The sFlt-1/PlGF-ratio and the risk of preeclampsia-related adverse outcomes in subsequent pregnancies with signs and symptoms of a preeclampsia.

OBJECTIVES: This study characterizes the outcome of two subsequent pregnancies with suspected preeclampsia (PE). We investigated the diagnostic accuracy of clinical signs, Doppler examinations, and the soluble fms-like tyrosine kinase-1 (sFlt-1) to placental growth factor (PlGF)-ratio to predict PE-related adverse outcomes (AO). The sFlt-1/PlGF-ratio of the first pregnancy was compared to the outcome of the subsequent pregnancy. STUDY DESIGN: A total of 1928 patients at risk for preeclampsia were screened, of them 1117 were eligible for inclusion. Of these, 84 women presented with suspected PE in two subsequent pregnancies. OUTCOME MEASURES: Diagnostic accuracy of clinical markers was assessed. Associations between the sFlt-1/PlGF-ratio in the first and the odds of an AO in the subsequent pregnancy were investigated with logistic regression. RESULTS: The prevalence of AOs decreased from 27.4 % in the first to 17.9 % in the second pregnancy. Comparison of the accuracy of the different clinical markers for an AO showed a high specificity for an sFlt-1/PlGF-ratio at the cut-off of ≥ 85 in both pregnancies (81.3 %, 95 % CI 63.6-92.8 vs 92.6 %,95 % CI 83.7-97.6), but a lower sensitivity in the second pregnancy (92.9 %, 95 % CI 66.1-99.8 vs 33.3%, 95 % CI 11.8-61.6). An elevated sFlt-1/PlGF-ratio in the first did not increase the odds of an AO in the subsequent pregnancy. CONCLUSIONS: The prevalence of AOs decreases in subsequent pregnancies. Our finding that the sFlt-1/PlGF-ratio of the first was not related to the outcome of the subsequent pregnancy suggests that angiogenic markers are only a within-pregnancy short-term tool to assess AOs.

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.

The CHANGED Score-A New Tool for the Prediction of Insulin Dependency in Gestational Diabetes.

Gestational diabetes (GDM) is a frequent complication during pregnancy. We aimed to develop a score to predict future insulin dependency in gestational diabetes (GDM). Data from 1611 patients from Charité Berlins gestational diabetes clinic from 2015 to 2022 were utilized. A stepwise backwards regression, including patient characteristics obtained at the initial presentation, was performed. Predictors examined included age, fasting blood glucose level, blood glucose levels one and two hours after oral glucose tolerance test, pre-pregnancy BMI, number of previous pregnancies and births, and fetal sex. The ideal cutoff value between high and low risk for insulin dependency was assessed and the score was internally validated. There were 1249 (77.5%) women diagnosed with dietary GDM and 362 (22.5%) were diagnosed with insulin-dependent GDM. The CHarité AssessmeNt of GEstational Diabetes (CHANGED) Score achieved an area under the curve of 0.77 (95% confidence interval 0.75-0.80; 0.75 in internal validation). The optimal cutoff value was calculated at a score value of 9 (72% sensitivity, 69% specificity). We developed an easily applicable tool to accurately predict insulin dependency in gestational diabetes. The CHANGED Score is routinely available and can potentially improve maternal and fetal outcomes.

Comparison of the Soluble fms-Like Tyrosine Kinase 1/Placental Growth Factor Ratio Alone versus a Multi-Marker Regression Model for the Prediction of Preeclampsia-Related Adverse Outcomes after 34 Weeks of Gestation.

INTRODUCTION: The objective of this retrospective study was to compare the predictive performance of the soluble fms-like tyrosine kinase 1 (sFlt-1)/placental growth factor (PlGF) ratio alone or in a multi-marker regression model for preeclampsia-related maternal and/or fetal adverse outcomes in women >34 weeks of gestation. METHODS: We analyzed the data collected from 655 women with suspected preeclampsia. Adverse outcomes were predicted by multivariable and univariable logistic regression models. The outcome of patients was evaluated within 14 days after presentation with signs and symptoms of preeclampsia or diagnosed preeclampsia. RESULTS: The full model integrating available, standard clinical information and the sFlt-1/PlGF ratio had the best predictive performance for adverse outcomes with an AUC of 72.6%, which corresponds to a sensitivity of 73.3% and specificity of 66.0%. The positive predictive value of the full model was 51.4%, and the negative predictive value was 83.5%. 24.5% of patients, who did not experience adverse outcomes but were classified as high risk by sFlt-1/PlGF ratio (≥38), were correctly classified by the regression model. The sFlt-1/PlGF ratio alone had a significantly lower AUC of 65.6%. CONCLUSIONS: Integrating angiogenic biomarkers in a regression model improved the prediction of preeclampsia-related adverse outcomes in women at risk after 34 weeks of gestation.

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.

Correlation between placental weight and angiogenic markers sFlt-1 and PlGF in women with preeclampsia and fetal growth restriction.

OBJECTIVES: The angiogenic factors sFlt-1 (soluble fms-like tyrosine kinase) and PlGF (Placental Growth Factor) play a key role in the pathophysiology, prediction and diagnosis of preeclampsia-associated pregnancy disorders. However, the correlation between maternal serum levels and the placental weight, especially in hypertensive pregnancy disorders is still unclear. STUDY DESIGN: Retrospectively, we analyzed data from a real-world cohort of patients with preeclampsia (PE), intrauterine growth restriction (IUGR), PE + IUGR and controls giving birth within 14 days from inclusion. Herein, correlational analyses were calculated between placental weight, maternal serum levels of sFlt-1, PlGF and the respective sFlt-1/PlGF-ratios. MAIN OUTCOME MEASURES AND RESULTS: This study included n = 328 patients (n = 134 with PE, n = 40 with IUGR and n = 25 showed PE + IUGR) and n = 129 controls. The gestational age-adjusted placental weight was significantly decreased in patients with PE ± IUGR, but not in PE alone, when comparing to controls. Correlation between PlGF and the placental weight was significantly positive and increasing with severity of disease (controls 0.134, p = 0.131, PE 0.419, p < 0.01, IUGR 0.517, p < 0.01, PE + IUGR r = 0.723, p < 0.01). Furthermore, an inverse correlation between the sFlt-1/PlGF-ratio and the placental weight was found. The sFlt-1/PlGF-ratio per gram placental weight was highest in patients with PE + IUGR and lowest in controls (0.6 (IQR 0.4-1.8) vs. 0.05 (IQR 0.02-0.15)). CONCLUSION: A correlation between the serum levels of sFlt-1 and PlGF and the placental weight is present in PE-associated pregnancy disorders. This mirrors the model of an angiogenic continuum in the placenta where the serum sFlt-1 to PlGF ratio increases with severity of the disease.