Search

Objective: Pregnancies with fetal growth restriction (FGR) are at increased risk for pre-eclampsia. Angiogenic markers including soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) are altered in pregnancies complicated by FGR, but their utility for predicting pre-eclampsia in growth-restricted pregnancies is uncertain. This study aimed to evaluate the prognostic value of angiogenic markers for predicting the development of pre-eclampsia in pregnancies with FGR and suspected pre-eclampsia., Methods: This was a retrospective study of singleton pregnancies with FGR, defined according to Delphi consensus criteria, which underwent sampling of sFlt-1 and PlGF for suspicion of pre-eclampsia at the Medical University of Vienna, Vienna, Austria, between 2013 and 2020. Women with an established diagnosis of pre-eclampsia at sampling were excluded. Cox regression analysis and logistic regression analysis were performed to evaluate the association of angiogenic markers with the development of pre-eclampsia at various timepoints., Results: In this cohort of 93 women, pre-eclampsia was diagnosed in 14 (15.1%) women within 1 week after sampling, 21 (22.6%) within 2 weeks after sampling and 38 (40.9%) at any time after assessment. The sFlt-1/PlGF ratio consistently showed a stronger association with the development of pre-eclampsia compared to sFlt-1 or PlGF alone (pre-eclampsia within 1 week: area under the receiver-operating-characteristics curve, 0.87 vs 0.82 vs 0.72). Models including the sFlt-1/PlGF ratio were associated more strongly with pre-eclampsia hazard compared to models including sFlt-1 or PlGF alone (concordance index, 0.790 vs 0.759 vs 0.755). The risk classification capability of the sFlt-1/PlGF ratio decreased after the 2-week timepoint. The established cut-off value for the sFlt-1/PlGF ratio of < 38 was effective for ruling out pre-eclampsia within 2 weeks, with a negative predictive value of 0.933 and sensitivity of 0.952., Conclusions: Use of the sFlt-1/PlGF ratio is preferrable to the use of PlGF alone for the prediction of pre-eclampsia in pregnancies with FGR. Established cut-offs for ruling out the development of pre-eclampsia in the short term seem to be effective in these patients. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology., (© 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.)

Objectives: Angiogenic marker assessment, such as the ratio of soluble fms-like tyrosine kinase-1 (sFlt-1) to placental growth factor (PlGF), is known to be a useful tool in the prediction of pre-eclampsia (PE). However, evidence from surveillance strategies in pregnancies with a PE diagnosis is lacking. Therefore, we aimed to assess the predictive performance of longitudinal maternal serum angiogenic marker assessment for both maternal and perinatal adverse outcomes when compared to standard laboratory parameters in pregnancies with confirmed PE., Methods: This was a retrospective analysis of prospectively collected data from January 2013 to December 2020 at the Medical University of Vienna. The inclusion criteria were singleton pregnancy with confirmed PE and post-diagnosis maternal serum angiogenic marker assessment at a minimum of two timepoints. The primary outcome was the predictive performance of longitudinal sFlt-1 and PlGF assessment for adverse maternal and perinatal outcomes compared to conventional laboratory monitoring at the same time in pregnancies with confirmed PE. Composite adverse maternal outcome included intensive care unit admission, pulmonary edema, eclampsia and/or death. Composite adverse perinatal outcome included stillbirth, neonatal death, placental abruption, neonatal intensive care unit admission, intraventricular hemorrhage, necrotizing enterocolitis, respiratory distress syndrome and/or mechanical ventilator support., Results: In total, 885 post-diagnosis sFlt-1/PlGF ratio measurements were obtained from 323 pregnant women with confirmed PE. For composite adverse maternal outcome, the highest standalone predictive accuracy was obtained using maternal serum sFlt-1/PlGF ratio (area under the receiver-operating-characteristics curve (AUC), 0.72 (95% CI, 0.62-0.81)), creatinine (AUC, 0.71 (95% CI, 0.62-0.81)) and lactate dehydrogenase (LDH) levels (AUC, 0.73 (95% CI, 0.65-0.81)). Maternal platelet levels (AUC, 0.65 (95% CI, 0.55-0.74)), serum alanine aminotransferase (ALT) (AUC, 0.59 (95% CI, 0.49-0.69)) and aspartate aminotransferase (AST) (AUC, 0.61 (95% CI, 0.51-0.71) levels had poor standalone predictive accuracy. The best prediction model consisted of a combination of maternal serum LDH, creatinine levels and sFlt-1/PlGF ratio, which had an AUC of 0.77 (95% CI, 0.68-0.85), significantly higher than sFlt-1/PlGF ratio alone (P = 0.037). For composite adverse perinatal outcome, the highest standalone predictive accuracy was obtained using maternal serum sFlt-1/PlGF ratio (AUC, 0.82 (95% CI, 0.75-0.89)) and creatinine (AUC, 0.74 (95% CI, 0.67-0.80)) levels, sFlt-1/PlGF ratio being superior to creatinine alone (P < 0.001). Maternal serum LDH levels (AUC, 0.65 (95% CI, 0.53-0.74)), platelet count (AUC, 0.57 (95% CI, 0.44-0.67)), ALT (AUC, 0.58 (95% CI, 0.48-0.67)) and AST (AUC, 0.58 (95% CI, 0.48-0.67)) levels had poor standalone predictive accuracy. No combination of biomarkers was superior to maternal serum sFlt-1/PlGF ratio alone for prediction of composite adverse perinatal outcome (P > 0.05 for all)., Conclusions: In pregnancies with confirmed PE, longitudinal maternal serum angiogenic marker assessment is a good predictor of adverse maternal and perinatal outcomes and superior to some conventional laboratory parameters. Further studies should focus on optimal surveillance following diagnosis of PE. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology., (© 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.)

