Serum Soluble Fms-like Tyrosine Kinase-1 Research Articles

How sFlt-1 can help after pre-eclampsia diagnosis.

Measurement of maternal serum soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF), and the ratio between the two, has been shown to predict preeclampsia. In women with suspected preeclampsia, an sFlt-1: PlGF ratio below 38 rules out the need for delivery in the subsequent week with a negative predictive value of 99.3% (95% CI 97.9 to 99.9%) (Zeisler H et al., N Engl J Med 2016;374:13-22). This test may be of particular benefit for women at low risk of developing the disease in the short term, as it may reduce unnecessary follow-up, investigations and admissions (Cerdeira AS et al., Hypertension 2019;74:983-990).

Placental function and fetal weight are associated with maternal hemodynamic indices in uncomplicated pregnancies at 35–37 weeks of gestation

Over the years, there has been an increasing interest in the assessment of maternal hemodynamic responses during pregnancy. With the use of both noninvasive devices and/or maternal echocardiography, it has been shown that mothers who have pregnancy complications have altered hemodynamics compared with those who have uncomplicated pregnancies. It also has been suggested that preexisting maternal cardiac changes might drive the development of complications in pregnancy that are associated with impaired placentation. To understand, however, this potential link in complicated pregnancies, it is important to clarify whether placental function is associated with maternal cardiac functional indices in normal pregnancies. To determine whether placental function, perfusion, and fetal weight are associated with maternal cardiac hemodynamic responses at 35-36 weeks of gestation in normal pregnancies. Prospective screening of women attending Kings' College Hospital for routine hospital visit at 35-37 weeks' gestation. We recorded maternal characteristics and measured mean arterial pressure, uterine artery pulsatility index, sonographic estimated fetal weight, and serum placental growth factor and soluble fms-like tyrosine kinase 1. We also performed maternal echocardiogram to assess cardiac output and peripheral vascular resistance as well as indices of diastolic and systolic function, including global longitudinal systolic function and left ventricular mass indexed to body surface area. We studied 1386 women. Maternal characteristics were associated with both maternal hemodynamics and functional and structural indices. Uterine artery pulsatility index was associated with left ventricular mass (P=.03) and global longitudinal systolic function (P=.017). There were significant nonlinear associations between placental growth factor and cardiac output and peripheral vascular resistance (P<.001 for both) and between soluble fms-like tyrosine kinase 1 and peripheral vascular resistance (P=.018). Estimated fetal weight was associated with maternal cardiac output (mean increase=0.186, 95% confidence interval, 0.133-0.238, P<.001) and peripheral vascular resistance (mean decrease=-0.164, 95% confidence interval, -0.217 to -0.111, P<.001). No association was noted between placental and fetal parameters and maternal cardiac functional and structural indices. In multivariable analysis, placental growth factor remained strongly associated with maternal cardiac output and peripheral vascular resistance (P=.002 for both) over and above maternal characteristics and estimated fetal weight. Estimated fetal weight was associated with left ventricular mass (0.102, 95% confidence interval, 0.044-0.162, P=.001). The results of this study suggest a strong link between maternal hemodynamic responses and fetoplacental needs across the whole spectrum in normal pregnancies. These findings would also indicate that to diagnose maternal cardiac dysfunction in pregnancies complicated by impaired placentation a more extensive echocardiographic assessment might be needed rather than relying on hemodynamics which are strongly associated with fetoplacental indices.

First trimester serum angiogenic and anti-angiogenic factors in women with chronic hypertension for the prediction of preeclampsia

