Language outcomes of preschool children who are HIV-exposed uninfected: An analysis of a South African cohort.

INTRODUCTION: There are approximately 16 million children who are HIV-exposed and uninfected (CHEU) worldwide. Studies suggest that CHEU are at risk for developmental impairment in infancy, particularly in language domains. However, there is limited research examining neurocognitive function in CHEU older than 2 years, including important pre-school years. This study aimed to investigate associations between HIV exposure without infection and neurocognitive outcomes and to determine risk factors for neurodevelopment in CHEU at age 3-4 years. METHODS: The Drakenstein Child Health Study is a South African population-based birth cohort which enrolled women in pregnancy with ongoing follow up. Neurocognitive outcomes were assessed in children at 3.5 years by trained assessors blinded to HIV status including general cognitive function, language, and memory, measured using the Kaufmann Assessment Battery for Children, Second Edition (KABC-II). Data were compared between CHEU and children who were HIV-unexposed uninfected (CHUU) using multivariable logistic and linear regression, including testing for effect modification; sex-stratified risk factor analyses were performed. RESULTS: A total of 497 children were included (97 [20%] CHEU; 400 [80%] CHUU; 50% male), with a mean age of 3.5 years (range 3.4-3.6). Groups had similar birth and household characteristics, although mothers of CHEU were older, on average. Overall, CHEU had lower expressive language scores compared to CHUU on unadjusted and adjusted analyses (effect size: -0.23 [95% CI -0.45, -0.01]). There were no group differences in general cognitive or memory function (p>0.05). On sex-stratified analyses, male CHEU were found to have higher odds of suboptimal cognitive development compared to male CHUU (aOR 2.28 [95% CI 1.06, 4.87], p = 0.034). Several other factors including birthweight, maternal education, maternal ART duration and HIV viral load during pregnancy were associated with cognition, memory, or expressive language outcomes in CHEU, dependent on child sex. INTERPRETATION: The findings suggest that perinatal HIV exposure continues to be associated with impaired language development across the preschool years, highlighting the importance of targeting early interventions to optimise language outcomes. Further, the results suggest the importance of demographic, biological and HIV-related variables influencing developmental outcomes in CHEU. The greater risk of suboptimal cognitive development in male CHEU requires investigation around sex-specific mechanisms.

Investigating pupillometry to detect emotional regulation difficulties in post-traumatic stress disorder.

OBJECTIVE: Individuals with posttraumatic stress disorder (PTSD) have been found to exhibit emotional regulation difficulties. However, the specific neural mechanisms that underlie these difficulties remain understudied. This study aimed to use pupillometry as an index function of parasympathetic nervous system activation, to investigate the mechanisms underlying emotional regulation difficulties in individuals with PTSD. METHOD: A total of 87 trauma-exposed mothers (34 with PTSD and 53 non-PTSD controls) completed an eye tracking assessment in which pupillary dilation in response to emotionally valenced stimuli was measured. The participants also completed two self-report measures of emotional regulation, namely the Difficulties in Emotional Regulation Scale and the Emotional Regulations Questionnaire. Linear mixed-effect modelling was used to assess potential group differences. RESULTS: The PTSD group exhibited increased pupillary dilation to positively valenced stimuli compared to the non-PTSD group. However, no significant associations between the self-report measures and pupillary response to emotionally valenced stimuli were found. CONCLUSION: Increased pupillary dilation in PTSD may reflect impaired parasympathetic nervous system processes. The lack of association of these measures with self-reported emotion regulation may suggest reporting biases. Larger studies with more generalised populations are required to consolidate these preliminary findings.

Maternal psychosocial risk factors and child gestational epigenetic age in a South African birth cohort study.

