Placental Growth Factor Ratio Research Articles

Evaluation of the Prognostic Value of the sFlt-1/PlGF Ratio in Early-Onset Preeclampsia.

Increased expression of soluble fms-like tyrosine kinase 1 (sFlt-1), associated with a decrease in placental growth factor (PlGF), plays a key role in the pathogenesis of preeclampsia (PE). We evaluated the prognostic value of the sFlt-1/PlGF ratio for the onset of adverse maternofetal outcomes (AMFO) in case of early-onset PE with attempted expectant management. From October 2016 through November 2018, all singleton pregnancies complicated by early-onset PE (before 34 weeks of gestation) were included in a cohort study. The plasma levels of sFlt-1 and PlGF were blindly measured on admission. For the statistical analysis, we performed a bivariate analysis, a comparison of the receiving operating characteristic curves and a survival analysis estimated by the Kaplan-Meier method. Among 109 early PE, AMFO occurred in 87 pregnancies (79.8%), mainly hemolysis, elevated liver enzymes, and low platelet count syndrome and severe fetal heart rate abnormalities requiring urgent delivery. The area under the curve (AUC) of sFlt-1/PlGF ratio was 0.82 (95% confidence interval [CI]: 0.73-0.88) for the risk of AMFO and the difference between the AUCs was significant for each separate standard parameter (p = 0.018 for initial diastolic blood pressure, p = 0.013 for alanine aminotransferase, p < 0.001 for uric acid). Pregnancies were best classified by a cutoff ratio of 293, with a sensitivity of 95% and a specificity of 50%. With a ratio value less than 293, no pregnancy was complicated or had been stopped during the first 5 days. A ratio more than 293 was associated with an increased risk of AMFO onset (hazard ratio [HR]: 3.61; 95% CI: 2.13-6.10; p < 0.001) and had a significant association with the length of time between the diagnosis of PE and delivery (HR: 2.49; 95% CI: 1.56-3.96; p < 0.001). The sFlt-1/PlGF ratio is an additional tool in the prediction of AMFO in proven early-onset PE, which is likely to improve care by anticipating severe complications. · The sFlt-1/PlGF ratio is associated with AMFO.. · It is an additional tool for physician.. · We proposed a 293 cutoff value for the ratio..

Prediction of Preeclampsia and Intrauterine Growth Restriction: Development of Machine Learning Models on a Prospective Cohort.

BackgroundPreeclampsia and intrauterine growth restriction are placental dysfunction–related disorders (PDDs) that require a referral decision be made within a certain time period. An appropriate prediction model should be developed for these diseases. However, previous models did not demonstrate robust performances and/or they were developed from datasets with highly imbalanced classes.ObjectiveIn this study, we developed a predictive model of PDDs by machine learning that uses features at 24-37 weeks’ gestation, including maternal characteristics, uterine artery (UtA) Doppler measures, soluble fms-like tyrosine kinase receptor-1 (sFlt-1), and placental growth factor (PlGF).MethodsA public dataset was taken from a prospective cohort study that included pregnant women with PDDs (66/95, 69%) and a control group (29/95, 31%). Preliminary selection of features was based on a statistical analysis using SAS 9.4 (SAS Institute). We used Weka (Waikato Environment for Knowledge Analysis) 3.8.3 (The University of Waikato, Hamilton, NZ) to automatically select the best model using its optimization algorithm. We also manually selected the best of 23 white-box models. Models, including those from recent studies, were also compared by interval estimation of evaluation metrics. We used the Matthew correlation coefficient (MCC) as the main metric. It is not overoptimistic to evaluate the performance of a prediction model developed from a dataset with a class imbalance. Repeated 10-fold cross-validation was applied.ResultsThe classification via regression model was chosen as the best model. Our model had a robust MCC (.93, 95% CI .87-1.00, vs .64, 95% CI .57-.71) and specificity (100%, 95% CI 100-100, vs 90%, 95% CI 90-90) compared to each metric of the best models from recent studies. The sensitivity of this model was not inferior (95%, 95% CI 91-100, vs 100%, 95% CI 92-100). The area under the receiver operating characteristic curve was also competitive (0.970, 95% CI 0.966-0.974, vs 0.987, 95% CI 0.980-0.994). Features in the best model were maternal weight, BMI, pulsatility index of the UtA, sFlt-1, and PlGF. The most important feature was the sFlt-1/PlGF ratio. This model used an M5P algorithm consisting of a decision tree and four linear models with different thresholds. Our study was also better than the best ones among recent studies in terms of the class balance and the size of the case class (66/95, 69%, vs 27/239, 11.3%).ConclusionsOur model had a robust predictive performance. It was also developed to deal with the problem of a class imbalance. In the context of clinical management, this model may improve maternal mortality and neonatal morbidity and reduce health care costs.

