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Antenatal melatonin as an antioxidant in human pregnancies complicated by fetal growth restriction--a phase I pilot clinical trial: study protocol.

ABSTRACT: 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.

SUBMITTER: Alers NO

PROVIDER: S-EPMC3884842 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Antenatal melatonin as an antioxidant in human pregnancies complicated by fetal growth restriction--a phase I pilot clinical trial: study protocol.

Alers Nicole O NO Jenkin Graham G Miller Suzanne L SL Wallace Euan M EM

BMJ open 20131223 12

<h4>Background</h4>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 ...[more]

PMID: 24366583

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Project description:IntroductionEarly-onset fetal growth restriction (FGR) requires timely, often preterm, delivery to prevent fetal hypoxia causing stillbirth or neurologic impairment. Antenatal corticosteroids (CCS) administration reduces neonatal morbidity and mortality following preterm birth, most effectively when administered within 1 week preceding delivery. Optimal timing of CCS administration is challenging in early-onset FGR, as the exact onset and course of fetal hypoxia are unpredictable. International guidelines do not provide a directive on this topic. In the Netherlands, two timing strategies are commonly practiced: administration of CCS when the umbilical artery shows (A) a pulsatility index above the 95thh centile and (B) absent or reversed end-diastolic velocity (a more progressed disease state). This study aims to (1) use practice variation to compare CCS timing strategies in early-onset FGR on fetal and neonatal outcomes and (2) develop a dynamic tool to predict the time interval in days until delivery, as a novel timing strategy for antenatal CCS in early-onset FGR.Methods and analysisA multicentre, retrospective cohort study will be performed including pregnancies complicated by early-onset FGR in six tertiary hospitals in the Netherlands in the period between 2012 and 2021 (estimated sample size n=1800). Main exclusion criteria are multiple pregnancies and fetal congenital or genetic abnormalities. Routinely collected data will be extracted from medical charts. Primary outcome for the comparison of the two CCS timing strategies is a composite of perinatal, neonatal and in-hospital mortality. Secondary outcomes include the COSGROVE core outcome set for FGR. A multivariable, mixed-effects model will be used to compare timing strategies on study outcomes. Primary outcome for the dynamic prediction tool is 'days until birth'.Ethics and disseminationThe need for ethical approval was waived by the Ethics Committee (University Medical Center Utrecht). Results will be published in open-access, peer-reviewed journals and disseminated by presentations at scientific conferences.Trial registration numberClinicalTrials.gov: NCT05606497.

Project description:BackgroundCurrent methods fail to accurately predict women at greatest risk of developing fetal growth restriction (FGR) or related adverse outcomes, including stillbirth. Sexual dimorphism in these adverse pregnancy outcomes is well documented as are sex-specific differences in gene and protein expression in the placenta. Circulating maternal serum microRNAs (miRNAs) offer potential as biomarkers that may also be informative of underlying pathology. We hypothesised that FGR would be associated with an altered miRNA profile and would differ depending on fetal sex.MethodsmiRNA expression profiles were assessed in maternal serum (> 36 weeks' gestation) from women delivering a severely FGR infant (defined as an individualised birthweight centile (IBC) < 3rd) and matched control participants (AGA; IBC = 20-80th), using miRNA arrays. qPCR was performed using specific miRNA primers in an expanded cohort of patients with IBC < 5th (n = 15 males, n = 16 females/group). Maternal serum human placental lactogen (hPL) was used as a proxy to determine if serum miRNAs were related to placental dysfunction. In silico analyses were performed to predict the potential functions of altered miRNAs.ResultsInitial analyses revealed 11 miRNAs were altered in maternal serum from FGR pregnancies. In silico analyses revealed all 11 altered miRNAs were located in a network of genes that regulate placental function. Subsequent analysis demonstrated four miRNAs showed sexually dimorphic patterns. miR-28-5p was reduced in FGR pregnancies (p < 0.01) only when there was a female offspring and miR-301a-3p was only reduced in FGR pregnancies with a male fetus (p < 0.05). miR-454-3p was decreased in FGR pregnancies (p < 0.05) regardless of fetal sex but was only positively correlated to hPL when the fetus was female. Conversely, miR-29c-3p was correlated to maternal hPL only when the fetus was male. Target genes for sexually dimorphic miRNAs reveal potential functional roles in the placenta including angiogenesis, placental growth, nutrient transport and apoptosis.ConclusionsThese studies have identified sexually dimorphic patterns for miRNAs in maternal serum in FGR. These miRNAs may have potential as non-invasive biomarkers for FGR and associated placental dysfunction. Further studies to determine if these miRNAs have potential functional roles in the placenta may provide greater understanding of the pathogenesis of placental dysfunction and the differing susceptibility of male and female fetuses to adverse in utero conditions.

