Serum Soluble Fms-like Tyrosine Kinase-1 Research Articles

Physalis angulata leaf extract ameliorates L-NG-nitroarginine methyl ester (L-NAME)-induced preeclampsia symptoms in rats through improved endothelial progenitor cells and endothelial cells due to reduced antiangiogenic factor and oxidative stress

Background: This study aimed to determine the ameliorative effects of Physalis angulata leaf extract on L-NG-nitroarginine methyl ester (L-NAME)-induced preeclampsia symptoms in rats. Methods: Phytochemical analysis of the extract was performed with liquid chromatography-high resolution mass spectrometry (LC-HRMS). Pregnant Wistar rats were randomly divided into five groups (n=6). Preeclampsia rats were injected with L-NAME on gestation days 9 to 18 (G9–G18), while sham rats were injected with the same vehicle volume. Three groups of preeclampsia rats were orally supplemented with the extract at doses of 500, 1500, and 2500 mg/kg body weight/day on G12–G18. The tail-cuff method measured blood pressures. Spectrophotometry determined urine protein levels. Serum soluble fms-like tyrosine kinase (sFlt)-1 levels were evaluated using an enzyme-linked immunosorbent assay (ELISA). Serum and placental malondialdehyde (MDA) levels, superoxide dismutase (SOD) activities, and nitric oxide (NO) levels were measured by colorimetry. Immunohistochemistry was used to determine tail artery endothelial nitric oxide synthase (eNOS), placental eNOS, and placental hypoxia-inducible factor (HIF)-1α expressions. Circulating angiogenic cells (CACs) and endothelial colony-forming cells (ECFCs) were counted using flow cytometry. Results: L-NAME injection increased blood pressures, 24-h total urine protein level, serum sFlt-1 level, serum and placental MDA levels, percentages of CACs and ECFCs, and placental HIF-1α expression. It also decreased serum and placental SOD activities, serum NO level, tail artery and placental eNOS expressions compared to the sham group. Physalis angulata leaf extract administration lowered blood pressures, urine protein level, sFlt-1 level, MDA levels, percentages of CACs and ECFCs, and placental HIF-1α expression. The extract increased SOD activities, NO level, tail artery and placental eNOS expressions compared to the preeclampsia group. Conclusions: Physalis angulata leaf extract reduces antiangiogenic factor and oxidative stress. It also enhances eNOS/NO signaling. Thus, it improves EPC and endothelial cell function and reverses L-NAME-induced hypertension and proteinuria in preeclampsia rats.

Comparison of ophthalmic artery Doppler with PlGF and sFlt-1/PlGF ratio at 35-37 weeks' gestation in prediction of imminent pre-eclampsia.

To compare the predictive performance for delivery with pre-eclampsia (PE) at < 3 weeks and at any stage after assessment at 35 + 0 to 36 + 6 weeks' gestation of serum placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1)/PlGF ratio with that of a competing-risks model utilizing maternal risk factors, mean arterial pressure (MAP) and ophthalmic artery peak systolic velocity (PSV) ratio. This was a prospective observational study of women attending for a routine hospital visit at 35 + 0 to 36 + 6 weeks' gestation. This visit included recording of maternal demographic characteristics and medical history, ultrasound examination of fetal anatomy and growth, assessment of flow velocity waveforms from the maternal ophthalmic arteries and measurement of MAP, serum PlGF and serum sFlt-1. The performance of screening for delivery with PE at < 3 weeks and at any time after the examination was assessed using areas under the receiver-operating-characteristics curves and detection rates (DRs), at a 10% false-positive rate (FPR). McNemar's test was used to compare DRs, at a 10% FPR, between screening by PlGF concentration, the sFlt-1/PlGF concentration ratio and the competing-risks model utilizing maternal risk factors, MAP and ophthalmic artery PSV ratio. Model-based estimates of screening performance for different methods of screening were also produced. The study population of 2338 pregnancies contained 75 (3.2%) cases that developed PE, including 30 (1.3%) that delivered with PE at < 3 weeks from assessment, and 2263 cases unaffected by PE. The DR of PE at < 3 weeks from assessment, at a 10% FPR, of sFlt-1/PlGF ratio (70.0% (95% CI, 50.6-85.3%)) was superior to that of PlGF (50.0% (95% CI, 31.3-68.7%)) or PSV ratio (56.7% (95% CI, 37.4-74.5%)) but inferior to that of the combination of maternal risk factors, MAP multiples of the median (MoM) and PSV ratio delta (96.7% (95% CI, 82.8-99.9%)). Similarly, the DR of PE at any stage after assessment of sFlt-1/PlGF ratio (62.7% (95% CI, 50.7-73.6%)) was superior to that of PlGF (52.0% (95% CI, 40.2-63.7%)) or PSV ratio (41.3% (95% CI, 30.1-53.3%)) but inferior to that of the combination of maternal risk factors, MAP MoM and PSV ratio delta (78.7% (95% CI, 67.7-87.3%)). The empirical results for DR at a 10% FPR were consistent with the modeled results, both for delivery with PE at < 3 weeks and at any time after assessment. Ophthalmic artery Doppler in combination with maternal risk factors and blood pressure could potentially replace measurement of PlGF and sFlt-1/PlGF ratio in the prediction of imminent PE. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

STATIN trial: predictive performance of competing-risks model in screening for pre-eclampsia at 35-37 weeks' gestation.

