A prospective cohort study of the value of maternal plasma concentrations of angiogenic and anti-angiogenic factors in early pregnancy and midtrimester in the identification of patients destined to develop preeclampsia

Abstract

OBJECTIVE Changes in the maternal plasma concentrations of angiogenic (such as PlGF and VEGF) and anti-angiogenic factors (such as sEng and sVEGFR-1) precede the clinical presentation of preeclampsia. This study was conducted to examine the role of maternal plasma PlGF, sEng and sVEGFR-1 concentrations in early pregnancy and midtrimester in the identification of patients destined to develop preeclampsia. METHODS This longitudinal cohort study included 1,622 consecutive singleton pregnant women. Plasma samples were obtained in early pregnancy (6–15 weeks) and midtrimester (20–25 weeks). Maternal plasma PlGF, sEng and sVEGFR-1 concentrations were determined using sensitive and specific immunoassays. The primary outcome was the development of preeclampsia. Secondary outcomes included term, preterm and early-onset preeclampsia. Receiving operating characteristic (ROC) curves, sensitivity, specificity, positive and negative likelihood ratios, and multivariable logistic regression were used for statistical analyses. A p-value of <0.05 was considered significant. RESULTS 1) The prevalence of preeclampsia, term, preterm (<37 weeks) and early-onset preeclampsia (<34 weeks) was 3.8% (62/1,622), 2.5% (40/1,622), 1.4% (22/1,622) and 0.6% (9/1,622), respectively; 2) Higher likelihood ratios were provided by ratios of midtrimester plasma concentrations of PlGF, sEng, and sVEGFR-1 than single analytes; 3) Individual angiogenic and anti-angiogenic factors did not perform well in the identification of preeclampsia as a whole; in particular, they perform poorly in the prediction of term preeclampsia; 4) In contrast, a combination of these analytes such as the PlGF/sEng ratio, its delta and slope had the best predictive performance with a sensitivity of 100%, a specificity of 98%–99%, and likelihood ratios for a positive test of 57.6, 55.6 and 89.6, respectively, for predicting early-onset preeclampsia. CONCLUSIONS 1) The PlGF/sEng ratio and its delta and slope had an excellent predictive performance for the prediction of early-onset preeclampsia, with very high likelihood ratios for a positive test result and very low likelihood ratios for a negative test result; and 2) Although the positive likelihood ratios are high and the positive predictive values low, the number of patients needed to be closely followed is 4:1 for the PlGF/sEng ratio and 3:1 for the slope of PlF/sEng.

Placental Pathology in Early-Onset and Late-Onset Fetal Growth Restriction

“…For example, analysis of serum levels of a number of anti-angiogenic factors, including soluble fms-like tyrosine kinase-1, soluble endoglin and soluble vascular endothelial growth factor receptor-1, and pro-angiogenic factors such as placental growth factor shows an association between preterm PET and high levels of anti-angiogenic factors together with low levels of placental growth factor [94,95,96,97,98,99,100]. Those with an ‘angiogenic' profile are associated with earlier preterm delivery and adverse outcomes, while non-angiogenic cases are not [100].…”

Prediction of the preeclampsia: a view of biochemical markers

“…In contrast, a large nested case-control study within a cohort of nearly 30,000 pregnant women in Norway showed that low sFlt1 in first trimester predicted early onset preeclampsia [41]. Kusanovic et al also had confirmed that low sFlt1 in first trimester predicting preterm (as well as term) preeclampsia [43] and Erez et al [42]. Although after adjusting for BMI, age and nulliparity, this significance had disappeared.…”

“…By the way this situation leads to a course of antagonizing the angiogenic factors such as PlGF. Some studies have found that low PlGF is a good predictive factor in first trimester for preeclampsia [39][40][41][42][43], while other studies showed no predictive value for PlGF in first trimester [44][45][46][47]. Most studies have found that low PlGF in the second trimester predicts later occurrence of preeclampsia [47][48][49][50][51][52][53][54].…”

Biomarkers in Preeclampsia

“…The index that has been extensively studied is sFlt-1:PlGF ratio, but many others have been proposed, such as PlGF:(sEng  sFlt-1), PlGF:sEng and PlGF:sFlt-1. 59 …”