Project description:IntroductionFetal growth restriction (FGR) is a serious pregnancy complication, associated with increased rates of perinatal death and morbidity among survivors. Most commonly FGR results from placental insufficiency, where the placenta fails to deliver the oxygen and nutrients required for normal fetal growth. This leads to fetal oxidative stress, resulting in organ damage through lipid peroxidation. The early developing brain is particularly susceptible, such that FGR is associated with poorer neurodevelopment, witnessed as cognitive and behavioural dysfunction, and cerebral palsy. Promisingly, melatonin, a lipid soluble antioxidant is neuroprotective in animal models of FGR. We present a protocol outlining a randomised, placebo-controlled trial to explore whether antenatal maternal melatonin supplementation in pregnancies with severe, early-onset FGR can improve neurodevelopment among survivors at 2 years of age.Methods and analysesWe will recruit 336 women with a singleton pregnancy complicated by FGR between 23+0 and 31+6 weeks gestation. Participants will be randomised, stratified by gestational age, to either 30 mg melatonin per day or a visually identical placebo, continued until birth. Measures of maternal and fetal health will be collected until birth. Timing of birth will be determined by the treating clinical team in discussion with the woman. Neonatal and infant neurodevelopmental assessments will be undertaken, consisting of brain MRI at term corrected age, general movements assessment at term and 3 months' corrected age, and Bayley Scales of Infant & Toddler Development-III and Infant Toddler Social Emotional Assessment at 2.5 years corrected age. Analyses will be on intention to treat. The primary outcome is a difference of 5 points in the cognitive domain of the Bayley-III. Secondary outcomes address maternal and fetal safety.Ethics and disseminationThis trial has Monash Health Human Research and Ethics committee approval (17-0000-583A). Findings will be disseminated through peer-reviewed publications, conference presentations and to participants.Trial registration numberACTRN12617001515381; Pre-results.

Project description:BACKGROUND:Affecting approximately 10% of pregnancies, fetal growth restriction (FGR), is the most important cause of perinatal mortality and morbidity. Impaired placental function and consequent mal-perfusion of the placenta is the leading cause of FGR. Although, screening for placental insufficiency based on uterine artery Doppler measurement is well established, there is no treatment option for pregnancies threatened by FGR. The organic nitrate pentaerithrityl tetranitrate (PETN) is widely used for the treatment of cardiovascular disease and has been shown to have protective effects on human endothelial cells. In a randomized placebo controlled pilot-study our group could demonstrate a risk reduction of 39% for the development of FGR, and FGR or death, by administering PETN to patients with impaired uterine artery Doppler at mid gestation. To confirm these results a prospective randomized placebo controlled double-blinded multicentre trial was now initiated. METHOD:The trial has been initiated in 14 centres in Germany. Inclusion criteria are abnormal uterine artery Doppler, defined by mean PI >?1.6, at 190 to 226?weeks of gestation in singleton pregnancies. Included patients will be monitored in 4-week intervals. Primary outcome measures are development of FGR (birth weight?<?10th percentile), severe FGR (birth weight?<?3rd centile) and perinatal death. Placental abruption, birth weight below the 3rd, 5th and 10th centile, development of FGR requiring delivery before 34?weeks` gestation, neonatal intensive care unit admission, and spontaneous preterm delivery <?34?weeks` and 37?weeks` gestation will be assessed as secondary endpoints. Patient enrolment was started in August 2017. Results are expected in 2020. DISCUSSION:During the past decade therapeutic agents with possible perfusion optimizing potential have been evaluated in clinical trials to treat FGR. Meta-analysis and sub-analysis of trials targeting preeclampsia revealed ASS to have a potential in reducing FGR. Phosphodiesterase-type-5 inhibitors have recently been tested in a worldwide RCT for therapy of established FGR, failing to show an effect on neonatal outcome. The ongoing multicenter trial will, by confirming our previous results, finally provide a therapeutic option in cases at risk for FGR. TRIAL REGISTRATION:DRKS00011374 registered at September 29th, 2017 and NCT03669185 , registered September 13th, 2018.

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Antenatal melatonin as an antioxidant in human pregnancies complicated by fetal growth restriction--a phase I pilot clinical trial: study protocol.

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Antenatal melatonin as an antioxidant in human pregnancies complicated by fetal growth restriction--a phase I pilot clinical trial: study protocol.

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