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

Abstract

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.

Early child development in children who are HIV‐exposed uninfected compared to children who are HIV‐unexposed: observational sub‐study of a cluster‐randomized trial in rural Zimbabwe

“…At 12 months of age, a study from South Africa found increased odds of cognitive and motor delay . At two years of age, a study from Botswana showed expressive language delay and a study from South Africa found receptive and expressive language delay . In contrast, a study from Uganda and Malawi did not find difference in neurodevelopmental outcomes in CHEU compared to CHU aged one to five years .…”

In Utero HIV Exposure and the Early Nutritional Environment Influence Infant Neurodevelopment: Findings from an Evidenced Review and Meta-Analysis

“…For the nine studies that included analyses on early life nutrition-related variables and infant neurodevelopment, cohort characteristics and comparison groups based on nutritional intervention (if relevant) are reported in Figure 2. Within these nine studies, two reported data on longitudinal neurodevelopmental assessments (for cognitive (n = 2), motor (n = 2), and language (n = 1) outcomes) [50,51], and seven reported cross-sectional assessment data (for cognitive (n = 7), motor (n = 7), language (n = 7), and behavioural (n = 3) outcomes) [52][53][54][55][56][57][58]. [34] of studies reporting on neurodevelopmental outcomes in infants in relation to HIV-exposure status.…”

Estimates of the global population of children who are HIV-exposed and uninfected, 2000–18: a modelling study

“…7,8 Additionally, some evidence suggests that suboptimal behavioural and neurological development observed among children who are HEU might be associated with preterm birth. [9][10][11] Although the evaluation of birth outcomes, particularly possible terato genicity of in-utero antiretroviral exposure has gained interest, the long-term safety of in-utero antiretrovirals and combination antiretroviral therapy remains poorly understood. [12][13][14] In addition to HIV and antiretroviral exposure, children who are HEU might be exposed to multiple risk factors in early life, including an immunologically perturbed in-utero environment, potential maternal physical and mental ill health, increased exposure to infectious pathogens, challenging socioeconomic circumstances, and suboptimal infant nutrition.…”