{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T21:15:32Z","timestamp":1785878132421,"version":"3.56.0"},"reference-count":32,"publisher":"American Medical Association (AMA)","issue":"11","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Netw Open"],"abstract":"\n Importance<\/jats:title>\n 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.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n 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)\u2013containing or nonnucleoside reverse transcriptase inhibitor (NNRTI)\u2013containing regimens.<\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n 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.<\/jats:p>\n <\/jats:sec>\n \n Exposure<\/jats:title>\n Initial maternal ART regimen during pregnancy.<\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n Neuropsychologists administered the Bayley Scales of Infant and Toddler Development\u20133rd 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.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n 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, \u22122.94; 95% CI, \u22125.47 to \u22120.41), language (adjusted mean difference, \u22121.96; 95% CI, \u22124.50 to 0.57), and motor development (adjusted mean difference, \u22121.60; 95% CI, \u22124.15 to 0.94) domains, with larger differences among infants whose mothers initiated ART during pregnancy.<\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n 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.<\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jamanetworkopen.2025.45652","type":"journal-article","created":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T16:31:25Z","timestamp":1764174685000},"page":"e2545652","source":"Crossref","is-referenced-by-count":3,"title":["Maternal Use of Integrase Strand Transfer Inhibitors During Pregnancy and Infant Neurodevelopment"],"prefix":"10.1001","volume":"8","author":[{"given":"Paige L.","family":"Williams","sequence":"first","affiliation":[{"name":"Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, Massachusetts"},{"name":"Center for Biostatistics in AIDS Research, Harvard T. H. Chan School of Public Health, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martha","family":"Boahene","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa E.","family":"Mash","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Northwestern University Feinberg School of Medicine, Chicago, Illinois"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellen G.","family":"Chadwick","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanling","family":"Huo","sequence":"additional","affiliation":[{"name":"Center for Biostatistics in AIDS Research, Harvard T. H. Chan School of Public Health, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen A.","family":"Spector","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Pediatrics, University of California, San Diego, and Rady Children\u2019s Hospital, San Diego"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janna","family":"Oetting","sequence":"additional","affiliation":[{"name":"Department of Communication Sciences and Disorders, Louisiana State University, Baton Rouge"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia A.","family":"Garvie","sequence":"additional","affiliation":[{"name":"Children\u2019s Diagnostic & Treatment Center, Ft Lauderdale, Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renee","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Illinois at Chicago, Chicago"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"10","published-online":{"date-parts":[[2025,11,26]]},"reference":[{"issue":"12","key":"zoi251236r1","doi-asserted-by":"publisher","first-page":"1533","DOI":"10.3390\/ph15121533","article-title":"HIV-1 Integrase strand transfer inhibitors and neurodevelopment.","volume":"15","author":"Foster","year":"2022","journal-title":"Pharmaceuticals (Basel)"},{"issue":"15","key":"zoi251236r2","doi-asserted-by":"publisher","first-page":"1308","DOI":"10.1001\/jama.2023.5076","article-title":"Antiretroviral treatment of HIV\/AIDS during pregnancy.","volume":"329","author":"Eke","year":"2023","journal-title":"JAMA"},{"issue":"11","key":"zoi251236r3","doi-asserted-by":"publisher","first-page":"1501","DOI":"10.1080\/14740338.2016.1226281","article-title":"Surveillance monitoring for safety of in utero antiretroviral therapy exposures: current strategies and challenges.","volume":"15","author":"Zash","year":"2016","journal-title":"Expert Opin Drug Saf"},{"issue":"10","key":"zoi251236r4","doi-asserted-by":"publisher","first-page":"1161","DOI":"10.1111\/dmcn.14921","article-title":"Neurological development of children who are HIV-exposed and uninfected.","volume":"63","author":"Toledo","year":"2021","journal-title":"Dev