linked to longer P1 VEP latencies. Results from these two sets of analyses suggest that prenatal alcohol and postnatal myelination may both separately impact VEP latency over infancy

Iron deficiency anaemia in mothers and infants with high inflammatory burden: Prevalence and profile in a South African birth cohort

The scarcity of epidemiological data on anaemia in low- and middle-income countries, coupled with contrasting approaches to the assessment of iron status with inflammation, represent critical research gaps. This study characterised the prevalence and profile of iron deficiency anaemia, including adjustment for inflammation, in mothers and infants from South Africa. Mother-child dyads (n = 394) were recruited (2021–2022) for the Khula birth cohort in Cape Town. Haematological metrics, iron metrics, and inflammatory biomarkers were obtained from mothers antenatally and 3–6 months postnatally, and infants 3–18 months postnatally. The extent to which inflammation impacted iron deficiency was assessed using two methods; Method A: higher serum ferritin thresholds for classifying iron status in participants with inflammation (World Health Organisation), Method B: Biomarkers Reflecting Inflammation and Nutritional Determinants of Anaemia (BRINDA) regression which corrects serum ferritin based on inflammatory biomarker concentrations. Prevalence of maternal anaemia was 34.74% (107/308) in pregnancy and 22.50% (54/240) in mothers at 3–6 months after childbirth. Of their infants, 46.82% (125/267) and 48.10% (136/283) were anaemic by 6–12 months and 12–18 months, respectively. Using Method A, the prevalence of maternal iron deficiency (regardless of anaemia), increased from 18.35% (20/109) to 55.04% (60/109) in pregnancy, and from 11.97% (28/234) to 46.58% (109/234) postnatally. Similarly, using Method B, maternal iron deficiency prevalence increased to 38.53% (42/109) in pregnancy, and 25.21% (59/234) postnatally. In infants at 12–18 months, the prevalence of iron deficiency increased from 19.79% (19/96) to 31.25% (30/96) and 32.29% (31/96) using Methods A and B, respectively. Approximately half of anaemia cases in mothers antenatally (50%; 20/40) and postnatally (45.10%; 23/51), and infants at 12–18 months (55.56%; 10/18), were attributable to iron deficiency. This is one of the first studies reporting the extent to which iron deficiency anaemia may be underestimated if inflammation is unaccounted for in South African mothers and infants

Codevelopment of gut microbial metabolism and visual neural circuitry over human infancy

Infancy is a time of elevated neuroplasticity supporting rapid brain and sensory development. The gut microbiome, also undergoing extensive developmental changes in early life, may influence brain development through the metabolism of neuroactive compounds. Here, we leverage longitudinal data from 194 South African infants across the first 18 months of life to show that microbial genes encoding enzymes that metabolize molecules playing a key role in modulating early neuroplasticity are associated with visual cortical neurodevelopment, measured by the Visual-Evoked Potential (VEP). Neuroactive compounds included neurotransmitters GABA and glutamate, the amino acid tryptophan, and short-chain fatty acids involved in myelination, including acetate and butyrate. Microbial gene sets around 4 months of age were strongly associated with the VEP from around 9–14 months of age and showed more associations than concurrently measured gene sets, suggesting that microbial metabolism in early life may affect subsequent neural plasticity and development. IMPORTANCE Over the past decade, extensive research has revealed strong links between the gut microbiome and the brain, at least in adults or those with neuropsychiatric disorders. This study explores how these associations emerge in early development using a longitudinal sample of 194 infants with repeated microbiome metabolism and electroencephalography (EEG) measures during the critical early period of visual cortex neuroplasticity. We examined microbial genes encoding enzymes for neuroactive compounds (e.g., GABA, glutamate, tryptophan, and short-chain fatty acids) and their association with the visual-evoked potential (VEP). Genes from 4-month stool samples strongly correlated with VEP features between 9 and 14 months, suggesting that early microbial metabolism influences later visual neurodevelopment. These prospective associations were more numerous than the concurrent ones. Our findings suggest that early gut microbiome metabolic potential plays a crucial role in shaping neural plasticity and visual neurodevelopment

Childhood trauma exposure and autonomic nervous system changes among children in a South African birth cohort

