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Objective: Alterations in regional neurometabolite levels as well as impaired neurodevelopmental outcomes have previously been observed in children who are HIV-exposed uninfected (CHEU). However, little is known about how neurometabolite profiles may relate to their developmental impairment. This study aimed to compare neurometabolite concentrations in school-aged CHEU and children who are HIV-unexposed (CHU) and to explore associations of neurometabolite profiles with functional neurodevelopment in the context of perinatal HIV exposure. Methods: We used 3 T single voxel proton magnetic resonance spectroscopy (1H-MRS) to quantify absolute and relative neurometabolites in the parietal gray and parietal white matter in school-aged CHEU and aged- and communitymatched CHU. Functional neurodevelopmental outcomes were assessed using the early learning outcome measure (ELOM) tool at 6 years of age. Results: Our study included 152 school-aged children (50% males), 110 CHEU and 42 CHU, with an average age of 74 months at the neuroimaging visit. In an adjusted multiple linear regression analysis, significantly lower glutamate (Glu) concentrations were found in CHEU as compared to CHU in the parietal gray matter (absolute Glu, p = 0.046; Glu/total creatine (Cr+PCr) ratios, p = 0.035) and lower total choline to creatine ratios (GPC+PCh/Cr+PCr) in the parietal white matter (p = 0.039). Using factor analysis and adjusted logistic regression analysis, a parietal gray matter Glu and myo-inositol (Ins) dominated factor was associated with HIV exposure status in both unadjusted (OR 0.55, 95% CI 0.17-0.45, p = 0.013) and adjusted analyses (OR 0.59, 95% CI 0.35-0.94, p = 0.031). With Ins as one of the dominating metabolites, this neurometabolic factor was similar to that found at the age of two years. Furthermore, this factor was also found to be correlated with ELOM scores of gross motor development in CHEU (Pearson's r = -0.48, p = 0.044). In addition, in CHEU, there was a significant association between Ins/Cr+PCr ratios in the parietal white matter and ELOM scores of fine motor coordination and visual motor integration in CHEU (Pearson's r = 0.51, p = 0.032). Conclusion: Reduced Glu concentrations in the parietal gray matter may suggest regional alterations in excitatory glutamatergic transmission pathways in the context of perinatal HIV and/or antiretroviral therapy (ART) exposure, while reduced Cho ratios in the parietal white matter suggest regional myelin loss. Identified associations between neurometabolite profiles and gross and fine motor developmental outcomes in CHEU are suggestive of a neurometabolic mechanism that may underlie impaired motor neurodevelopmental outcomes observed in CHEU. [ABSTRACT FROM AUTHOR]

Mental health problems often begin in early childhood. However, the associations of various individual and contextual risk factors with mental health in the preschool period are incompletely understood, particularly in low- to middle-income countries (LMICs) where multiple risk factors co-exist. To address this gap, we prospectively followed 981 children in a South African birth cohort, the Drakenstein Child Health Study, assessing pre-and postnatal exposures and risk factors. The predictive value of these factors for child mental health (assessed by the Child Behavior Checklist) was modeled using structural equation modeling. We identified two key pathways to greater externalizing behavior: (1) prenatal exposure to substances (alcohol and smoking) directly predicted increased externalizing behavior (β = 0.24, p < 0.001); this relationship was partially mediated by an aspect of infant temperament (negative emotionality; β = 0.05, p = 0.016); (2) lower socioeconomic status and associated maternal prenatal depression predicted more coercive parenting, which in turn predicted increased externalizing behavior (β = 0.18, p = 0.001). Findings in this high-risk LMIC cohort cohere with research from higher income contexts, and indicate the need to introduce integrated screening and intervention strategies for maternal prenatal substance use and depression, and promoting positive parenting across the preschool period. [ABSTRACT FROM AUTHOR]