An imbalance between angiogenic and antiangiogenic factors is thought to be a central pathogenetic mechanism in preeclampsia. In pregnancies that subsequently experience preeclampsia, the maternal serum concentration of the angiogenic placental growth factor is decreased from as early as the first trimester of pregnancy, and the concentration of the antiangiogenic soluble fms-like tyrosine kinase-1 is increased in the last few weeks before the clinical presentation of the disease. Chronic hypertension, which complicates 1-2% of pregnancies, is the highest risk factor for the development of preeclampsia among all other factors in maternal demographic characteristics and medical history. Two previous studies in women with chronic hypertension reported that first-trimester serum placental growth factor and soluble fms-like tyrosine kinase-1 levels were not significantly different between those who experienced superimposed preeclampsia and those who did not, whereas a third study reported that concentrations of placental growth factor were decreased. The purpose of this study was to investigate whether, in women with chronic hypertension, serum concentrations of placental growth factor and soluble fms-like tyrosine kinase-1 and soluble fms-like tyrosine kinase-1/placental growth factor ratio at 11+0-13+6 weeks gestation are different between those women who experienced superimposed preeclampsia and those who did not and to compare these values with those in normotensive control subjects. The study population comprised 650 women with chronic hypertension, which included 202 women who experienced superimposed preeclampsia and 448 women who did not experience preeclampsia, and 142 normotensive control subjects. Maternal serum concentration of placental growth factor and soluble fms-like tyrosine kinase-1 were measured by an automated biochemical analyzer and converted into multiples of the expected median with the use of multivariate regression analysis in the control group. Comparisons of placental growth factor and soluble fms-like tyrosine kinase-1 levels and soluble fms-like tyrosine kinase-1/placental growth factor ratio in multiples of the expected median values between the 2 groups of chronic hypertension and the control subjects were made with the analysis of variance or the Kruskal-Wallis test. In the group of women with chronic hypertension who experienced preeclampsia compared with those women who did not experience preeclampsia, there were significantly lower median concentrations of serum placental growth factor multiples of the expected median (0.904 [interquartile range, 0.771-1.052] vs 0.948 [interquartile range, 0.814-1.093]; P=.014) and soluble fms-like tyrosine kinase-1 multiples of the expected median (0.895 [interquartile range, 0.760-1.033] vs 0.938 [interquartile range, 0.807-1.095]; P=.013); they were both lower than in the normotensive control subjects (1.009 [interquartile range, 0.901-1.111] and 0.991 [interquartile range, 0.861-1.159], respectively; P<.01 for both). There were no significant differences among the 3 groups in soluble fms-like tyrosine kinase-1/placental growth factor ratios. In women with chronic hypertension, serum placental growth factor and soluble fms-like tyrosine kinase-1 levels provided poor prediction of superimposed preeclampsia (area under the curve, 0.567 [95% confidence interval, 0.537-0.615] and 0.546 [95% confidence interval, 0.507-0.585], respectively). Women with chronic hypertension, and particularly those who subsequently experienced preeclampsia, have reduced first-trimester concentrations of both placental growth factor and soluble fms-like tyrosine kinase-1.

Prediction of adverse perinatal outcome by serum placental growth factor and soluble fms-like tyrosine kinase-1 in women undergoing induction of labor.

To investigate the additive value of serum placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1), measured within 24 h prior to induction of labor, to the performance of screening for adverse perinatal outcome provided by maternal risk factors and the cerebroplacental ratio (CPR). This was a prospective observational study of 795 singleton pregnancies undergoing induction of labor at ≥ 37 weeks' gestation. Before induction of labor, Doppler ultrasound was used to measure the pulsatility index (PI) in the umbilical artery (UA) and fetal middle cerebral artery (MCA) and maternal blood was obtained for measurement of serum PlGF and sFlt-1. The measured UA-PI, MCA-PI and their ratio (CPR) were converted to multiples of the median (MoM) after adjustment for gestational age, and the measured PlGF and sFlt-1 were converted to MoM after adjustment for gestational age, maternal characteristics and the machine used for the assays. Univariable and multivariable logistic regression analysis was used to determine factors that provided a significant contribution in the prediction of adverse perinatal outcome, defined as the presence of any one of Cesarean section for non-reassuring fetal status in labor, umbilical arterial or venous cord blood pH ≤ 7 and ≤ 7.1, respectively, 5-min Apgar score < 7 or admission to the neonatal intensive care unit for ≥ 24 h. The detection rate (DR) and false-positive rate (FPR) in screening for adverse perinatal outcome were determined. In pregnancies with adverse perinatal outcome, compared to those without, median serum PlGF MoM was lower (0.44; interquartile range (IQR), 0.30-0.82 vs 0.60; IQR, 0.36-1.07; P = 0.003), but median sFlt-1 MoM was not significantly different (P = 0.080). Multivariable regression analysis demonstrated that, in the prediction of adverse perinatal outcome, there was significant contribution from maternal risk factors and CPR MoM but not PlGF MoM or sFlt-1 MoM. The performance of screening for adverse perinatal outcome achieved by maternal risk factors alone (DR of 28.9% at FPR of 10%) was not improved by the addition of CPR (DR of 33.8% at FPR of 10%) (area under the curve, 0.702; 95%CI, 0.654-0.750 vs 0.712; 95%CI, 0.664-0.760; P = 0.233). Serum PlGF and sFlt-1, measured within 24 h prior to induction of labor, do not provide a significant additional contribution to maternal risk factors in the prediction of adverse perinatal outcome. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Relationships of serum placental growth factor and soluble fms-like tyrosine kinase-1 with fetal and uterine artery Doppler indices in pre-eclampsia.

To compare serum placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) concentrations among women with pre-eclampsia and healthy control women and to evaluate the associations of serum PlGF and sFlt-1 with fetal and uterine artery Doppler indices in pre-eclampsia. A prospective cross-sectional study of 33 women with pre-eclampsia and 33 normotensive pregnant women attending a university hospital in China between January and November 2014. Serum PlGF and sFlt-1 were assayed by enzyme linked immunosorbent assays. Doppler indices of the uterine artery, umbilical artery, fetal middle cerebral artery, and ductus venosus were measured. The pulsatility index of the uterine artery was negatively correlated with PlGF (r, -0.487; P=0.004) and positively correlated with sFlt-1 (r, 0.420; P=0.015). Gestational age at birth was positively correlated with PlGF (r, 0.601, P<0.001) and negatively correlated with sFlt-1 (r, -0.568; P=0.001). Birth weight was positively correlated with PlGF (r, 0.555; P=0.001) and negatively correlated with sFlt-1 (r, -0.552; P=0.001). Apgar score was negatively correlated with sFlt-1 (r, -0.427; P=0.017). Lower PlGF and higher sFlt-1 levels in maternal serum were significantly associated with increased uterine arterial impedance in pre-eclampsia.

