Soluble fms-like tyrosine kinase-1 to placental growth factor ratio: ruling out pre-eclampsia for up to 4 weeks and value of retesting.

OBJECTIVES: The soluble fms-like tyrosine kinase-1 (sFlt-1) to placental growth factor (PlGF) ratio is generally elevated some time before and at the clinical onset of pre-eclampsia. The PROGNOSIS study validated a sFlt-1/PlGF ratio cut-off of ≤ 38 to rule out the onset of pre-eclampsia within 1 week of testing in women with suspected disease. The aim of this study was to assess the predictive value of the sFlt-1/PlGF ratio to rule out the onset of pre-eclampsia for up to 4 weeks, and to assess the value of repeat measurements. METHODS: This was an exploratory post-hoc analysis of data from the PROGNOSIS study performed in pregnant women aged ≥ 18 years with suspected pre-eclampsia, who were at 24 + 0 to 36 + 6 weeks' gestation at their first clinic visit. Serum samples were collected at the first visit and weekly thereafter. sFlt-1 and PlGF levels were measured using Elecsys® sFlt-1 and PlGF immunoassays. Whether the sFlt-1/PlGF ratio cut-off of ≤ 38 used to rule out the onset of pre-eclampsia within 1 week could predict the absence of pre-eclampsia 2, 3, and 4 weeks post-baseline was assessed. The value of repeat sFlt-1/PlGF testing was assessed by examining the difference in sFlt-1/PlGF ratio 2 and 3 weeks after the first measurement in women with, and those without, pre-eclampsia or adverse fetal outcome. RESULTS: On analysis of 550 women, sFlt-1/PlGF ratio ≤ 38 ruled out the onset of pre-eclampsia 2 and 3 weeks post-baseline with high negative predictive values (NPV) of 97.9% and 95.7%, respectively. The onset of pre-eclampsia within 4 weeks was ruled out with a high NPV (94.3%) and high sensitivity and specificity (66.2% and 83.1%, respectively). Compared with women who did not develop pre-eclampsia, those who developed pre-eclampsia had significantly larger median increases in sFlt-1/PlGF ratio at 2 weeks (∆, 31.22 vs 1.45; P < 0.001) and at 3 weeks (∆, 48.97 vs 2.39; P < 0.001) after their initial visit. Women who developed pre-eclampsia and/or adverse fetal outcome compared with those who did not had a significantly greater median increase in sFlt-1/PlGF ratio over the same period (∆, 21.22 vs 1.40; P < 0.001 at 2 weeks; ∆, 34.95 vs 2.30; P < 0.001 at 3 weeks). CONCLUSION: The Elecsys® immunoassay sFlt-1/PlGF ratio can help to rule out the onset of pre-eclampsia for 4 weeks in women with suspected pre-eclampsia. © 2018 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Implantación del cociente sFlt-1/PlGF para la predicción y el diagnóstico de la preeclampsia en embarazos únicos: implicaciones para la práctica clínica / Implantation of the sFlt-1 / PlGF ratio for the prediction and diagnosis of Preeclampsia in single pregnancies: implications for clinical practice

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A comparison of the diagnostic utility of the sFlt-1/PlGF ratio versus PlGF alone for the detection of preeclampsia/HELLP syndrome.

OBJECTIVE: The Elecsys(®) immunoassay sFlt-1/PlGF ratio and the Triage(®) PlGF assay were compared (in a prospective, multicenter, case-control study) for diagnosis of preeclampsia/hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome. METHODS: Women in European perinatal care centers with singleton pregnancies were enrolled: 178 cases had confirmed preeclampsia and 391 controls had normal outcome. Patients in the preeclampsia/HELLP syndrome group were matched pairwise by gestational week to healthy controls (1:2). Maternal blood samples were analyzed using (a) fully automated Elecsys PlGF and Elecsys sFlt-1 immunoassays with two cutoffs (early-onset [<34 weeks] ≤33, ≥85; late-onset [≥34 weeks] ≤33, ≥110), and (b) Triage PlGF immunoassay (single cutoff). Diagnostic performance and utility were assessed. RESULTS: Respectively, 83 and 95 women had early-onset or late-onset preeclampsia/HELLP syndrome. The overall diagnostic performance of the Elecsys immunoassay sFlt-1/PlGF ratio (area under the curve [AUC] 0.941) was higher than for Triage PlGF (AUC 0.917). The Elecsys immunoassay sFlt-1/PlGF ratio sensitivity and specificity was: 94.0% (95% confidence interval [CI] 86.5-98.0) and 99.4% (95% CI: 96.8-99.9) for early-onset preeclampsia; and 89.5% (95% CI: 81.5-94.8) and 95.4% (95% CI: 91.7-97.8) for late-onset preeclampsia. The Triage assay sensitivity and specificity was: 96.4% (95% CI: 89.8-99.3) and 88.5% (95% CI: 82.8-92.8) (early-onset); and 90.5% (95% CI: 83-96) and 64.5% (95% CI: 57.8-70.9) (late onset). CONCLUSIONS: The fully automated Elecsys immunoassay sFlt-1/PlGF ratio provides improved diagnostic utility over the Triage PlGF assay with improved specificity for the clinical management of pregnant women with suspected preeclampsia/HELLP syndrome.