Placental Growth Factor and Soluble, Fms-Like Tyrosine Kinase-1 in Preeclampsia: A Case-Cohort (PEARL) Study.

Preeclampsia is associated with a higher maternal blood levels of soluble fms-like tyrosine kinase-1 (sFlt-1) and lower levels of placental growth factor (PlGF) that appear before clinical onset. We aimed to estimate the normal progression of these biomarkers in normal pregnancies and in those affected by preeclampsia. We conducted a case-cohort study including low-risk nulliparous women recruited at 11-13 weeks gestation (cohort) and women with preeclampsia (cases). Maternal blood was collected at different points during pregnancy including at the time of diagnosis of preeclampsia for cases. Maternal serum PlGF and sFlt-1 concentrations and the sFlt-1/PlGF ratio were measured using B•R•A•H•M•S plus KRYPTOR automated assays and were compared between patients in both groups matched for gestational age. Cases were stratified as early- (≤34 weeks), intermediate- (35-37 weeks) and late-onset (>37 weeks) preeclampsia. The cohort consisted of 45 women whose results were compared with those of 31 women who developed preeclampsia, diagnosed at a median gestational age of 32 weeks (range 25-38 weeks). We observed that sFlt-1, PlGF and their ratio fluctuated during pregnancy in both groups, with a significant correlation with gestational age after 28 weeks (P < 0.05). We observed a significant difference between cases and controls, with a median ratio 100 times higher in early preeclampsia (P < 0.001), 13 times higher in intermediate preeclampsia (P < 0.001), but no significant difference between groups in late-onset preeclampsia with matched controls. PlGF, sFlt-1, and their ratio may be useful in the prediction and diagnosis of early- and intermediate-onset preeclampsia but are not useful for late-onset preeclampsia.

Rule-in thresholds for DELFIA Xpress PlGF 1-2-3 test for suspected pre-eclampsia.

We aimed to establish a rule-in threshold for the DELFIA Xpress placental growth factor (PlGF) 1-2-3 test. Plasma EDTA samples from 305 women presenting with suspected pre-eclampsia before 35weeks' gestation were analysed using three different PlGF-based tests: PlGF 1-2-3 test (Perkin Elmer); Triage PlGF test (Quidel); Elecsys immunoassay sFlt-1/PlGF ratio (Roche). The rule-in threshold for PlGF 1-2-3 test created with equivalent specificity of the Quidel and Roche tests was 50pg/ml. This can be used as a rule-in test for diagnosis of preterm pre-eclampsiarequiring delivery within 14days (specificity 95.0% (95% CI 91.7-97.2%), positive predictive value50 (95% CI 30.6-69.4%), positive likelihood ratio 10.7 (5.8-20).

Verification of placental growth factor and soluble-fms-like tyrosine kinase 1 assay performance in late pregnancy and their diagnostic test accuracy in women with reduced fetal movement.