The developmental origins of disease hypothesis posits that early life stress, such as childhood trauma and adversities, can permanently affect health in later life (Gluckman et al., 2005). Consistent with this hypothesis, childhood trauma exposure has been robustly associated with both mental and physical health problems throughout the lifespan (Hogg et al., 2022; Suglia et al., 2015). It has been theorised that neurobiological changes in the body’s stress response systems, including in the autonomic nervous system (ANS), drive these long-term adverse effects of childhood trauma (Agorastos et al., 2018; Beilharz et al., 2020). A key area of growing concern is the robust association between childhood trauma and an increased risk of cardiovascular diseases (CVDs; Jacquet-Smailovic et al., 2022; Suglia et al., 2015), which are among the leading causes of death worldwide (WHO, 2019). However, robust evidence investigating early markers of cardiovascular function is limited. Given that research has consistently found that elevated heart rate (HR) measured in the aftermath of a traumatic event is associated with subsequently reporting more post-traumatic stress symptoms (Morris et al., 2016), and that both childhood trauma and elevated resting HR are associated with increased risk of CVDs (Aune et al., 2017), it is theorised that childhood trauma is associated with a persistently elevated HR. However, research has yielded mixed findings across both adult and youth samples, with trauma linked to both elevated (Beilharz et al., 2020; Pretty et al., 2013) and reduced resting HR (Bailey et al., 2025; Krenichyn et al., 2001) in some studies, and no effects in others (MacMillan et al., 2009; Sigrist et al., 2021). It has been theorised that trauma exposure, particularly cumulative or prolonged traumas, during critical developmental periods could result in chronic hyperactivation or hypoactivation of the stress response system, dependent on trauma timing (e.g., early childhood vs. adolescence; Agorastos et al., 2018) or the type and extent of trauma exposure (Herzog et al., 2018), which could offer some explanation for this mixed pattern of findings. However, there are several key limitations of the existing evidence which may have also contributed to these findings. Firstly, most research has been conducted with relatively small sample sizes and has been conducted primarily in high-income countries. Youth in low- and middle-income countries (LMICs) are especially underrepresented despite the majority of the world’s children living in LMICs (UNICEF, 2005), and these youth being disproportionately more likely to be exposed to traumas than youth in high-income countries (WHO, 2002). More than 75% of children in South Africa were estimated to have been exposed to at least one traumatic event before age 6 years (Tsunga et al., 2023); estimates from high-income country cohorts demonstrate substantially lower rates of trauma exposure even when participants are older (Lewis et al., 2019). Secondly, most studies have used cross-sectional designs. For studies with adults, childhood trauma exposure is therefore reported retrospectively which may introduce significant recall bias. Additionally, cross-sectional studies recruit participants following trauma exposure; therefore the ability to draw causal conclusions regarding trauma-HR associations is limited. Furthermore, because participants have been recruited following trauma exposure, most individuals have been exposed to single-incident traumas, such as road traffic accidents and other accidental injuries. Research has shown that interpersonal childhood traumas, especially those occurring within the family, such as physical, sexual, and domestic violence, are the strongest predictors of psychopathology (Green et al., 2010; McLaughlin et al., 2010). The underrepresentation of these more severe or chronic/repeated traumas in the existing literature may therefore offer some explanation for the mixed findings across studies. Finally, a limitation of all the aforementioned studies is that HR was measured at a single timepoint. HR is not static and decreases naturally with age (Sarganas et al., 2017). Research should therefore utilise repeated measurements of HR to investigate whether childhood trauma exposure is associated with changes in HR development (e.g., slowing of the normal pattern of decline with advancing age). Heart rate variability (HRV), the variation in time intervals between heartbeats, has also been of particular interest in the traumatic stress literature, as it is viewed as a more sensitive measure of ANS function (Appelhans & Luecken, 2006), through indices that capture sympathetic and parasympathetic activity (Nagpal et al., 2013). Lower HRV is thought to reflect impaired functioning/regulation of the ANS, which negatively affects the body’s ability to cope with stressors (Sigrist et al., 2021), and research has shown lower HRV to be associated with an increased risk of cardiovascular events (Hillebrand et al., 2013). Research with adults has shown associations between childhood trauma and reduced resting HRV (Bussone et al., 2023; Jin et al., 2018), though research with youth samples has not observed such effects (MacArthur, 2011; Michels et al., 2013), suggesting that the impact of childhood trauma on HRV may not be evident until later life. Finally, childhood trauma exposures have been associated with blunted ANS reactivity to stressors (Busso et al., 2017; Voellmin et al., 2015). However, again, this evidence is limited by small sample sizes, the use of cross-sectional designs, and an underrepresentation of LMIC samples. To address these limitations of the existing literature, the present study will use data from the Drakenstein Child Health Study (Donald et al., 2018; Stein et al., 2015; Zar et al., 2015), an ongoing prospective birth cohort located in Cape Town, South Africa, to conduct a longitudinal investigation of the impact of childhood trauma on ANS functioning in children living in a LMIC. Research Questions & Aims: 1. Does childhood trauma exposure predict the average levels and rate of change of resting HR during childhood? We aim to estimate change in resting HR between ages 4 and 8 years using growth curve modelling, and to examine trauma exposure up to age 4.5 years as a time-invariant predictor of the resultant growth factors. 2. Is childhood trauma exposure associated with resting HRV during childhood? We aim to use linear regression analyses to examine cross-sectional and longitudinal associations between childhood trauma exposure (assessed at ages 4.5 and 8 years) and indices of resting HRV at age 8. 3. Is childhood trauma exposure associated with altered autonomic reactivity to stress? We aim to use linear regression analyses to examine cross-sectional and longitudinal associations between childhood trauma exposure (assessed at ages 4.5 and 8 years) and HR and HRV reactivity in response to stress at age 8 years (captured via residualized change scores)

