Melatonin treatment for neonatal encephalopathy

Area of Science:

• Neonatalogy
• Neuroscience
• Pharmacology

Background:

• Neonatal encephalopathy (NE) affects over a million newborns annually, leading to significant mortality and long-term neurodevelopmental disability (NDD).
• Therapeutic hypothermia (TH) is the sole established treatment but has limitations, particularly in low-resource settings.
• Melatonin, with its anti-inflammatory properties, shows promise as a neuroprotective agent in NE, but its efficacy in human neonates requires clarification.

Purpose of the Study:

• To assess the effects and safety of melatonin, alone or with TH, compared to standard care for newborns with NE.
• To evaluate melatonin's impact on survival and neurological sequelae in NE.

Main Methods:

• A systematic review and meta-analysis of randomized and quasi-randomized controlled trials.
• Included studies compared melatonin plus TH versus standard care (with TH), and melatonin monotherapy versus standard care (without TH).
• Searches were conducted across multiple databases, with the latest search on August 18, 2025.

Main Results:

• Four trials with 155 participants were included, all judged to have a low risk of bias.
• Evidence regarding melatonin's effect on the composite outcome of mortality or NDD at 18 months is very uncertain due to limited data (one pilot study).
• Very low-certainty evidence exists for melatonin's effect on mortality and brain MRI abnormalities, with no significant findings reported for multiorgan dysfunction or anti-seizure medication use.

Conclusions:

• The current data on melatonin for NE are of very low certainty, precluding definitive conclusions.
• The effects of melatonin on neonatal mortality and neurodevelopmental outcomes remain uncertain.
• Larger, high-quality randomized trials are urgently needed to establish the role of melatonin in managing NE.