Maternal serum sFlt-1/PlGF ratio in twin pregnancies with and without pre-eclampsia in comparison with singleton pregnancies.

OBJECTIVE: In singleton pregnancies, soluble fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF) and the sFlt-1/PlGF ratio have shown utility as a diagnostic test for pre-eclampsia (PE). The objective of this study was to characterize the maternal serum levels of sFlt-1, PlGF and sFlt-1/PlGF ratio in normal and pre-eclamptic twin pregnancies. METHODS: In a European multicenter case-control study, 49 women with a twin pregnancy were enrolled, including 31 uneventful and 18 pre-eclamptic pregnancies. sFlt-1 and PlGF were measured and receiver-operating characteristics (ROC) analysis was performed. The median sFlt-1 and PlGF serum concentrations and sFlt-1/PlGF ratio were compared with those of a singleton cohort, matched for gestational age, with PE (n = 54) and with an uncomplicated pregnancy outcome (n = 238). RESULTS: In twin pregnancies with PE, sFlt-1 levels and the sFlt-1/PlGF ratio were increased and PlGF levels were decreased as compared with those of twin gestations with an uneventful pregnancy outcome (20 011.50 ± 2330.35 pg/mL vs 4503.00 ± 2012.05 pg/mL (P ≤ 0.001), 164.22 ± 31.35 vs 13.29 ± 319.64 (P ≤ 0.001), and 138.80 ± 20.04 pg/mL vs 403.00 ± 193.10 pg/mL (P ≤ 0.001), respectively). The sFlt-1/PlGF ratio did not differ between twin pregnancies with PE and singleton pregnancies with PE. In twin pregnancies with an uneventful outcome, sFlt-1 levels and sFlt-1/PlGF ratio were increased, but no differences in PlGF concentration were found when compared with that of singleton controls. ROC analysis determined 53 as an optimal cut-off of the sFlt-1/PlGF ratio for diagnosing PE in twin gestations, yielding a sensitivity of 94.4% and a specificity of 74.2%. The cut-off values established for singleton pregnancies, of 33 and 85, led to sensitivities of 100% and 83.3%, and specificities of 67.7% and 80.6%, when used to detect PE in twin pregnancies. CONCLUSIONS: Significant differences in the serum marker levels in singleton vs twin pregnancies were detected. Reference ranges of sFlt-1, PlGF and their ratio in singleton pregnancies are therefore not transferable to twin pregnancies.

Uterine artery Doppler, birth weight and timing of onset of pre-eclampsia: providing insights into the dual etiology of late-onset pre-eclampsia.

OBJECTIVE: To investigate the relationship between uterine artery Doppler ultrasound indices and birth weight in women with early-, intermediate- and late-onset pre-eclampsia as compared with women with uneventful pregnancy outcome. METHODS: In a retrospective, observational cohort study, uterine artery Doppler assessment was carried out at 18+0 to 23+6 weeks' gestation in 26,893 women attending for routine antenatal care in a tertiary care center. The mean resistance index (RI) and its relationship to the outcome of pregnancy and birth-weight centiles were evaluated. RESULTS: Uterine artery RI showed a significant, negative correlation with birth weight (r= -0.20, P<0.0001). Patients with early-onset pre-eclampsia had an increased prevalence of high uterine artery mean RI, above the 90(th) centile, corresponding to an increased proportion of small-for-gestational age (SGA) neonates with a birth weight below the 10(th) centile. In late-onset pre-eclampsia, however, there was an unexpectedly higher proportion of large-for-gestational-age (LGA) neonates with a birth weight above the 90(th) centile without a concurrent increase in the prevalence of low uterine artery mean RI below the 10(th) centile. CONCLUSIONS: The finding of a bimodal skewed distribution of birth weight, with neonates exhibiting a higher prevalence of both LGA and SGA with late-onset pre-eclampsia, indicates that there are two types of late-onset pre-eclampsia. These findings explain the poor performance of mid-trimester uterine artery Doppler in predicting pre-eclampsia at term and provide insights into the placental origins of the early and late forms of pre-eclampsia.