Purpose: Hypertensive disorders of pregnancy are still a leading cause of maternal and neonatal morbidity and mortality worldwide. Women with a history of preeclampsia have an increased risk for future cardiovascular and cerebrovascular disease, renal disease as well as diabetes mellitus. There is little knowledge on postpartum risk management. The aim of this study was to assess follow-up care for patients after pre-eclampsia or HELLP syndrome., Methods: This questionnaire-based cross-sectional study aimed to evaluate the current recommendations of obstetricians in Austria regarding follow-up care, long-term risk counselling and risk of recurrence in future pregnancies after preeclampsia or HELLP syndrome. Data were collected using a survey, based on recommendations given by three substantial guidelines on hypertensive disorders of pregnancy, which was distributed via e-mail to 69 public obstetric departments in Austria. Each obstetric department was required to answer one questionnaire per local protocol., Results: Our results revealed that of the 48 participating hospitals most obstetricians are aware of the importance of follow-up care for women after a pregnancy complicated by preeclampsia. Our data show that most physicians counselled patients about the future cardiovascular health risks associated with preeclampsia or HELLP syndrome (79.2%). Most obstetricians recommended lifestyle modification (77.1%) and continued blood pressure measurements (97.9%). All centers stated to counsel about the risk of recurrence (100%). However, counselling regarding follow-up care to exclude kidney damage (37.5%) and underlying diseases like thrombophilia (39.6%) were less prioritized., Conclusions: We were able to show that counselling concerning the risk of long-term cardiovascular disease and risk of recurrence after a pregnancy complicated by preeclampsia or HELLP syndrome has been established in obstetric departments in public hospitals. Regarding the evaluation of underlying chronic diseases such as thrombophilia or renal disease, as well as counselling on the future risk of renal disease is still improvable according to our data. Further evaluation of follow-up care after hypertensive disorders of pregnancy in the outpatient and private sector and implementation of structured guidelines for follow-up, as well as screening for cardiovascular disease are necessary to ensure adequate risk management and to provide opportunities for prevention., (© 2021. The Author(s).)

