Maternal Serum Soluble Fms-like Tyrosine Research Articles

Maternal serum soluble fms-like tyrosine kinase-1–to–placental growth factor ratio distinguishes growth-restricted from non–growth-restricted small-for-gestational-age fetuses

Fetal growth restriction secondary to chronic placental insufficiency is a major cause of perinatal morbidity and mortality. A significant proportion of fetuses with fetal growth restriction are small for gestational age, defined as a birthweight of ≤10th percentile. However, not all small-for-gestational-age fetuses are growth restricted. Some are constitutionally small and otherwise healthy. It is important to distinguish between small-for-gestational-age fetuses with and without fetal growth restriction to ensure appropriate interventions in small-for-gestational-age fetuses with fetal growth restriction and to minimize unnecessary interventions in healthy small-for-gestational-age fetuses. The maternal serum ratio of soluble fms-like tyrosine kinase-1 and placental growth factor is an indicator of placental insufficiency in the latter half of pregnancy. As such, the soluble fms-like tyrosine kinase-1-to-placental growth factor ratio may be a clinically useful tool to distinguish between small-for-gestational-age fetuses with and without fetal growth restriction. This study aimed to determine whether the soluble fms-like tyrosine kinase-1-to-placental growth factor ratio can distinguish between small-for-gestational-age fetuses with and without fetal growth restriction with a birthweight of ≤10th percentile. A retrospective audit of 233 singleton pregnancies delivering an infant with a birthweight of ≤10th percentile corrected for gestational age with an antenatal maternal serum soluble fms-like tyrosine kinase-1-to-placental growth factor result was performed. Fetal growth restriction was defined as a birthweight of ≤10th percentile with an umbilical artery pulsatility index of >95th percentile, fetal middle cerebral artery pulsatility index of <5th percentile, amniotic fluid index of <6 cm, and/or cerebroplacental ratio of <1st percentile. The soluble fms-like tyrosine kinase-1-to-placental growth factor ratios before delivery between fetuses with and without fetal growth restriction (121 [fetal growth restriction] vs 112 [no fetal growth restriction]) were compared. The Student t test and Fisher exact test were used to compare cases and controls. The Mann-Whitney U test, linear regression analysis, and Spearman correlation coefficient (Rho) were used to examine associations between the soluble fms-like tyrosine kinase-1-to-placental growth factor ratio and fetal outcomes to determine whether the soluble fms-like tyrosine kinase-1-to-placental growth factor ratio served as a prognostic marker of fetal growth restriction severity. The mean soluble fms-like tyrosine kinase-1-to-placental growth factor ratio was increased in fetal growth restriction cases compared with non-fetal growth restriction controls (234.3±25.0 vs 67.4±7.7, respectively; P<.0001). When controlling for preeclampsia, which is associated with placental insufficiency, fetal growth restriction cases still demonstrated an independent increase in the soluble fms-like tyrosine kinase-1-to-placental growth factor ratio (effect size, 0.865; 95% confidence interval, 0.509-1.220; P<.001). The soluble fms-like tyrosine kinase-1-to-placental growth factor ratio was negatively correlated with birthweight percentiles in pregnancies delivering an infant with a birthweight of ≤10th percentile (r=-0.3565; P<.0001). This association was maintained for fetuses with fetal growth restriction (r=-0.2309; P<.05), whereas fetuses without fetal growth restriction had no significant correlation between the soluble fms-like tyrosine kinase-1-to-placental growth factor ratio and neonatal birthweight percentiles. The soluble fms-like tyrosine kinase-1-to-placental growth factor ratio was significantly higher in small-for-gestational-age fetuses with fetal growth restriction than small-for-gestational-age fetuses without fetal growth restriction, independent of preeclampsia. Furthermore, the soluble fms-like tyrosine kinase-1-to-placental growth factor ratio was negatively correlated with fetal growth restriction birthweight percentiles, suggesting that it may be a clinical measure of fetal growth restriction severity. Therefore, the ratio may usefully delineate fetal growth restriction from constitutionally small but otherwise healthy fetuses antenatally, allowing for timely interventions in small-for-gestational-age cases with fetal growth restriction and unnecessary interventions to be minimized in small-for-gestational-age cases without fetal growth restriction.