Accelerated epigenetic aging relative to chronological age has been found to be associated with higher risk of mortality in adults. However, little is known about whether and how in utero exposures might shape child gestational epigenetic age (EA) at birth. We aimed to explore associations between maternal psychosocial risk factors and deviation in child gestational EA at birth (i.e., greater or lower EA relative to chronological age) in a South African birth cohort study-the Drakenstein Child Health Study. Maternal psychosocial risk factors included trauma/stressor exposure; posttraumatic stress disorder (PTSD); depression; psychological distress; and alcohol/tobacco use. Child gestational EA at birth was calculated using an epigenetic clock previously devised for neonates; and gestational EA deviation was calculated as the residuals of the linear model between EA and chronological gestational age. Bivariate linear regression was then used to explore unadjusted associations between maternal/child risk factors and child gestational EA residuals at birth. Thereafter, a multivariable regression method was used to determine adjusted associations. Data from 271 maternal-child dyads were included in the current analysis. In the multivariable regression model, maternal PTSD was significantly and negatively associated with child gestational EA residuals at birth (ß = -1.95; p = 0.018), controlling for study site, sex of the child, head circumference at birth, birthweight, mode of delivery, maternal estimated household income, body mass index (BMI) at enrolment, HIV status, anaemia, psychological distress, and prenatal tobacco or alcohol use. Given the novelty of this preliminary finding, and its potential translational relevance, further studies to delineate underlying biological pathways and to explore clinical implications of EA deviation are warranted.

Prenatal alcohol exposure is associated with early motor, but not language development in a South African cohort.

OBJECTIVE: To investigate the association of prenatal alcohol exposure (PAE) and early neurodevelopment in the first 2 years of life, adjusting for maternal socio-demographic and psychosocial factors, in the Drakenstein Child Health Study (DCHS), a South African birth cohort study. METHODS: The DCHS comprises a population-based birth cohort of 1143 children, of which a subsample completed the Bayley Scales of Infant Development-III (BSID-III) at 6 (n = 260) and 24 months of age (n = 734). A subset of alcohol-exposed and -unexposed children was included in this analysis at age 6 (n = 52 exposed; n = 104 unexposed) and 24 months (n = 92 exposed; n = 184 unexposed). Multiple hierarchical regression was used to explore the associations of PAE with motor and language development. RESULTS: PAE was significantly associated with decreased gross motor [odds ratio (OR) = 0.16, 95% confidence interval (CI) = 0.06-0.44, p = 0.001] or fine motor (OR = 0.16, 95% CI = 0.06-0.46, p = 0.001) functioning after adjusting for maternal socio-demographic and psychosocial factors at 6 months of age only. No significant effects were found in either receptive or expressive communication and cognitive outcomes at either time points. CONCLUSION: PAE has potentially important consequences for motor development in the first 2 years of life, a period during which the most rapid growth and maturation occur. These findings highlight the importance of identifying high-risk families in order to provide preventive interventions, particularly in antenatal clinics and early intervention services.

Neurodevelopment of HIV-exposed uninfected children in South Africa: outcomes from an observational birth cohort study.

