Pentaerythrityl tetranitrate improves the outcome of children born to mothers with compromised uterine perfusion-12-months follow-up and safety data of the double-blind randomized PETN trial.

BACKGROUND: This is a follow-up study to the pentaerythrityl tetranitrate randomized controlled multicenter trial that reports neonatal outcome data of newborns admitted to neonatal intensive care units and outcome data of the offspring at 12 months of age. OBJECTIVE: We present data on adverse events reported during the study to document the safety of pentaerythrityl tetranitrate treatment during pregnancy. To further evaluate the effects of pentaerythrityl tetranitrate on neonatal and long-term outcomes, we present follow up data from of 240 children at 12 months of age, including information on height, weight, head circumference, developmental milestones, and the presence of chronic disease and of 144 newborns admitted to the neonatal intensive care unit during the trial. STUDY DESIGN: The pentaerythrityl tetranitrate trial was a randomized, double-blind, placebo-controlled study designed to assess the efficacy and safety of the nitric oxide-donor pentaerythrityl tetranitrate in the prevention of fetal growth restriction and perinatal death in pregnancies complicated by abnormal placental perfusion. RESULTS: Results at 12 months demonstrated that significantly more children were age appropriately developed without impairments in the pentaerythrityl tetranitrate group (P=.018). In addition, the presence of chronic disease was lower in the pentaerythrityl tetranitrate group (P=.041). Outcome data of the 144 newborns admitted to the neonatal intensive care unit did not reveal differences between the treatment and placebo groups. There were no differences in the number or nature of reported adverse events between the study groups. CONCLUSION: The analysis shows that study children born in the pentaerythrityl tetranitrate cohort have a clear advantage compared with the placebo group at the age of 12 months, as evidenced by the increased incidence of normal development without the presence of chronic disease. Although safety has been proven, further follow-up studies are necessary to justify pentaerythrityl tetranitrate treatment during pregnancies complicated by impaired uterine perfusion.

Effect of pentaerythritol tetranitrate (PETN) on the development of fetal growth restriction in pregnancies with impaired uteroplacental perfusion at midgestation-a randomized trial.

BACKGROUND: Fetal growth restriction is strongly associated with impaired placentation and abnormal uteroplacental blood flow. Nitric oxide donors such as pentaerythritol tetranitrate are strong vasodilators and protect the endothelium. Recently, we demonstrated in a randomized controlled pilot study a 38% relative risk reduction for the development of fetal growth restriction or perinatal death following administration of pentaerythritol tetranitrate to pregnant women at risk, identified by impaired uterine perfusion at midgestation. Results of this monocenter study prompted the hypothesis that pentaerythritol tetranitrate might have an effect in pregnancies with compromised placental function as a secondary prophylaxis. OBJECTIVE: This study aimed to test the hypothesis that the nitric oxide donor pentaerythritol tetranitrate reduces fetal growth restriction and perinatal death in pregnant women with impaired placental perfusion at midgestation in a multicenter trial. STUDY DESIGN: In this multicenter, randomized, double-blind, placebo-controlled trial, 2 parallel groups of pregnant women presenting with a mean uterine artery pulsatility index >95th percentile at 19+0 to 22+6 weeks of gestation were randomized to 50-mg Pentalong or placebo twice daily. Participants were assigned to high- or low-risk groups according to their medical history before randomization was performed block-wise with a fixed block length stratified by center and risk group. The primary efficacy endpoint was the composite outcome of perinatal death or development of fetal growth restriction. Secondary endpoints were neonatal and maternal outcome parameters. RESULTS: Between August 2017 and March 2020, 317 participants were included in the study and 307 were analyzed. The cumulative incidence of the primary outcome was 41.1% in the pentaerythritol tetranitrate group and 45.5% in the placebo group (unadjusted relative risk, 0.90; 95% confidence interval, 0.69-1.17; adjusted relative risk, 0.90; 95% confidence interval, 0.69-1.17; P=.43). Secondary outcomes such as preterm birth (unadjusted relative risk, 0.73; 95% confidence interval, 0.56-0.94; adjusted relative risk, 0.73; 95% confidence interval, 0.56-0.94; P=.01) and pregnancy-induced hypertension (unadjusted relative risk, 0.65; 95% confidence interval, 0.46-0.93; adjusted relative risk, 0.65; 95% confidence interval, 0.46-0.92; P=0.01) were reduced. CONCLUSION: Our study failed to show an impact of pentaerythritol tetranitrate on the development of fetal growth restriction and perinatal death in pregnant women with impaired uterine perfusion at midgestation. Pentaerythritol tetranitrate significantly reduced secondary outcome parameters such as the incidence of preterm birth and pregnancy-induced hypertension in these pregnancies.