Objective: Although the most recent guidance from the International Society for the Study of Hypertension in Pregnancy (ISSHP) has highlighted the role of angiogenic marker assessment in the diagnosis of pre-eclampsia (PE) in women with chronic hypertension, the ISSHP has withheld recommending its implementation due to the limited available evidence in this group of women. Therefore, we aimed to investigate the value of soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) assessment in women with chronic hypertension and suspected superimposed PE., Methods: This was a retrospective analysis of prospectively collected data recorded in an electronic database between January 2013 and October 2019. Women with chronic hypertension and singleton pregnancy who had suspected superimposed PE were included. Superimposed PE was suspected in women presenting with worsening hypertension, epigastric pain, new-onset edema, dyspnea or neurological symptoms. The exclusion criteria were delivery within 1 week after assessment for reasons other than PE, chronic kidney disease, history of cardiac disease, fetal aneuploidy, genetic syndrome or major structural anomaly and missing pregnancy outcome. Maternal serum angiogenic markers (sFlt-1, PlGF and sFlt-1/PlGF ratio) were measured. The primary outcome was the utility of angiogenic markers in the prediction of superimposed PE. Predictive accuracy was assessed for superimposed PE diagnosed at different timepoints, including within 1 week after assessment and any time before birth. The secondary outcome was comparison of adverse maternal and perinatal outcomes between women with superimposed PE diagnosed according to the traditional ISSHP criteria and those diagnosed according to extended criteria including angiogenic markers. The predictive accuracy of each angiogenic marker was assessed using receiver-operating-characteristics-curve analysis. Area under the curve (AUC) values were compared using De Long's test. A sensitivity analysis was planned for gestational age at assessment. The association of various variables with composite adverse maternal and perinatal outcomes was assessed using binomial regression., Results: The study included 142 pregnant women with chronic hypertension and suspected superimposed PE, of whom 25 (17.6%) developed PE within 1 week after assessment, 52 (36.6%) developed PE at any timepoint before birth and 90 (63.4%) delivered without PE. Maternal serum angiogenic imbalance was associated significantly with superimposed PE diagnosed according to the ISSHP criteria within 1 week or at any time after assessment (P < 0.001 for both). The predictive accuracy of maternal serum sFlt-1/PlGF ratio for superimposed PE diagnosed within 1 week after assessment was superior to that of maternal serum PlGF level (AUC, 0.91 vs 0.86; P = 0.032). The addition of angiogenic imbalance to the traditional ISSHP diagnostic criteria was associated with an increase in the detection rate (35.1% increase; 95% credible interval (CrI), 16.6-53.6%) and positive (9.6% increase; 95% CrI, 0.0-20.6%) and negative (3.1% increase; 95% CrI, 1.3-4.9%) predictive values for composite adverse maternal outcome, with high posterior probabilities of an increase in each predictive accuracy parameter (> 99.9%, 95.6% and > 99.9%, respectively), without a meaningful decrease in specificity. The addition of angiogenic imbalance improved the detection rate for composite adverse perinatal outcome (20.6% increase; 95% CrI, 0.0-42.2%), with a high posterior probability (96.9%). There was a corresponding drop in specificity (5.7% decrease; 95% CrI, -2.3% to 13.6%), with a posterior probability of 91.8%., Conclusions: In women with chronic hypertension and suspected superimposed PE, addition of maternal serum angiogenic markers to the traditional diagnostic criteria for superimposed PE improved significantly the sensitivity for the prediction of both maternal and perinatal adverse outcomes. Implementation of angiogenic marker assessment in the evaluation of pregnant women with chronic hypertension should therefore be considered. © 2021 International Society of Ultrasound in Obstetrics and Gynecology., (© 2021 International Society of Ultrasound in Obstetrics and Gynecology.)

Background Women with chronic hypertension face a 5- to 6-fold increased risk of developing preeclampsia compared with normotensive women. Angiogenic markers, especially soluble fms-like kinase 1 (sFlt-1) and placental growth factor (PlGF), were identified as clinically useful markers predicting the development of preeclampsia, but data on the prediction of superimposed preeclampsia are scarce. Therefore, we aimed to evaluate the predictive value of the sFlt-1/PlGF ratio for delivery because of superimposed preeclampsia in women with chronic hypertension. Methods and Results This retrospective study included 142 women with chronic hypertension and suspected superimposed preeclampsia. Twenty-seven women (19.0%) delivered because of maternal indications only, 17 women (12.0%) because of fetal indications primarily, and 98 women (69.0%) for other reasons. Women who both delivered because of maternal indications and for fetal indications had a significantly higher sFlt-1/PlGF ratio (median 99.9 and 120.2 versus 7.3, respectively, P <0.001 for both) and lower PlGF levels (median 73.6 and 53.3 versus 320.0 pg/mL, respectively, P <0.001 for both) compared with women who delivered for other reasons. SFlt-1/PlGF ratio and PlGF were strong predictors for delivery because of superimposed preeclampsia, whether for maternal or fetal indications ( P <0.05). Half of women with angiogenic imbalance (sFlt-1/PlGF ratio ≥85 or PlGF levels <100 pg/mL) delivered because of maternal or fetal indications within 1.6 weeks (95% CI, 1.0-2.4 weeks). Conclusions Angiogenic marker imbalance in women with suspected superimposed preeclampsia can predict delivery because of maternal and fetal indications related to superimposed preeclampsia and is associated with a significantly shorter time to delivery interval.