To examine the predictive performance of a previously reported competing-risks model of screening for pre-eclampsia (PE) at 35-37 weeks' gestation by combinations of maternal risk factors, mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI), serum placental growth factor (PlGF) and serum soluble fms-like tyrosine kinase-1 (sFlt-1) in a validation dataset derived from the screened population of the STATIN study. This was a prospective third-trimester multicenter study of screening for PE in singleton pregnancies by means of a previously reported algorithm that combines maternal risk factors and biomarkers. Women in the high-risk group were invited to participate in a trial of pravastatin vs placebo, but the trial showed no evidence of an effect of pravastatin in the prevention of PE. Patient-specific risks of delivery with PE were calculated using the competing-risks model, and the performance of screening for PE by maternal risk factors alone and by various combinations of risk factors with MAP, UtA-PI, PlGF and sFlt-1 was assessed. The predictive performance of the model was examined by, first, the ability of the model to discriminate between the PE and no-PE groups using the area under the receiver-operating-characteristics curve (AUC) and the detection rate at a fixed false-positive rate of 10%, and, second, calibration by measurements of calibration slope and calibration-in-the-large. The study population of 29 677 pregnancies contained 653 that developed PE. In screening for PE by a combination of maternal risk factors, MAP, PlGF and sFlt-1 (triple test), the detection rate at a 10% false-positive rate was 79% (95% CI, 76-82%) and the results were consistent with the data used for developing the algorithm. Addition of UtA-PI did not improve the prediction provided by the triple test. The AUC for the triple test was 0.923 (95% CI, 0.913-0.932), demonstrating very high discrimination between affected and unaffected pregnancies. Similarly, the calibration slope was 0.875 (95% CI, 0.831-0.919), demonstrating good agreement between the predicted risk and observed incidence of PE. The competing-risks model provides an effective and reproducible method for third-trimester prediction of term PE. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Maternal Cardiac Function at Midgestation and Development of Preeclampsia

BackgroundPreeclampsia (PE) is an independent risk factor for adverse maternal cardiovascular outcomes. The role of maternal cardiac function in the pathophysiology of PE remains unclear. ObjectivesThis study sought to describe differences in cardiac function at midgestation between women who develop PE and those with uncomplicated pregnancy and to establish whether routine cardiac assessment at midgestation can improve performance of screening for PE achieved by established biomarkers. MethodsMean arterial pressure was measured, medical history was obtained, and left ventricular (LV) systolic and diastolic functions were assessed using standard echocardiography and speckle tracking imaging. Uterine artery pulsatility index and serum placental growth factor and soluble fms-like tyrosine kinase-1 were measured. ResultsIn 4,795 pregnancies, 126 (2.6%) developed PE. Following multivariable analysis, peripheral vascular resistance was significantly higher and LV global longitudinal systolic strain, ejection fraction, cardiac output, and left atrial area were mildly lower in women who developed PE compared to those who did not. There was a weak association between maternal cardiovascular indices and biomarkers of placental perfusion and function. Cardiac indices did not improve the performance of screening for PE on top of maternal risk factors, mean arterial pressure, and biomarkers of placental perfusion and function. ConclusionWomen who develop PE have an increase in peripheral vascular resistance and a mild reduction in LV functional cardiac indices long before PE development. However, cardiac indices do not improve the performance of screening for PE; thus, their routine clinical use is not advocated.

Mortality and Postdischarge Acute Care Utilization for Cardiovascular Conditions at Safety-Net Versus Non–Safety-Net Hospitals

Preeclampsia (PE) is an independent risk factor for adverse maternal cardiovascular outcomes. The role of maternal cardiac function in the pathophysiology of PE remains unclear.This study sought to describe differences in cardiac function at midgestation between women who develop PE and those with uncomplicated pregnancy and to establish whether routine cardiac assessment at midgestation can improve performance of screening for PE achieved by established biomarkers.Mean arterial pressure was measured, medical history was obtained, and left ventricular (LV) systolic and diastolic functions were assessed using standard echocardiography and speckle tracking imaging. Uterine artery pulsatility index and serum placental growth factor and soluble fms-like tyrosine kinase-1 were measured.In 4,795 pregnancies, 126 (2.6%) developed PE. Following multivariable analysis, peripheral vascular resistance was significantly higher and LV global longitudinal systolic strain, ejection fraction, cardiac output, and left atrial area were mildly lower in women who developed PE compared to those who did not. There was a weak association between maternal cardiovascular indices and biomarkers of placental perfusion and function. Cardiac indices did not improve the performance of screening for PE on top of maternal risk factors, mean arterial pressure, and biomarkers of placental perfusion and function.Women who develop PE have an increase in peripheral vascular resistance and a mild reduction in LV functional cardiac indices long before PE development. However, cardiac indices do not improve the performance of screening for PE; thus, their routine clinical use is not advocated.

