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Background: Low sFlt-1 (soluble Fms-like tyrosine kinase-1) and ET-1 (endothelin-1) levels have been reported in preeclamptic women using proton pump inhibitors., Methods: Here, we examined whether the proton pump inhibitor omeprazole could acutely reduce sFlt-1 and ET-1 (measured as CT-proET-1 [C-terminal pro-endothelin-1]), or increase free PlGF (placental growth factor) in 20 women with confirmed preeclampsia. Primary outcome was specified as the difference in sFlt-1, PlGF, or CT-proET-1 after 4 days of omeprazole versus 20 preeclamptic women not receiving omeprazole., Results: Mean maternal age was 30 years, and median gestational age was 30 +3 weeks. Baseline sFlt-1 levels were identical in both groups, and the same was true for PlGF or CT-proET-1. After 4 days, sFlt-1 levels remained similar in women not receiving omeprazole compared with women receiving omeprazole, while the levels of PlGF and CT-proET-1 also did not differ between groups. Women receiving omeprazole had a similar prolongation of pregnancy after inclusion compared with those in the nonomeprazole group (median 15 versus 14 days). Except for a higher neonatal intubation rate in the nonomeprazole group (31% versus 4%, P =0.02), there were no differences in maternal/perinatal complications. Finally, making use of the placenta perfusion model, we established that both omeprazole and its S-isomer, esomeprazole, when maternally applied, reached the fetal compartment (fetal-to-maternal ratio's 0.43-0.59), while only esomeprazole inhibited placental sFlt-1 release., Conclusions: Administration of omeprazole to women with confirmed preeclampsia does not alter their circulating levels of sFlt-1, PlGF, or ET-1, arguing against a role of this drug as a treatment for this syndrome.

Objectives: Preeclampsia is associated with hypertension in later life, but the underlying pathophysiological mechanisms remain uncertain. We aimed to explore whether the angiogenic markers soluble Fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) measured in women with preeclampsia could be associated with hypertension 1 year after delivery., Methods: This is a secondary analysis of a prospective cohort study, originally aimed to evaluate the use of sFlt-1/PlGF ratio to predict adverse outcome in women with (suspected) preeclampsia. Office blood pressure (BP) was evaluated at 1 year postpartum in women who had a confirmed diagnosis of preeclampsia within one week of biomarker measurement., Results: Eighty women were included with a median (interquartile range) gestational age (GA) at biomarker measurement of 30 (27-33) weeks. Twenty-three (29%) women had hypertension 1 year postpartum. These women showed higher median SBP during their pregnancy and lower GA at PE diagnosis compared to women without hypertension. Median PlGF levels were lower in women with hypertension 1 year postpartum compared to women without hypertension (23 vs. 48 pg/mL, p = 0.017), while no differences in sFlt-1 or sFlt-1/PlGF ratio were observed. Multivariable analysis adjusted for GA did not show significant association between PlGF (nor sFlt-1, sFlt-1/PlGF ratio) and hypertension 1 year postpartum (OR [95% CI] 0.9 [0.2-4.4], p = 0.97)., Conclusion: Our data indicate that sFlt-1, PlGF or their ratio measured during pregnancy are not suitable for the prediction of hypertension 1 year postpartum and hence guiding follow-up of women with previous preeclampsia., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Background We aimed to evaluate the value of inhibin A and PAPP-A2 (pregnancy-associated plasma protein-A2) as novel biomarkers in the prediction of preeclampsia-related complications and how they compare with angiogenic biomarkers. Methods and Results Making use of a secondary analysis of a prospective, multicenter, observational study, intended to evaluate the usefulness of sFlt-1 (soluble Fms-like tyrosine kinase-1)/PlGF (placental growth factor) ratio, we measured inhibin A and PAPP-A2 levels in 524 women with suspected/confirmed preeclampsia. Women had a median gestational age of 35 weeks (range, 20-41 weeks) while preeclampsia occurred in 170 (32%) women. Levels of inhibin A and PAPP-A2 were significantly increased in women with preeclampsia and in maternal perfusate of preeclamptic placentas. Inhibin A and PAPP-A2 (C-index = 0.73 and 0.75) significantly improved the prediction of maternal complications when added on top of the traditional criteria; gestational age, parity, proteinuria, and diastolic blood pressure (C-index = 0.60). PAPP-A2 was able to improve the C-index from 0.75 to 0.77 when added on top of the sFlt-1/PlGF ratio for the prediction of maternal complications. To discriminate fetal/neonatal complications on top of traditional criteria, inhibin A and PAPP-A2 showed additive value (C-index = 0.79 to 0.80 and 0.82, respectively) but their discriminative ability remained inferior to that of sFlt-1/PlGF ratio or PlGF. Interestingly, the PAPP-A2/PlGF ratio alone showed remarkable value to predict pregnancy complications, being superior to sFlt-1/PlGF ratio in the case of maternal complications. Conclusions Inhibin A and PAPP-A2 show significant potential to predict preeclampsia-related pregnancy complications and might prove beneficial on top of the angiogenic markers.