Effects of Prenatal Alcohol Exposure on the Volumes of the Lateral and Medial Walls of the Intraparietal Sulcus

Fetal alcohol spectrum disorders (FASD) continue to be the leading preventable cause of intellectual disability in the U.S., Europe, and in endemic areas, such as the Western Cape region of South Africa. Arithmetic is highly sensitive to prenatal alcohol exposure (PAE). The intraparietal sulcus (IPS) is known to play a critical role in number processing. In this study, we investigate whether smaller IPS volumes play a role in the number-processing deficits observed in children with PAE. Participants were 52 9- to 14-year-old children from a historically disadvantaged community in Cape Town, who are participating in our ongoing studies on the effects of PAE on the brain. The IPS was manually parcellated into its medial (MIPS) and lateral (LIPS) walls on magnetic resonance images. The study aimed to examine: (1) the effects of PAE on IPS regional volumes and asymmetry, (2) whether IPS regional volumes are related to number processing performance and, if so, whether these relations are moderated by PAE and (3) potential mediation by regional IPS volumes of the relation between PAE and number processing performance. Total intracranial volume (TIV) was associated with volumes in all regions except the right LIPS. Both left MIPS and left LIPS volumes were significantly smaller in children in the fetal alcohol syndrome (FAS)/partial FAS (PFAS) group compared to controls. The finding in the left LIPS remained significant after controlling for potential confounders and after adjustment for the smaller overall brain size of the children in the FAS/PFAS group. Smaller left LIPS volumes in the FAS/PFAS group may account for the absence of left-right asymmetry in the LIPS in children with FAS/PFAS compared to controls and nonsyndromal heavily exposed (HE) children. Bilaterally, larger MIPS volumes were associated with better WISC IQ Arithmetic scores. These effects, however, were not moderated by the degree of PAE, and regional IPS volumes did not mediate the effect of PAE on WISC Arithmetic scores. Although we found that certain regions of the IPS were smaller in children with FAS and PFAS, these PAE-induced changes in IPS volume did not mediate the alcohol-related deficits in arithmetic.</jats:p

Psychosocial Predictors of Infant and Young Child Feeding Practices Among Mother-Child Dyads in Malawi and South Africa.

Maternal capacity to adhere to recommended infant and young child feeding (IYCF) practices may be influenced by psychosocial factors. However, research examining associations between psychosocial factors and IYCF practices, and in particular complementary feeding indicators, is limited. As part of the Khula birth cohort study, we aimed to investigate associations between maternal depression, exposure to intimate partner violence (IPV), social support and stimulating home environments with IYCF practices among mother-child dyads in Malawi (n = 153) and South Africa (n = 255). When children were 10-16 months of age, mothers completed a series of psychosocial and child diet questionnaires. Regression modelling assessed associations between maternal psychosocial measures and IYCF indicators, adjusting for maternal age, education, marital status and household socioeconomic status. IYCF practices were suboptimal in both settings, with 50%-54% meeting the minimum dietary diversity (MDD), 67%-73% the minimum meal frequency (MMF) and 39%-45% the minimum acceptable diet (MAD) indicators. In South Africa, mothers exposed to IPV in the previous 12 months were less likely to meet the MDD and MAD recommendations (MDD: OR 0.38, 95% CI: 0.19, 0.75; p = 0.006; MAD: OR 0.41, 95% CI: 0.20, 0.85; p = 0.02). There was a significant positive association between stimulation (i.e., more books/toys/play activities) and dietary diversity scores in South Africa. In adjusted analyses, maternal depression and social support were not significantly associated with IYCF indicators in either setting. IYCF programmes may benefit from supporting maternal psychosocial wellbeing and integrating nurturing care to improve children's dietary intakes, growth and development

Associations between maternal capabilities for care and nurturing care behaviours among mother-child dyads in Malawi and South Africa.