Association between serum soluble fms-like tyrosine kinase-1 and the central choroidal thickness during pregnancy: a prospective study

ObjectiveTo investigate the association between serum soluble fms-like tyrosine kinase-1 (sFlt-1) and the choroidal structure during the pregnancy.Methods and analysisThis prospective study enrolled 24 eyes of 12 consecutive healthy pregnant...

Mean arterial pressure for predicting preeclampsia in Asian women: a longitudinal cohort study

ObjectivePrevious studies suggested mean arterial pressure (MAP) had moderate predictive values in the first and second trimesters for the prediction of preeclampsia. However, the performance of MAP in Asian women...

Expression and significance of serum soluble fms-like tyrosine kinase 1 (sFlt-1), CXC chemokine ligand 16 (CXCL16), and lipocalin 2 (LCN-2) in pregnant women with preeclampsia.

To explore the value of serum soluble fms-like tyrosine kinase 1 (sFlt-1), CXC chemokine ligand 16 (CXCL16), and lipocalin 2 (LCN-2) in the diagnosis and grading of preeclampsia (PE). A total of 186 patients with PE diagnosed and treated in our hospital were included. According to the disease severity, the patients were divided into the mild PE group (99 cases) and the severe PE group (87 cases). A total of 72 healthy pregnant women who underwent antenatal care were selected as the healthy control group. The levels of serum sFlt-1, CXCL16, and LCN-2 before medication were compared among the patients, and the diagnosis and grading value of the above 3 indicators were analyzed. For PE patients vs. healthy controls, the levels of sFlt-1 (132.71±14.49 vs. 68.43±9.28 µg/L), CXCL16 (2.15±0.35 vs. 0.61±0.12 µg/L), and LCN-2 (70.81±8.25 vs. 19.22±3.14 µg/L) were all significantly higher in PE patients than in the healthy controls (P<0.05). For severe PE vs. mild PE, the levels of sFlt-1 (142.16±20.23 vs. 124.41±10.36 µg/L), CXCL16 (2.87±0.59 vs. 1.51±0.28 µg/L), and LCN-2 (90.76±10.16 vs. 53.27±6.19 µg/L) in the severe PE group were higher than those in the mild PE group (P<0.05). Receiver operating characteristic curve (ROC) analysis showed that when the cut-off values of sFlt-1, CXCL16, and LCN-2 were 99.65, 1.36, and 0.84 µg/L, respectively, the diagnostic efficacy of PE was the highest. With these cut-off values, the diagnostic sensitivities of sFlt-1, CXCL16, and LCN-2 were 86.67%, 73.33%, and 93.33%, respectively. The specificities of sFlt-1, CXCL16, and LCN-2 were 80.00%, 86.67%, and 60.00%, respectively. The areas under the curves (AUC) of sFlt-1, CXCL16, and LCN-2 were 0.764, 0.769, and 0.831, respectively. When the cut-off values for sFlt-1, CXCL16, and LCN-2 were 135.16, 2.24, and 70.38 µg/L, respectively, the efficacy was the highest in distinguishing mild and severe PE. With these cut-off values, the AUC values of sFlt-1, CXCL16, and LCN-2 were 0.837, 0.808, and 0.869, respectively. sFlt-1, CXCL16, and LCN-2 have certain significance in the diagnosis and grading of PE. Among them, LCN-2 has the highest correlation with the diagnosis and grading of PE.

SFlt-1, Not PlGF, Is Related to Twin Gestation Choronicity in the First and Third Trimesters of Pregnancy.

Background: Preeclampsia occurs more often in dichorionic than in monochorionic twin pregnancy. We hypothesize that serum concentrations of biomarkers: placental growth factor (PlGF), serum soluble fms-like tyrosine kinase-1 (sFlt-1), and endoglin (Eng) differ between monochorionic and dichorionic twin pregnancies. Methods: A prospective observational study including 43 monochorionic and 36 dichorionic twin gestation was conducted. Blood samples were collected twice from all participants: between 11 + 0 and 13 + 6 and between 32 + 0 and 34 + 0 weeks of gestation. PlGF, sFlt-1 and Eng were measured using immnunoenzymatic assays. Results: We found a significantly higher concentration of sFlt-1 in dichorionic in comparison to monochorionic pregnancies in both the first and third trimesters. PlGF and sEng levels did not differ between mono- and dichorionic gestation in both study periods. sFlt-1 level was related to twin gestation chorionicity, while PlGF expression was not. PlGF, sFlt-1 and sEng concentrations increased significantly during gestation and were much higher in the third trimester compared to the values measured in the first trimester. Conclusions: Angiogenic biomarkers expression differ between dichorionic and monochorionic twin pregnancy. The sFlt-1 level is related to chorionicity of a twin gestation.

Model for Early Prediction of Preeclampsia: A Nested Case Controlled Study in Indian Women.