Increased soluble fms-like tyrosine kinase 1 after ischemia reperfusion contributes to adverse clinical outcomes following kidney transplantation

Renal ischemia reperfusion injury (IRI) adversely affects clinical outcomes following kidney transplantation. Understanding the cellular mechanisms and the changes in gene/protein expression following IRI may help to improve these outcomes. Serum soluble fms-like tyrosine kinase 1 (sFlt-1), a circulating antiangiogenic protein, is increased in the first week following kidney transplantation. We evaluated the casual relationship of elevated sFlt-1 levels with renal microvascular dysfunction following IRI in a longitudinal study of 93 kidney transplant recipients and in several animal models. Transplant recipients with higher sFlt-1 levels had higher odds of delayed graft function, graft rejection, impaired graft function, and death. In a subgroup of 25 participants who underwent kidney biopsy within 4 months of kidney transplantation, peritubular capillary area was lower in those with elevated serum sFtl-1 levels. The administration of recombinant sFlt-1 into rodents resulted in significant structural and functional changes of the renal microvasculature, including reduced peritubular capillary density and intracapillary blood volume, and lead to increased expression of inflammatory genes and increased fibrosis. In a murine model of IRI, the kidney was a site of sFlt-1 production, and systemic neutralization of sFlt-1 preserved peritubular capillary density and alleviated renal fibrosis. Our data indicate that high sFlt-1 levels after IRI play an important role in the pathogenesis of microvascular dysfunction, thereby contributing to adverse clinical outcomes following kidney transplantation.

Prediction of imminent preeclampsia at 35–37 weeks gestation

In the weeks preceding the clinical onset of preeclampsia, the maternal serum level of the angiogenic placental growth factor is decreased and that of the antiangiogenic factor soluble fms-like tyrosine kinase-1 is increased. Women presenting at specialist clinics with signs or symptoms of hypertensive disorders have been stratified according to concentrations of placental growth factor or the ratio of concentrations of soluble fms-like tyrosine kinase-1 and placental growth factor to determine clinical management for the subsequent 1-4 weeks. An alternative approach for the prediction of preeclampsia is use of the competing risks model, a Bayes' theorem based method, to derive patient-specific risk for preeclampsia by various combinations of maternal characteristics and medical history with multiples of the median values of biomarkers. The purpose of this study was to compare the performance of screening for delivery with preeclampsia at ≤2 and ≤4 weeks after assessment at 35+0-36+6 weeks gestation between the use of percentile cut-offs in placental growth factor alone or the soluble fms-like tyrosine kinase-1/placental growth factor ratio and the competing risks model. This was a prospective observational study in women who attended a routine hospital visit at 35+0-36+6 weeks gestation in 2 maternity hospitals in England. The visits included the recording of maternal demographic characteristics and medical history and the measurement of serum placental growth factor and soluble fms-like tyrosine kinase-1 and mean arterial pressure. The areas under the receiver operating characteristics curves were used to compare the predictive performance for preeclampsia with delivery at ≤2 and ≤4 weeks from assessment of screening by placental growth factor alone and the soluble fms-like tyrosine kinase-1/placental growth factor ratio with that of a previously developed competing risks model with a combination of maternal factors, placental growth factor, soluble fms-like tyrosine kinase-1, and mean arterial pressure (triple test). First, the study population of 15,247 pregnancies included 326 pregnancies (2.1%) that subsequently experienced preeclampsia. Second, in the screening for delivery with preeclampsia at ≤2 and ≤4 weeks from assessment, the performance of the triple test was superior to that of placental growth factor alone or the soluble fms-like tyrosine kinase-1/placental growth factor ratio. The area under the receiver operating characteristics curves for preeclampsia at ≤2 weeks in screening by the triple test (0.975; 95% confidence interval, 0.964-0.985) was higher than that of placental growth factor alone (0.900; 95% confidence interval, 0.866-0.935; P<.0001) and the soluble fms-like tyrosine kinase-1/placental growth factor ratio (0.932; 95% confidence interval, 0.904-0.960; P=.0001). Similarly, the areas under the receiver operating characteristics curves for preeclampsia at ≤4 weeks in screening by the triple test (0.907; 95% confidence interval, 0.886-0.928) was higher than that of placental growth factor alone (0.827; 95% confidence interval, 0.800-0.854; P<.0001) or the soluble fms-like tyrosine kinase-1/placental growth factor ratio (0.857; 95% confidence interval, 0.830-0.883; P<.0001). Third, at most, screen-positive rates of 2-30% the detection rate of delivery with preeclampsia at ≤2 and ≤4 weeks that was achieved by the triple test was approximately 10% higher than that of the soluble fms-like tyrosine kinase-1/placental growth factor ratio and 20% higher than that of placental growth factor alone; the negative predictive value was similar for the 3 tests. At 35+0-36+6 weeks gestation, the performance of screening for imminent delivery with preeclampsia by the competing risks model is superior to that of placental growth factor alone or the soluble fms-like tyrosine kinase-1/placental growth factor ratio.

