Children who are HIV-exposed uninfected (CHEU) are at a higher risk of morbidity, adverse birth outcomes, hindrances in growth, and poor mental health compared to children who are HIV-unexposed uninfected (CHUU). In sub-Saharan Africa (SSA), the CHEU population makes up about 20% of all children under age 15 years, and the SSA region is estimated to have the largest number of children under age 5 years at risk of scoring under their developmental potential. In addition, factors such as parental caregiving and environmental influences greatly impact a child’s neurodevelopment, and these delays can be reverse if intervention occurs early enough. The authors of research published in Journal of the International AIDS Society assess the associations between caregiver and household factors, HIV and antiretroviral therapy (ART) exposure, and child neurodevelopment in Kenya.
Key Takeaways
- Comparable Neurodevelopment Scores Between CHEU and CHUU: Children who are HIV-exposed uninfected (CHEU) and children who are HIV-unexposed uninfected (CHUU) demonstrated overall comparable neurodevelopment scores, with CHEU showing higher scores in the language domain. This finding challenges previous notions of significant developmental disparities between the 2 groups.
- Factors Associated with Lower Neurodevelopment Scores: Lower neurodevelopment scores were associated with various factors, including male gender, preterm birth, lower perceived social support, and maternal reports of intimate partner violence. Specifically, lower development in CHEU was linked to having a deceased or absent father, a single or widowed mother, and in utero exposure to efavirenz (EFV)-based antiretroviral therapy regimens.
- Impact of Maternal ART Regimen on Neurodevelopment: The study found a significant association between the maternal ART regimen used during pregnancy and neurodevelopment. Children who were exposed to EFV-based regimens had lower gross motor scores compared to those exposed to dolutegravir (DTG)-based regimens, suggesting a potential influence of ART choice on the neurodevelopmental outcomes of HIV-exposed children.
Authors of the exploratory analysis identified cofactors associated with child neurodevelopment among the subset of children who reached 1 year of age and had complete neurodevelopmental assessments by June 2023. To measure child neurodevelopment, the investigators administered a test designed to generate scores across 4 domains—social, language, fine motor, and gross motor—with 36 to 42 pass/fail items in each category. In addition, assessors underwent a training curriculum, with each assessor conducting at least 10 supervised practice assessments prior to receiving certification and the start of the study. Assessments that were incomplete or invalid were excluded from the analysis.
From March 2021 to June 2022, mothers with and without HIV were enrolled with their infants (aged 4 to 10 weeks) during routine 6-week postnatal care visits across 7 different sites. In addition, the mother-infant pairs are followed every 6 months until the children are 3 years of age. A primary exposure of interest was maternal HIV status (CHEU vs CHUU).
The women involved in the study self-reported their HIV status. Infants who were born to women living with HIV were tested for HIV DNA on dried blood spots at 6 weeks, 6 months, and 12 months, and were then tested using an HIV antibody test at 18 months. Further, infant HIV status was gathered at each time point to ensure CHEU remained HIV-negative. A small population of the 709 CHEU (n = 34) that were included in the analysis had pending HIV test results by the time the analysis started.
In addition, mothers living with HIV were asked questions regarding their experience with status disclosure to their partners as well as ART initiation, duration, and regimen. Data on maternal ART regimens were abstracted from medical records, as well as information on any changes in regimens during or after pregnancy. The investigators note that women who received dolutegravir (DTG)-only regimens were compared to those who received efavirenz (EFV)-only regimens.
The findings indicate that CHEU and CHUU had overall comparable neurodevelopment scores, with CHEU having higher scores in the language domain. Lower child neurodevelopment scores were associated with males, preterm birth, lower perceived level of social support, and maternal report of intimate partner violence (IPV); however, lower child development among CHEU only were associated with having a deceased or absent father, single or widowed mother, and in utero exposure to EFV-based ART regimens.
Compared to female children, male children scored much lower in the social (adjusted coeff: -0.18, 95% CI: -0.33, -0.02, p = 0.02) and language domains (adjusted coeff: -0.18, 95% CI: -0.33, -0.02, p = 0.02). In addition, children who were born preterm scored lower in gross motor than children who were born full-term (adjusted coeff: -1.38, 95% CI: -2.05, -0.71, p < 0.001). IPV was significantly associated with lower fine motor (adjusted coeff: −0.76, 95% CI: −1.40, −0.13, p = 0.02) and gross motor scores (adjusted coeff: −1.07, 95% CI: −1.81, −0.33, p < 0.01). Low gross motor was also associated with lower levels of maternal perceived social support (adjusted coeff: −0.31, 95% CI: −0.56, −0.06, p = 0.02); however, it was not associated with other mental health measures. Male CHEU consistently scored lower than female CHEU in the social domain (adjusted coeff: −0.58, 95% CI: −0.97, −0.20, p < 0.01), and CHEU born preterm scored significantly lower in the gross motor domains compared to CHEU born full-term (adjusted coeff: −1.00, 95% CI: −1.95, −0.05, p = 0.04).
Further, neurodevelopment was significantly associated with the maternal ART regimen used during pregnancy. Gross motor scores were significantly lower with most-recent in utero exposure to EFV-based regimens than DTG-based regimens (adjusted coeff: −0.47, 95% CI: −0.92, −0.02, p = 0.04). This finding was the same in sensitivity analyses comparing CHEU exposed exclusively to EFV to those exposed exclusively to DTG.
A limitation of the study is the enrollment of infants at 6 weeks of age, as that may result in selection bias due to the exclusion of infants potentially at the greatest risk of neurodevelopmental delay (eg, preterm and/or hospitalized infants, infants who did not return for a 6-week visit). Further, approximately 11% of the study population were lost-to-follow-up by their 12-month visit, resulting in mother-infant pairs who were disengaged in routine postnatal care and at an elevated risk of poorer outcomes. A small population (5%) of the CHEU aged 1 year had pending HIV test results at the beginning of the analysis, posing a risk for misclassification of child HIV status.
The study authors acknowledged that the HIV-negative statuses of mothers of CHUU at 1 year postpartum were not confirmed; however, the investigators anticipate less than 1% of women would have changed status between 6 weeks and 12 months postpartum. In addition, the study did not include mothers younger than 18 years of age, mothers who were not engaged in postnatal care or prevention of vertical transmission programs, and children whose mothers died prior to the child reaching 6 weeks of age. Further, differential misclassification and recall bias could potentially impact findings if mothers have psychological distress.
The investigators note that it is important to develop strategies that incorporate neurodevelopmental screening programs into health systems that have clear referral pathways that aid in the early identification of neurodevelopmental delays. In addition, the study authors note that high frequency of DTG use during pregnancy could be an explanation for similar overall scores between CHEU and CHUU; however, that would require further research.
Reference
Bulterys, MA, Njuguna, I, King'e, M, et al. Neurodevelopment of children who are HIV-exposed and uninfected in Kenya. J Int AIDS Soc., 26: e26149. doi:10.1002/jia2.26149