Preeclampsia (PE) affects 5-7% of the pregnancies worldwide, and is one of the most dreaded disorders of pregnancy contributing to maternal and neonatal mortality. PE is mostly presented in the third trimester of pregnancy. Here, we used serum placental growth factor (PIGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) to develop a model for predicting PE in Indian women in early second trimester. In this case-control study, a total 1452 healthy pregnant women were recruited. Blood samples were collected at the following gestational weeks (GWs), 12-20 (GW1), 21-28 (GW2) and 29-term (GW3), and post-delivery. Body mass index (BMI) was calculated by anthropometric measurements. Serum sFlt-1, PIGF and VEGF were analyzed by ELISA. A predictive model for PE was developed using multivariable logistic regression analysis. In PE cases, serum PlGF and VEGF levels were significantly lower at each GW, while serum sFlt-1 was lower only at GW1, relative to age-matched controls, (n = 132/group). Age-matched comparison between PE cases and controls indicated that sFlt-1 was associated with decreased PE outcome (Odds ratio. OR = 0.988, CI = 0.982-0.993), whereas sFlt-1/PlGF ratio (OR = 1.577, CI = 1.344-1.920) and BMI (OR = 1.334, CI = 1.187-1.520) were associated with increased PE outcome. Logistic regression was used to develop a predictive model for PE at GW1. Using testing dataset, model was externally validated which resulted in 88% accuracy in predicting PE cases at 0.5 probability cutoff. Prediction model using sFlt-1, sFlt-1/PlGF ratio and BMI may be useful to predict PE as early as 12-20weeks in women with optimal sensitivity and specificity.

Pravastatin Versus Placebo in Pregnancies at High Risk of Term Preeclampsia.

Effective screening for term preeclampsia is provided by a combination of maternal factors with measurements of mean arterial pressure, serum placental growth factor, and serum soluble fms-like tyrosine kinase-1 at 35 to 37 weeks of gestation, with a detection rate of ≈75% at a screen-positive rate of 10%. However, there is no known intervention to reduce the incidence of the disease. In this multicenter, double-blind, placebo-controlled trial, we randomly assigned 1120 women with singleton pregnancies at high risk of term preeclampsia to receive pravastatin at a dose of 20 mg/d or placebo from 35 to 37 weeks of gestation until delivery or 41 weeks. The primary outcome was delivery with preeclampsia at any time after randomization. The analysis was performed according to intention to treat. A total of 29 women withdrew consent during the trial. Preeclampsia occurred in 14.6% (80 of 548) of participants in the pravastatin group and in 13.6% (74 of 543) in the placebo group. Allowing for the effect of risk at the time of screening and participating center, the mixed-effects Cox regression showed no evidence of an effect of pravastatin (hazard ratio for statin/placebo, 1.08 [95% CI, 0.78-1.49]; P=0.65). There was no evidence of interaction between the effect of pravastatin, estimated risk of preeclampsia, pregnancy history, adherence, and aspirin treatment. There was no significant between-group difference in the incidence of any secondary outcomes, including gestational hypertension, stillbirth, abruption, delivery of small for gestational age neonates, neonatal death, or neonatal morbidity. There was no significant between-group difference in the treatment effects on serum placental growth factor and soluble fms-like tyrosine kinase-1 concentrations 1 and 3 weeks after randomization. Adherence was good, with reported intake of ≥80% of the required number of tablets in 89% of participants. There were no significant between-group differences in neonatal adverse outcomes or other adverse events. Pravastatin in women at high risk of term preeclampsia did not reduce the incidence of delivery with preeclampsia. Registration: URL: https://www.isrctn.com; Unique identifier ISRCTN16123934.

Effect of esomeprazole on maternal serum soluble fms-like tyrosine kinase-1 and endoglin in patients with early-onset preeclampsia

Objective: This study evaluates the effect of esomeprazole on the maternal serum levels of soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng) in patients with early-onset preeclampsia.Methods: A randomized, double-blind, placebo-controlled trial was carried out in a tertiary University hospital between March 2018, and September 2019 (Clinical Trials.Gov: NCT03213639). The study included women between 28 and 31+6 weeks gestational age who had been diagnosed as preeclampsia without severe features. They were randomly assigned in a 1:1 ratio into an esomeprazole group, which received esomeprazole 40 mg orally once a day, and a placebo group, which received one placebo tablet daily. Blood samples were obtained to assess levels of serum sFlt-1and sEng using ELISA testing. The primary outcome was the difference between the mean serum level of sFlt-1 and sEng at the start of treatment and at the termination of pregnancy in both groups.Results: Eighty-eight patients were randomly assigned into both groups (44 in each). No statistically significant difference was found in the levels of sFlt-1 between both groups at admission and termination of pregnancy. The number of days of treatment for the esomeprazole group was slightly longer than the placebo group (11.4±9.4 vs. 10.3±6.3 days, P=0.515). No statistically significant difference in the rate of maternal and fetal complications occurred between the two groups. No side effects from the study medications were reported.Conclusions: Esomeprazole, at the dosage used in this study did not effectively lower the serum levels of sFlt-1 and sEng in patients with early-onset preeclampsia. Furthermore, it did not prolong the duration of pregnancy, nor did it decrease maternal or fetal complications.

