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Does Pentaerytrithyltetranitrate reduce fetal growth restriction in pregnancies complicated by uterine mal-perfusion? Study protocol of the PETN-study: a randomized controlled multicenter-trial.

ABSTRACT: 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?

SUBMITTER: Groten T

PROVIDER: S-EPMC6744635 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Does Pentaerytrithyltetranitrate reduce fetal growth restriction in pregnancies complicated by uterine mal-perfusion? Study protocol of the PETN-study: a randomized controlled multicenter-trial.

Groten T T Lehmann T T Schleußner E E

BMC pregnancy and childbirth 20190914 1

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

PMID: 31521118

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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:Background At present, the prevalence of pregestational diabetes is 2.2% with an overall prevalence of hyperglycaemia in pregnancy of about 16.2%. Fetuses of diabetic mothers are at risk of functional cardiac abnormalities without structural cardiac anomalies especially in the third trimester. The main aim of this study was to assess the association of diabetes with different fetal echocardiographic parameters. Methods A case control study comprising a total of 120 pregnant women (60 cases and 60 controls). The cases group included fetuses of mothers known to have pre-gestational type 2 diabetes (DM group) while the control group included fetuses of euglycaemic healthy pregnant women. They were examined twice at 23–24 weeks' gestation (visit 1) and followed up at 27–28 weeks’ gestation (visit 2). The Modified Myocardial Performance Index (Mod MPI) was obtained in all fetuses. Also, M-mode echocardiography was used to measure the interventricular septum thickness at diastole in a transverse four chamber view. Results There was a significant increase in Iso-volumetric contraction time (ICT) (45.4 ms ± 8.9), Iso-volumetric relaxation time (IRT) (54.7 ms ± 11.22), Interventricular septal thickness (IVST) (4.08 mm ± 0.8), aortic acceleration time (AAT) (54.16 ms ± 12.77) and MPI (0.64 ± 0.09) in the diabetic group compared to the normal control group ICT (38.5 ms ± 9.59), IRT (46.13 ms ± 10.29), IVST (3.17 mm ± 0.6), AAT (49.73 ms ± 10.68) and MPI (0.5 ± 0.1) (all P values were < 0.001). When comparing parameters assessed at both visits among diabetic patients, there was a significant increase in IVST in the second visit (4.74 ± 0.78 mm) compared to the first visit (4.08 ± 0.8 mm) (P value < 0.05). The incidence of hypertrophic cardiomyopathy (HCM) was significantly higher in diabetic patients than in the control group. This is was observed in both first and second visit (33.4% and 56.7%) (P value < 0.001). Conclusions Fetuses of diabetic pregnant females show a significant increase in MPI, decrease in E\A ratio and HCM. These alterations in cardiac functions and structure were found to be continuous throughout the period of time between the two visits. Supplementary Information The online version contains supplementary material available at 10.1186/s12884-022-04969-5.

Project description: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.

Project description:BackgroundIn twin pregnancies complicated by selective fetal growth restriction (sFGR), if the smaller twin is in the state of impending intra-uterine death (IUD), immediate delivery will reduce the risk of IUD of the smaller twin while exposing the larger twin to iatrogenic preterm birth (PTB). Therefore, the management options would either be to maintain pregnancy for the maturation of the larger twin despite the risk of IUD of the smaller twin or immediate delivery to prevent IUD of the smaller twin. However, the optimal gestational age of management transition from maintaining pregnancy to immediate delivery has not been established. The objective of this study was to evaluate the physician's perspective on the optimal timing of immediate delivery in twin pregnancies complicated by sFGR.MethodsAn online cross-sectional survey was performed with obstetricians and gynecologists (OBGYN) in South Korea. The questionnaire asked the following: (1) whether participants would maintain or immediately deliver a twin pregnancy complicated by sFGR with signs of impending IUD of the smaller twin; (2) the optimal gestational age of management transition from maintaining pregnancy to immediate delivery in a twin pregnancy with impending IUD of the smaller twin; and (3) the limit of viability and intact survival in general preterm neonates.ResultsA total of 156 OBGYN answered the questionnaires. In a clinical scenario of dichorionic (DC) twin pregnancy complicated by sFGR with signs of impending IUD of the smaller twin, 57.1% of the participants answered that they would immediately deliver the twin pregnancy. However, 90.4% answered that they would immediately deliver the pregnancy in the same scenario for monochorionic (MC) twin pregnancy. The participants designated 30 weeks for DC twin and 28 weeks for MC twin pregnancies as the optimal gestational age of management transition from maintaining pregnancy to immediate delivery. The participants regarded 24 weeks as the limit of viability and 30 weeks as the limit of intact survival in general preterm neonates. The optimal gestational age of management transition for DC twin pregnancy was correlated with the limit of intact survival in general preterm neonates (p < 0.001), but not with the limit of viability. However, the optimal gestational age of management transition for MC twin pregnancy was associated with both the limit of intact survival (p = 0.012) and viability with marginal significance (p = 0.062).ConclusionsParticipants preferred to immediately deliver twin pregnancies complicated by sFGR with impending IUD of the smaller twin at the limit of intact survival (30 weeks) for DC twin pregnancies and at the midway between the limit of intact survival and viability (28 weeks) for MC twin pregnancies. More research is needed to establish guidelines regarding the optimal delivery timing for twin pregnancies complicated by sFGR.

Dataset Information

Does Pentaerytrithyltetranitrate reduce fetal growth restriction in pregnancies complicated by uterine mal-perfusion? Study protocol of the PETN-study: a randomized controlled multicenter-trial.

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Does Pentaerytrithyltetranitrate reduce fetal growth restriction in pregnancies complicated by uterine mal-perfusion? Study protocol of the PETN-study: a randomized controlled multicenter-trial.

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