Placental growth factor (PlGF) and soluble-fms-like tyrosine kinase 1 (sFlt-1) are biomarkers of placental function used to aid the diagnosis and prediction of pregnancy complications. This work verified the analytical performance of both biomarkers and provides preliminary diagnostic accuracy data to identify adverse pregnancy outcome in women with reduced fetal movement. Verification of sFlt-1 and PlGF assays included a comparative accuracy assessment of 24 serum samples analysed at six different sites and laboratory-specific precision estimates. The sFlt-1/PlGF ratio was assessed in serum samples obtained prospectively from 295 women with reduced fetal movement ≥36 weeks' gestation; diagnostic accuracy was evaluated using 2 × 2 tables and area under the receiver operator characteristic (AUROC) curve. Regression analysis showed that performance between sites was good with Passing-Bablok slopes ranging from 0.96 to 1.05 (sFlt-1) and 0.93 to 1.08 (PlGF). All sites had a mean bias <15%, although there was poorer agreement at the lowest PlGF concentrations. All within- and between-batch coefficients of variation were <10%. In 289 women with an appropriately grown fetus, an sFlt-1/PlGF ratio ≥38 had a sensitivity of 0.20 (95% confidence interval [CI] 0.07, 0.41), specificity of 0.88 (95% CI 0.83, 0.92) and AUROC curve of 0.58 (95% CI 0.47, 0.68) to identify adverse pregnancy outcome. Analytical performance of the sFlt-1 and PlGF assays was comparable across different sites. The sensitivity of sFlt-1/PlGF to identify adverse pregnancy outcome in women with reduced fetal movement was considered acceptable, in the absence of other tests, to progress to a pilot randomized controlled trial.

Soluble fms-like tyrosine kinase 1 and placental growth factor ratio for predicting preeclampsia in elderly gravida

ABSTRACT Objective To determine the predictive value of plasma soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF) ratio for detection of preeclampsia in elderly gravida at 16–18 weeks of gestation and to identify whether abnormalities of this ratio are associated with any other pregnancy complications or not. Methods Blood samples of 300 cases were collected. Plasma sFlt-1 and PlGF levels were measured using an automated immunoassay. Results Sensitivity and specificity for plasma sFlt-1/PlGF ratio above 9.8 for preeclampsia prediction were 85.7% and 61.2%, respectively. The sensitivity and specificity to predict early onset preeclampsia were 100% and 61.1%, respectively. Women with abnormal plasma sFlt-1/PlGF ratio were not associated with any other pregnancy complications. Conclusion sFlt-1/PlGF ratio at 16–18 weeks of gestation in elderly gravida has a high sensitivity for predicting preeclampsia, especially early onset preeclampsia.

A maternal serum metabolite ratio predicts fetal growth restriction at term.

Fetal growth restriction (FGR) is the major single cause of stillbirth1 and is also associated with neonatal morbidity and mortality2,3, impaired health and educational achievement in childhood4,5 and with a range of diseases in later life6. Effective screening and intervention for FGR is an unmet clinical need. Here, we performed ultrahigh performance liquid chromatography-tandem mass spectroscopy (UPLC-MS/MS) metabolomics on maternal serum at 12, 20 and 28 weeks of gestational age (wkGA) using 175 cases of term FGR and 299 controls from the Pregnancy Outcome Prediction (POP) study, conducted in Cambridge, UK, to identify predictive metabolites. Internal validation using 36 wkGA samples demonstrated that a ratio of the products of the relative concentrations of two positively associated metabolites (1-(1-enyl-stearoyl)-2-oleoyl-GPC (P-18:0/18:1) and 1,5-anhydroglucitol) to the product of the relative concentrations of two negatively associated metabolites (5α-androstan-3α,17α-diol disulfate and N1,N12-diacetylspermine) predicted FGR at term. The ratio had approximately double the discrimination as compared to a previously developed angiogenic biomarker7, the soluble fms-like tyrosine kinase 1:placental growth factor (sFLT1:PlGF) ratio (AUC 0.78 versus 0.64, P = 0.0001). We validated the predictive performance of the metabolite ratio in two sub-samples of a demographically dissimilar cohort, Born in Bradford (BiB), conducted in Bradford, UK (P = 0.0002). Screening and intervention using this metabolite ratio in conjunction with ultrasonic imaging at around 36 wkGA could plausibly prevent adverse events through enhanced fetal monitoring and targeted induction of labor.