Biomarkers at 6 weeks' gestation in the prediction of early miscarriage in pregnancy following assisted reproductive technology.

Miscarriage is a major concern in early pregnancy among women having conceived with assisted reproductive treatments. This study aimed to examine potential miscarriage-related biophysical and biochemical markers at 6 weeks' gestation among women with confirmed clinical pregnancy following in vitro fertilization (IVF)/embryo transfer (ET) and evaluate the performance of a model combining maternal factors, biophysical and biochemical markers at 6 weeks' gestation in the prediction of first trimester miscarriage among singleton pregnancies following IVF/ET. A prospective cohort study was conducted in a teaching hospital between December 2017 and January 2020 including women who conceived through IVF/ET. Maternal mean arterial pressure, ultrasound markers including mean gestational sac diameter, fetal heart activity, crown rump length and mean uterine artery pulsatility index (mUTPI) and biochemical biomarkers including maternal serum soluble fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF), kisspeptin and glycodelin-A were measured at 6 weeks' gestation. Logistic regression analysis was carried out to determine significant predictors of miscarriage prior to 13 weeks' gestation and performance of screening was estimated by receiver-operating characteristics curve analysis. Among 169 included pregnancies, 145 (85.8%) pregnancies progressed to beyond 13 weeks' gestation and had live births whereas 24 (14.2%) pregnancies resulted in a miscarriage during the first trimester. In the miscarriage group, compared to the live birth group, maternal age, body mass index, and mean arterial pressure were significantly increased; mean gestational sac diameter, crown rump length, mUTPI, serum sFlt-1, glycodelin-A, and the rate of positive fetal heart activity were significantly decreased, while no significant differences were detected in PlGF and kisspeptin. Significant prediction for miscarriage before 13 weeks' gestation was provided by maternal age, fetal heart activity, mUTPI, and serum glycodelin-A. The combination of maternal age, ultrasound (fetal heart activity and mUTPI), and biochemical (glycodelin-A) markers achieved the highest area under the curve (AUC: 0.918, 95% CI 0.866-0.955), with estimated detection rates of 54.2% and 70.8% for miscarriage before 13 weeks' gestation, at fixed false positive rates of 5% and 10%, respectively. A combination of maternal age, fetal heart activity, mUTPI, and serum glycodelin-A at 6 weeks' gestation could effectively identify IVF/ET pregnancies at risk of first trimester miscarriage.

Value of soluble fms-like tyrosine kinase-1/placental growth factor test in third trimester of pregnancy for predicting preeclampsia in asymptomatic women.

To estimate the value of screening maternal serum soluble fms-like tyrosine kinase/placental growth factor (sFlt-1/PlGF) ratio in asymptomatic women during 3rd trimester to predict preeclampsia (PE) development. The investigated group comprised of 178 pregnant women. During this gestation, 24 cases had developed PE and 12 isolated gestational hypertension (GH); whereas 142 remained normotensive. Blood samples were collected between 180 and 259 gestational days (g.d.) when the participants were asymptomatic. Serums were analyzed using the BRAHMS sFlt-1 Kryptor/BRAHMS PlGF plus Kryptor PE ratio test (Thermo Fisher Scientific, Henningdorf, Germany). High-risk pregnancies for the PE development were defined as sFlt-1/PlGF>38. The detection rate (DR) for manifestation of PE≤30days after sampling was 83.3% and overall DR during pregnancy 58.3%. Ten of 15 women having false positive prediction of PE suffered from GH, preterm birth and/or delivery of a small-for-gestational-age-newborn. False positive rate was significantly higher at 239-253 g.d. compared to sampling at 210-224 g.d. and 225-238 g.d. (21.9% vs. 7.8% and 5.3%; p < 0.05). The sFlt-1/PlGF test during 180-259 g.d. detected approximately half of subsequent PE cases. An optimal time to use the test for screening purposes was estimated 225-238 g.d. (DR 66.7%). False positive test results were more common to cases with other adverse pregnancy outcomes and samples drawn at higher gestational age.