Med Child Neurol"},{"issue":"9","key":"zoi251236r5","doi-asserted-by":"publisher","first-page":"1377","DOI":"10.1097\/QAD.0000000000002550","article-title":"Safety of in utero antiretroviral (ARV) exposure: neurologic outcomes in children who are who are HIV-exposed but uninfected.","volume":"34","author":"Crowell","year":"2020","journal-title":"AIDS"},{"issue":"2","key":"zoi251236r6","doi-asserted-by":"publisher","first-page":"e250","DOI":"10.1542\/peds.2009-1112","article-title":"Neurodevelopment and in utero antiretroviral exposure of HIV-exposed uninfected infants.","volume":"125","author":"Williams","year":"2010","journal-title":"Pediatrics"},{"issue":"6","key":"zoi251236r7","doi-asserted-by":"publisher","first-page":"648","DOI":"10.1097\/INF.0b013e318284129a","article-title":"Safety of perinatal exposure to antiretroviral medications: developmental outcomes in infants.","volume":"32","author":"Sirois","year":"2013","journal-title":"Pediatr Infect Dis J"},{"issue":"11","key":"zoi251236r8","doi-asserted-by":"publisher","first-page":"1128","DOI":"10.1097\/INF.0000000000000410","article-title":"Safety of in utero and neonatal antiretroviral exposure: cognitive and academic outcomes in HIV-exposed, uninfected children 5-13 years of age.","volume":"33","author":"Nozyce","year":"2014","journal-title":"Pediatr Infect Dis J"},{"issue":"3","key":"zoi251236r9","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1089\/apc.2022.0189","article-title":"In utero antiretroviral exposure and risk of neurodevelopmental problems in HIV-exposed uninfected 5-year-old children.","volume":"37","author":"Yao","year":"2023","journal-title":"AIDS Patient Care STDS"},{"issue":"8","key":"zoi251236r10","doi-asserted-by":"publisher","first-page":"1267","DOI":"10.1097\/QAD.0000000000001052","article-title":"Atazanavir exposure in utero and neurodevelopment in infants: a comparative safety study.","volume":"30","author":"Caniglia","year":"2016","journal-title":"AIDS"},{"issue":"6","key":"zoi251236r11","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1016\/S2352-4642(22)00071-2","article-title":"Early neurodevelopment of HIV-exposed uninfected children in the era of antiretroviral therapy: a systematic review and meta-analysis.","volume":"6","author":"Wedderburn","year":"2022","journal-title":"Lancet Child Adolesc Health"},{"issue":"17","key":"zoi251236r12","doi-asserted-by":"publisher","first-page":"2583","DOI":"10.1097\/QAD.0000000000001985","article-title":"Neurodevelopmental outcomes and in-utero antiretroviral exposure in HIV-exposed uninfected children.","volume":"32","author":"Piske","year":"2018","journal-title":"AIDS"},{"issue":"5","key":"zoi251236r14","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijantimicag.2021.106343","article-title":"HIV-1 integrase strand transfer inhibitors: a review of current drugs, recent advances and drug resistance.","volume":"57","author":"Mbhele","year":"2021","journal-title":"Int J Antimicrob Agents"},{"issue":"2","key":"zoi251236r15","doi-asserted-by":"publisher","first-page":"614","DOI":"10.1002\/ijgo.14705","article-title":"Type and timing of antiretroviral therapy during pregnancy: Impact on risk of preterm delivery and small-for-gestational age births in Canada, a retrospective cohort study.","volume":"162","author":"Schneidman","year":"2023","journal-title":"Int J Gynaecol Obstet"},{"key":"zoi251236r16","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2024.1323813","article-title":"Comparative risk of adverse perinatal outcomes associated with classes of antiretroviral therapy in pregnant women living with HIV: systematic review and meta-analysis.","volume":"11","author":"Beck","year":"2024","journal-title":"Front Med (Lausanne)"},{"issue":"9","key":"zoi251236r17","doi-asserted-by":"publisher","first-page":"950","DOI":"10.1093\/aje\/kwr401","article-title":"A trigger-based design for evaluating the safety of in utero antiretroviral exposure in uninfected children of human immunodeficiency virus-infected mothers.","volume":"175","author":"Williams","year":"2012","journal-title":"Am J Epidemiol"},{"key":"zoi251236r18","doi-asserted-by":"publisher","first-page":"199","DOI":"10.3389\/fimmu.2016.00199","article-title":"The PHACS SMARTT study: assessment of the safety of in utero exposure to antiretroviral drugs.","volume":"7","author":"Van Dyke","year":"2016","journal-title":"Front Immunol"},{"issue":"1","key":"zoi251236r19","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1097\/QAD.0000000000000916","article-title":"Antiretroviral exposure during pregnancy and adverse outcomes in HIV-exposed uninfected infants and children using a trigger-based