OS066. Intrauterine CYP2J2 expression and circulatingepoxyeicosatrienoic acid levels in preeclampsia.

INTRODUCTION: The cytochrome P450 (CYP)-system regulates vascular functions, inflammation, and angiogenesis that are mechanistically important in preeclampsia. OBJECTIVES: The aim of this study was to analyze the dysregulation of the Cytochrome P450 in the pathogenesis of preeclampsia. METHODS: We performed microarray screening of placenta and decidua from 25 preeclamptic women and 23 controls. Results were confirmed by realtime RT-PCR, immunohistochemistry and Serum of patients were analyzed by HPLC tandem mass spectrometry. For functional testing we did cardiomyocyte contraction bioassay and myograph studies. The reduced uterine perfusion pressure (RUPP) rat model was proceed for interventional study. RESULTS: In microarray studies the CYP subfamily 2J polypeptide 2 (CYP2J2) was upregulated in preeclamptic decidual tissue (3.9 fold, p<0.0001) and in preeclamptic placenta (1.55 fold, p<0.001). RT-PCR confirmed the upregulation and immunohistochemistry, localized CYP2J2 in trophoblasts of villi and deciduas at week 12 and term. The CYP2J2 metabolites were analyzed by HPLC tandem mass spectrometry. 5,6- epoxyeicosatrienoic acids (EET), 14,15-EET, and the corresponding dihydroxyeicosatrienoic acids (DHET), were elevated in preeclamptic women compared to controls in the latter two-thirds of pregnancy and after delivery. Stimulation of the trophoblast-derived cell line SGHPL-4 with the preeclampsia-associated cytokine tumor necrosis factor-a enhanced CYP2J2 gene and protein expression. For functional testing, 5,6-EET increased the beating rate of neonatal cardiomyocytes in a bioassay and downregulated large-conductance calcium-activated potassium channel KCa 1.1 activity. In the RUPP rat model of preeclampsia, we observed elevated EET, DHET, and preeclamptic features that were ameliorated by the CYP inhibitor MsPPOH. Uterine arterial rings of rats also dilated in response to MsPPOH. CONCLUSION: Our data implicate CYP2J2 in the pathogenesis of preeclampsia and as a potential candidate for the disturbed uteroplacental remodeling, leading to hypertension and endothelial dysfunction.

PP051. Prediction of preeclampsia with the sFlt-1/PLGF ratio: impact of the slope of repeated measurements.

INTRODUCTION: Patients with preeclampsia (PE) exhibit different serum concentrations of sFlt-1 and PlGF. The sFlt-1/PlGF ratio can be used as an aid in the diagnosis of preeclampsia. OBJECTIVES: The objective of this study was to explore the use of the sFlt-1/PlGF ratio as an aid in the prediction of preeclampsia in women with a high risk of the condition. METHODS: 150 patients with high risk of preeclampsia were included in this prospective study. Groups were compared according to the outcome of pregnancy: healthy pregnant women (controls, n=114), pregnancies complicated by intrauterine growth restriction without PE (IUGR, n=14), early PE<34 weeks of gestation (early PE, n=6) and late PE⩾34 weeks of gestation (late PE, n=16). Measurements of sFlt-1 and PlGF were performed on the automated Elecsys system. Statistical comparison of the sFlt-1/PlGF ratio in different outcome groups and multilevel analysis for logistic data using the random slope model was performed. RESULTS: We found significant differences in the sFlt-1/PlGF ratio between the outcome groups in weeks 24-36 of gestation (p=0,05). A significant difference in the sFlt-1/PlGF ratio between controls, IUGR and PE (early and late PE) could be measured up to six weeks before diagnosis (PE) or birth (IUGR, controls) (p=0,05). The random slope model showed significant different slopes (p=0,05) for individual outcome groups (controls 0,657; IUGR 1,786; early PE 1,951; late PE 0,881). CONCLUSION: The sFlt-1/PlGF ratio is able to identify pathologic pregnancy outcomes in gestational weeks 24-36. Prediction is feasible up to six weeks before clinical diagnosis (PE) or 6 weeks before birth (IUGR, controls). Repeated measurements are necessary beginning in 24 weeks of gestation with a maximum distance of six weeks. The slope between two measurements of the sFlt-1/PlGF ratio is predictive of further pregnancy outcome and the risk of developing preeclampsia.