BACKGROUND: HIV infection is known to cause developmental delay, but the effects of HIV exposure without infection during pregnancy on child development are unclear. We compared the neurodevelopmental outcomes of HIV-exposed uninfected and HIV-unexposed children during their first 2 years of life. METHODS: Pregnant women (>18 years of age) at 20-28 weeks' gestation were enrolled into the Drakenstein Child Health cohort study while attending routine antenatal appointments at one of two peri-urban community-based clinics in Paarl, South Africa. Livebirths born to enrolled women during follow-up were included in the birth cohort. Mothers and infants received antenatal and postnatal HIV testing and antiretroviral therapy per local guidelines. Developmental assessments on the Bayley Scales of Infant and Toddler Development, third edition (BSID-III), were done in a subgroup of infants at 6 months of age, and in the full cohort at 24 months of age, with assessors masked to HIV exposure status. Mean raw scores and the proportions of children categorised as having a delay (scores <-2 SDs from the reference mean) on BSID-III were compared between HIV-exposed uninfected and HIV-unexposed children. FINDINGS: 1225 women were enrolled between March 5, 2012, and March 31, 2015. Of 1143 livebirths, 1065 (93%) children were in follow-up at 6 months and 1000 (87%) at 24 months. Two children were diagnosed with HIV infection between birth and 24-month follow-up and were excluded from the analysis. BSID-III assessments were done in 260 (24%) randomly selected children (61 HIV-exposed uninfected, 199 HIV-unexposed) at 6 months and in 732 (73%) children (168 HIV-exposed uninfected, 564 HIV-unexposed) at 24 months. All HIV-exposed uninfected children were exposed to antiretrovirals (88% to maternal triple antiretroviral therapy). BSID-III outcomes did not significantly differ between HIV-exposed uninfected and HIV-unexposed children at 6 months. At 24 months, HIV-exposed uninfected children scored lower than HIV-unexposed for receptive language (adjusted mean difference -1·03 [95% CI -1·69 to -0·37]) and expressive language (-1·17 [-2·09 to -0·24]), whereas adjusted differences in cognitive (-0·45 [-1·32 to 0·43]), fine motor (0·09 [-0·49 to 0·66]), and gross motor (-0·41 [-1·09 to 0·27]) domain scores between groups were not significant. Correspondingly, the proportions of HIV-exposed uninfected children with developmental delay were higher than those of HIV-unexposed children for receptive language (adjusted odds ratio 1·96 [95% CI 1·09 to 3·52]) and expressive language (2·14 [1·11 to 4·15]). INTERPRETATION: Uninfected children exposed to maternal HIV infection and antiretroviral therapy have increased odds of receptive and expressive language delays at 2 years of age. Further long-term work is needed to understand developmental outcomes of HIV-exposed uninfected children, especially in regions such as sub-Saharan Africa that have a high prevalence of HIV exposure among children. FUNDING: Bill & Melinda Gates Foundation, SA Medical Research Council, Wellcome Trust.

Risk and protective factors for child development: An observational South African birth cohort.

BACKGROUND: Approximately 250 million (43%) children under the age of 5 years in low- and middle-income countries (LMICs) are failing to meet their developmental potential. Risk factors are recognised to contribute to this loss of human potential. Expanding understanding of the risks that lead to poor outcomes and which protective factors contribute to resilience in children may be critical to improving disparities. METHODS AND FINDINGS: The Drakenstein Child Health Study is a population-based birth cohort in the Western Cape, South Africa. Pregnant women were enrolled between 20 and 28 weeks' gestation from two community clinics from 2012 to 2015; sociodemographic and psychosocial data were collected antenatally. Mothers and children were followed through birth until 2 years of age. Developmental assessments were conducted by trained assessors blinded to background, using the Bayley-III Scales of Infant and Toddler Development (BSID-III), validated for use in South Africa, at 24 months of age. The study assessed all available children at 24 months; however, some children were not able to attend, because of loss to follow-up or unavailability of a caregiver or child at the correct age. Of 1,143 live births, 1,002 were in follow-up at 24 months, and a total of 734 children (73%) had developmental assessments, of which 354 (48.2%) were girls. This sample was characterised by low household employment (n = 183; 24.9%) and household income (n = 287; 39.1% earning 1 domain affected, and 75 (10.2%) had delay in all domains. Bivariate and multivariable analyses revealed several factors that were associated with developmental outcomes. These included protective factors (maternal education, higher birth weight, and socioeconomic status) and risk factors (maternal anaemia in pregnancy, depression or lifetime intimate partner violence, and maternal HIV infection). Boys consistently performed worse than girls (in cognition [ß = -0.74; 95% CI -1.46 to -0.03, p = 0.042], receptive language [ß = -1.10; 95% CI -1.70 to -0.49, p < 0.001], expressive language [ß = -1.65; 95% CI -2.46 to -0.84, p < 0.001], and fine motor [ß = -0.70; 95% CI -1.20 to -0.20, p = 0.006] scales). There was evidence that child sex interacted with risk and protective factors including birth weight, maternal anaemia in pregnancy, and socioeconomic factors. Important limitations of the study include attrition of sample from birth to assessment age and missing data in some exposure areas from those assessed. CONCLUSIONS: This study provides reliable developmental data from a sub-Saharan African setting in a well-characterised sample of mother-child dyads. Our findings highlight not only the important protective effects of maternal education, birth weight, and socioeconomic status for developmental outcomes but also sex differences in developmental outcomes and key risk and protective factors for each group.

