Neuroprotective effects of maternal melatonin administration in early-onset placental insufficiency and fetal growth restriction

Background: Early-onset fetal growth restriction (FGR) is associated with adverse outcomes. We hypothesised that maternal melatonin administration will improve fetal brain structure in FGR. Methods: Surgery was performed on twin-bearing ewes at 88 days (0.6 gestation), and FGR induced in one twin via single umbilical artery ligation. Melatonin was administered intravenously (6 mg/day) to a group of ewes commencing on day of surgery until 127 days (0.85 gestation), when the ewe/fetuses were euthanized, and fetal brains collected. Results: Study groups were control (n = 5), FGR (n = 5), control+melatonin (control+MLT; n = 6) and FGR+melatonin (FGR + MLT; n = 6). Melatonin administration did not significantly alter fetal body or brain weights. Myelin (CNPase+) fibre density was reduced in FGR vs. control animals in most brain regions examined (p < 0.05) and melatonin treatment restored CNPase fibre density. Similar but less pronounced effect was seen with mature myelin (MBP+) staining. Significant differences in activated microglia (Iba-1) activity were seen between lamb groups (MLT mitigated FGR effect) in periventricular white matter, subventricular zone and external capsule (p < 0.05). Similar effects were seen in astrogliosis (GFAP) in intragyral white matter and cortex. Conclusions: Maternal melatonin administration in early onset FGR led to improved myelination of white matter brain regions, possibly mediated by decreased inflammation. Impact: Maternal melatonin administration might lead to neuroprotection in the growth-restricted fetus, possibly via dampening neuroinflammation and enhancing myelination.This preclinical study adds to the body of work on this topic, and informs clinical translation.Neuroprotection likely to improve long-term outcomes of this vulnerable infant group.