Melatonin treatment for neonatal encephalopathy.

rationaleNeonatal encephalopathy (NE) affects 1.15 million newborns annually and is associated with a high incidence of mortality and long-term neurodevelopmental disability (NDD). Therapeutic hypothermia (TH) is the only proven therapeutic intervention available. However, it is only partially effective, and evidence suggests it is not safe in low-income countries. Melatonin is a promising neuroprotective treatment in NE as it provides anti-inflammatory properties. Pre-clinical models have demonstrated improved outcomes with melatonin. However, its effect on human newborns is unclear.

objectivesTo evaluate the effects and safety of melatonin treatment compared to standard care, with or without therapeutic hypothermia, on survival and neurological sequelae in newborns with neonatal encephalopathy. SEARCH

methodsWe used CENTRAL, MEDLINE, two other databases, and two trial registers, together with reference checking and citation searching, to identify studies for inclusion in the review. The latest search date was 18 August 2025. ELIGIBILITY CRITERIA: We included all randomised and quasi-randomised controlled trials in newborns with NE comparing the use of melatonin and TH versus standard treatment (including TH), and also melatonin monotherapy versus standard treatment (with no TH). We excluded cross-over randomised trials and non-randomised cohort studies. We excluded studies that included preterm newborns born at less than 34 weeks gestational age (GA) or studies that included newborns with major congenital anomalies. OUTCOMES: The critical outcome for both comparisons was the combined outcome of mortality or NDD at ≥ 18 months of age. Our important outcomes included differences in mortality (up to one month), NDD (at ≥ 18 months), abnormalities on a brain MRI (at one month), multiorgan dysfunction (up to one month), and use of anti-seizure medications (up to one month). RISK OF BIAS: We used the Cochrane risk of bias tool (RoB 1) to assess bias in the included studies. SYNTHESIS

methodsWe synthesised results for each outcome using meta-analysis by calculating odds ratios with 95% confidence intervals. Where this was not possible due to the nature of the data, we summarised the results narratively. We used GRADE to assess the certainty of evidence for prespecified outcomes. We examined the effects of melatonin treatment and TH versus standard care (with TH) and the effects of melatonin monotherapy versus standard care (without TH). INCLUDED STUDIES: We included four studies including 155 participants. Sample sizes ranged from 20 to 80 participants per study. The mean age of participants ranged from 36.8 to 39.5 weeks' GA at birth. The proportion of males in the studies ranged from 54% to 76%. The proportion of participants with severe NE ranged from 20% to 59%. Follow-up periods ranged from time of discharge to 18 months of life. SYNTHESIS OF

resultsWe identified four randomised controlled trials (155 participants). Two studies compared melatonin and TH versus standard treatment (with TH) (55 participants), and two studies compared melatonin monotherapy versus standard treatment (without TH) (100 participants). The studies recruited participants born at term or late preterm with NE. We judged the studies to have an overall low risk of bias. Composite outcome of mortality or neurodevelopmental disability (NDD), assessed at 18 months of age or over One study reported this outcome, and compared melatonin and TH to standard care (with TH). It was a pilot study with an insufficient sample size. The evidence is very uncertain about the effect of melatonin on death of newborns with NE or neurodevelopmental disability in newborns who survived (1 study, 25 participants; very low-certainty evidence). Mortality in the first month after birth The evidence is very uncertain about the effect of melatonin and TH compared to standard care (with TH) on reduction in mortality (OR 0.39, 95% CI 0.06 to 2.37; I² = 0%; 2 studies, 55 participants; very low-certainty evidence). The evidence is very uncertain about the effect of melatonin monotherapy compared to standard care (without TH) on reduction in mortality (OR 0.24, 95% CI 0.08 to 0.69; I² = 0%; 2 studies, 100 participants; very low-certainty evidence). Incidence of neurodevelopmental disability, assessed at 18 months of age or over One included study reported this outcome, and compared melatonin and TH to standard treatment (with TH). It was a pilot study with an insufficient sample size. The evidence is very uncertain about the effect of melatonin on reduction in neurodevelopmental disability (1 study, 25 participants; very low-certainty evidence). Abnormalities on brain MRI in the first month after birth: basal ganglia and thalamus Two included studies reported this outcome. Both studies compared melatonin and TH to standard care (with TH). The evidence is very uncertain about the effect of melatonin on MRI abnormalities in the basal ganglia and thalamus (OR 0.90, 95% CI 0.29 to 2.81; I² = 0%; 2 studies, 50 participants; very low-certainty evidence). Abnormalities on brain MRI in the first month after birth: white matter Two included studies reported this outcome. Both studies compared melatonin and TH to standard care (with TH). The evidence is very uncertain about the effect of melatonin on MRI abnormalities in the white matter (OR 0.32, 95% CI 0.02 to 6.04; I² = 64%; 2 studies, 50 participants; very low-certainty evidence). Multiorgan dysfunction or the use of anti-seizure medications in the first month after birth No study reported these outcomes. AUTHORS'

conclusionsThe available data are of very low certainty, so we cannot draw conclusions about the effects of melatonin treatment on outcomes in newborns with neonatal encephalopathy. Only one pilot study of 25 participants reported our critical outcome. The evidence is very uncertain about the effect of melatonin on death of newborns with neonatal encephalopathy or neurodevelopmental disability in the newborns who survive. We are uncertain about the effect of melatonin on mortality in the first month of life and on the incidence of abnormalities in magnetic resonance imaging of the brain. Overall, the evidence to date for melatonin treatment in neonatal encephalopathy is uncertain, and larger randomised trials are urgently required.

fundingThis research was conducted as part of the NEPTuNE Collaboration, funded by the Health Research Board of Ireland. REGISTRATION: Protocol available via DOI 10.1002/14651858.CD013754.