Induction of Labor at Term with Oral Misoprostol or as a Vaginal Insert and Dinoprostone Vaginal Insert - A Multicenter Prospective Cohort Study.

Introduction The efficacy, safety, and perinatal outcome of oral misoprostol (OM), a misoprostol vaginal insert (MVI), and a dinoprostone vaginal insert (DVI) for induction of labor at term was examined in a prospective multicenter cohort study (ethics committee vote 4154-07/14). The primary aims of the study were the induction-birth interval (IBI), the cumulative delivery rates after 12 h, 24 h, and 48 h as well as the mode of delivery. Method 322 pregnant women were included in four German tertiary perinatal centers (MVI 110, DVI 64, OM 148). They did not vary in age or BMI. Statistical analysis was carried out using a multivariate linear regression analysis and binary logistic regression analysis. Results With regards to the median IBI, MVI and OM were equally effective and superior to the DVI (MVI 823 min [202, 5587]; DVI 1226 min [209, 4909]; OM 847 min [105, 5201]; p = 0.006). Within 24 hours, 64% were able to deliver with DVI, 85.5% with MVI and 87.5% with OM (p < 0.01). The rates of secondary Caesarean sections (MVI 24.5%; DVI 26.6%; OM 18.9%) did not differ significantly. Uterine tachysystole was found in 20% with MVI, 4.7% with DVI and 1.4% with OM (p < 0.001). A uterine rupture did not occur in any of the cases. Perinatal acidosis occurred (umbilical cord arterial pH < 7.10) in 8.3% with MVI, 4.7 with DVI and 1% with OM (p = 0.32). Neonatal condition was only impaired in three cases (5-minute Apgar score < 5). Summary Induction of labor at term using the prostaglandins misoprostol and dinoprostone is an effective intervention that is safe for the mother and child. Oral application of misoprostol demonstrated the highest efficacy while maintaining a favorable safety profile.

Bone development in female rats maintained with soy-free or soy-containing food as determined by computer-assisted tomography and serum bone markers.

The development of bone in immature rats and in aged rats has not been thoroughly studied. Therefore, we investigated the development of bones in young, middle-aged, and aged female rats. Because most rat chows contain soy proteins, including estrogenic isoflavones, as a source of protein, comparison of effects on mineral density and on areas of the cancellous and cortical parts of the metaphysis of the tibia as measured by quantitative computer tomography in animals fed with soy-free and soy-containing food was made. As surrogate parameters of bone metabolism serum, osteocalcin (OC) and the breakdown products of bone collagen--the Crosslaps--were also determined. The cancellous density increased between day 25 after birth to reach peak bone mass at 90 days of age; in 18-and 20-month-old animals, significant reduction was observed that was more profound in the animals fed with soy-free food. Serum OC and the Crosslaps were highest in 15-day-old and lowest in 9-, 18-, and 20-month-old animals. Animals fed with soy-containing food had significantly higher osteocalcin levels at day 15 and at 9 and 18 months of age. In the aged animals, intake of soy isoflavones that have an estrogenic effect appears to exert beneficial effects as these aged animals lost less cancellous bone, as indicated by their surrogate parameters of metabolism in the serum. It is concluded that exorbitantly high bone turnover is present in immature and peripubertal rats. Raising and keeping female rats under soy-free or soy-containing conditions has marked effects on several bone parameters that are of particular relevance in aged animals.