Background: Exposure to indoor air pollution during pregnancy has been linked to neurodevelopmental delay in toddlers. Epigenetic modification, particularly DNA methylation (DNAm), may explain this link. In this study, we employed three high-dimensional mediation analysis methods (HIMA, DACT, and gHMA) followed by causal mediation analysis to identify differentially methylated CpG sites and genes that mediate the association between indoor air pollution and neurodevelopmental delay. Analyses were performed using data from 142 mother to child pairs from a South African birth cohort, the Drakenstein Child Health Study. DNAm from cord blood was measured using the Infinium MethylationEPIC and HumanMethylation450 arrays. Neurodevelopment was assessed at age 2 years using the Bayley Scores of Infant and Toddler Development, 3rd edition across four domains (cognitive development, general adaptive behavior, language, and motor function). Particulate matter with an aerodynamic diameter of 10 μm or less (PM10) was measured inside participants' homes during the second trimester of pregnancy. Results: A total of 29 CpG sites and 4 genes (GOPC, RP11-74K11.1, DYRK1A, RNMT) were identified as significant mediators of the association between PM10 and cognitive neurodevelopment. The estimated proportion mediated (95%-confidence interval) ranged from 0.29 [0.01, 0.86] for cg00694520 to 0.54 [0.11, 1.56] for cg05023582. Conclusions: Our findings suggest that DNAm may mediate the association between prenatal PM10 exposure and cognitive neurodevelopment. DYRK1A and several genes that our CpG sites mapped to, including CNKSR1, IPO13, IFNGR1, LONP2, and CDH1, are associated with biological pathways implicated in cognitive neurodevelopment and three of our identified CpG sites (cg23560546 [DAPL1], cg22572779 [C6orf218], cg15000966 [NT5C]) have been previously associated with fetal brain development. These findings are novel and add to the limited literature investigating the relationship between indoor air pollution, DNAm, and neurodevelopment, particularly in low- and middle-income country settings and non-white populations. [ABSTRACT FROM AUTHOR]

Introduction: Exposure to maternal HIV in pregnancy may be a risk factor for impaired child neurodevelopment during the first years of life. Altered neurometabolites have been associated with HIV exposure in older children and may help explain the mechanisms underlying this risk. For the first time, we explored neurometabolic profiles of children who are HIV-exposed and uninfected (CHEU) compared to children who are HIV-unexposed (CHU) at 2-3 years of age. Methods: The South African Drakenstein Child Health Study enrolled women during pregnancy and is following mother-child pairs through childhood. MRI scans were acquired on a sub-group of children at 2-3 years. We used single voxel magnetic resonance spectroscopy to measure brain metabolite ratios to total creatine in the parietal grey matter, and left and right parietal white matter of 83 children (36 CHEU; 47 CHU). Using factor analysis, we explored brain metabolite patterns in predefined parietal voxels in these groups using logistic regression models. Differences in relative concentrations of individual metabolites (n-acetyl-aspartate, myo-inositol, total choline, and glutamate) to total creatine between CHEU and CHU groups were also examined. Results: Factor analysis revealed four different metabolite patterns, each one characterized by covarying ratios of a single metabolite in parietal grey and white matter. The cross-regional pattern dominated by myo-inositol, a marker for glial reactivity and inflammation, was associated with HIV exposure status (OR 1.63; 95% CI 1.11–2.50) which held after adjusting for child age, sex, and maternal alcohol use during pregnancy (OR 1.59; 95% CI 1.07 –2.47). Additionally, higher relative concentrations of myo-inositol to total creatine were found in left and right parietal white matter of CHEU compared to CHU (p=0.025 and p=0.001 respectively). Discussion: Increased ratios of myo-inositol to total creatine in parietal brain regions at age 2-3 years in CHEU are suggestive of early and ongoing neuroinflammatory processes. Altered relative concentrations of neurometabolites were found predominantly in the white matter, which is sensitive to neuroinflammation, and may contribute to developmental risk in this population. Future work on the trajectory of myo-inositol over time in CHEU, alongside markers of neurocognitive development, and the potential for specific neurodevelopmental interventions will be useful. [ABSTRACT FROM AUTHOR]

• Immune markers are increased in pregnant women with depressive symptoms. • Antenatal depressive symptoms are associated with follow-up early life inflammation. • Children exposed to antenatal depression presented with language delay at 2-years. • Infant IL-1β mediated the association of depressive symptoms with impaired language. Antenatal exposure to maternal psychological adversity, including depression, increases the risk of impaired neurodevelopment in children. The underlying biological mechanisms remain unclear, especially in early life during critical windows of development and maturation. This study investigated the association of antenatal maternal depression, maternal and early life inflammatory markers and neurodevelopmental outcomes in children at 2 years of age. A subgroup of mothers and their children (n = 255) that were enrolled in a South African birth cohort study, the Drakenstein Child Health Study, were followed from the antenatal period through to 2 years of child age. Maternal depressive symptoms were measured by the Beck Depression Inventory (BDI-II) at 26 weeks gestation. Serum inflammatory markers [granulocyte–macrophage colony-stimulating factor (GM-CSF), interferon-γ (IFN-γ), interleukin IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, IL-13, tumour necrosis factor-α (TNF-α), neutrophil gelatinase-associated lipocalin (NGAL) and metalloproteinase-9 (MMP-9)] were measured in mothers at enrolment and in their children at 6–10 weeks and at 2 years. Neurodevelopment was assessed at 2 years using the Bayley Scales of Infant and Toddler Development III. Antenatal depressive symptoms (present in 25% of the mothers) were significantly associated with higher levels of IL-7 (p = 0.008), IL-8 (p = 0.019) and TNF-α (p = 0.031) in the mothers after correcting for sociodemographic and lifestyle factors. Serum IL-1β and NGAL levels were significantly elevated over time in children born to mothers with depressive symptoms compared to those without depression, after controlling for maternal and child health and sociodemographic factors. Elevated infant IL-1β at 6–10 weeks of age partially mediated the association of maternal depressive symptoms with poorer language scores at 2 years. Alterations in early life immunity, as reflected by elevated IL-1β, is a potential pathway through which antenatal maternal depressive symptoms may impact language development in young children. [ABSTRACT FROM AUTHOR]

