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.

Victor Ayodeji Ayeni, Aisha Adam Abdullahi, Abdulmuminu Isah, Love Bukola Ayamolowo, Timothy Adeyemi, Motunrayo Adebukunola Oladimeji, Ufuoma Shalom Ahwinahwi, Vitalis Ikenna Chukwuike, Oluchukwu Perpetual Okeke, Olunike Rebecca Abodunrin, Folahanmi Tomiwa Akinsolu, Olajide Odunayo Sobande

Journal: PloS one 2025;20(12):e0337798

PMID: 41343532

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Abstract

BACKGROUND

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.

METHODS

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.

RESULTS

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.

CONCLUSION

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.

Copyright: © 2025 Ayeni et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Address: Department of Paediatrics, Babcock University, Ilishan-Remo, Nigeria.; Department of Epidemiology and Population Health, Kano Independent Research Centre Trust (KIRCT), Kano State, Nigeria.; Department of Clinical Pharmacy and Pharmacy Management, University of Nigeria.; Department of Nursing Science, Obafemi Awolowo University, Ile-Ife, Nigeria.; Department of Physiotherapy, Bowen University, Iwo, Osun State, Nigeria.; Department of Anaesthesia, Lagos University Teaching Hospital, Idi-Araba, Lagos.; Department of Pharmacy, Delta State University, Abraka, Nigeria.; International Institute of Biomedical Tissue Engineering and Regenerative Medicine Research Unit, Department of Industrial and Medicinal Chemistry, David Umahi Federal University of Health Sciences, Uburu, Ebonyi State, Nigeria.; Nigerian Institute of Medical Research Foundation, Yaba, Lagos State, Nigeria.; Department of Epidemiology and Biostatistics, Nanjing Medical University, Nanjing, China.; Lead City University, Department of Public Health, Ibadan, Nigeria.; Nigerian Institute of Medical Research Foundation, Yaba, Lagos State, Nigeria.

DOI: 10.1371/journal.pone.0337798

MeSH Terms: Humans, Neuroprotective Agents, Asphyxia Neonatorum, Infant, Newborn, Randomized Controlled Trials as Topic, Developing Countries, Melatonin