Maternal plasma concentrations of angiogenic/anti-angiogenic factors are of prognostic value in patients presenting to the obstetrical triage area with the suspicion of preeclampsia

Abstract

Objective To determine if maternal plasma concentrations of placental growth factor (PlGF), soluble endoglin (sEng), soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) and -2 could identify patients at risk for developing preeclampsia (PE) requiring preterm delivery. Study design Patients presenting with the diagnosis ‘rule out PE’ to the obstetrical triage area of our hospital at <37 weeks of gestation (n=87) were included in this study. Delivery outcomes were used to classify patients into 4 groups: I) patients without PE or those with gestational hypertension (GHTN) or chronic hypertension (CHTN) who subsequently developed PE at term (n=19); II): mild PE who delivered at term (n=15); III): mild disease (mild PE, GHTN, CHTN) who subsequently developed severe PE requiring preterm delivery (n=26); and IV): diagnosis of severe PE (n=27). Plasma concentrations of PlGF, sEng, sVEGFR-1 and -2 were determined at the time of presentation by ELISA. Reference ranges for analytes were constructed by quantile regression in our laboratory (n=180; 1,046 samples). Comparisons among groups were performed using multiples of the median (MoM) and parametric statistics after log transformation. Receiver operating characteristic curves, logistic regression and survival analysis were employed for analysis. Results The mean MoM plasma concentration of PlGF/sVEGFR-1, PlGF/sEng, PlGF, sVEGFR-1 and -2, and sEng in Group III was significantly different from Group II (all p<0.05). A plasma concentration of PlGF/sVEGFR-1 ≤ 0.05 MoM or PlGF/sEng ≤ 0.07 MoM had the highest likelihood ratio of a positive test (8.3, 95% CI 2.8–25 and 8.6, 95% CI 2.9–25, respectively), while that of PlGF ≤0.396 MoM had the lowest likelihood ratio of a negative test (0.08, 95% CI 0.03–0.25). The association between low plasma concentrations of PlGF/sVEGFR-1 (≤0.05 MoM) as well as that of PlGF/sEng (≤ 0.07 MoM) and the development of severe PE remained significant after adjusting for gestational age at presentation, average systolic and diastolic blood pressure, and a history of chronic hypertension [adjusted odds ratio (OR) = 27 (95% CI 6.4–109) and adjusted OR 30 (95% CI 6.9–126), respectively]. Among patients who presented <34 weeks gestation (n=59), a plasma concentration of PlGF/sVEGFR-1 <0.033 MoM identified patients who delivered within 2 weeks because of PE with a sensitivity of 93% (25/27) and a specificity of 78% (25/32). This cut-off was associated with a shorter interval-to-delivery due to PE [hazard ratio = 6 (95% CI 2.5–14.6)]. Conclusions Plasma concentrations of angiogenic/anti-angiogenic factors are of prognostic value in the obstetrical triage area. These observations support the value of these biomarkers in the clinical setting for the identification of the patient at risk for disease progression requiring preterm delivery.

The Promise of Angiogenic Markers for the Early Diagnosis and Prediction of Preeclampsia

“…Early confirmation of preeclampsia is particularly useful in patients who present very prematurely, in whom accurate diagnosis is critical for management. In this regard, 2 recent studies demonstrated not only that the measurement of angiogenic factors is useful in the triage setting for diagnosing preeclampsia, but also that it may be useful for the identification of patients at risk for adverse outcomes and preterm delivery (83,84 ).…”

Maternal plasma concentrations of sST2 and angiogenic/anti-angiogenic factors in preeclampsia

“…Plasma concentrations of the angiogenic factor, placental growth factor (PlGF), are decreased [69,70,92,93,96,[100][101][102], and the anti-angiogenic factors (soluble vascular endothelial growth factor receptor-1 [sVEGFR-1] and soluble endoglin [sEng]) are elevated both prior to [67,72,[119][120][121][122][123][124][125] and at the time of diagnosis [94,95,[97][98][99]. Moreover, the concentrations of these factors can be used to predict the outcome of the disease in patients presented to the obstetrical triage area [73,75,126,127]. However, the prognostic performance of these biomarkers evaluated in the mid-trimester for late-onset preeclampsia has been suboptimal [105,[128][129][130][131].…”

“…Considerable effort has been made to identify biomarkers that could predict women who will develop preeclampsia [63][64][65][66][67][68][69][70][71][72][73][74][75][76][77][78]. Although markers of systemic inflammation [79,80] and endothelial dysfunction [81][82][83][84][85][86][87][88] in maternal blood have been associated with preeclampsia, their prognostic performance for the identification of patients with preeclampsia prior to diagnosis has been disappointing [79][80][81]83,[89][90][91].…”

New Developments in the Pathogenesis of Preeclampsia

“…This simple, quantitative, rapid test outperformed the standard battery of clinical diagnostic measures including blood pressure, proteinuria, uric acid, and other laboratory assays 57 . Importantly, sFlt1 and/or PlGF levels at presentation were strongly associated with the remaining duration of pregnancy 53,[57][58][59][60] . We also recently evaluated the role of sEng measurements and found that it has comparable performance to sFlt1/PlGF ratio 61 .…”