The sFlt-1 (soluble fms-like tyrosine kinase-1), PlGF (placental growth factor), and their ratio are useful for predicting delivery because of preeclampsia in singleton pregnancies. Evidence on the utility of sFlt-1/PlGF ratio in twin pregnancies is lacking. We aimed to evaluate the predictive value of sFlt-1/PlGF ratio for delivery because of preeclampsia in twins. A retrospective data analysis of 164 twin pregnancies with suspected preeclampsia was performed. The sFlt-1/PlGF ratio, which was known to clinicians, was significantly higher in women who delivered within 1 and 2 weeks compared with those who did not (median: 98.9 and 84.2 versus 23.5 pg/mL, respectively; P <0.001). The area under the curve values sFlt-1/PlGF ratio levels were 0.88 (95% CI, 0.83-0.84) and 0.88 (95% CI, 0.83-0.93) for predicting delivery because of preeclampsia within 1 and 2 weeks of blood sampling, respectively. The predictive accuracy of sFlt-1/PlGF was independent of gestational age at sampling and chorionicity ( P >0.100 for interaction). The area under the curve values of sFlt-1/PlGF were significantly higher than for PlGF alone (mean 0.88 and 0.88 versus 0.81 and 0.80) for predicting delivery because of preeclampsia within 1 and 2 weeks of blood sampling ( P =0.055 and 0.001, respectively). sFlt-1/PlGF ratio lower than 38 was able to rule-out delivery within 1 and 2 weeks with a negative predictive value of 98.8% and 96.4% for delivery because of preeclampsia within 1 and 2 weeks, respectively. A cutoff of 38 is applicable for ruling out delivery because of preeclampsia in twin pregnancies.

Objective: Oxidative stress and mitochondrial dysfunction may play a crucial role in preeclampsia (PE). The aim of this study was to investigate differences in maternal levels of serum-mitochondrial (mt) DNA, a proposed biomarker for mitochondrial dysfunction, in women with PE compared to healthy pregnant women., Study Design: Using samples obtained from the prospective Biobank study, we measured serum-mtDNA levels in pregnant women diagnosed with PE and in women with uneventful pregnancies, matched for gestational and maternal age, BMI, and smoking status. In a second step, we performed a generalized linear model to detect associations between mtDNA-serum-levels and certain conditions during pregnancy., Results: Mean mtDNA levels were significantly higher in PE (n = 20) than in matched controls (n = 20) and were 0.00767 (SD 0.00255) U/L and 0.00513 (SD 0.00458) U/L, respectively (p = 0.038). We did not find a significant correlation between higher mtDNA levels and early onset PE, IUGR, maternal age, or maternal BMI. Interestingly, increased mtDNA levels were significantly associated with female fetal sex (p = 0.003)., Conclusion: Our findings strengthen the hypothesis postulating that oxidative stress and mitochondrial dysfunction are key factors in the pathophysiology of PE. More prospective studies are highly warranted to further investigate the role of mtDNA in PE and assess the usefulness as a possible biomarker for PE., (Copyright © 2018 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

The significance of antibodies directed against paternal epitopes in the context of obstetric disorders is discussed controversially. In this study anti-HLA and anti-MIC-A antibodies were analysed in sera of women with uneventful pregnancy (n = 101), preeclampsia (PE, n = 55) and gestational diabetes (GDM, n = 36) using antigen specific microbeads. While two thirds of the women with uneventful pregnancy or GDM were HLA and MIC-A antibody positive in gestational week 11 to 13 with a modest increase towards the end of pregnancy, women with PE showed an inverse kinetic: 90% were HLA antibody positive in gestational week 11 to 13 and only 10% showed HLA reactivities at the end of the pregnancy. HLA antibody binding strength was more pronounced in gestational week 14 to 17 in patients with PE compared to women with uneventful pregnancy (maximum median fluorescence intensity of the highest ranked positive bead 7403, IQR 2193-7938 vs. 1093, IQR 395-5689; p = 0.04) and was able to predict PE with an AUC of 0.80 (95% CI 0.67-0.93; p = 0.002). Our data suggest a pathophysiological involvement of HLA antibodies in PE. HLA antibody quantification in early pregnancy may provide a useful tool to increase diagnostic awareness in women prone to develop PE.