Preeclampsia (PE) is a pregnancy complication, featuring elevated blood pressure and proteinuria, with no appropriate treatment. Activation of the endothelin system has emerged as an important pathway in PE pathophysiology based on experimental PE models where endothelin receptor antagonists (ERAs) prevented or attenuated hypertension and proteinuria. Hence, ERAs have been suggested as potential therapy for PE. However, developmental toxicity studies in animals have shown severe teratogenic effects of ERAs, particularly craniofacial malformations. Nonetheless, sporadic cases of pregnancy in women using ERAs to treat pulmonary hypertension have been described. In this review we give an overview of cases describing ERA use in pregnancy and critically address their possible teratogenic effects. A systematic search in literature yielded 18 articles describing 39 cases with ERA exposure during human pregnancy. In most cases there was only exposure in the first trimester, but exposure later or throughout pregnancy was reported in five cases. Elective termination of pregnancy was performed in 12 pregnancies (31%), two ended in a spontaneous miscarriage (5%) and no fetal congenital abnormalities have been described in the remaining cases. These preliminary findings support the idea that ERA treatment for severe, early onset PE might be an option if applied later in pregnancy, when organogenesis is completed to avoid teratogenic risks. However, third trimester toxicology studies are warranted to evaluate drug safety. Subsequently, it remains to be established whether ERA treatment is effective for alleviating maternal symptoms, as demonstrated in preclinical PE models, allowing pregnancy prolongation without leading to adverse neonatal outcomes., (© 2019 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Objective: A sFlt-1/PlGF ratio of ≤38 has been reported to predict the absence of preeclampsia (PE) in singleton pregnancies. We evaluated whether a sFlt-1/PlGF ratio of ≤38 could be used to predict the absence of PE in twin pregnancies and maternal and fetal/neonatal complications., Methods: This is a secondary analysis of a prospective multicenter cohort study that enrolled women with suspected or confirmed PE with the aim of evaluating the use of the sFlt-1, PlGF and their ratio to predict maternal and fetal/neonatal complications. Twin and singleton pregnancies with clinically suspected or confirmed PE were matched for gestational age and parity. Blood samples were drawn at time of study entry, but serum values of sFlt-1 and PlGF and their ratio were determined postpartum., Results: Twenty-one women with twin and 21 with singleton gestations were included at a median gestational age of 30 weeks. At inclusion PE was diagnosed in 13 twin and 15 singleton pregnancies. In comparison to singleton control pregnancies, twin controls had a significantly higher sFlt-1 (6377 vs. 1732 pg/ml, p = 0.008), a higher sFlt-1/PlGF ratio 26 vs. 3 p = 0.361) and a lower PlGF (228 vs. 440 pg/ml p = 0.479). Compared to singleton preeclamptic pregnancies values of sFlt-1 (9134 vs. 8625 pg/ml) did not differ, whereas values of PlGF (185 vs. 33 pg/ml, p < 0.001) were higher and values of the ratio (49 vs. 158, p = 0.002) were lower in preeclamptic twin pregnancies. All preeclamptic patients with a singleton pregnancy had a ratio >38, but only 5 of the 13 patients with a preeclamptic twin pregnancy. Conversely, the ratio was ≤38 in 5 of the 6 control singleton, but in only 4 of the 8 control twin pregnancies. When classified according to a ratio ≤38 or >38 at inclusion, maternal complications occurred more frequently in patients with a ratio >38 both in singleton and twin pregnancies. In singleton pregnancies fetal/neonatal complications, except one admission to NICU, only occurred in patients with a ratio >38. In twin pregnancies fetal/neonatal complications occurred equally frequent in women with a ratio ≤38 or >38., Conclusion: Serum sFlt-1 levels are considerably higher in twin than in singleton control gestations. A sFlt-1/PlGF ratio of ≤38 to predict short-term absence of PE is not applicable to twin pregnancies in predicting either the absence of PE or the absence of adverse pregnancy outcomes., (Copyright © 2018. Published by Elsevier B.V.)