PP059. Angiogenic factors and risk of preeclampsia related adverse outcomes in twin pregnancies.

INTRODUCTION: Preeclampsia (PE) is a pregnancy specific hypertensive disorder with an overall incidence of 5-8% among all pregnancies.Incidence of PE in twins is about 2-4 fold higher compared to singletons.Angiogenic factors are implicated in pathogenesis of PE and related adverse outcomes.No studies exist evaluating angiogenic factor assessment in twin pregnancies complicated by PE or use of these proteins for prediction of PE-related adverse outcomes in twins. OBJECTIVES: Our objective was to evaluate whether angiogenic factor levels correlate with the diagnosis of PE and predict adverse maternal and perinatal outcomes in women with twin pregnancy. METHODS: This was a prospective cohort study of women with suspected PE and twin pregnancy from July 2009-August 2011.Antiangiogenic soluble fms-like tyrosine kinase 1 (sFlt1) and proangiogenic placental growth factor (PlGF) were measured at presentation on an automated platform.Diagnosis of hypertension PE during pregnancy was based on ACOG criteria.All diagnoses and outcomes were recorded 2 weeks later.An adverse outcome was defined as hemolysis elevated liver enzymes and low platelets (HELLP) syndrome; disseminated intravascular coagulation (DIC); abruption; pulmonary edema; cerebral hemorrhage; maternal, fetal and neonatal death; eclampsia; acute renal failure; small for gestational age; and indicated delivery.Data are presented as median (interquartile range).We computed the area under the curve (AUC) from the receiver operating characteristic curves to evaluate the ability of clinical values to discriminate between women who would and would not develop an adverse outcome within 2 weeks. RESULTS: There were 79 women with twin gestation who presented to triage for evaluation of PE. The median gestational age at enrollment was 33.9 (31.9-36.0) weeks.The incidence of PE was 58.2%, of which 60.9% was mild and 39.1% was severe.The median sFlt1/PlGF ratio was 72.2 (42.5-111.9) in women with PE compared to 47.4 (5.5-82.2) in women with no hypertensive disorder (P=0.052).Among the 52 (65.8%) women who experienced an adverse outcome within 2 weeks, the median sFlt1/PlGF ratio at presentation was elevated [74.2 (43.5-110.5)] compared to the 27 (34.2%) women without an adverse outcome [36.2 (7.1-71.3); P=0.0003].Among those presenting at <34 weeks (n=40), the difference in sFlt1/PlGF ratio was more striking [97.7 (76.6-178.1) versus 31.7 (6.5-48.7); P=0.001].When using only the highest systolic blood pressure at presentation and proteinuria the AUC was 0.61.Adding the sFlt1/PlGF ratio significantly improved the AUC to 0.77 (P=0.01).When restricting to women who presented at <34 weeks, a similar, although not statistically significant, improvement was seen when adding the sFlt1/PlGF ratio (AUC=0.85) compared with blood pressure and proteinuria alone(AUC=0.69;P=0.08). CONCLUSION: In women with twin pregnancy and suspected PE, the sFlt1/PlGF ratio at the time of initial evaluation is associated with subsequent diagnosis of PE and, more importantly, PE-related adverse maternal and perinatal outcomes. These findings are similar to singleton pregnancies and may implicate similar pathogenic pathways.

Changes in endovascular trophoblast invasion and spiral artery remodelling at term in a transgenic preeclamptic rat model.