Adequate nurturing care behaviours, including feeding practices, health-seeking and psychosocial stimulation, are crucial for the optimal health, growth and development of young children. However, several factors, recognised as maternal 'capabilities for care', can influence a mother's capability to provide adequate care, namely knowledge/beliefs, physical health and nutritional status, mental health, autonomy, reasonable workload/time availability and social support. As part of the Khula birth cohort study, we aimed to investigate if maternal capabilities for care are associated with nurturing care behaviours among mother-child dyads in Malawi (n = 122) and South Africa (n = 206). When children were 10-16 months of age, mothers competed a series of self-reported sociodemographic, child diet and health and psychosocial questionnaires. Six maternal capabilities for care were considered: haemoglobin concentration, mental health, employment, decision-making autonomy, support for childcare and social support. The nurturing care behaviours were feeding practices, complete immunisation status appropriate to chid age and psychosocial stimulation within the home environment. Regression modelling assessed associations between maternal capabilities for care and each care behaviour, adjusting for child sex, maternal age and education level and household socioeconomic status. Associations between maternal capabilities for care and nurturing care behaviours differed by care behaviour and setting. Maternal employment and decision-making as measures of autonomy, support with childcare as a measure of reasonable workload and reported social support were the maternal capabilities most consistently associated with feeding practices, complete immunisation status and stimulation practices, although the direction of associations differed between settings. Maternal haemoglobin and mental health were associated with one care behaviour each (stimulation and feeding practices, respectively). Measuring and understanding how various maternal capabilities influence caregiving across contexts is essential for empowering caregivers to provide optimal care. Interventions, programmes and policies that seek to improve child health, growth and development through enhanced nurturing care practices should strengthen multiple maternal capabilities

Characterizing developing executive functions in the first 1000 days in South Africa and Malawi: The Khula Study

The term ‘executive functions’ (EFs) refers to a set of skills that support flexible control over thought and action. Classic EFs (working memory, inhibitory control, and cognitive flexibility) do not show measurable stable function until after the third year of life and continue to develop into early adulthood. However, even at the earliest ages, these EFs are shown to have value for predicting school readiness and academic achievement. They continue to have predictive value for success, mental health, and general well-being across the lifespan including in ageing populations. As such, understanding the developing brain and cognitive developmental dynamics that set the stage for the development of EFs, in the first three years of life, is crucial for developing programming that supports healthy EFs development. The goal of this manuscript is to describe the goals, hypotheses, participant populations, and methodology of the Khula Study. Khula is a multi-modal multi-site longitudinal birth cohort study designed to characterise emerging EFs in the first 1000 days of life in global majority settings. Most research to date has been conducted in highincome countries rather than low- and middle-income countries that comprise most of the world’s child population. We assert that understanding and supporting EF development has global importance, but this must be done with the understanding that EFs are skills that develop within the context of adaptation to one’s environment. As such, the Khula Study aims to understand which EF influences are common across cultures but also which are culture specific. We will address these questions by incorporating data from South Africa and Malawi to understand influences on EF development and outcomes for children living in these contexts. We enrolled 394 mothers (84% antenatally) from Gugulethu in Cape Town, South Africa and 507 mothers (42% antenatally) from Blantyre, Malawi

Evaluating a novel high-density EEG sensor net structure for improving inclusivity in infants with curly or tightly coiled hair

Electroencephalography (EEG) is an important tool in the field of developmental cognitive neuroscience for indexing neural activity. However, racial biases persist in EEG research that limit the utility of this tool. One bias comes from the structure of EEG nets/caps that do not facilitate equitable data collection across hair textures and types. Recent efforts have improved EEG net/cap design, but these solutions can be time-intensive, reduce sensor density, and are more difficult to implement in younger populations. The present study focused on testing EEG sensor net designs over infancy. Specifically, we compared EEG data quality and retention between two high-density saline-based EEG sensor net designs from the same company (Magstim EGI, Whitland, UK) within the same infants during a baseline EEG paradigm. We found that within infants, the tall sensor nets resulted in lower impedances during collection, including lower impedances in the key online reference electrode for those with greater hair heights and resulted in a greater number of usable EEG channels and data segments retained during pre-processing. These results suggest that along with other best practices, the modified tall sensor net design is useful for improving data quality and retention in infant participants with curly or tightly-coiled hair