To assess the incremental value of a single determination of the serum levels of sFlt-1 (soluble Fms-like tyrosine kinase 1) and PlGF (placental growth factor) or their ratio, without using cutoff values, for the prediction of maternal and fetal/neonatal complications and pregnancy prolongation, 620 women with suspected/confirmed preeclampsia, aged 18 to 48 years, were included in a prospective, multicenter, observational cohort study. Women had singleton pregnancies and a median pregnancy duration of 34 (range, 20-41) weeks. Complications occurred in 118 women and 248 fetuses. The median duration between admission and delivery was 12 days. To predict prolongation, PlGF showed the highest incremental value ( R 2 =0.72) on top of traditional predictors (gestational age at inclusion, diastolic blood pressure, proteinuria, creatinine, uric acid, alanine transaminase, lactate dehydrogenase, and platelets) compared with R 2 =0.53 for the traditional predictors only. sFlt-1 showed the highest value to discriminate women with and without maternal complications (C-index=0.83 versus 0.72 for the traditional predictors only), and the sFlt-1/PlGF ratio showed the highest value to discriminate fetal/neonatal complications (C-index=0.86 versus 0.78 for the traditional predictors only). Applying previously suggested cutoff values for the sFlt-1/PlGF ratio yielded lower incremental values than applying continuous values. In conclusion, sFlt-1 and PlGF are strong and independent predictors for days until delivery along with maternal and fetal/neonatal complications on top of the traditional criteria. Their use as continuous variables (instead of applying cutoff values for different gestational ages) should now be tested in a prospective manner, making use of an algorithm calculating the risk of an individual woman with suspected/confirmed preeclampsia to develop complications., (© 2017 American Heart Association, Inc.)

Patients with preeclampsia display elevated placenta-derived sFlt-1 (soluble Fms-like tyrosine kinase-1) and endoglin levels and decreased placental growth factor levels. Proton pump inhibitors (PPIs) decrease trophoblast sFlt-1 and endoglin secretion in vitro. PPIs are used during pregnancy to combat reflux disease. Here, we investigated whether PPIs affect sFlt-1 in women with confirmed/suspected preeclampsia, making use of a prospective cohort study involving 430 women. Of these women, 40 took PPIs (6 esomeprazole, 32 omeprazole, and 2 pantoprazole) for 8 to 45 (median 29) days before sFlt-1 measurement. Measurements were only made once, at study entry between weeks 20 and 41 (median 33 weeks). PPI use was associated with lower sFlt-1 levels, with no change in placental growth factor levels, both when compared with all non-PPI users and with 80 gestational age-matched controls selected from the non-PPI users. No sFlt-1/placental growth factor alterations were observed in women using ferrous fumarate or macrogol while, as expected, women using antihypertensive medication displayed higher sFlt-1 levels and lower placental growth factor levels. The PPI use-associated decrease in sFlt-1 was independent of the application of antihypertensive drugs and also occurred when restricting our analysis to patients with hypertensive disease of pregnancy at study entry. PPI users displayed more cases with preexisting proteinuria, less gestational hypertension, and a lower number of neonatal sepsis cases. Finally, their plasma endoglin and endothelin-1 levels were lower while sFlt-1 levels correlated positively with both. In conclusion, PPI use associates with low sFlt-1, endoglin, and endothelin-1 levels, warranting prospective trials to investigate the therapeutic potential of PPIs in preeclampsia., (© 2017 American Heart Association, Inc.)

Pre-eclampsia (PE) is the most frequently encountered medical complication during pregnancy. It is characterized by a rise in systemic vascular resistance with a relatively low cardiac output and hypovolemia, combined with severe proteinuria. Despite the hypovolemia, renin-angiotensin system (RAS) activity is suppressed and aldosterone levels are decreased to the same degree as renin. This suggests that the RAS is not the cause of the hypertension in PE, but rather that its suppression is the consequence of the rise in blood pressure. Abnormal placentation early in pregnancy is widely assumed to be an important initial event in the onset of PE. Eventually, this results in the release of anti-angiogenic factors [in particular, soluble Fms-like tyrosine kinase-1 (sFlt-1)] and cytokines, leading to generalized vascular dysfunction. Elevated sFlt-1 levels bind and inactivate vascular endothelial growth factor (VEGF). Of interest, VEGF inhibition with drugs like sunitinib, applied in cancer patients, results in a PE-like syndrome, characterized by hypertension, proteinuria and renal toxicity. Both in cancer patients treated with sunitinib and in pregnant women with PE, significant rises in endothelin-1 occur. Multiple regression analysis revealed that endothelin-1 is an independent determinant of the hypertension and proteinuria in PE, and additionally a renin suppressor. Moreover, studies in animal models representative of PE, have shown that endothelin receptor blockers prevent the development of this disease. Similarly, endothelin receptor blockers are protective during sunitinib treatment. Taken together, activation of the endothelin system emerges as an important pathway causing the clinical manifestations of PE. This paper critically addresses this concept, taking into consideration both clinical and preclinical data, and simultaneously discusses the therapeutic consequences of this observation., (© The Author(s), 2016.)