As a follow-up to our previous study which revealed a surprisingly deeper endovascular trophoblast (ET) invasion on day 18 in a transgenic preeclamptic (PE) rat model (hAngiotensinogen female symbol x hRenin male symbol) compared to non-PE controls, we examined further changes in ET invasion and associated spiral artery (SA) remodelling at term (day 21). PE transgenic rats and non-PE reversely mated (RM) transgenic rats were compared to normal SD rats (C). Sections were stained to visualize trophoblast, fibrinoid, vascular smooth muscle (VSM) and endothelium. SA were evaluated in three depth levels in the mesometrial triangle (MT) using the KS-400 image analysis system. In separate transgenic rats, Doppler ultrasound was performed in uterine arteries, and the resistance indices (RI) were calculated. Although for the whole MT differences in ET invasion were no longer significant between the PE and C, indicating a partial catching up in C rats, there was still significantly more ET in the deepest level in the PE group as compared to the C and RM groups. At the same time the SA walls in PE rats contained significantly more fibrinoid (versus RM and C) and VSM (versus C). In all SA cross-sections, re-endothelialisation was prominent, but significantly different between PE and C group. The Doppler results showed a significantly lower RI in the arcuate uterine artery of the PE group compared to the C group. There was no evidence of elimination of deeply invaded ET at term, previously considered as a possible mechanism for restriction of vascular remodelling in human PE. The differences in vascular remodelling, previously described on day 18 by histology and Doppler data, were maintained on day 21, but there was extensive endothelial repair in the three groups. Atherosis-like lesions were observed in the three groups, most frequently in the RM group, but were never associated with placental infarcts.

[Use of angiogenic factors (sFlt-1/PlGF ratio) to confirm the diagnosis of preeclampsia in clinical routine: first experience]. / Angiogene Faktoren zur Diagnosesicherung bei Präeklampsie in der klinischen Routine: erste Erfahrungen.

INTRODUCTION: In the clinical routine, the diagnosis of preeclampsia is often challenging. Not all pregnant women with signs and symptoms of preeclampsia develop the disease. Recently, the assessment of the sFlt-1/PlGF ratio in the serum of pregnant women has been proposed as an aid in the diagnosis of preeclampsia. PATIENTS AND METHODS: In a retrospective, monocentric case-control study, we reviewed 30 cases of patients who presented with the clinical symptoms of hypertensive disorders of pregnancy in the delivery ward. Next to the standard diagnostic algorithm for preeclampsia, the sFlt-1/PlGF ratio was determined using the automated Elecsys® platform. RESULTS: In 12/30 cases (40%), the diagnosis of a hypertensive pregnancy disorder was confirmed with an sFlt1/PlGF ratio of >85. In 18/30 (60%) cases, a ratio <85 excluded the diagnosis of preeclampsia at the time of presentation and allowed an adaptation of the patient's surveillance programme. CONCLUSION: In the clinical setting of "suspected preeclampsia", determination of the sFlt-1/PlGF ratio can serve as an aid in the diagnosis of hypertensive disorders in pregnancy. The reliable exclusion of the diagnosis "preeclampsia" can help in an appropriate and cost-effective management of patients with signs and symptoms of the disease.

Endovascular trophoblast invasion, spiral artery remodelling and uteroplacental haemodynamics in a transgenic rat model of pre-eclampsia.

The aim of the present study was to evaluate the depth of endovascular trophoblast invasion and associated remodelling of spiral arteries in a transgenic model of pre-eclampsia in the rat, a species showing a comparable deep invasion during normal pregnancy as the human. Pre-eclamptic (PE) transgenic rats (TGR) (hAngiotensinogen female x hRenin male) and non-PE reversely mated (RM) TGR rats were compared to normal Sprague-Dawley rats (C). Day 18 implantation sites were collected and the presence of endovascular trophoblast, fibrinoid, endothelial and smooth muscle cells were evaluated in spiral arteries in three parallel layers in the mesometrial triangle using an image analysis system (KS-400). In a separate group of animals peak-systolic and end-diastolic velocities were measured by Doppler in uterine and arcuate arteries, and the resistance indices (RI) were calculated. In PE and RM rats, the entire mesometrial triangle contained significantly more endovascular trophoblast and vascular fibrinoid deposits than the C group. No difference was found between the groups in the overall amount of smooth muscle surrounding the lumen, but in the PE and RM groups significantly more muscle was present in parts of the contours covered by trophoblast. There was significantly less CD31-positive endothelium in the total lumen contours of the PE and RM groups than in the C group, but in parts of the contours covered by trophoblast more residual endothelium was present in both TGR groups. Comparison of the three layers indicated deeper invasion in both the PE and RM groups than in the C group. By Doppler analysis of the proximal uterine artery the RI was found to be significantly lower in the PE and the RM group than in the C group. In the arcuate artery, the RI was significantly lower in the PE group as compared to the RM and C groups. We conclude that in this transgenic PE rat model there is deeper endovascular invasion of spiral arteries and decreased RI of uterine arteries at day 18 of pregnancy.