Slowing of fetal growth and elevated maternal serum sFLT1:PlGF are associated with early term spontaneous labor

BackgroundThe physiological control of human parturition at term is unknown.ObjectiveThis study aimed to test the hypothesis that slowing of fetal growth or elevated maternal serum levels of markers of placental hypoxia in late gestation will be associated with earlier term labor.Study DesignWe observed 2208 women having first births and performed serial blinded ultrasonography and immunoassay of soluble fms-like tyrosine kinase-1 and placenta growth factor. We estimated the probability of spontaneous delivery from 37 weeks of gestational age concerning (1) fetal growth between 20 and 36 weeks of gestational age and (2) the maternal serum soluble fms-like tyrosine kinase-1–to–placenta growth factor ratio measured at approximately 36 weeks of gestational age. Data were analyzed using logistic regression and Cox regression.ResultsFetal size at 36 weeks of gestational age was not independently associated with the timing of delivery at term. However, there was an inverse relationship between fetal growth between 20 weeks of gestational age and 36 weeks of gestational age and the probability of spontaneous labor at 37 to 38 weeks’ gestation (hazard ratio [95% confidence interval] for a 50 percentile increase in abdominal circumference growth velocity, 0.60 [0.47–0.78]; P=.0001). This association was weaker at 39 to 40 weeks’ gestation (0.83 [0.74–0.93]; P=.0013), and there was no association at ≥41 weeks’ gestation. Very similar associations were observed for estimated fetal weight growth velocity. There was a positive relationship between soluble fms-like tyrosine kinase-1–to–placenta growth factor ratio and the probability of spontaneous labor at 37 to 38 weeks’ gestation (hazard ratio [95% confidence interval] for a 50 percentile increase in soluble fms-like tyrosine kinase-1–to–placenta growth factor ratio, 3.05 [2.32–4.02]; P<.0001). This association was weaker at 39 to 40 weeks’ gestation (1.46 [1.30–1.63]; P<.0001), and there was no association at ≥41 weeks’ gestation. Adjustment for maternal characteristics was without material effect on any of these associations.ConclusionSlowing of fetal growth and biomarkers of placental insufficiency were associated with an increased probability of early onset of spontaneous term labor. We speculated that progressive placental insufficiency may be a physiological phenomenon that occurs with advancing gestational age near and at term and promotes the initiation of labor.

Real-world data on the clinical use of angiogenic factors in pregnancies with placental dysfunction

In routine clinical practice, angiogenic factor measurement can facilitate prediction and diagnosis of preeclampsia and other manifestations of placental dysfunction (eg, intrauterine growth restriction). This real-world data analysis investigated the utility of soluble fms-like tyrosine kinase-1 and placental growth factor for preeclampsia and placental dysfunction. Blood serum soluble fms-like tyrosine kinase-1 and placental growth factor were measured using Elecsys soluble fms-like tyrosine kinase-1 and placental growth factor immunoassays (cobas e analyzer; Roche Diagnostics). Overall, 283 unselected singleton pregnancies with ≥1 determination of soluble fms-like tyrosine kinase-1-to-placental growth factor ratio were included. Distribution of the ratio at admission was normal (<38 [58.7%]), intermediate (38-85/110 [19.1%]), or pathologic (>85/110 [22.3%]). Overall, 15.5% had preeclampsia or hemolysis, elevated liver enzyme levels, and low platelet count, and 15.5% of women had intrauterine growth restriction. Increasing soluble fms-like tyrosine kinase-1-to-placental growth factor ratio was associated with an increase in priority of delivery (r=0.38; P<.001). The percentage of patients who developed preeclampsia by soluble fms-like tyrosine kinase-1-to-placental growth factor ratio at admission was 5.4% (normal), 7.4% (intermediate), and 49.2% (pathologic). The greatest difference in soluble fms-like tyrosine kinase-1-to-placental growth factor ratio from admission to birth occurred in pathologic pregnancies (171.12 vs 39.84 for normal pregnancies). Soluble fms-like tyrosine kinase-1-to-placental growth factor ratio correlated inversely with gestational age at delivery, birthweight, and prolongation time. There was no significant relation between the prolongation period or the gestational age at first determination to the increase of soluble fms-like tyrosine kinase-1 and placental growth factor between admission and delivery (ΔQ). This analysis used a real-world approach to investigate the clinical utility of the soluble fms-like tyrosine kinase-1-to-placental growth factor ratio in placental dysfunction. Confirming the results of prospective studies, we observed a positive correlation between soluble fms-like tyrosine kinase-1-to-placental growth factor ratio and severity of placental dysfunction and a negative association with time to delivery. In a real-world setting, the soluble fms-like tyrosine kinase-1-placental growth factor ratio stratifies patients with normal outcome and outcome complicated by placental dysfunction.

