{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T13:56:37Z","timestamp":1787320597686,"version":"build-2736575974"},"reference-count":48,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T00:00:00Z","timestamp":1764806400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Nigerian Institute of Medical Research Foundation","award":["NF-GMTP-24-152809"],"award-info":[{"award-number":["NF-GMTP-24-152809"]}]},{"name":"Nigerian Institute of Medical Research Foundation","award":["NF-GMTP-24-152809"],"award-info":[{"award-number":["NF-GMTP-24-152809"]}]},{"name":"Nigerian Institute of Medical Research Foundation","award":["NF-GMTP-24-152809"],"award-info":[{"award-number":["NF-GMTP-24-152809"]}]},{"name":"Nigerian Institute of Medical Research Foundation","award":["NF-GMTP-24-152809"],"award-info":[{"award-number":["NF-GMTP-24-152809"]}]},{"name":"Nigerian Institute of Medical Research Foundation","award":["NF-GMTP-24-152809"],"award-info":[{"award-number":["NF-GMTP-24-152809"]}]},{"name":"Nigerian Institute of Medical Research Foundation","award":["NF-GMTP-24-152809"],"award-info":[{"award-number":["NF-GMTP-24-152809"]}]},{"name":"Nigerian Institute of Medical Research Foundation","award":["NF-GMTP-24-152809"],"award-info":[{"award-number":["NF-GMTP-24-152809"]}]},{"name":"Nigerian Institute of Medical Research Foundation","award":["NF-GMTP-24-152809"],"award-info":[{"award-number":["NF-GMTP-24-152809"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Perinatal asphyxia (PA) is a major contributor to neonatal mortality and long-term neurodevelopmental impairment, particularly in low- and middle-income countries (LMICs), where the effectiveness of therapeutic hypothermia remains limited. Pharmacologic neuroprotective agents have shown potential as alternative treatments, but their efficacy in low-income and lower-middle-income countries (LILMICs) is not well established. This systematic review aimed to assess the effectiveness of pharmacologic interventions in neonates with PA in LILMICs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A systematic search of PubMed, Web of Science, CINAHL, and Google Scholar was conducted for randomised controlled trials (RCTs) published between 2000 and 2024. Eligible studies compared pharmacologic neuroprotective agents with placebo or standard care, excluding therapeutic hypothermia, among neonates diagnosed with PA in LILMICs. Data on survival and neurodevelopmental outcomes were extracted and synthesized; meta-analyses were conducted where appropriate.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Twelve RCTs involving 1,008 neonates were included. The majority (91.7%) of studies were conducted in Asia, with only one study from Africa. Magnesium sulphate was the most frequently evaluated agent (66.7% of studies), followed by melatonin, topiramate, erythropoietin, and citicoline. Melatonin was associated with improved survival, and all agents showed improved short-term neurological outcomes. Neurodevelopmental outcomes at 3, 6, 12, and 19 months were generally favourable, though data remained limited.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec004\">\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Pharmacologic neuroprotective agents show promise in improving survival and neurological outcomes in neonates with PA in LILMICs. However, more robust, multi-center RCTs are needed to confirm their efficacy and establish them as feasible alternatives to therapeutic hypothermia in these settings.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pone.0337798","type":"journal-article","created":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T18:43:58Z","timestamp":1764873838000},"page":"e0337798","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Pharmacologic neuroprotective agents for the treatment of perinatal asphyxia in low-income and lower-middle-income countries: A systematic review and meta-analysis of randomised controlled trials"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8626-7181","authenticated-orcid":true,"given":"Victor Ayodeji","family":"Ayeni","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aisha Adam","family":"Abdullahi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdulmuminu","family":"Isah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Love Bukola","family":"Ayamolowo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy","family":"Adeyemi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Motunrayo Adebukunola","family":"Oladimeji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ufuoma Shalom","family":"Ahwinahwi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vitalis Ikenna","family":"Chukwuike","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oluchukwu Perpetual","family":"Okeke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olunike Rebecca","family":"Abodunrin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6782-9820","authenticated-orcid":true,"given":"Folahanmi Tomiwa","family":"Akinsolu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9577-8330","authenticated-orcid":true,"given":"Olajide Odunayo","family":"Sobande","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,12,4]]},"reference":[{"key":"pone.0337798.ref001","unstructured":"WHO. Newborn mortality. [Cited 2024 September 8]. https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/newborn-mortality"},{"issue":"1","key":"pone.0337798.ref002","article-title":"Newborn mortality in sub-saharan africa: why is perinatal asphyxia still a major cause?","volume":"85","author":"F Usman","year":"2019","journal-title":"Ann Glob Health"},{"key":"pone.0337798.ref003","article-title":"Birth asphyxia","volume-title":"StatPearls","author":"M Gillam-Krakauer","year":"2024"},{"issue":"4","key":"pone.0337798.ref004","doi-asserted-by":"crossref","first-page":"347","DOI":"10.3233\/NPM-16152","article-title":"Hypoxic-ischemic brain injury: Planned delivery before intrapartum events","volume":"10","author":"D Odd","year":"2017","journal-title":"J Neonatal Perinatal Med"},{"key":"pone.0337798.ref005","unstructured":"Groenendaal F, van Bel F. Perinatal asphyxia in term and late preterm infants. 2024."},{"key":"pone.0337798.ref006","unstructured":"Health - United Nations Sustainable Development. [Cited 2024 February 23]. https:\/\/www.un.org\/sustainabledevelopment\/health\/"},{"key":"pone.0337798.ref007","volume-title":"Multiple Indicator Cluster Survey 2021, Survey Findings Report","author":"National Bureau of Statistics (NBS) and United Nations Children\u2019s Fund (UNICEF)","year":"2022"},{"issue":"6","key":"pone.0337798.ref008","article-title":"Neonatal interventions for preventing cerebral palsy: an overview of Cochrane Systematic Reviews","volume":"6","author":"E Shepherd","year":"2018","journal-title":"Cochrane Database Syst Rev"},{"key":"pone.0337798.ref009","article-title":"Therapeutic hypothermia in neonatal hypoxic encephalopathy: A systematic review and meta-analysis","author":"JL Mathew","year":"2022","journal-title":"J Glob Health"},{"issue":"9","key":"pone.0337798.ref010","doi-asserted-by":"crossref","DOI":"10.1016\/S2214-109X(21)00343-0","article-title":"Hypoxic ischaemic encephalopathy in low resource settings\u2014time to stop 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