{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T06:38:17Z","timestamp":1787726297850,"version":"build-2784847793"},"reference-count":56,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2025,5,7]],"date-time":"2025-05-07T00:00:00Z","timestamp":1746576000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:sec id=\"sec019\">\n<jats:title>Background<\/jats:title>\n<jats:p>Fear of severe adverse reaction (SAR) and reluctance of health care providers to administer intramuscular injections are major contributing factors to poor adherence of benzathine penicillin G (BPG) in the management of rheumatic heart disease (RHD). However, data on the risk of SARs following BPG injections for RHD are relatively limited and inconclusive. Our systematic review and meta-analysis aimed to evaluate the incidence of SARs associated with BPG injections used for secondary prophylaxis of RHD.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec020\">\n<jats:title>Methods<\/jats:title>\n<jats:p>A systematic literature search of PubMed, Scopus and Web of Science databases was conducted to identify relevant studies reporting adverse reactions following BPG injections in patients with acute rheumatic fever (ARF) and\/or RHD. A random effect meta-analysis was performed to estimate the pooled incidence of SARs.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec021\">\n<jats:title>Result<\/jats:title>\n<jats:p>Nine studies (eight cohort and one randomized controlled trial), comprising 11,587 participants and\u2009&gt;\u2009154,760 BPG injections, were included in the analysis. The pooled incidence of SARs was 9.7 per 10,000 cases (95% CI: 0.1\u201329.2) and 1.1 per 10,000 BPG injections (95% CI: 0.4\u20132.2). Six fatal reactions were reported (0.05% of patients and 24% of SARs), all occurring in patients with severe RHD.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec022\">\n<jats:title>Conclusion<\/jats:title>\n<jats:p>SARs following BPG injections in patients with ARF or RHD are rare. Our findings highlight the importance of balancing the low rate of SARs against the benefits of BPG in secondary prophylaxis for RHD, particularly in high-risk populations. High-quality longitudinal research and comprehensive adverse reaction reporting are essential to address safety concerns among healthcare providers and patients that impact BPG delivery.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0322873","type":"journal-article","created":{"date-parts":[[2025,5,7]],"date-time":"2025-05-07T17:45:16Z","timestamp":1746639916000},"page":"e0322873","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Severe adverse reactions to benzathine penicillin G in rheumatic heart disease: A systematic review and meta-analysis"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7613-0384","authenticated-orcid":true,"given":"Eshetie Melese","family":"Birru","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kefyalew Addis","family":"Alene","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4334-5351","authenticated-orcid":true,"given":"Laurens","family":"Manning","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin T.","family":"Batty","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brioni R.","family":"Moore","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,5,7]]},"reference":[{"key":"pone.0322873.ref001","doi-asserted-by":"crossref","first-page":"15084","DOI":"10.1038\/nrdp.2015.84","article-title":"Acute rheumatic fever and rheumatic heart disease","volume":"2","author":"JR Carapetis","year":"2016","journal-title":"Nat Rev Dis Primers"},{"issue":"1","key":"pone.0322873.ref002","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1186\/s13075-022-02829-3","article-title":"Global burden of rheumatic heart disease: trends from 1990 to 2019","volume":"24","author":"Z Ou","year":"2022","journal-title":"Arthritis Res Ther"},{"issue":"1","key":"pone.0322873.ref003","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1097\/MOP.0000000000000164","article-title":"Controlling acute rheumatic fever and rheumatic heart disease in developing countries: are we getting closer?","volume":"27","author":"JL de Dassel","year":"2015","journal-title":"Curr Opin Pediatr"},{"issue":"5","key":"pone.0322873.ref004","doi-asserted-by":"crossref","first-page":"221.e1","DOI":"10.5694\/mja15.00139","article-title":"Rheumatic heart disease in Indigenous children in northern Australia: differences in prevalence and the challenges of screening","volume":"203","author":"KV Roberts","year":"2015","journal-title":"Med J Aust"},{"issue":"6","key":"pone.0322873.ref005","doi-asserted-by":"crossref","first-page":"e00668","DOI":"10.1002\/prp2.668","article-title":"Quality of benzathine penicillin G: A multinational cross-sectional study","volume":"8","author":"RM Hand","year":"2020","journal-title":"Pharmacol Res Perspect"},{"issue":"3","key":"pone.0322873.ref006","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.gheart.2013.08.011","article-title":"Benzathine penicillin G for the management of RHD: concerns about quality and access, and opportunities for intervention and improvement","volume":"8","author":"R Wyber","year":"2013","journal-title":"Glob Heart"},{"issue":"5","key":"pone.0322873.ref007","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1038\/nrcardio.2013.34","article-title":"Position statement of the World Heart Federation on the prevention and control of rheumatic heart disease","volume":"10","author":"World Heart Federation","year":"2013","journal-title":"Nat Rev Cardiol"},{"key":"pone.0322873.ref008","volume-title":"Expert Consultation. 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