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.

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.

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).

Maternal serum soluble fms‐like tyrosine kinase‐1 at 12, 22, 32 and 36 weeks' gestation in screening for pre‐eclampsia

To examine the distribution of maternal serum soluble fms-like tyrosine kinase-1 (sFlt-1) at 12, 22, 32 and 36 weeks' gestation in singleton pregnancies that develop pre-eclampsia (PE) and examine the performance of this biomarker in screening for PE. Serum sFlt-1 was measured in 7066 cases at 11-13 weeks, 8079 cases at 19-24 weeks, 8472 at 30-34 weeks and 4043 at 35-37 weeks. Bayes' theorem was used to combine the a-priori risk from maternal characteristics and medical history with serum levels of sFlt-1. The performance of screening for PE in women requiring delivery < 32, between 32 + 0 and 36 + 6 and ≥ 37 weeks' gestation was estimated. In pregnancies that developed PE, serum sFlt-1 was increased and the separation in multiples of the median (MoM) values from normal was greater with earlier, compared to later, gestational age at which delivery for PE became necessary. In pregnancies that developed PE, the slope of the regression lines of sFlt-1 MoM with gestational age at delivery increased with advancing gestational age at screening. Measurement of sFlt-1 at 11-13 weeks did not improve the prediction of PE achieved by maternal factors alone, sFlt-1 at 19-24 weeks improved the prediction of PE delivering < 37 weeks but not for PE delivering ≥ 37 weeks, sFlt-1 at 30-34 weeks improved the prediction of PE delivering < 37 and PE delivering ≥ 37 weeks and sFlt-1 at 35-37 weeks improved the prediction of PE delivering ≥ 37 weeks. The detection rates (DRs), at a false-positive rate (FPR) of 10%, of PE delivering < 32 weeks were 52% and 65% with screening at 12 and 22 weeks, respectively. The DRs for PE delivering between 32 + 0 and 36 + 6 weeks were 44%, 44% and 93% with screening at 12, 22 and 32 weeks. The DR for PE delivering ≥ 37 weeks were 37%, 37%, 52% and 69% with screening at 12, 22, 32 and 36 weeks, respectively. The performance of combined screening with maternal factors, medical history and serum sFlt-1 is superior for detection of early, compared to late, PE and improves with advancing gestational age at screening. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

Serum soluble fms-like tyrosine kinase-1 in the three trimesters of pregnancy: effects of maternal characteristics and medical history.

To define the contribution of maternal variables which influence the measured level of maternal serum soluble fms-like tyrosine kinase-1 (sFlt-1) in screening for pregnancy complications. Maternal characteristics and medical history were recorded and serum sFlt-1 was measured in women with a singleton pregnancy attending for three routine hospital visits at 11 + 0 to 13 + 6, 19 + 0 to 24 + 6 and 30 + 0 to 34 + 6 or 35 + 0 to 37 + 6 weeks' gestation. For pregnancies delivering phenotypically normal live births or stillbirths ≥ 24 weeks' gestation, variables from maternal demographic characteristics and medical history that are important in the prediction of sFlt-1 were determined from a linear mixed-effects multiple regression. Serum sFlt-1 was measured in 7066 cases in the first trimester, 8078 in the second trimester and 10,464 in the third trimester. Significant independent contributions to serum sFlt-1 were provided by gestational age, maternal weight, racial origin, cigarette smoking, birth-weight Z-score of the neonate in the previous pregnancy and interpregnancy interval. Random-effects multiple regression analysis was used to define the contribution of maternal variables that influence the measured level of serum sFlt-1 and express the values as multiples of the median (MoMs). The model was shown to provide an adequate fit of MoM values for all covariates, both in pregnancies that developed pre-eclampsia and in those without this pregnancy complication. A model was fitted to express measured serum sFlt-1 across the three trimesters of pregnancy as MoMs, after adjusting for variables from maternal characteristics and medical history that affect this measurement.