Combining Biomarkers to Predict Pregnancy Complications and Redefine Preeclampsia: The Angiogenic-Placental Syndrome.

Placental dysfunction underlies a spectrum of perinatal pathologies, including preeclampsia and fetal growth restriction. Angiogenesis-related factors, including sFlt-1 (soluble fms-like tyrosine kinase 1) and PlGF (placental growth factor), play an important role in placental dysfunction; altered levels are detectable several weeks before onset of pregnancy complications. In vitro diagnostic tests for these biomarkers can improve early diagnosis and facilitate prediction of maternal and fetal outcomes. We assessed evidence for combining angiogenic biomarkers with other biomarkers or clinical parameters to predict maternal/fetal outcomes in pregnant women with placental dysfunction. Pooled information on placental perfusion (ultrasonography, mean arterial pressure), clinical characteristics, and biomarker levels (PlGF) can improve first-trimester prediction and preeclampsia diagnosis. Angiogenic factors (sFlt-1/PlGF ratio; PlGF alone) with or without clinical characteristics can facilitate second-/third-trimester prediction of early-onset and late-onset preeclampsia. A combination of increased sFlt-1/PlGF ratio and ultrasound can rule out early fetal growth restriction. The sFlt-1/PlGF ratio is also a reliable tool for discriminating between pregnancy-related hypertensive disorders, including superimposed preeclampsia and gestational hypertension. Analysis of angiogenic factors with or without uterine Doppler substantially improves sensitivity and specificity for predicting adverse outcomes and iatrogenic preterm delivery. We propose to extend the American College of Obstetricians and Gynecologists definition of preeclampsia in the future to include the combination of new-onset hypertension and new-onset of altered angiogenic factors (sFlt-1/PlGF ratio or PlGF alone). In summary, altered angiogenic biomarkers indicate placental dysfunction, and their implementation into clinical practice will help reduce the considerable burden of morbidity and mortality associated with adverse pregnancy outcomes as a consequence of angiogenic-placental syndrome.

Diagnostic accuracy of sFlt1/PlGF ratio as a marker for preeclampsia

BackgroundPreeclampsia (PE) is a serious complication of pregnancy and one of the main causes of maternal and neonatal mortality and morbidity in the world. Finding a biomarker with high sensitivity and specificity could lead to prediction and early diagnosis of the disease and reduces its complications. In this study, we evaluated diagnostic accuracy of Soluble fms-like tyrosine kinase-1 (sFlt-1) to Placental growth factor (PlGF) ratio for diagnosis of PE.MethodsThe cases included 23 mild, 15 severe preeclamptic patients, and 20 normal term pregnant women as control referred to GYN ward of the Persian Gulf Hospital in Bandar Abbas from 2014 to 2016. Levels of sFlt-1 and PlGF were measured. Receiver Operating Characteristic (ROC) curve analysis was applied to calculate diagnostic accuracy of sFlt-1/PlGF ratio.ResultsThe mean Level of sFlt-1/PlGF in PE patients (91.33 ng/ml) was significantly higher than control women (17.62) (P<0.001). ROC curve analysis showed sFlt-1/PlGF ratio diagnostic accuracy in preeclamptic patients with Area Under Curve (AUC) of 0.90, the best cut-off value of 24.96, sensitivity and specificity of 84.2 and 85.0%, respectively.ConclusionsOur data showed sFlt-1/PlGF ratio has higher accuracy for differentiating PE patients from non-PEs in comparison with its power for differentiating severe or early onset forms of the disease.

From first-trimester screening to risk stratification of evolving pre-eclampsia in second and third trimesters of pregnancy: comprehensive approach.

