Maternal Use of Integrase Strand Transfer Inhibitors During Pregnancy and Infant Neurodevelopment

Importance Current perinatal HIV treatment guidelines recommend inclusion of integrase strand transfer inhibitors (INSTIs), but few studies have evaluated the safety of INSTIs for infant neurodevelopment. Objective To compare the neurodevelopment of infants born between 2012 and 2023 with in utero exposure to INSTI-containing antiretroviral treatment (ART) regimens with that of infants exposed to protease inhibitor (PI) –containing or nonnucleoside reverse transcriptase inhibitor (NNRTI) –containing regimens. Design, Setting, and Participants This prospective cohort study was conducted in 22 US-based academic research centers among women with HIV and their uninfected infants born between January 1, 2012, and December 31, 2023, and exposed in utero to INSTI-based, PI-based, or NNRTI-based combination ART regimens. The children underwent neurodevelopmental assessments at 1 year of age. Data were analyzed between January 13 and September 5, 2025. Exposure Initial maternal ART regimen during pregnancy. Main Outcomes and Measures Neuropsychologists administered the Bayley Scales of Infant and Toddler Development–3rd Edition (Bayley-III) to children at 1 year of age. Mean differences by drug class were calculated for Bayley-III cognitive, language, and motor development domain scores, adjusting for confounders. Stratified analyses were conducted by timing of maternal ART initiation. Results A total of 1006 infants born between 2012 and 2023 with a Bayley-III assessment at 1 year of age were included. The mean (SD) maternal age at delivery was 30. 3 (6. 0) years; 663 mothers (65. 9%) had an annual income of less than 20 000; and 125 (12. 4%) had perinatally acquired HIV. Of the 1006 infants, 306 were exposed in utero to an initial INSTI-based maternal ART regimen, 473 to a PI-based regimen, and 227 to an NNRTI-based regimen; 531 (52. 8%) were exposed from conception. Overall, mean (SD) scores for cognitive (101. 7 14. 2), language (95. 5 13. 8), and motor development (96. 4 13. 2) domains were near reference standards (100 15). There was no difference in Bayley-III cognitive, language, or motor development domain scores between those exposed to INSTI-based vs PI-based regimens. However, INSTI-exposed infants had slightly lower mean scores than infants exposed to NNRTI-based regimens for cognitive (adjusted mean difference, −2. 94; 95% CI, −5. 47 to −0. 41), language (adjusted mean difference, −1. 96; 95% CI, −4. 50 to 0. 57), and motor development (adjusted mean difference, −1. 60; 95% CI, −4. 15 to 0. 94) domains, with larger differences among infants whose mothers initiated ART during pregnancy. Conclusions and Relevance In this cohort study, infants exposed in utero to INSTI-based ART regimens had mean neurodevelopmental scores similar to those for infants exposed to PI-based regimens but lower than those for infants exposed to NNRTI-based regimens, particularly when their mothers initiated ART after conception. Notably, adjusted mean cognitive domain scores for INSTI-exposed infants were close to the expected population mean of 100, while NNRTI-exposed infants scored 4 to 5 points above the population mean. These findings support continued inclusion of INSTIs in first-line regimens for pregnant women with HIV.