Efficacy of melatonin in term neonatal models of perinatal hypoxia-ischaemia

Objective: Neonatal encephalopathy (NE) is an important cause of mortality and disability worldwide. Therapeutic hypothermia (HT) is an effective therapy, however not all babies benefit. Novel agents are urgently needed to improve outcomes. Melatonin in preclinical studies has promising neuroprotective properties. This meta-analysis assessed the efficacy of melatonin in term animal models of NE on cerebral infarct size, neurobehavioural tests and cell death. Methods: A literature search was carried out using Embase, MEDLINE and Web of Science (31 May 2021). We identified 14 studies and performed a meta-analysis with a random effects model using standardised mean difference (SMD) as the effect size. The risk of bias was assessed using the Systematic Review Centre for Laboratory animal Experimentation tool and publication bias was assessed with funnel plots, and adjusted using trim and fill analysis. Subgroup and meta-regression analyses were performed to assess the effects of study design variables. Results: We observed significant reduction in brain infarct size (SMD -2.05, 95% CI [-2.93, -1.16] ), improved neurobehavioural outcomes (SMD -0.86, 95% CI [-1.23, -0.53]) and reduction in cell death (SMD -0.60, 95% CI [-1.06, -0.14]) favouring treatment with melatonin. Neuroprotection was evident as a single therapy and combined with HT. Subgroup analysis showed greater efficacy with melatonin given before or immediately after injury and with ethanol excipients. The overall effect size remained robust even after adjustment for publication bias. Interpretation: These studies demonstrate a significant neuroprotective efficacy of melatonin in term neonatal models of hypoxia-ischaemia, and suggest melatonin is a strong candidate for translation to clinical trials in babies with moderate-severe NE.