Preeclampsia and associated hypertensive disorders of pregnancy represent a leading cause of global maternal and neonatal morbidity and mortality. Identification of women at high risk for developing preterm-preeclampsia and prophylaxis with low-dose aspirin has the potential to significantly reduce the rate of preterm-preeclampsia. In addition, risk assessment and monitoring of women in the second and third trimester of pregnancy, to aid in early detection of evolving disease, timely referral to specialist care, and active monitoring of women with confirmed or suspected preeclampsia is essential for improving maternal and neonatal outcomes. The angiogenesis-related biomarkers sFlt-1 and PlGF have been shown to have clinical value to aid in the prediction, diagnosis, and risk stratification of preeclampsia when used either alone or in combination with other risk factors. However, currently there is no consensus on the optimum strategy to link first trimester screening for preterm-preeclampsia with appropriate second and third trimester risk assessment strategies. This opinion paper will outline the current evidence for first trimester preeclampsia screening and prevention, as well as the evidence for various risk stratification approaches for detection of evolving preeclampsia through the second and third trimesters of pregnancy, and proposes a potential model integrating these tools. This article is protected by copyright. All rights reserved.

Retrospective evaluation of established cut-off values for the sFlt-1/PlGF ratio for predicting imminent delivery in preeclampsia patients.

The outcome of preeclampsia is difficult to predict. Laboratory markers such as soluble fms-like tyrosine kinase (sFlt-1) and placental growth factor (PlGF) are thought to be predictive factors. A 2012 study by Verlohren et al. evaluated cut-off values for assessing time to delivery in patients with elevated sFlt-1/PlGF ratios. The present study aimed to evaluate findings in patients with elevated sFlt-1/PlGF ratios who gave birth at Kepler University Hospital in Linz, Austria. The hypothesis was tested, that our patients show longer pregnancy duration despite elevated sFlt-1/PlGF ratios. This retrospective data analysis included all patients with sFlt-1/PlGF ratios above the established cut-off values between January 2014 and October 2017. Two groups were analyzed relative to gestational age and were matched with healthy controls: 24+0 to 33+6 gestational weeks, sFlt-1/PlGF ratio >655.2; and 34+0 to 36+6 gestational weeks, sFlt-1/PlGF ratio >201. sFlt-1/PlGF ratio and time to delivery correlation. In the <34-week group, 43.2% of the patients delivered beyond 48h, with a mean sFlt-1/PlGF ratio of 885.06, showing a significantly lower sFlt-1/PlGF ratio than patients who delivered within 2days (P=0.04). In the >34-week group, 66.7% were still pregnant after 48h, with a mean sFlt-1/PlGF ratio of 273.7. The sFlt-1/PlGF ratio appears to be a powerful tool for diagnosing and predicting preeclampsia. However, the data do not confirm the cut-off values described earlier, with longer pregnancy durations in this group of patients.

Preeclampsia Screening Using the Ratio of Soluble FMS-Like Tyrosine Kinase-1 to Placental Growth Factor During Pregnancy in Pregnant Korean Women

We retrospectively investigated soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) ratios and screen-positive rates according to cutoff values for preeclampsia risk assessment based on the number of fetuses. sFlt-1/PlGF ratios < 38.0 and < 53.0 were defined as low risk of preeclampsia (screen negative) for singleton and twin pregnancies, respectively. During the study period, 442 test results from 403 pregnant women (374 with singleton and 29 twin pregnancies) from 32 local clinics and hospitals were analyzed. The overall rate of positive preeclampsia screening was 25.1% and this rate was higher when gestational age was ≥ 34 weeks than when it was < 34 weeks (58.7% vs. 18.6%, p < 0.05). Among 34 women with follow-up results, a change in interpretation category was observed during the follow-up period at ≥ 4.8 weeks for singleton and ≥ 1.6 weeks for twin pregnancies, respectively. This study may help to understand the sFlt-1/PlGF ratio in pregnant Korean women.