Background: The ability to identify patients at risk for developing preeclampsia is important for preventing morbidity and mortality in both the mother and child. Although CYFRA 21-1 (a fragment of Cytokeratin 19) is considered a promising biomarker for diagnosing preeclampsia, little is known regarding the levels of CYFRA 21-1 during pregnancy. Here, we measured serum CYFRA 21-1 levels in women with an uneventful pregnancy and in women whose pregnancy was complicated by preeclampsia. Furthermore we evaluated whether maternal CYFRA 21-1 levels can be used to predict and/or diagnose preeclampsia., Methods: Longitudinal, sequential blood samples were collected prospectively at seven predetermined visits during pregnancy. Maternal CYFRA 21-1 levels were measured in 50 women with an uneventful pregnancy (control group) and in 10 asymptomatic women whose pregnancy was later complicated by preeclampsia (PE&#95;long group). In addition, CYFRA 21-1 levels were measured from a single sample collected from a separate group of 50 pregnant women with symptomatic preeclampsia (PE&#95;state group)., Results: The CYFRA 21-1 levels were significantly higher in the PE&#95;state group compared to the control group (p < 0.001). In the PE&#95;long group, CYFRA 21-1 levels were lower from gestational week 11 through 17, but were higher than the control group from gestational weeks 18 through 36. Out of the ROC curves that were calculated to investigate the predictive and diagnostic properties of CYFRA 21-1 levels for preeclampsia, the ROC curve for diagnosing preeclampsia in gestational week 28-32 showed the largest AUC of 0.92, at a cut-off point of 3.1 ng/ml, leading to sensitivity of 92 % and specificity of 80 %., Conclusions: The elevated serum levels of CYFRA 21-1 observed in both groups of women with preeclampsia may reflect endothelial damage and/or dysfunction. Our results suggest that maternal serum CYFRA 21-1 is a promising biomarker for diagnosing preeclampsia. Although its value for predicting the long-term occurrence of subsequent preeclampsia may be limited, our findings indicate a trend towards elevated maternal CYFRA 21-1 levels preceding the short-term occurrence of preeclampsia in asymptomatic women. Additional prospective longitudinal studies are needed in order to determine the value of measuring maternal serum CYFRA 21-1 in predicting preeclampsia.

Objective: Preeclampsia (PE) is a frequent pregnancy-related disease and a major cause of maternal and fetal morbidity and mortality. Despite that, exact mechanisms of its pathophysiology remain largely unknown. In pregnancies complicated by PE, changes in the regulation of apoptosis seem to result in increased apoptotic shedding of trophoblast particles (TPs) into maternal circulation. Since the number of TP in peripheral blood is low, their detection necessitates pre-analytical enrichment., Methods: In this prospective multicenter pilot study we aimed to analyze TP in peripheral blood of 29 women with PE and of 13 unaffected controls using the OncoQuick®plus system for cell enrichment. Using immunocytochemistry, slides were evaluated microscopically for TP. Statistical analyses were performed using Welch's t-test or Fisher's exact test., Results: TP were detected in 10 (34.5%) women with PE and in two (15.4%) of unaffected controls. More than one TP were only found in PE. Comparing the mean counts of TP between groups, we detected significantly more TP in PE (p = 0.046)., Conclusions: The OncoQuick®plus system can be applied to detect TP in both women with PE and in normotensive pregnancies. Longitudinal studies investigating the role of TP as a screening method for patients at risk for PE are warranted.

Introduction: The role of preeclampsia (PE) in affecting bone metabolism could not be clarified in the past years. Recently Sclerostin, a new marker of bone metabolism which is known to have an inhibitory effect on bone formation causing osteoporosis, was discovered., Objective: To investigate serum levels of Sclerostin and markers of bone turnover in women with normotensive pregnancies and pregnancies complicated by PE., Methods: In this prospective study we enrolled 22 women with PE and 22 healthy pregnant women to observe serum levels of carboxyterminal propeptide of type I collagen (PICP), cross-linked carboxyl terminal telopeptide of the type I collagen (ICTP), calcium, phosphate, 25-hydroxyvitamin D and parathyroid hormone. In 16 preeclamptic and 16 healthy pregnant women, serum Sclerostin levels were analyzed., Results: Serum levels of Sclerostin (mean ± standard deviation: healthy 10.5 ± 8.1 pmol/l versus PE 11.5 ± 9.4 pmol/l, p = 0.768), ICTP (healthy 0.3 ± 0.2 ng/ml versus PE 0.4 ± 0.1 ng/ml, p = 0.462), PICP (healthy 59.9 ± 49.9 ng/ml versus PE 89.0 ± 62.0 ng/ml, p = 0.094), phosphate (healthy 1.1 ± 0.2 mmol/l versus PE 1.2 ± 0.4 mmol/l, p = 0.162) and parathyroid hormone (healthy 26.9 ± 14 pg/ml versus PE 35.3 ± 17.6 pg/ml, p = 0.08) showed no significant differences between the groups. Significantly lower serum calcium (healthy 2.3 ± 0.1 mmol/l versus PE 2.2 ± 0.2 mmol/l, p < 0.005) and serum 25-Hydroxyvitamin D (healthy 39.3 ± 16.7 nmol/l versus PE 23.9 ± 16.9 nmol/l, p < 0.005) were observed in preeclamptic women., Conclusion: Pregnancies complicated by PE show no signs of high bone turnover and may not lead to a higher risk of osteoporosis in later life.