Angiogenic markers and their longitudinal change for predicting adverse outcomes in pregnant women with chronic hypertension

Women with chronic hypertension are at increased risk for adverse maternal and perinatal outcomes. Maternal serum angiogenic markers, such as soluble fms-like tyrosine kinase 1 and placental growth factor, can be used to triage women with suspected preeclampsia. However, data about these markers in pregnant women with chronic hypertension are scarce. We aimed to evaluate the predictive accuracy of maternal serum levels of soluble fms-like tyrosine kinase 1, placental growth factor, and their ratio for predicting adverse maternal and perinatal outcomes in women with chronic hypertension. This was a retrospective analysis of prospectively collected data from January 2013 to October 2019 at the University of Vienna Hospital, Vienna, Austria. The inclusion criteria were pregnant women with chronic hypertension and suspected preeclampsia. The primary outcome of this study was the prognostic performance of angiogenic markers for the prediction of adverse maternal and perinatal outcomes in pregnant women with chronic hypertension. The accuracy of angiogenic markers for predicting adverse composite outcomes was assessed with a binomial logistic regression. The accuracy of each marker was assessed using receiver operating characteristics curves and area under the curve values. Area under the curve values were compared using De Long's test. Of the 145 included women with chronic hypertension and suspected superimposed preeclampsia, 26 (17.9%) women developed complications (ie, composite adverse maternal or fetal outcomes) within 1 week of assessment (average gestational age at assessment, 29.9 weeks) and 35 (24.1%) developed complications at any time (average gestational age at assessment, 30.1 weeks). In women who developed complications at any time, the median maternal serum soluble fms-like tyrosine kinase-1 to placental growth factor ratio was 149.4 (interquartile range, 64.6-457.4) compared with 8.0 (interquartile range, 3.37-41.2) for women who did not develop complications (P<.001). The area under the curve values for the maternal serum soluble fms-like tyrosine kinase-1 to placental growth factor ratio Z-score (0.95; 95% confidence interval, 0.90-0.99) and placental growth factor level Z-score (0.94; 95% confidence interval, 0.88-0.99) for predicting complications within 1 week of assessment were very high. The area under the curve values for new-onset edema (0.61; 95% confidence interval, 0.52-0.70), proteinuria (0.62; 95% confidence interval, 0.52-0.71), high mean arterial pressure (0.52; 95% confidence interval, 0.50-0.54), and other symptoms of preeclampsia (0.57; 95% confidence interval, 0.49-0.65) were all significantly lower than for the angiogenic markers (P<.001 for all). Women who had an angiogenic imbalance and/or proteinuria had the highest rate of complications (28/57, 49.1%). The rate of complications in women with an angiogenic imbalance and/or proteinuria was significantly higher than in women with either proteinuria, other symptoms, or intrauterine growth restriction in the absence of an angiogenic imbalance (49.1% vs 16.7%; P=.039). The highest positive and negative predictive values for predicting adverse outcomes were demonstrated by an angiogenic imbalance and/or proteinuria criteria with a positive predictive value of 49.1% (95% confidence interval, 50.4%-57.9%) and a negative predictive value of 92% (95% confidence interval, 85.5%-95.8%). Longitudinal changes in measurements of the gestational age-corrected ratio of soluble fms-like tyrosine kinase-1 to placental growth factor up to the last measurement had a significantly higher area under the curve value than the last measurement alone (area under the curve, 0.95; 95% confidence interval, 0.92-0.99 vs 0.87; 95% confidence interval, 0.79-0.95; P=.024) CONCLUSION: Maternal serum angiogenic markers are superior to clinical assessment in predicting adverse maternal and perinatal outcomes in pregnant women with chronic hypertension. Repeated measurements of the ratio of soluble fms-like tyrosine kinase-1 to placental growth factor seems beneficial given the better predictive accuracy compared with a single measurement alone. The use of angiogenic makers should be implemented in clinical management guidelines for pregnant women with chronic hypertension.

Maternal cardiac function at 19-23 weeks' gestation in prediction of pre-eclampsia.

First, to examine the factors from maternal characteristics and medical history that affect maternal cardiovascular indices, and, second, to examine the potential value of maternal cardiovascular indices at 19-23 weeks' gestation, on their own and in combination with maternal factors and the established biomarkers of pre-eclampsia (PE), including uterine artery pulsatility index (UtA-PI), mean arterial pressure (MAP), serum placental growth factor (PlGF) and serum soluble fms-like tyrosine kinase-1 (sFlt-1), in the prediction of subsequent development of PE. This was a prospective observational study in women attending for a routine hospital visit at 19 + 1 to 23 + 3 weeks' gestation. This visit included recording of maternal demographic characteristics and medical history, assessment of maternal E/A ratio, E/e' ratio, myocardial performance index, global longitudinal systolic strain, left ventricular ejection fraction, peripheral vascular resistance, left ventricular cardiac output and left ventricular mass indexed for body surface area, and measurement of MAP, UtA-PI, serum PlGF and serum sFlt-1. The measurements of the eight maternal cardiac indices were standardized to remove the effects of maternal characteristics and elements from the medical history. The competing-risks model was used to estimate the individual patient-specific risks of delivery with PE and determine the detection rate, at a 10% false-positive rate, in screening by a combination of maternal demographic characteristics and medical history with biomarkers. The study population of 2853 pregnancies contained 76 (2.7%) that developed PE. In pregnancies that subsequently developed PE, there was evidence of altered cardiac geometry, impaired myocardial function and increased peripheral vascular resistance. All maternal cardiovascular indices were affected significantly by maternal demographic characteristics and elements of medical history known to be associated with an increased risk for subsequent development of PE. After adjustment for maternal demographic characteristics and medical history, the only cardiovascular index that was affected significantly by subsequent development of PE was peripheral vascular resistance. Peripheral vascular resistance multiples of the median (MoM) was correlated with MAP MoM, which is not surprising because blood pressure is involved in the estimation of both. There were weak correlations between several cardiovascular indices and MAP MoM, but none was correlated with MoM values of UtA-PI, PlGF or sFlt-1. The performance of screening for delivery with PE at < 37 weeks' gestation or delivery with PE at any gestational age in screening by maternal demographic characteristics and medical history or combinations of maternal factors with MAP, UtA-PI, PlGF and sFlt-1 was not improved by the addition of peripheral vascular resistance. Assessment of maternal cardiovascular function provides information on the pathophysiology of PE but is not useful in the prediction of PE. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Ophthalmic artery Doppler in combination with other biomarkers in prediction of pre-eclampsia at 35-37 weeks' gestation.