Prediction of small for gestational age neonates: screening by maternal factors, fetal biometry, and biomarkers at 35–37 weeks’ gestation

Small for gestational age (SGA) neonates are at increased risk for perinatal mortality and morbidity; however, the risks can be substantially reduced if the condition is identified prenatally, because in such cases close monitoring and appropriate timing of delivery and prompt neonatal care can be undertaken. The traditional approach of identifying pregnancies with SGA fetuses is maternal abdominal palpation and serial measurements of symphysial-fundal height, but the detection rate of this approach is less than 30%. A higher performance of screening for SGA is achieved by sonographic fetal biometry during the third trimester; screening at 30-34 weeks' gestation identifies about 80% of SGA neonates delivering preterm but only 50% of those delivering at term, at a screen-positive rate of 10%. There is some evidence that routine ultrasound examination at 36 weeks' gestation is more effective than that at 32 weeks in predicting birth of SGA neonates. To investigate the potential value of maternal characteristics and medical history, sonographically estimated fetal weight (EFW) and biomarkers of impaired placentation at 35+0- 36+6 weeks' gestation in the prediction of delivery of SGA neonates. A dataset of 19,209 singleton pregnancies undergoing screening at 35+0-36+6 weeks' gestation was divided into a training set and a validation set. The training dataset was used to develop models from multivariable logistic regression analysis to determine whether the addition of uterine artery pulsatility index (UtA-PI), umbilical artery PI (UA-PI), fetal middle cerebral artery PI (MCA-PI), maternal serum placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFLT) would improve the performance of maternal factors and EFW in the prediction of delivery of SGA neonates. The models were then tested in the validation dataset to assess performance of screening. First, in the training dataset, in the SGA group, compared to those with birthweight in ≥10th percentile, the median multiple of the median (MoM) values of PlGF and MCA-PI were reduced, whereas UtA-PI, UA-PI, and sFLT were increased. Second, multivariable regression analysis demonstrated that in the prediction of SGA in <10th percentile there were significant contributions from maternal factors, EFW Z-score, UtA-PI MoM, MCA-PI MoM, and PlGF MoM. Third, in the validation dataset, prediction of 90% of SGA neonates delivering within 2 weeks of assessment was achieved by a screen-positive rate of 67% (95% confidence interval [CI], 64-70%) in screening by maternal factors, 23% (95% CI, 20-26%) by maternal factors, and EFW and 21% (95% CI, 19-24%) by the addition of biomarkers. Fourth, prediction of 90% of SGA neonates delivering at any stage after assessment was achieved by a screen-positive rate of 66% (95% CI, 65-67%) in screening by maternal factors, 32% (95% CI, 31-33%) by maternal factors and EFW and 30% (95% CI, 29-31%) by the addition of biomarkers. The addition of biomarkers of impaired placentation only marginally improves the predictive performance for delivery of SGA neonates achieved by maternal factors and fetal biometry at 35+0-36+6 weeks' gestation.

181. Predictive value of the sFlt-1/PlGF ratio in preecalmpsia with or without fetal growth restriction

Introduction Preeclampsia is a pregnancy-specific multisystemic disorders with an incidence of 2–5% worldwide. Placental deficient was thought to be the main reason for preeclampsia. Reduced uteroplacental blood flow can also cause fetal growth restriction (FGR). Hypothesis Evaluating serum soluble fms-like tyrosine kinase-1 (sFlt-1), serum placental growth factor (PlGF) and the sFlt-1/PlGF ratio in preeclampsia with or without FGR can help clinicians to make decision. Methods 17 singleton pregnancies women was diagnosed as preeclampsia with (n = 5) or without FGR (n = 12) in third trimester (>28 weeks) from March to April 2018. Serum sFlt-1 and PlGF were estimated when they admitted. The sFlt-1, PlGF, and the maternal basic data were obtained. This study was approved by the Ethics Committee for Guangzhou Women and Children’s Medical Center. Results The sFlt-1/PlGF ratio in preeclampsia with FGR group was significantly increased compared with another group (227.33 ± 80.51 vs.121.15 ± 55.80, P = 0.007). The mean systolic pressure (157 ± 9 vs. 142 ± 11 mmHg) and diastolic pressure (100 ± 6 vs. 92 ± 7 mmHg) were higher in FGR group (P Conclusion High serum levels of sFlt-1 and low serum levels of PlGF have been proposed as useful predictors for the subsequent development of preeclampsia. Abnormal placental implantation with endothelial dysfunction may also result in FGR. The sFlt-1 and PlGF are the inflammatory factors from placenta which may indicate the inflammation of maternal-fetal interface. Coincidence of the high ratio in these two obstetrical complications may suggesting that an inflammatory mechanism may have an important role in preeclampsia with FGR. The higher ratio might predict preeclampsia with FGR, which can influence clinical intervention.