Drakenstein Child Health Study (DCHS): investigating determinants of early child development and cognition.

INTRODUCTION: There is growing awareness that psychosocial risk and resilience factors in early life play a key role in influencing later health. Most work has been done in high-income settings, rather than low-income and middle-income countries (LMICs), where the majority of the global childhood population resides. The few studies with well-defined cohorts in LMICs have employed various methods and measures, making comparisons across studies challenging. This presentation describes the methodology for infant and child developmental measures used in the Drakenstein Child Health Study (DCHS), a multidisciplinary longitudinal birth cohort study in South Africa. METHODS AND ANALYSIS: We outline a multilevel approach combining a range of measures including parental reports, behaviour observations, clinician-administered scales and brain imaging. Using this approach, we aim at a longitudinal perspective of developmental, cognitive, socioemotional and neurophysiological outcomes in a birth cohort of children in an LMIC. ETHICS AND DISSEMINATION: The study was approved by the faculty of Health Sciences, Human Research Ethics Committee, University of Cape Town (401/2009), Stellenbosch University (N12/02/0002) and the Western Cape Provincial Health Research committee (2011RP45). DISCUSSION: Children in the DCHS develop in a context typical of many communities in South Africa and other LMICs. There is a critical need for research in LMICs to elucidate underlying factors that inform risk for, and resilience to, poor developmental outcomes in infants born into high-risk communities. Such work may inform effective intervention strategies appropriate to this context.

Effect of Hazardous Alcohol Use During Pregnancy on Growth Outcomes at Birth: Findings from a South African Cohort Study.

BACKGROUND: Cohort studies have noted associations between hazardous alcohol use during pregnancy and infant growth outcomes, but many have not controlled for potential psychosocial confounders. To assess the unique contribution of hazardous alcohol use, we examined its effect on infant growth outcomes while controlling for maternal psychosocial stressors and hazardous tobacco and drug use in a cohort of 986 pregnant South African women enrolled into the Drakenstein Child Health Study between 2012 and 2015. METHODS: Data on psychosocial stressors and maternal risk behaviors were collected between 28 and 32 weeks of gestation. Participants were categorized as hazardous alcohol users if they obtained moderate or high scores (>10) on the Alcohol, Smoking and Substance Involvement Screening Test at this assessment or retrospectively reported drinking at least 2 drinks weekly during any trimester of pregnancy. Infant growth outcomes were recorded at delivery. Multivariable regression models examined correlates of hazardous alcohol use and associations between hazardous alcohol use and birth outcomes. RESULTS: Overall, 13% of mothers reported hazardous alcohol use. Recent exposure to intimate partner violence (adjusted odds ratio (aOR) = 2.08; 95% confidence interval (CI): 1.37, 3.18) and hazardous tobacco use (aOR = 5.03; 95% CI: 2.97, 8.52) were significant correlates of hazardous alcohol use. After controlling for potential psychosocial confounders, hazardous alcohol use remained associated with lower infant weight-for-age (B = -0.35, 95% CI: -0.56, -0.14), height-for-age (B = -0.46, 95% CI: -0.76, -0.17), and head-circumference-for-age z-scores (B = -0.43, 95% CI: -0.69, -0.17). CONCLUSIONS: Interventions to reduce hazardous alcohol use among pregnant women in South Africa are needed to prevent alcohol-related infant growth restrictions. As these growth deficits may lead to neurodevelopmental consequences, it is critical to identify alcohol-related growth restrictions at birth and link exposed infants to early interventions for neurodevelopment.