Objective: To evaluate the additive value of the sFlt-1/PlGF ratio for diagnosing preeclampsia (PE) and predicting prolongation of pregnancy and adverse outcome in a cohort of women with PE or at high risk of PE., Study Design: Patients with suspected or confirmed clinical PE were recruited. At time of inclusion blood for measurement of sFlt-1and PlGF was taken. Values were determined after delivery. A cut-off ratio of ≥85 was defined as a positive test., Results: A total of 107 patients were included. Of the patients, 62 (58%) met the clinical criteria of PE at time of blood sampling. In 10% of these patients (n=6) the ratio was <85 (false negative), whereas in 7% (n=3) of patients without clinical PE the ratio was ≥85 (false positive), resulting in positive and negative predictive values of 95% and 88% respectively. One patient with false positive ratio developed superimposed PE and 2 developed gestational hypertension, and adverse outcome occurred in all three. An adverse pregnancy outcome was only encountered in 1 of the 6 patients with a false negative ratio. Using a binary regression model with adjustment for gestational age <34 weeks, the adverse outcome risk was 11 times increased on the basis of clinical PE, and 30 times on the basis of an elevated ratio (P=0.036)., Conclusion: The additive value of an increased ratio for diagnosing PE is limited since most patients with clinical PE also have a positive ratio. However, an elevated ratio is superior to the clinical diagnosis of PE for predicting an adverse pregnancy outcome. Furthermore, irrespective of clinical PE, a low ratio is inversely correlated with prolongation of pregnancy., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Purpose of Review: Preeclampsia is a systemic, pregnancy-related disorder featuring hypertension and proteinuria arising from placental overproduction of soluble FMS-like tyrosine kinase-1, resulting in an antiangiogenic state because of the inhibition of the vascular endothelial growth factor (VEGF) family. Similarly, antiangiogenetic treatment aimed at targeting VEGF in patients with cancer is associated with a preeclampsia-like syndrome. In this study we discuss the pathophysiological role of an activated endothelin system in both conditions., Recent Findings: In different experimental forms of preeclampsia, in clinical preeclampsia, and in cancer patients on antiangiogenic treatment, activation of the endothelin axis invariably occurs and this activation is directly related to the circulating level of sFlt-1 or the intensity of antiangiogenic treatment. Administration of endothelin receptor A-selective or dual endothelin receptor antagonists can prevent or largely attenuate the hypertension and proteinuria in experimental forms of preeclampsia, as well as in rats exposed to receptor tyrosine-kinase inhibitors targeting VEGF-signaling, supporting the concept that activation of the endothelin axis plays a key role in the manifestations of these disorders., Summary: Activation of the endothelin axis has now emerged as a crucial player in the manifestations of preeclampsia and following antiangiogenic treatment. As a consequence, blockade of the endothelin system may be considered as a treatment option both in preeclampsia and in antiangiogenesis-induced hypertension and renal toxicity in patients with cancer.

Women with preeclampsia display low renin-angiotensin-aldosterone system activity and a high antiangiogenic state, the latter characterized by high levels of soluble Fms-like tyrosine kinase (sFlt)-1 and reduced placental growth factor levels. To investigate whether renin-angiotensin-aldosterone system suppression in preeclampsia is because of this disturbed angiogenic balance, we measured mean arterial pressure, creatinine, endothelin-1 (ET-1), and renin-angiotensin-aldosterone system components in pregnant women with a high (≥85; n=38) or low (<85; n=65) soluble Fms-like tyrosine kinase-1/placental growth factor ratio. Plasma ET-1 levels were increased in women with a high ratio, whereas their plasma renin activity and plasma concentrations of renin, angiotensinogen, and aldosterone were decreased. Plasma renin activity-aldosterone relationships were identical in both the groups. Multiple regression analysis revealed that plasma renin concentration correlated independently with mean arterial pressure and plasma ET-1. Plasma ET-1 correlated positively with soluble Fms-like tyrosine kinase-1 and negatively with plasma renin concentration, and urinary protein correlated with plasma ET-1 and mean arterial pressure. Despite the lower plasma levels of renin and angiotensinogen in the high-ratio group, their urinary levels of these components were elevated. Correction for albumin revealed that this was because of increased glomerular filtration. Subcutaneous arteries obtained from patients with preeclampsia displayed an enhanced, AT2 receptor-mediated response to angiotensin II. In conclusion, a high antiangiogenic state associates with ET-1 activation, which together with the increased mean arterial pressure may underlie the parallel reductions in renin and aldosterone in preeclampsia. Because ET-1 also was a major determinant of urinary protein, our data reveal a key role for ET-1 in the pathogenesis of preeclampsia. Finally, the enhanced angiotensin responsiveness in preeclampsia involves constrictor AT2 receptors., (© 2015 American Heart Association, Inc.)