The Ritchie Centre, Monash Institute of Medical Research, Monash University, Clayton, Victoria, Australia.
BMJ Open. 2013 Dec 23;3(12):e004141. doi: 10.1136/bmjopen-2013-004141.
Fetal growth restriction complicates about 5% of pregnancies and is commonly caused by placental dysfunction. It is associated with increased risks of perinatal mortality and short-term and long-term morbidity, such as cerebral palsy. Chronic in utero hypoxaemia, inflammation and oxidative stress are likely culprits contributing to the long-term neurological sequelae of fetal growth restriction. In this regard, we propose that melatonin, a powerful antioxidant, might mitigate morbidity and/or mortality associated with fetal growth restriction. Melatonin has an excellent biosafety profile and crosses the placenta and blood-brain barrier. We present the protocol for a phase I clinical trial to investigate the efficacy of maternal oral melatonin administration in women with a pregnancy complicated by fetal growth restriction.
The proposed trial is a single-arm, open-label clinical trial involving 12 women. Severe, early onset fetal growth restriction will be diagnosed by an estimated fetal weight ≤10th centile in combination with abnormal fetoplacental Doppler studies, occurring before 34 weeks of pregnancy. Baseline measurements of maternal and fetal well-being, levels of oxidative stress and ultrasound and Doppler measurements will be obtained at the time of diagnosis of fetal growth restriction. Women will then start melatonin treatment (4 mg) twice daily until birth. The primary outcomes are the levels of oxidative stress in the maternal and fetal circulation and placenta. Secondary outcomes are fetoplacental Doppler studies (uterine artery, umbilical artery middle cerebral artery and ductus venosus), fetal biometry, fetal biophysical profile and a composite determination of neonatal outcome. A historical cohort of gestational-matched fetal growth restriction and a healthy pregnancy cohort will be used as comparators.
Ethical approval has been obtained from Monash Health Human Research Ethics Committee B (HREC12133B). Data will be presented at international conferences and published in peer-reviewed journals.
Clinical Trials, protocol registration system: NCT01695070.
胎儿生长受限是一种较为常见的妊娠并发症，约占 5%，其主要病因是胎盘功能障碍。胎儿生长受限与围产期死亡率以及短期和长期发病率（如脑瘫）的增加有关。慢性宫内缺氧、炎症和氧化应激可能是导致胎儿生长受限的长期神经后遗症的罪魁祸首。在这方面，我们认为褪黑素作为一种强大的抗氧化剂，可能减轻与胎儿生长受限相关的发病率和/或死亡率。褪黑素具有良好的生物安全性，可穿过胎盘和血脑屏障。我们提出了一项关于母体口服褪黑素治疗胎儿生长受限孕妇的 I 期临床试验方案。
该试验为单臂、开放标签临床试验，涉及 12 名女性。严重的早期胎儿生长受限将通过估计胎儿体重≤第 10 百分位数与异常胎儿胎盘多普勒研究相结合来诊断，其发生在妊娠 34 周之前。在诊断胎儿生长受限时，将获得母体和胎儿健康状况、氧化应激水平以及超声和多普勒测量的基线数据。然后，女性将开始每天两次接受褪黑素治疗（4 毫克）直至分娩。主要结局是母胎循环和胎盘的氧化应激水平。次要结局是胎儿胎盘多普勒研究（子宫动脉、脐动脉、大脑中动脉和静脉导管）、胎儿生物测量、胎儿生物物理特征以及新生儿结局的综合判断。将使用妊娠匹配的胎儿生长受限的历史队列和健康妊娠队列作为对照组。
蒙纳士健康人体研究伦理委员会 B（HREC12133B）已获得伦理批准。数据将在国际会议上展示，并发表在同行评议期刊上。
临床试验，方案注册系统：NCT01695070。