Psychological stressors are prevalent during pregnancy, particularly in low- and middle-income countries (LMICs). A number of studies have demonstrated that prenatal exposure to maternal psychological distress may alter the expression of placental and/or umbilical cord blood (UCB) genes. However, findings have thus far been inconsistent, and the molecular mechanisms underlying these transgenerational effects are currently not well understood. This study aimed to investigate these transgenerational mechanisms using child gene expression profiles, with data from the Drakenstein Child Health Study (DCHS) – an ongoing, longitudinal birth cohort study in South Africa. The Self-Reporting Questionnaire 20 (SRQ-20) was used as a measure of prenatal maternal psychological distress, and a cut-off score >/= 8 was used to dichotomise participants as "high-risk" versus "low-risk". RNA sequencing of umbilical cord blood samples was performed, on newborns exposed to prenatal maternal psychological distress (N=38) and compared to unexposed newborns (N=195). The linear modelling frameworks of the Limma-Voom R-package were applied to identify differentially expressed genes (DEGs) between exposed versus unexposed neonates. Covariates in these analyses included sex of the newborn, gestational age, maternal (self-reported) ethnicity, maternal HIV status, maternal hypertension, maternal prenatal alcohol consumption, maternal prenatal smoking, batch number and RNA integrity number. Thereafter, a gene set enrichment analysis (GSEA) was undertaken to identify significantly enriched pathways. Data from 234 mother-child dyads were included in this analysis. At genome-wide FDR < 0.05, no genes were found to be significantly differentially expressed between newborns exposed to prenatal maternal psychological distress, versus unexposed newborns, after controlling for relevant covariates. However, GSEA (at a nominal p-value < 0.01) demonstrated significant upregulation of genes differentially expressed between exposed versus unexposed newborns, in a number of MSigDB gene set pathways - namely, a) G2M checkpoint, (b) E2F targets, (c) mitotic spindle, (d) MTORC1 signalling, (e) heme metabolism and (f) oestrogen response late. Taken together, the findings suggest that genes differentially expressed between newborns exposed to prenatal maternal psychological distress are significantly upregulated in pathways associated with cell cycle and growth, oestrogen response and heme metabolism. Thus, multiple biological processes may be disrupted by an unfavourable intrauterine environment. Future research to replicate these findings and investigate potential developmental sequelae of these molecular changes would be warranted. [ABSTRACT FROM AUTHOR]

Epigenetic age (EA) acceleration (i.e., higher EA relative to chronological age) has been associated with adverse health outcomes and mortality in adults; and early pubertal development in adolescence. However, potential associations between gestational EA deviation (i.e., accelerated or decelerated EA relative to chronological age) at birth and childhood mental health outcomes remain poorly understood. This study aimed to investigate the association between gestational EA deviation and developmental and mental health outcomes in early childhood - a critical period of neurodevelopment. Data were analysed from the Drakenstein Child Health Study (DCHS), a longitudinal birth cohort study in South Africa. Using DNAm data from umbilical cord blood samples, gestational EA deviation at birth was calculated as the residuals after regressing predicted EA estimates on chronological gestational age. Child developmental and mental health outcomes were assessed with the Bayley Scales of Infant and Toddler Development Third Edition and Child Behavior Checklist. Initially, bivariate linear regression was employed to explore unadjusted associations between gestational EA residuals at birth, and child developmental and mental health outcomes. Thereafter, multivariable linear regression models were used to determine adjusted associations. All models were controlled for socioeconomic status (SES), maternal substance use (alcohol consumption and tobacco smoking), maternal HIV status, maternal anaemia, child anthropometric measures (child sex, birthweight, gestational age), and the first 10 genomic principal components to adjust for population stratification. A study sample of 275 children from the DCHS was included in this analysis. In the adjusted multivariable models, no significant associations were found between gestational EA deviation at birth and developmental or mental health outcomes in the index children, between ages 24 and 60 months. However, trend-level associations between gestational EA deviation at birth and externalising symptoms were observed at 24 months, for both the unadjusted model (β = −0.185, p = 0.0718) and the adjusted model (β = -0.169, p= 0.104). These preliminary findings suggest a need for further, more well-powered studies to investigate the potential clinical and translational utility of gestational EA deviation at birth. [ABSTRACT FROM AUTHOR]