To examine the potential value of maternal ophthalmic artery Doppler at 35-37 weeks' gestation in combination with the established biomarkers of pre-eclampsia (PE), including mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI), serum placental growth factor (PlGF) and serum soluble fms-like tyrosine kinase-1 (sFlt-1), in the prediction of subsequent development of PE. This was a prospective observational study in women attending for a routine hospital visit at 35 + 0 to 36 + 6 weeks' gestation. This visit included recording of maternal demographic characteristics and medical history, ultrasound examination for fetal anatomy and growth, assessment of flow velocity waveforms from the maternal ophthalmic arteries, and measurement of MAP, UtA-PI, serum PlGF and serum sFlt-1. The competing-risks model was used to estimate the individual patient-specific risks of delivery with PE at any time and at < 3 weeks after assessment by a combination of maternal demographic characteristics and medical history with biomarkers. The area under the receiver-operating-characteristics curve and detection rate (DR) of delivery with PE, at a 10% false-positive rate (FPR), in screening by combinations of maternal factors with ophthalmic artery second to first peak of systolic velocity ratio (PSV ratio), MAP, UtA-PI, serum PlGF and serum sFlt-1 were determined. The modeled performance of screening for PE was also estimated. The study population of 2287 pregnancies contained 60 (2.6%) that developed PE, including 19 (0.8%) that delivered with PE at < 3 weeks after assessment. The PSV ratio improved the prediction of PE with delivery at any stage after assessment provided by maternal factors alone (from 25.4% to 50.6%), maternal factors and MAP (54.3% to 62.7%), maternal factors, MAP and PlGF (68.3% to 70.8%) and maternal factors, MAP, PlGF and sFlt-1 (75.7% to 76.7%), at a FPR of 10%. The PSV ratio also improved the prediction of PE with delivery at < 3 weeks after assessment provided by maternal factors alone (from 31.0% to 69.4%), maternal factors and MAP (74.1% to 83.4%), maternal factors, MAP and UtA-PI (77.1% to 85.0%) and maternal factors, MAP and PlGF (84.8% to 88.6%). The empirical results for DR at a 10% FPR were consistent with the modeled results. Screening by a combination of maternal factors with MAP and PSV ratio also detected 59.4% (95% CI, 58.6-82.5%) of cases of gestational hypertension with delivery at any stage after assessment, and 86.7% (95% CI, 82.4-100%) of those with delivery at < 3 weeks after assessment. Ophthalmic artery Doppler could potentially improve the performance of screening for PE at 35-37 weeks, especially imminent PE with delivery within 3 weeks after assessment, but further studies are needed to validate this finding. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Serum placental growth factor and soluble fms-like tyrosine kinase-1 in preeclamptic women at their third trimester of pregnancy

Background: Preeclampsia (PE) affects approximately 3% of all pregnancies, and it is still a major cause of the adverse perinatal outcome. PE is a multisystem disease characterized by the development of hypertension and proteinuria. Although PE etiology is not fully known, the placenta seems to play a central role in the development of the disease. The inadequate placentation process results in a change in angiogenic factors levels, such as the soluble form of vascular endothelial growth factor receptor type 1 (sFlt-1) and placental growth factor (PLGF). Objectives: To investigate the correlation between serum PLGF with soluble sFLT-1 in preeclamptic women at their third trimester. Methods: A case-control study was carried out from August 2018 till January 2019. In this study, pregnant women were collected from the Al-Elweyia, Al-Hakeem, and Al-Imamain Alkadhimain medical city. The practical part was conducted at the College of Medicine, Al-Nahrain University. The patient group includes 50 preeclamptic women in the third trimester (25 mild and 25 severe). Fifty healthy pregnant women (at their third trimester of gestation) were selected as control. Patients and control were compared for age, serum PLGF, and Sflt-1. Results: Serum PLGF levels were decreased significantly among women who developed PE (2.14±0.029 pg/ml, 2.44±0.038 pg/ml vs. 2.68±0.017 pg/ml; p&lt;0.05) severe PE, Mild PE, and the control group respectively, while, serum sFlt1 levels were increased significantly (p&lt;0.05) between the groups of PE, (5.81±0.025, 5.51±0.024, 5.19±0.017 pg/ml) severe, mild and control, respectively. Conclusions: Serum sFlt-1 and PLGF can be considered promising biomarkers for the preeclampsia. sFlt-1 and PLGF the ROC cut-offs (5.67 ng/ml, 2.09 ng/ml, respectively), the specificity and sensitivity of serum PLGF is more than that of serum sFlt-1, for the diagnosis of preeclampsia during the third trimester of pregnancy.

