Early Oral Melatonin Supplementation Supports White Matter Maturation in Preterm Infants: Neuroprotective Insights of an Antioxidant Molecule

Preterm birth is associated with increased oxidative stress and brain dysmaturation, contributing to adverse neurodevelopmental outcomes. Preterm infants are physiologically unable to produce melatonin during early postnatal life, potentially increasing their vulnerability to oxidative injury. We planned and conducted a prospective, multicentre, randomized, double-blind, placebo-controlled study to investigate whether 15 days of early oral melatonin (ME) supplementation after birth increases ME levels and reduces oxidative stress in preterm newborns at the end of administration period. The level of malondialdehyde (MDA), a lipid peroxidation product, was considered an early biological marker of the efficacy of ME treatment. The results of the first phase of the study are already available to view on Journal of Pineal Research. Here, we presented the results of the second phase of the trial, in which we investigated whether early oral ME supplementation supports clinical outcomes and brain maturation at term-equivalent age (TEA) in 54 infants with a gestational age of <= 29 weeks + 6 days, who received either oral ME or a placebo (PL) for 15 days after birth. No significant differences were observed between groups in the incidence of major neonatal comorbidities in particular patent ductus arteriosus (PDA), sepsis, necrotizing enterocolitis (NEC), bronchopulmonary dysplasia (BPD) and retinopathy of prematurity (ROP). Cranial ultrasound findings and clinical assessments using General Movements (GMs), the Neonatal Neurobehavioral Scale (NNNS), and the NAVEG scale showed comparable results. On the other hand, magnetic resonance imaging (MRI) revealed a significantly higher total brain maturity score in ME-treated infants compared with the PL group (46 vs. 43; p = 0.011), with in particular more advanced white matter and subplate compartment maturation. Quantitative MRI analysis demonstrated significantly higher T1-weighted/T2-weighted signal ratio values in major white matter tracts, including the pyramidal tract, consistent with enhanced myelination. Additionally, we observed a positive trend in the association between reduced serum MDA levels-reflecting lower lipid peroxidation-at the end of ME administration and higher T1-weighted/T2-weighted ratio values in the pyramidal bundles in subjects at TEA. These findings suggest that early oral melatonin supplementation supports cerebral white matter maturation in preterm infants, potentially through antioxidant mechanisms. Melatonin may represent a promising adjunctive strategy to mitigate oxidative stress-related brain dysmaturation in this vulnerable population, warranting further investigation in larger trials.Trial Registration: ClinicalTrials.gov Registration Number: NCT04235673; Web link to study on registry: https://clinicaltrials.gov/study/NCT04235673