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With scale\u2010up of maternal antiretroviral therapy, most children remain HIV\u2010exposed uninfected (HEU) and the benefits of universal co\u2010trimoxazole are uncertain. We assessed the effect of co\u2010trimoxazole on mortality and morbidity of children who are HEU.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We performed a systematic review (PROSPERO number: CRD42021215059). We systematically searched MEDLINE, Embase, Cochrane CENTRAL, Global Health, CINAHL Plus, Africa\u2010Wide Information, SciELO and WHO Global Index Medicus for peer\u2010reviewed articles from inception to 4th January 2022 without limits. Ongoing randomized controlled trials (RCTs) were identified through registries. We included RCTs reporting mortality or morbidity in children who are HEU receiving co\u2010trimoxazole versus no prophylaxis\/placebo. The risk of bias was assessed using the Cochrane 2.0 tool. Data were summarized using narrative synthesis and findings were stratified by malaria endemicity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We screened 1257 records and included seven reports from four RCTs. Two trials from Botswana and South Africa of 4067 children who are HEU found no difference in mortality or infectious morbidity in children randomized to co\u2010trimoxazole prophylaxis started at 2\u20136 weeks of age compared to those randomized to placebo or no treatment, although event rates were low. Sub\u2010studies found that antimicrobial resistance was higher in infants receiving co\u2010trimoxazole. Two trials in Uganda investigating prolonged co\u2010trimoxazole after breastfeeding cessation showed protection against malaria but no other morbidity or mortality differences. All trials had some concerns or a high risk of bias, which limited the certainty of evidence.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>Studies show no clinical benefit of co\u2010trimoxazole prophylaxis in children who are HEU, except to prevent malaria. Potential harms were identified for co\u2010trimoxazole prophylaxis leading to antimicrobial resistance. The trials in non\u2010malarial regions were conducted in populations with low mortality potentially reducing generalizability to other settings.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>In low\u2010mortality settings with few HIV transmissions and well\u2010performing early infant diagnosis and treatment programmes, universal co\u2010trimoxazole may not be required.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jia2.26079","type":"journal-article","created":{"date-parts":[[2023,6,9]],"date-time":"2023-06-09T07:34:33Z","timestamp":1686296073000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Co\u2010trimoxazole prophylaxis for children who are HIV\u2010exposed and uninfected: a systematic review"],"prefix":"10.1002","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4887-1644","authenticated-orcid":false,"given":"Catherine J.","family":"Wedderburn","sequence":"first","affiliation":[{"name":"Department of Paediatrics and Child Health and Neuroscience Institute University of Cape Town  Cape Town South Africa"},{"name":"Medical Research Council Clinical Trials Unit at University College London  London UK"},{"name":"Department of Clinical Research London School of Hygiene &amp; Tropical Medicine  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9122-9748","authenticated-orcid":false,"given":"Ceri","family":"Evans","sequence":"additional","affiliation":[{"name":"Blizard Institute Queen Mary University of London  London UK"},{"name":"Zvitambo Institute for Maternal and Child Health Research  Harare Zimbabwe"},{"name":"Department of Clinical Infection Microbiology and Immunology University of Liverpool  Liverpool UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy L.","family":"Slogrove","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and Child Health Faculty of Medicine &amp; Health Sciences Stellenbosch University  Worcester South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea M.","family":"Rehman","sequence":"additional","affiliation":[{"name":"MRC International Statistics &amp; Epidemiology Group Department of Infectious Disease Epidemiology London School of Hygiene &amp; Tropical Medicine  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana M.","family":"Gibb","sequence":"additional","affiliation":[{"name":"Medical Research Council Clinical Trials Unit at University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew J.","family":"Prendergast","sequence":"additional","affiliation":[{"name":"Blizard Institute Queen Mary University of London  London UK"},{"name":"Zvitambo Institute for Maternal and Child Health Research  Harare Zimbabwe"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5485-8692","authenticated-orcid":false,"given":"Martina","family":"Penazzato","sequence":"additional","affiliation":[{"name":"Department of Global HIV Hepatitis and Sexually Transmitted Infections Programmes World Health Organization  Geneva Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,6,9]]},"reference":[{"key":"e_1_2_11_2_1","unstructured":"UNAIDS.AIDSinfo. 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