177: Metabolomic biomarkers in midtrimester maternal plasma can accurately predict the development of preeclampsia

Early identification of patients at risk of developing preeclampsia (PE) would allow providers to tailor their prenatal management and adopt preventive strategies, such as low-dose aspirin. This study investigates the ability of metabolomic biomarkers in mid-trimester maternal plasma to predict PE. In the mid-trimester study population, a case-control study was conducted including 33 pregnant women with mid-trimester maternal plasma (gestational age [GA], 16-24 weeks) who subsequently developed PE and 66 GA-matched controls with normal outcomes. Mid-trimester maternal plasma was comprehensively profiled for primary metabolomic and lipidomic signatures using gas chromatography time-of-flight mass spectrometry and liquid chromatography Orbitrap mass spectrometry. In the at-delivery study population, a retrospective cohort study was conducted using plasma samples collected from women who were delivered in the late preterm period for PE(n=13) or other causes(n=21), and the metabolomic biomarkers in maternal plasma collected at delivery were compared based on the indication of delivery. Performance of the metabolomic panel was compared also to soluble fms-like tyrosine kinase-1(sFlt-1) and placental growth factor(PlGF) in maternal plasma. In the mid-trimester study population, 329 metabolites were identified and semi-quantitated. Binary logistic regression analysis proposed a mid-trimester biomarker panel for the prediction of PE with five metabolites (SM C28:1, SM C30:1, lysoPC C19:0, lysoPE C20:0, propane-1,3-diol). This metabolomic model predicted PE better than PlGF alone (AUC=0.87[95% CI, 0.78-0.93] vs 0.65[0.55-0.74]; p< 0.005) (Figure) or sFlt-1/PlGF ratio (data not shown). In the at-delivery study population, we confirmed the ability of this biomarker panel to distinguish PE from non-PE, with comparable discrimination power to that of sFlt-1/PlGF ratio (data not shown). Integrative metabolomic biomarker panel in mid-trimester maternal plasma can accurately predict the subsequent development of PE, and also showed good discriminatory power at the time of delivery.

Factors of angiogenesis and placental hormones in pregnant women with arterial hypertension

The changes of the factors of angiogenesis and hormones of pregnancy in pregnant women with hypertension of I and II stages has been studied inadequately and their interaction in such patients is not fully elucidated at present time. Aim. To detect peculiarities of angiogenesis factors and placental hormones in pregnant women with arterial hypertension I and II grades in comparison with results of healthy pregnant women. Materials and methods. A one-time study of pregnant women was performed in pregnancy of 12–13 weeks in all groups. 88 pregnant women were inspected. The 1st basic group consisted of 28 pregnant women with AH of I grade; the 2nd group consisted of 33 pregnant women with AH of II grade; the comparison group included 27 women without AH. The following hormones were determined: HCG, PG, E. Among the angiogenesis indices, the placental growth factor (PGF), as a pro-angiogenic factor and placental soluble fms-like tyrosine kinase (sFlt-1) was determined as an anti-angiogenic factor, sFlt-1/PGF ratio was also estimated. Statistical analysis was done by using “Statistica for Windows 13” (StatSoft Inc., № JPZ804I382130ARCN10-J). Results. Pregnant women in 1st group were the youngest: the average age was 26.4 ± 0.8 years versus 33.8 ± 0.6 years in 2nd group and 32.0 ± 1.0 years in control group, P ˂ 0.001. PGF levels were decreased in both 1st (17.5 ± 3.4 pg/ml) and 2nd groups (13.5 ± 2.5 pg/ml) in comparison with results in 3rd group (46.1 ± 7.0 pg/ml), P ˂ 0.001. We didn’t find statistical differences between results of women with AH of I and II degree, P ˃ 0.05. Contrary to previous results, sFlt-1 levels were increased in both 1st and 2nd groups, P ˂ 0.05: 1703.1 ± 99.2 pg/ml in 1st group and 1673.7 ± 93.5 pg/ml in 2nd group versus 1384.4 ± 77.1 pg/ml in control group, but they weren’t different between basic groups, P ˃ 0.05. As a result, sFlt-1/PGF ratio level was increased in both 1st (273.3 ± 54.6 units) and 2nd (415.8 ± 79.0 units) groups in comparison with control (46.6 ± 9.4 units), P ˂ 0.001. We didn’t set statistical differences in hormones levels among pregnant patients. PGF level was connected with E (r = -0.54, P ˂ 0.01) and HCG (r = -0.42, P ˂ 0.05) levels in pregnant women with AH of I degree. It was connected with HCG level in control group, but this correlation was contrary: r = +0.63, P ˂ 0.001. Conclusions. Pregnant women with AH in I trimester have disturbances in balance between pro-angiogenic and anti-angiogenic factors with prevalence of sFlt-1 and reducing of PGF in blood serum. Due to such disbalance in pregnant women with AH of I grade correlation between angiogenesis factors and hormones changed from direct to inverse.