Ophthalmic artery Doppler in combination with other biomarkers in prediction of pre-eclampsia at 19-23 weeks' gestation.

To examine the potential value of maternal ophthalmic artery Doppler at 19-23 weeks' gestation on its own and in combination with the established biomarkers of pre-eclampsia (PE), including uterine artery (UtA) pulsatility index (PI), mean arterial pressure (MAP), serum placental growth factor (PlGF) and serum soluble fms-like tyrosine kinase-1 (sFlt-1), in the prediction of subsequent development of PE. This was a prospective observational study of women attending for a routine hospital visit at 19 + 1 to 23 + 3 weeks' gestation. This visit included recording of maternal demographic characteristics and medical history, ultrasound examination for fetal anatomy and growth, assessment of flow velocity waveforms from the maternal ophthalmic arteries, and measurement of MAP, UtA-PI, serum PlGF and serum sFlt-1. Waveforms were obtained from the ophthalmic arteries in sequence from the right eye, left eye and again from the right and then left eye. We recorded the average of the four measurements, two from each eye, for the following four indices: first peak of systolic velocity; second peak of systolic velocity; PI; and the ratio of the second to first peak of systolic velocity (PSV ratio). The measurements of the four indices were standardized to remove the effects of maternal characteristics and elements from the medical history. The competing-risks model was used to estimate the individual patient-specific risks of delivery with PE at < 37 and ≥ 37 weeks' gestation and to determine the area under the receiver-operating-characteristics curve (AUC) and detection rate (DR), at a 10% false-positive rate (FPR), in screening by a combination of maternal demographic characteristics and medical history with biomarkers. The modeled performance of screening for PE was also estimated. The study population of 2853 pregnancies contained 76 (2.7%) that developed PE, including 18 (0.6%) that delivered with PE at < 37 weeks' gestation. The ophthalmic artery PSV ratio was significantly increased in PE pregnancies, and the PE effect depended on gestational age at delivery; the deviation from normal was greater for early than late PE. The second peak of systolic velocity was also increased in PE pregnancies, but the effect did not depend on gestational age at delivery. The other two ophthalmic artery indices of first peak of systolic velocity and PI were not significantly affected by PE. The PSV ratio improved the prediction of preterm PE provided by maternal factors alone (from 56.1% to 80.2%), maternal factors, MAP and UtA-PI (80.7% to 87.9%), maternal factors, MAP, UtA-PI and PlGF (85.5% to 90.3%) and maternal factors, MAP, UtA-PI, PlGF and sFlt-1 (84.9% to 89.8%), at a FPR of 10%. The PSV ratio also improved the prediction of term PE provided by maternal factors alone (from 33.8% to 46.0%), maternal factors, MAP and UtA-PI (46.6% to 54.2%), maternal factors, MAP, UtA-PI and PlGF (45.2% to 53.4%) and maternal factors, MAP, UtA-PI, PlGF and sFlt-1 (43.0% to 51.2%), at a FPR of 10%. The empirical results for DR at a 10% FPR were consistent with the modeled results. The second peak of systolic velocity did not improve the prediction of either preterm or term PE provided by maternal factors alone. Ophthalmic artery PSV ratio at 19-23 weeks' gestation, both on its own and in combination with other biomarkers, is potentially useful for prediction of subsequent development of PE, especially preterm PE, but larger studies are needed to validate this finding. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Astragaloside IV ameliorates preeclampsia-induced oxidative stress through the Nrf2/HO-1 pathway in a rat model.

Preeclampsia (PE) can cause serious health problems for pregnant women and their infants. Astragaloside IV has been shown to exert cardioprotective, anti-inflammatory, and antioxidative effects on various disorders. We aimed to study the effects of Astragaloside IV on PE symptoms using an NG-nitro-l-arginine methyl ester (l-NAME)-induced rat model of PE. The pregnant rats' physiological features, including blood pressure, urine protein, serum soluble fms-like tyrosine kinase-1(sFlt-1)/placental growth factor (PlGF) ratio, and weight of placenta, as well as the weight, length, and survival of pups, were documented. The expression levels of target genes were analyzed by Western blot and qRT-PCR assays. The levels of target secreted proteins were determined by ELISA. We demonstrated that the administration of Astragaloside IV might exert a multitude of beneficial effects on attenuated PE symptoms in a rat model of PE. We further revealed that the effects of Astragaloside IV on PE rats were achieved, at least partially, through elimination of oxidative stress and stimulation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway. Our study indicated that Astragaloside IV may serve as a promising candidate for the development of new therapeutic methods for patients with PE.