Antenatal Melatonin Supplementation for Neuroprotection in Fetal Growth Restriction

Fetal growth restriction (FGR) is a significant health care issue, affecting 20,000 Australian pregnancies every year. Undetected FGR is one of the key risk factors for stillbirth, but FGR can also cause significant impairments in short and long-term health outcomes for the child. It is a major risk factor for preterm birth and is a recognised causal pathway to the neurodevelopmental injury underlying cognitive and behavioural impairment and cerebral palsy. Current obstetric care is focused on the detection of the growth restricted fetus and then ultrasound assessment of fetal wellbeing to guide timing of delivery. This approach seeks to maximize the gestational age of the fetus at delivery to minimise the risks of prematurity, while delivering the fetus in time to reduce the likelihood of stillbirth. Currently, no therapies exist that can maximize fetal wellbeing in the setting of growth restriction and minimise the frequency of antenatally acquired brain injury due to in-utero hypoxia. This triple-blind, randomized, parallel group, placebo-controlled trial will administer maternal melatonin or placebo supplementation antenatally in the setting of early-onset severe FGR to determine whether melatonin can PROTECT the fetal brain and lead to improved neurodevelopmental outcomes.

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 Покажи пълното описание...

Inclusion Criteria: 1. Singleton Pregnancy 2. Severe fetal growth restriction, defined as: * Abdominal circumference ≤3rd centile for gestational age according to charts supplied that have been adapted from Westerway et al; or * Abdominal circumference \<10th centile in combination with at least one abnormal fetoplacental Doppler study, being: * Uterine artery (raised pulsatility index ≥95th centile) * Umbilical artery (pulsatility index ≥95th centile or absent/reversed end-diastolic flow) 3. Confirmed 23+0 - 31+6 weeks' gestation 4. Age ≥18 years 5. Understand English Exclusion Criteria: 1. A fetus with a known chromosomal, major structural anomaly or non-placental cause of fetal growth restriction 2. Pregnancies requiring immediate delivery (e.g. absent A wave in ductus venosus, preterminal CTG or biophysical profile) 3. Co-recruitment in another clinical trial where a pharmaceutical product or nutritional supplement impacting on oxidative stress is the trial intervention. 4. Currently prescribed Fluvoxamine