Screening for pre-eclampsia at 35-37 weeks' gestation.

To examine the performance of screening for pre-eclampsia (PE) at 35-37 weeks' gestation by maternal factors and combinations of 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). This was a prospective observational study in women with singleton pregnancy attending for an ultrasound scan at 35 + 0 to 36 + 6 weeks as part of routine pregnancy care. Bayes' theorem was used to combine the prior distribution of gestational age at delivery with PE, obtained from maternal characteristics and medical history, with various combinations of biomarker multiples of the median (MoM) values to derive the patient-specific risks of delivery with PE. The performance of such screening was estimated. The study population of 13 350 pregnancies included 272 (2.0%) that subsequently developed PE. In pregnancies that developed PE, the MoM values of MAP, UtA-PI and sFlt-1 were increased and PlGF MoM was decreased. At a risk cut-off of 1 in 20, the proportion of the population stratified into high risk was about 10% of the total, and the proportion of cases of PE contained within this high-risk group was 28% with screening by maternal factors alone; the detection rate increased to 53% with the addition of MAP, 67% with the addition of MAP and PlGF and 70% with the addition of MAP, PlGF and sFlt-1. The performance of screening was not improved by the addition of UtA-PI. The performance of screening depended on the racial origin of the women; in screening by a combination of maternal factors, MAP, PlGF and sFlt-1 and use of the risk cut-off of 1 in 20, the detection rate and screen-positive rate were 66% and 9.5%, respectively, for Caucasian women and 88% and 18% for those of Afro-Caribbean racial origin. Screening by maternal factors and biomarkers at 35-37 weeks' gestation can identify a high proportion of pregnancies that develop late PE. The performance of screening depends on the racial origin of the women. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Prognostic value of serum soluble FMS-like tyrosine kinase (sFlt-1) levels in pre-eclampsia and eclampsia; a prospective cohort study

ABSTRACT Objective: To evaluate the levels of circulating sFlt-1 in pre-eclampsia (PE) and eclampsia patients and to assess its prognostic value in detection of PE complications. Methods: The present study was a prospective cohort study conducted in tertiary hospital between January and December 2016. Included patients were divided into two groups; (Group I) severe PE group and (Group II) eclampsia group. Age-, parity-, and gestational age-matched women had approached to participate in the study as a control group (Group III). Serum sFlt-1 levels were measured at inclusion and 2 days later with all basic investigations. Patients were followed up until delivery to record any complications. Correlation analysis was performed between the serum sFlt-1 levels and clinical, laboratory investigations. Receiver operating characteristic analysis was constructed for the evaluation of the area under curve (AUC) as well as the sensitivity and specificity regarding the cutoff point of sFlt-1 level that predict occurrence of complications. Results: The study included 84 women. Women with complicated severe PE showed higher sFlt-1 levels than in non-complicated cases (120.2 ± 19.6 versus 72.2 ± 19.6, p < 0.001). Similarly, the mean serum level of sFlt-1 in complicated eclampsia was higher than in non-complicated cases (298.3 ± 75.2 versus 128.1 ± 36.5, p < 0.001) (OR = 1.119, 95% CI: 10.057–1.184, p < 0.001). SFlt-1 levels were strongly correlated with systolic blood pressure (r = 0.641) and diastolic blood pressure (r = 0.540) (p < 0.001 and p < 0.001, respectively). At cutoff point 102.60 ng/ml of sFlt-1 levels, the sensitivity was 90% and specificity was 80% with AUC = 0.923, 95% CI: 0.871–0.975. Conclusions: Serum sFlt-1 can be used as a prognostic marker to predict the occurrence of complications of preeclampsia.

How to identify pregnant women at risk of pre-eclampsia? - a review of the current literature.

Pre-eclampsia remains a major cause of poor perinatal outcome worldwide. As administering acetylsalicylic acid in a high risk population reduces the risk of PE, it is essential to identify women at risk of PE. Several algorithms for PE risk assessment have been developed. They include maternal factors combined with uterine artery pulsatility index, mean arterial pressure, serum pregnancy-associated plasma protein-A, placental growth factor, and serum soluble fms-like tyrosine kinase-1. Beside PE prophylaxis with acetylsalicylic acid, a proper management of women considered at a high risk of PE is essential. The sFlt-1:PlGF ratio between 20 and 34 + 6 weeks may be used to predict a short-term absence of PE or to predict the risk of PE diagnosis within 4 weeks and a significant shortening of the duration of pregnancy associated with it. The sFlt-1:PlGF ratio may be helpful in deciding about hospitalization or choosing the optimal time for corticosteroid administration in women at risk of PE. It may also help to reduce overall healthcare costs.