A Case Report of Influence of Free Tyrosine Kinase/Placental Growth Factor (SFLT-1/PLGF) Ratio Test for Preeclampsia on Clinical Decision Making in Screening Positive Women

Summary Preeclampsia (PE) is characterized by hypertension and proteinuria after the 20th gestational week (GW). It is a significant cause of maternal and fetal perinatal morbidity and mortality during pregnancy. There is increasing evidence suggesting that PE is due to an impaired balance between maternal placental angiogenic and antiangiogenic factors that harm maternal vascular endothelium. The study aimed to assess the clinical and financial aspects of introducing into practice the soluble fms-like tyrosine kinase (sFlt-1) to placental growth factor (PlGF) ratio test to improve the management of preeclampsia and adverse pregnancy outcome, intrauterine growth retardation, iatrogenic prematurity, and placental abruption. We report a case study in which we used the sFlt-1/PlGF ratio in the management of a high-risk pregnancy. Unnecessary hospitalization was avoided, and the patient was managed appropriately.

Association between the fetal cerebroplacental ratio and biomarkers of hypoxia and angiogenesis in the maternal circulation at term

ObjectivesA low fetal cerebroplacental ratio (CPR) in late pregnancy is a marker of a fetus that has failed to reach its growth potential and is associated with a variety of perinatal and pregnancy complications. It is not known if it is also correlated with aberrations in angiogenic, hypoxia-responsive or inflammatory cytokine levels in the maternal circulation. We investigated if there were any differences in levels of biomarkers of angiogenesis, endothelial cell dysfunction, hypoxia and/or inflammation in term pregnancies with a low fetal CPR compared to controls. We hypothesized that as the CPR is a marker of suboptimal growth, this would be reflected in a shift towards upregulation of hypoxia-responsive factors even in non-small for gestational age fetuses. Study designWe used Multiplex ELISA to measure a panel of 28 candidate biomarkers of angiogenesis and/or hypoxia in pre-labour maternal plasma from 113 women at term, stratified for CPR <10th centile vs. CPR >10th centile. Plasma levels of the biomarkers were measured using 2 multiplex Luminex assays - a commercially available human angiogenesis/growth factor panel (R&D Systems®), comprising 15 analytes and an in-house custom panel of a further 13 candidate biomarkers. ResultsOf the 28 candidate biomarkers investigated, we found significantly elevated levels of Carbonic Anhydrase 9 and soluble Fms-like tyrosine kinase (Vascular Endothelial Growth Factor Receptor 1), and lower levels of Placental Growth Factor in plasma from women with a low fetal CPR. The soluble Fms-like tyrosine kinase-1/Placental Growth Factor ratio was also markedly elevated in this cohort. We also demonstrated significant inverse correlations between the fetal CPR and Carbonic Anydrase 9, soluble Fms-like tyrosine kinase and Hepatocyte Growth Factor. ConclusionsA low fetal CPR is associated with changes in some hypoxia-responsive and angiogenesis factors in the maternal circulation in pregnancies with normally grown fetuses.

A more accurate prediction to rule in and rule out pre-eclampsia using the sFlt-1/PlGF ratio and NT-proBNP as biomarkers.

