A Triple-blinded, Randomized, Parallel-group Placebo-controlled Trial to Assess the Impact of Maternal Antenatal Melatonin Supplementation on Early Childhood Neurodevelopmental Outcomes in the Setting of Severe Preterm Fetal Growth Restriction

Following detection of FGR, current goals in clinical care center on assessment of fetal wellbeing and evidence of a physiological adaption to placental insufficiency. This information guides the timing of steroids, if indicated, and planning of delivery to minimise the likelihood of stillbirth. Magnesium sulphate is the only available therapy shown to improve fetal brain development in the setting of placental insufficiency and hypoxia. Magnesium sulphate works through reducing glutamate release in a hypoxic environment, likely minimising hypoxic brain injury. It appears to reduce the risk of subsequent cerebral palsy by approximately 30%. However, magnesium sulphate is only used in the hours immediately before birth, while a significant proportion of underlying brain injury in FGR probably occurs over the preceding days to weeks. The use of a safe, maternally administered supplement commenced in the weeks prior to birth could provide further significant benefits in reducing the complications faced by premature infants in the setting of placental insufficiency.

Melatonin (5-methoxy-N-acetyltryptamine) is an endogenous lipid-soluble hormone produced primarily by the pineal gland in humans. It provides circadian and seasonal timing cues due to neuroendocrine control in response to daylight. As such, melatonin secretion is relatively low during the daytime, with an exponential increase in synthesis and secretion occurring from mid-afternoon and peaking at midnight.

In addition to timing cues, melatonin is a powerful antioxidant, acting both as a direct scavenger of oxygen free radicals, especially the highly damaging hydroxyl radical, and indirectly via up-regulation of antioxidant enzymes including glutathione peroxidase, glutathione-reductase, superoxide dismutase and catalase. The metabolites of melatonin provide further anti-oxidant effect.

Melatonin is an appealing treatment for use as a fetal neuroprotectant in pregnancy, as it freely crosses the placenta and blood-brain barrier. It also has an excellent safety profile with no known adverse effects. Placentae express receptors for melatonin, and thus melatonin may protect against oxidative stress generated by ischaemia-reperfusion injury of the placenta.

Melatonin has been studied in several clinical trials related to human reproduction and for different purposes. However, no randomized trial assessing the role of melatonin in fetal neuroprotection has been completed. Melatonin has been evaluated in assisted reproductive technology where the quality of oocytes is vital for the success of in-vitro fertilization (IVF). Melatonin and myo-inositol are two compounds found in the follicular fluid that are important for oocyte maturation and quality. Tamura et al. (in 2008) and Rizzo et al. (in 2010) conducted clinical studies where they co-treated patients with 2milligram (mg) and 3mg melatonin respectively. The patients in the Tamura et al. study were given melatonin from the fifth day of the previous menstrual cycle until the day of oocyte retrieval. Both studies revealed improved oocyte quality, but the tendency to increase pregnancy rates failed to reach statistical significance. A study conducted by Unfer et al. in 2011 administered 2g myo-inositol, 200µg folic acid plus 3mg melatonin per day for 3-months to women who failed to become pregnant in previous IVF cycles, at the commencement of a new IVF cycle. This treatment resulted in a total of 13 pregnancies, 9 of which were confirmed ultrasonographically and 4 undergoing spontaneous abortion. Treatment continued after completion of the IVF cycle, throughout pregnancy until delivery. Treatment was associated with better quality oocytes and more successful pregnancies. All babies that were born from melatonin-treated pregnancies were in healthy condition with no abnormalities.