Management of pregnancies after combined screening for pre‐eclampsia at 19–24 weeks' gestation

To estimate the patient-specific risk of pre-eclampsia (PE) at 19-24 weeks' gestation by maternal factors and combinations of 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). On the basis of the risk of PE, the women would be stratified into high-, intermediate- and low-risk management groups. The high-risk group would require close monitoring for high blood pressure and proteinuria at 24-31 weeks. The intermediate-risk group, together with the undelivered pregnancies from the high-risk group, would have reassessment of risk for PE at 32 weeks to identify those who would require close monitoring for high blood pressure and proteinuria at 32-35 weeks. All pregnancies would have reassessment of risk for PE at 36 weeks to define the plan for further monitoring and delivery. This was a prospective observational study of women attending for an ultrasound scan at 19-24 weeks as part of routine pregnancy care. Patient-specific risks of delivery with PE at < 32 and at < 36 weeks' gestation were calculated using the competing-risks model to combine the prior distribution of gestational age at delivery with PE, obtained from maternal characteristics and medical history, with multiples of the median (MoM) values of MAP, UtA-PI, PlGF and sFlt-1. Different risk cut-offs were used to vary the proportion of the population stratified into high-, intermediate- and low-risk groups, and the performance of screening for delivery with PE at < 32 weeks' gestation and at 32 + 0 to 35 + 6 weeks was estimated. The study population of 16 254 singleton pregnancies included 467 (2.9%) that subsequently developed PE (23 delivered at < 32 weeks, 58 delivered at 32 + 0 to 35 + 6 weeks and 386 delivered at ≥ 36 weeks). Using a risk of > 1 in 25 for PE at < 32weeks' gestation and risk of > 1 in 150 for PE at < 36weeks, the proportion of the population stratified into the high-risk group was about 1% of the total, and the proportion of cases of PE at < 32 weeks' gestation contained within this high-risk group varied from about 35% with screening by maternal factors and MAP, to 78% with maternal factors, MAP and UtA-PI, and up to 100% with maternal factors, MAP, UtA-PI and PlGF, with or without sFlt-1. Similarly, the proportion of the population requiring reassessment of risk at 32 weeks' gestation and the proportion of cases of PE at 32 + 0 to 35 + 6 weeks contained within this population varied, respectively, from about 18% and 79% with screening by maternal factors and MAP, to 10% and 90% with maternal factors, MAP, UtA-PI and PlGF, with or without sFlt-1. In the new pyramid of pregnancy care, assessment of risk for PE at 19-24 weeks' gestation can stratify the population into those requiring intensive monitoring at 24-31 weeks and those in need of reassessment at 32 weeks. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Proposed clinical management of pregnancies after combined screening for pre-eclampsia at 19-24 weeks' gestation.

To estimate the patient-specific risk of pre-eclampsia (PE) at 19-24 weeks' gestation by a combination of maternal characteristics and medical history with multiples of the median (MoM) values of 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), and stratify women into high-, intermediate- and low-risk management groups. This was a prospective observational study in women attending a second-trimester ultrasound scan at 19-24 weeks as part of routine pregnancy care. Patient-specific risks of delivery with PE < 32 weeks and < 36 weeks' gestation were calculated using the competing-risks model to combine the prior risk from maternal characteristics and medical history with MoM values of MAP, UtA-PI, PlGF and sFlt-1. On the basis of these risks, the population was stratified into high-, intermediate- and low-risk groups. Different risk cut-offs were used to vary the proportion of the population stratified into each risk category and the performance of screening for delivery with PE at < 32 weeks' gestation, at 32-35 weeks and at ≥ 36 weeks was estimated. In addition to empirical performance, we also derived model-based performance because the number of cases of PE delivering < 32 weeks was low. The study population of 7748 singleton pregnancies included 268 (3.5%) that subsequently developed PE. Using a risk cut-off of 1 in 100 for PE delivering < 32 weeks' gestation and a risk cut-off of 1 in 300 for PE delivering < 36 weeks, the proportion of the population stratified into high-, intermediate- and low-risk was 0.9%, 17.2% and 81.9%, respectively. The high-risk group contained 97% of pregnancies with PE < 32 weeks and 45% of those with PE at 32-35 weeks. The intermediate-risk group contained a further 46% of women with PE at 32-35 weeks. The low-risk group contained only 0.03% of pregnancies with PE < 32 weeks and 9% of those with PE at 32-35 weeks. Risk stratification of PE by the combined test at 19-24 weeks' gestation can identify, first, a group which constitutes < 1% of the total population and contains > 95% of those that will develop PE < 32 weeks and are in need of intensive monitoring at 24-31 weeks and, second, a group which constitutes < 20% of the total and contains > 90% of those that will develop PE at 32-35 weeks and are in need of reassessment at 32 weeks. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Proposed clinical management of pregnancies after combined screening for pre-eclampsia at 35-37 weeks' gestation.

To estimate the patient-specific risk of pre-eclampsia (PE) at 35-37 weeks' gestation by a combination of maternal characteristics and medical history with multiples of the median (MoM) values of 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), and stratify women into high-, intermediate- and low-risk management groups. This was a prospective observational study in women attending a third-trimester ultrasound scan at 35-37 weeks as part of routine pregnancy care. Patient-specific risks of delivery with PE at < 4 weeks from assessment and PE at < 42 weeks' gestation were calculated using the competing-risks model to combine the prior risk from maternal characteristics and medical history with MoM values of MAP, UtA-PI, PlGF and sFlt-1. On the basis of these risks, the population was stratified into high-, intermediate- and low-risk groups. Different risk cut-offs were used to vary the proportion of the population stratified into each risk category and the performance of screening for delivery with PE at < 40 and ≥ 40 weeks' gestation was estimated. The study population of 3703 singleton pregnancies included 38 (1.0%) with PE < 40 weeks' gestation and 22 (0.6%) with PE ≥ 40 weeks. Using a risk cut-off of 1 in 50 for PE delivering at < 4 weeks after assessment to define the high-risk group and a risk cut-off of < 1 in 100 for PE delivering at < 42 weeks' gestation to define the low-risk group, the proportion of the population stratified into high, intermediate and low risk was 12.7%, 28.8% and 58.5%, respectively. The high-risk group contained 92% of pregnancies with PE at < 40 weeks' gestation and 73% of those with PE at ≥ 40 weeks. The intermediate-risk group contained a further 27% of women with PE at ≥ 40 weeks. In the low-risk group, none of the women developed PE at < 40 or ≥ 40 weeks' gestation. The study presents risk stratification of PE by the combined test at 35-37 weeks, aiming to identify a high-risk group in need of intensive monitoring from the time of the initial assessment and up to 40 weeks' gestation, an intermediate-risk group in need of reassessment at 40 weeks' gestation and a low-risk group that can be reassured that they are unlikely to develop PE. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Serum placental growth factor and soluble fms-like tyrosine kinase 1 at mid-gestation in healthy women: Association with small-for-gestational-age neonates.

This study was performed to determine the associations between serum placental growth factor (PlGF) and soluble fms-like tyrosine kinase 1 (sFlt-1) levels at mid-gestation with the risk of small-for-gestational-age (SGA) neonates born at gestational week (GW) ≥ 36 in healthy women. PlGF and sFlt-1 concentrations were determined at GW 24-27 in 183 women with births at GW≥36, but without gestational diabetes mellitus and hypertension. Thirteen (7.1%) SGA neonates were born. Median (range) GW at blood sampling was similar between women with and without SGA (25 [24-25] and 24 [24-27], respectively, P = 0.671). Pre-pregnancy body mass index (BMI) and PlGF levels were significantly lower in women with than without SGA, while sFlt-1 levels and sFlt-1:PlGF ratio (sFlt-1/PlGF) did not differ significantly between the two groups. PlGF and sFlt-1/PlGF, but not BMI or sFlt-1, showed significant correlations with birthweight z-score; the correlation was positive for PlGF and negative for sFlt-1/PlGF. Women with PlGF level< 10th percentile and those with sFlt-1/PlGF level> 90th percentile showed significantly increased risk of SGA compared to those with respective counterpart characteristics; relative risk was 3.8 (95% confidence interval, 1.3-11.3; 21% [4/19] vs 5.5% [9/164]) for PlGF and 7.9 (95% confidence interval, 3.0-20.8, 33.3% [6/18] vs 4.2% [7/165]) for sFlt-1/PlGF. Maternal PlGF and sFlt-1/PlGF determined during GW 24-27 were associated with the risk of SGA neonates born at GW ≥ 36, even in women with uncomplicated pregnancies.

Proposed clinical management of pregnancies after combined screening for pre-eclampsia at 30-34 weeks' gestation.

To estimate the patient-specific risk of pre-eclampsia (PE) at 30-34 weeks' gestation by a combination of maternal characteristics and medical history with multiples of the median (MoM) values of 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), and stratify women into high-, intermediate- and low-risk management groups. This was a prospective observational study in women attending a third-trimester ultrasound scan at 30-34 weeks as part of routine pregnancy care. Patient-specific risks of delivery with PE at < 4 weeks from assessment and at < 40 weeks' gestation were calculated using the competing-risks model to combine the prior risk from maternal characteristics and medical history with MoM values of MAP, UtA-PI, PlGF and sFlt-1. On the basis of these risks, the population was stratified into high-, intermediate- and low-risk groups. Different risk cut-offs were used to vary the proportion of the population stratified into each risk category and the performance of screening for delivery with PE at < 4 weeks from assessment and delivery with PE from 4 weeks after assessment and up to 40 weeks' gestation was estimated. The study population of 8128 singleton pregnancies included 234 (2.9%) that subsequently developed PE. Using a risk cut-off of 1 in 50 for PE delivering at < 4 weeks and a risk cut-off of 1 in 150 for PE delivering at < 40 weeks' gestation, the proportion of the population stratified into high, intermediate and low risk was about 3%, 26% and 71%, respectively. The high-risk group contained 90% of pregnancies with PE at < 4 weeks and 40% of those with PE at 4 weeks from assessment to 40 weeks' gestation. The intermediate-risk group contained a further 49% of women with PE at 4 weeks from assessment to 40 gestational weeks. In the low-risk group, none of the women developed PE at < 4 weeks and only 0.3% developed PE at 4 weeks to 40 gestational weeks. The study presents risk stratification of PE by the combined test at 30-34 weeks, aiming to identify a high-risk group in need of intensive monitoring from the time of the initial assessment and up to 40 weeks' gestation and an intermediate-risk group in need of monitoring from 4 weeks after the initial assessment and up to 40 weeks' gestation. All pregnancies would need to be reassessed at 40 weeks' gestation. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

