Melatonin as a Therapy for Preterm Brain Injury: What Is the Evidence?

Abstract

Despite significant improvements in survival following preterm birth in recent years, the neurodevelopmental burden of prematurity, with its long-term cognitive and behavioral consequences, remains a significant challenge in neonatology. Neuroprotective treatment options to improve neurodevelopmental outcomes in preterm infants are therefore urgently needed. Alleviating inflammatory and oxidative stress (OS), melatonin might modify important triggers of preterm brain injury, a complex combination of destructive and developmental abnormalities termed encephalopathy of prematurity (EoP). Preliminary data also suggests that melatonin has a direct neurotrophic impact, emphasizing its therapeutic potential with a favorable safety profile in the preterm setting. The current review outlines the most important pathomechanisms underlying preterm brain injury and correlates them with melatonin’s neuroprotective potential, while underlining significant pharmacokinetic/pharmacodynamic uncertainties that need to be addressed in future studies.

Melatonin in Human Breast Milk and Its Potential Role in Circadian Entrainment: A Nod towards Chrononutrition?

“…As a quasi-counterbalance, the mother's milk for preterm infants includes even higher melatonin concentrations, with a greater amplitude between day and night-time milk and colostrum with the highest melatonin content [55]. Nonetheless, throughout their intensive care period, preterms are still prone to desynchronized feeding schedules and no cycled lighting [1,12,80] and may therefore lack chronobiological adherence and rhythmicity. Accordingly, chrononutrition, i.e., appropriately timed feeding schedules might be particularly reasonable, which holds true for every newborn but should be even more emphasized in preterms based on the previously described high risk factors.…”

“…Rhythmic melatonin secretion by the pineal gland only starts two to three months after birth; thus, neonates may lack adequate amounts of melatonin during this postnatal period [10,11]. In preterm neonates, this period of circadian melatonin deprivation is even more prolonged, making them more vulnerable to chronobiotic dysregulation and inflammatory conditions [10,12] So, for several months after birth, neonates rely at least partly on exogenous melatonin supplied by mother's breast milk [13][14][15][16].…”