Value of second trimester maternal serum sFlt-1, PlGF and their ratio in the prediction of preeclampsia

To study the value of second trimester maternal serum soluble Fms-like tyrosine kinase 1 (sFlt-1), placenta grouth factor (PlGF) and their ratio in the prediction of preeclampsia. In this nested case-control study, we collected second trimester maternal serum samples at 15-20 weeks and 24-28 weeks of gestation from those who developed gestational hypertensive disorders. Maternal serum sFlt-1 and PlGF were measured by electrochemiluminescence immunoassay on an automated platform. The value of sFlt-1, PlGF and their ratio were compared between gestational hypertensive group and the control group. Totally 41 patients with preeclampsia, 44 patients with gestational hypertension and 88 women with normal pregnancy outcomes were included in this study. There was no difference of age, gravidity, parity and preconception body mass index (BMI) between these three groups (P > 0.05) .Gestational week at delivery and neonatal birth weight were different between preeclampsia group and the control group (P < 0.01). The mean value of sFlt-1, PlGF and sFlt-1/PlGF ratio was (1 658 ± 488) µg/L, (141 ± 80) µg/L and 17 ± 9 in preeclampsia group, (1 945 ± 575) µg/L, (143 ± 52) µg/L and 15 ± 6 in gestational hypertension group, and (2 084 ± 741) µg/L, (65 ± 58) µg/L and 16 ± 9 in the control group at 15-20 weeks of gestation. There was no difference of sFlt-1, PlGF value and their ratio among the three groups at 15-20 weeks of gestation (P > 0.05) . The median value of sFlt-1, PlGF and sFlt-1/PlGF ratio were 8 525 µg/L, 35 µg/L and 398.0 in preeclampsia group, 905 µg/L, 336 µg/L and 2.7 in gestational hypertension group, 1 028 µg/L, 477 µg/L and 2.3 in the control group at 24-28 weeks of gestation. The value of sFlt-1, PlGF and their ratio was significantly different between preeclampsia group and the control group at 24-28 weeks of gestation (P < 0.01) . PlGF value was different between gestational hypertension group and the control group (P < 0.01) . The sensitivity and specificity of serum sFlt-1, PlGF and sFlt-1/PlGF ratio at 24-28 weeks of gestation to predict preeclampsia were 93% and 99% for sFlt-1 (cut off value 2 500 µg/L), 92% and 77% for PlGF (cut off value 270 µg/L) , 89% and 99% for sFlt-1/PlGF ratio (cut off value 11) . The value of sFlt-1, PlGF and their ratio at 24-28 weeks of gestation was significantly changed before clinical onset of preeclampsia.Use these serum indicators to predict preeclampsia will hopefully provide objective evidence for the management of patients who will develop preeclampsia later.

Maternal serum soluble fms-like tyrosine kinase 1 concentrations are not increased in early pregnancy and decrease more slowly postpartum in women who develop preeclampsia

We measured maternal serum soluble fms-like tyrosine kinase 1 concentrations across pregnancy and immediately postpartum in women who developed preeclampsia and normal pregnant women. This was a nested case control study of 113 normal pregnant women and 55 women with preeclampsia. Serum soluble fms-like tyrosine kinase 1 concentrations increased similarly in early pregnancy in both groups. Mean serum soluble fms-like tyrosine kinase 1 concentrations were increased in women who developed preeclampsia, compared with normal pregnant women, and this increase was most pronounced in severe preeclampsia. However, many women with preeclampsia had soluble fms-like tyrosine kinase 1 concentrations similar to normal pregnant women. Lastly, soluble fms-like tyrosine kinase 1 decreased rapidly after delivery, but this decrease was significantly slower in women with severe preeclampsia. Increased soluble fms-like tyrosine kinase 1 is not an early-pregnancy event among women who later develop preeclampsia. Increased soluble fms-like tyrosine kinase 1 is more likely to be present in women with severe preeclampsia, but it is not present in all women with preeclampsia. Soluble fms-like tyrosine kinase 1 concentrations decrease more slowly after delivery in women with preeclampsia, consistent with a decreased rate of excretion or continued production.