Background The management of potential pre-eclamptic patients using the soluble FMS-like tyrosine kinase 1 (sFlt-1)/ placental growth factor (PlGF) ratio is characterised by frequent false-positive results. Methods A retrospective cohort study was conducted to identify and validate cut-off values, obtained using a machine learning model, for the sFlt-1/PlGF ratio and NT-proBNP that would be predictive of the absence or presence of early-onset pre-eclampsia (PE) in singleton pregnancies presenting at 24 to 33 + 6 weeks of gestation. Results For the development cohort, we defined two sFlt-1/PlGF ratio cut-off values of 23 and 45 to rule out and rule in early-onset PE at any time between 24 and 33 + 6 weeks of gestation. Using an sFlt-1/PlGF ratio cut-off value of 23, the negative predictive value (NPV) for the development of early-onset PE was 100% (95% confidence interval [CI]: 99.5-100). The positive predictive value (PPV) of an sFlt-1/PlGF ratio >45 for a diagnosis of early-onset PE was 49.5% (95% CI: 45.8-55.6). When an NT-proBNP value >174 was combined with an sFlt-1/PlGF ratio >45, the PPV was 86% (95% CI: 79.2-92.6). In the validation cohort, the negative and positive values were very similar to those found for the development cohort. Conclusions An sFlt-1/PlGF ratio <23 rules out early-onset PE between 24 and 33 + 6 weeks of gestation at any time, with an NPV of 100%. An sFlt-1/PlGF ratio >45 with an NT-proBNP value >174 significantly enhances the probability of developing early-onset PE.

Role of sFlt-1/PlGF ratio and feto-maternal Doppler for the prediction of adverse perinatal outcome in late-onset pre-eclampsia.

The sFlt-1 (soluble fms-like tyrosine kinase-1)/PlGF (placental growth factor) ratio and uterine artery Doppler have shown to be helpful in the diagnosis of pre-eclampsia (PE). The predictive value of the cerebroplacental ratio (CPR) regarding adverse perinatal outcome (APO) in low-risk pregnancies is intensively discussed. We evaluated the extent to which sFlt-1/PlGF ratio and feto-maternal Doppler may be useful in predicting APO in singleton pregnancies complicated by late-onset PE and/or HELLP syndrome. This is a retrospective study from 2010 to 2018 consisting of singleton pregnancies with confirmed diagnosis of late-onset (lo ≥ 34weeks) PE/HELLP syndrome in which sFlt-1/PlGF ratio and feto-maternal Doppler (mUtA-PI: mean uterine artery pulsatility index and CPR) were determined. The ability of sFlt-1/PlGF ratio, mUtA-PI, CPR and their combination to predict APO or SGA was evaluated using receiver operating characteristic (ROC) curves. 67 patients were included in the final analysis. Of these, sFlt-1/PlGF was > 110 (defining angiogenic lo PE) in 40.3% (27/67), mUtA-PI was above the 95th centile in 34.3% (23/67) patients and CPR was lower than the 5th centile in 10.4% (7/67). Abnormal sFlt-1/PlGF and mUtA-PI as well as CPR were associated with a lower birth weight (BW). Late-preterm birth (< 37weeks) as well as postnatal diagnosis of small for gestational age (SGA: BW < 3rd centile) was significantly more often in angiogenic lo PE cases. Neither sFlt-1/PIGF nor CPR or mUtA-PI were APO predictors. Only for sFlt-1/PlGF, ROC analysis revealed a significant predictive value for postnatal SGA (AUC = 0.856, p = 0.001, 95% CI 0.75-0.97). There was no statistical added value of combined SGA predictors as compared to sFlt-1/PlGF alone. In patients with lo PE, adding sFlt-1/PlGF ratio to routine antepartum fetal surveillance may be useful to identify cases of postnatal SGA. However, further prospective studies are warranted to define the role of feto-maternal Doppler and sFlt-1/PlGF ratio as outcome predictors.

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.

Angiogenic factors during pregnancy in Asian women with elevated blood pressure in early pregnancy and the risk of preeclampsia: a longitudinal cohort study

ObjectiveIt remains unclear what roles placenta-originated angiogenic factors play in the pathogenesis of preeclampsia among hypertensive women. We compared maternal soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor...