Growth, physical and cognitive function in children who are born HIV-free: school-age follow-up of a cluster-randomized trial in rural Zimbabwe

Background Globally, over 16 million children were exposed to HIV during pregnancy but remain HIV-free at birth and throughout childhood. Children born HIV-free (CBHF) have higher morbidity and mortality and poorer neurodevelopment in early life compared to children who are HIV-unexposed (CHU), but long-term outcomes remain uncertain. We characterized school-age growth, cognitive and physical function in CBHF and CHU previously enrolled in the Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial in rural Zimbabwe. Methods and Findings Children in SHINE who had been followed to age 18 months, were re-enrolled to this follow-up study if they were aged 7 years, resident in Shurugwi district, and had a known pregnancy HIV exposure status. From 5280 pregnant women originally enrolled, 264 CBHF and 990 CHU were evaluated at age 7 years using the School-Age Health, Activity, Resilience, Anthropometry and Neurocognitive (SAHARAN) toolbox. Cognitive function was evaluated using the Kaufman Assessment Battery for Children (KABC-II), with additional tools measuring executive function, literacy, numeracy, fine motor skills and socioemotional function. Physical function was assessed using standing broad jump and handgrip for strength, and the shuttle-run test for cardiovascular fitness. Growth was assessed by anthropometry. Body composition was assessed by bioimpedance analysis for lean mass and skinfold thicknesses for fat mass. A caregiver questionnaire measured demographics, socioeconomic status, nurturing, child discipline, food and water insecurity. We prespecified the primary comparisons and used generalized estimating equations (GEE) with an exchangeable working correlation structure to account for clustering. Adjusted models used covariates derived from directed acyclic graphs, with separate models adjusted for contemporary and early-life variables. We found strong evidence that cognitive function was lower for CBHF compared to CHU across multiple domains. The adjusted mean difference in the mental processing index (MPI), derived from KABC-II, was 3 points lower (95%CI 2, 4; P<0.001) in CBHF versus CHU. Similarly, the school achievement test (SAT) of literacy and numeracy was 7 points lower (95%CI 4, 11, P<0.001) and executive function, measured by the Plus-EF tablet-based test, was 5 points lower (95%CI 2, 8; P<0.001) in CBHF compared to CHU. CBHF also had smaller head circumferences by 0.3cm (95%CI 0.1, 0.5; P=0.009). CBHF had fewer years of schooling exposure and caregiver schooling, with higher rates of caregiver depression. CBHF had lower cardiovascular fitness from the shuttle-run test with a maximal oxygen consumption (VO2max) 0.8 ml/kg/min (95%CI 0.4, 1.2; P<0.001) lower than CHU. We found no evidence of differences in other growth, body composition or physical function outcomes. The main limitation of our study is that it was restricted to one of two previous study districts, with possible survivor bias and selection bias from children who had moved away. Conclusions CBHF have reductions in cognitive function, head circumference and cardiovascular fitness compared to CHU at 7 years of age. Further research is needed to define the biological and psychosocial mechanisms underlying these differences, to inform future interventions that help CBHF thrive across the life-course. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial PACTR202201828512110 ### Clinical Protocols ### Funding Statement Funded by Wellcome Trust (grants 220671/Z/20/Z (JDP) and 108065/Z/15/Z (AJP)), (https://wellcome.org/) National Institutes of Health (grant R61HD103101) (https://www.nih.gov/), Thrasher Research Fund (grant 15250) (https://www.thrasherresearch.org/) and Innovative Methods and Metrics for Agriculture and Nutrition Actions (IMMANA grant 3.02) (https://www.anh-academy.org/immana). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Medical Research Council of Zimbabwe approved the study protocol (MRCZ/A/1675). The SHINE follow-up study was registered with the Pan-African Clinical Trials Registry (PACTR202201828512110). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data will be freely available as individual participant data on ClinEpiDB with an accompanying data dictionary at http://ClinEpiDB.org from 2025. Researchers must agree to the policies and comply with the mechanism of ClinepiDB to access data housed on this platform. Prior to that time, data are available upon reasonable request from the Zvitambo Institute for Maternal and Child Health Research, by contacting Dr Robert Ntozini (r.ntozini@zvitambo.com)