The effects of sildenafil citrate on urinary podocin and nephrin mRNA expression in an L-NAME model of pre-eclampsia.

We investigated the effects of sildenafil citrate (SC) on podocyturia in N ω-nitro-L-arginine methyl ester hydrochloride (L-NAME) model of pre-eclampsia (PE). One hundred and twenty Sprague-Dawley rats (SDR) were divided into five groups like pregnant control (PC), early-onset PE (EOPE), late-onset PE(LOPE), early and late-onset PE with SC-treated groups [EOPE (SC); LOPE (SC)]. PE was induced in SDR by oral administration of L-NAME in drinking water for 4-8days for EOPE and 8-14day for LOPE. The blood pressure, urine volume and total urine protein were increased in EOPE and LOPE groups when compared to PC, and all the above parameters decreased in EOPE (SC) and LOPE (SC) groups when compared to EOPE and LOPE groups, respectively. The EOPE and LOPE groups showed an increase in urinary nephrin mRNA and podocin mRNA levels compared to PC group. Increases in serum and renal soluble fms-like tyrosine kinase-1 (sFlt-1) expression levels and decreases in renal vascular endothelial growth factor (VEGF) expression and serum placenta growth factor (PlGF) levels were observed in EOPE and LOPE groups when compared to PC group. In addition, decreases in serum and renal sFlt-1 expression levels and increases in renal VEGF expression and serum PlGF levels were observed in EOPE (SC) and LOPE (SC) groups when compared to EOPE and LOPE groups, respectively. The light microscopy showed that the renal tissue of L-NAME-treated rats had extensive glomerular damage, tubular damage and infiltration by mononuclear cells when compared to PC group. Therefore, SC ameliorated podocyturia through its effects on the antiangiogenic/angiogenic status in this animal model.

Expression of Soluble Endoglin and sFlt-1 in Peripheral Blood of Preeclampsia

Objective To investigate the expression and significance of serum soluble endoglin (sEng) and soluble fms-like tyrosine kinase 1 (sFlt-1) in preeclampsia. Methods Serum levels of sEng 1 and sFlt-1 were determined by enzyme linked immunosorbent assay. Results The serum level of sEng of the preeclampsia group (6.39±2.15) ng/ml was significantly higher than that of the control (2.16±0.31) ng/ml, P<0.01, especially of early-onset severe preeclampsia. The serum level of sFlt-1 of the preeclampsia group (411.11±80.19) pg/ml was significantly higher than that of the third trimester group (27.57±4.36) pg/ml, but sFlt-1 did not correlate with the most severe forms of the disease. Conclusion Serum levels of sEng and sFlt-1 are significantly increased in preeclampsia, and the serum level of sEng is even higher in severe preeclampsia patients.

Competing-risks model in screening for pre-eclampsia by maternal factors and biomarkers at 35-37 weeks' gestation

To develop a model for prediction of term pre-eclampsia (PE) based on a combination of maternal factors and late third-trimester biomarkers. Data were derived from prospective screening for adverse obstetric outcomes in women attending their routine hospital visit at 35-37 weeks' gestation in two maternity hospitals in the UK. Uterine artery pulsatility index (UtA-PI) was measured in 5362 pregnancies, mean arterial pressure (MAP) in 5386 and serum placental growth factor (PlGF) and serum soluble fms-like tyrosine kinase-1 (sFlt-1) in 3920. Bayes' theorem was used to combine the a-priori risk of PE from maternal factors with various combinations of biomarkers, expressed as multiples of the median (MoM). Five-fold cross-validation was used to estimate the performance of screening for PE, requiring delivery at some stage after assessment. The empirical performance of screening was compared to model predictions. In pregnancies that developed PE, the values of MAP, UtA-PI and sFlt-1 were increased and PlGF was decreased compared to unaffected pregnancies. For all biomarkers evaluated, the deviation from normal was inversely related to the gestational age at which delivery became necessary for maternal or fetal indications. Screening by maternal factors and by a combination of maternal factors with all biomarkers predicted 35% and 84% of PE, respectively, at a 10% false-positive rate. A combination of maternal factors and biomarkers at 35-37 weeks' gestation can provide effective screening for term PE. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.