design.","volume":"30","author":"Williams","year":"2016","journal-title":"AIDS"},{"issue":"10","key":"zoi251236r21","doi-asserted-by":"publisher","first-page":"e406","DOI":"10.1097\/INF.0b013e31829b80ee","article-title":"Evaluation of risk for late language emergence after in utero antiretroviral drug exposure in HIV-exposed uninfected infants.","volume":"32","author":"Rice","year":"2013","journal-title":"Pediatr Infect Dis J"},{"issue":"4","key":"zoi251236r23","doi-asserted-by":"publisher","first-page":"962","DOI":"10.1111\/j.1541-0420.2005.00377.x","article-title":"Doubly robust estimation in missing data and causal inference models.","volume":"61","author":"Bang","year":"2005","journal-title":"Biometrics"},{"issue":"7","key":"zoi251236r24","doi-asserted-by":"publisher","first-page":"761","DOI":"10.1093\/aje\/kwq439","article-title":"Doubly robust estimation of causal effects.","volume":"173","author":"Funk","year":"2011","journal-title":"Am J Epidemiol"},{"key":"zoi251236r25","doi-asserted-by":"publisher","DOI":"10.1177\/0962280217732597","article-title":"A hierarchical modeling approach for assessing the safety of exposure to complex antiretroviral drug regimens during pregnancy.","author":"Correia","journal-title":"Stat Methods Med Res"},{"issue":"1","key":"zoi251236r26","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/j.antiviral.2009.09.014","article-title":"Nucleoside and nucleotide HIV reverse transcriptase inhibitors: 25 years after zidovudine.","volume":"85","author":"Cihlar","year":"2010","journal-title":"Antiviral Res"},{"issue":"1","key":"zoi251236r27","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/j.antiviral.2009.09.008","article-title":"Non-nucleoside reverse transcriptase inhibitors (NNRTIs), their discovery, development, and use in the treatment of HIV-1 infection: a review of the last 20 years (1989-2009).","volume":"85","author":"de B\u00e9thune","year":"2010","journal-title":"Antiviral Res"},{"issue":"1","key":"zoi251236r28","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1016\/j.antiviral.2009.10.003","article-title":"Fifteen years of HIV protease inhibitors: raising the barrier to resistance.","volume":"85","author":"Wensing","year":"2010","journal-title":"Antiviral Res"},{"issue":"1","key":"zoi251236r29","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCOUTCOMES.119.006065","article-title":"Doubly robust estimation of causal effect: upping the odds of getting the right answers.","volume":"13","author":"Li","year":"2020","journal-title":"Circ Cardiovasc Qual Outcomes"},{"issue":"16","key":"zoi251236r30","doi-asserted-by":"publisher","first-page":"2337","DOI":"10.1097\/QAD.0000000000001988","article-title":"Cardiac status of perinatally HIV-infected children: assessing combination antiretroviral regimens in observational studies.","volume":"32","author":"Williams","year":"2018","journal-title":"AIDS"},{"issue":"1","key":"zoi251236r31","doi-asserted-by":"publisher","first-page":"e49","DOI":"10.1016\/S2352-3018(19)30340-6","article-title":"Association of maternal antiretroviral use with microcephaly in children who are HIV-exposed but uninfected (SMARTT): a prospective cohort study.","volume":"7","author":"Williams","year":"2020","journal-title":"Lancet HIV"},{"issue":"12","key":"zoi251236r32","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2019.17669","article-title":"Antiretroviral prescribing practices among pregnant women living with HIV in the United States, 2008-2017.","volume":"2","author":"Powis","year":"2019","journal-title":"JAMA Netw Open"},{"key":"zoi251236r20","volume-title":"Bayley Scales of Infant and Toddler Development","author":"Bayley","year":"2006","edition":"3rd ed"},{"key":"zoi251236r22","volume-title":"MacArthur-Bates Communicative Development Inventories","author":"Fenson","year":"2007"},{"key":"zoi251236r13","unstructured":"Recommendations for the use of antiretroviral drugs during pregnancy and interventions to reduce perinatal HIV transmission in the United States. Dept of Health and Human Services. Accessed April 4, 2025. https:\/\/clinicalinfo.hiv.gov\/en\/guidelines\/perinatal\/whats-new"}],"container-title":["JAMA Network Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/jamanetwork.com\/journals\/jamanetworkopen\/articlepdf\/2842065\/williams_2025_oi_251236_1763583137.23884.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T16:31:26Z","timestamp":1764174686000},"score":1,"resource":{"primary":{"URL":"https:\/\/jamanetwork.com\/journals\/jamanetworkopen\/fullarticle\/2842065"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,26]]},"references-count":32,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2025,11,3]]}},"URL":"https:\/\/doi.org\/10.1001\/jamanetworkopen.2025.45652","relation":{},"ISSN":["2574-3805"],"issn-type":[{"value":"2574-3805","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,26]]}}}