Sequential Changes in Antiangiogenic Factors in Early Pregnancy and Risk of Developing Preeclampsia

Abstract

Abstract-Concentrations of soluble fms-like tyrosine kinase 1 (sFlt1) and soluble endoglin (sEng) increase in maternal blood with the approach of clinical preeclampsia. Although alterations in these circulating antiangiogenic factors herald the signs and symptoms of preeclampsia, in vitro studies suggest they may also play a role in regulating early placental cytotrophoblast functions. Early pregnancy changes in sFlt1 and sEng may thus identify women destined to develop preeclampsia. We performed a nested case-control study of 39 women who developed preeclampsia and 147 contemporaneous normotensive controls each with serum collected in the first (11 to 13 weeks of gestation) and second (17 to 20 weeks) trimesters. Whereas levels of sFlt1 and sEng at 11 to 13 weeks were similar between cases and controls (sFlt1: 3.5Ϯ0.3 ng/mL versus 3.0Ϯ0.1, Pϭ0.14; sEng 6.9Ϯ0.3 ng/mL versus 6.6Ϯ0.2, Pϭ0.37, respectively), at 17 to 20 weeks both were elevated in the women destined to develop preeclampsia (sFlt1: 4.1Ϯ0.5 ng/mL versus 3.1Ϯ0. Key Words: antiangiogenic factors Ⅲ sFlt1 Ⅲ soluble endoglin Ⅲ preeclampsia Ⅲ predictive test P reeclampsia affects 3% to 5% of pregnancies and causes substantial maternal and neonatal morbidity and mortality. 1 Predicting the development of preeclampsia is important both for prevention (when useful preventive measures become available) and for early referral of high risk pregnancies. Measures to predict preeclampsia, however, are not standardized, and currently there are no reliable biomarkers that are routinely measured in the clinic.Recently, our improved understanding of the pathogenesis of preeclampsia 2,3 has raised the possibility that blood levels of antiangiogenic proteins 4,5 might eventually be used to predict this devastating condition. Circulating soluble fmslike tyrosine kinase 1 (sFlt1) and soluble endoglin (sEng) have been hypothesized to play a pathogenic role in preeclampsia. Adenoviral overexpression of sFlt1 and sEng induce development of preeclampsia-like illness in rats. 6 Furthermore, alterations in circulating sFlt1 and sEng are noted several weeks preceding clinical signs. 5 Although there is evidence that angiogenic factor alterations may be strongly associated with the development of the clinical preeclampsia, it is surprising that their levels are not dramatically altered during early pregnancy (11 to 18 weeks of gestation) when the abnormal placentation associated with severe premature preeclampsia develops. This led us to hypothesize that sequential angiogenic factor changes from the first to the second trimesters of pregnancy might differ in women destined to develop preeclampsia, explaining the apparent paradox and that these changes could have predictive value. The aim of the present study, therefore, was to measure concentrations of sFlt1 and sEng in paired serum specimens collected in first and second trimesters from women with well-characterized pregnancy outcomes followed prospectively during pregnancy. Methods Study PopulationWe performed a nested case-cont...

Novel Angiogenic Factors for Predicting Preeclampsia: sFlt-1, PlGF, and Soluble Endoglin~!2008-08-29~!2008-12-15~!2009-01-02~!

“…Very interestingly, sEng levels increased significantly before the onset of disease in women with preterm preeclampsia (< 37 weeks) by 11-9 weeks, and in term preeclampsia (at > 37 weeks) by 14-12 weeks respectively [43]. The second trimester sEng has been suggested as a marker for predicting preterm and severe preeclampsia [59,60]. Soluble Endoglin has also been demonstrated fairly good diagnostic utilities to differentiate preeclampsia from normal pregnancy, gestational hypertension and chronic hypertension with sensitivities of 84-90%, specificities of 79-95%, positive LR of 4-17.9, negative LR of 0.1-0.2, and area under the ROC curve of 0.75-0.93 [35].…”

Anti-angiogenic factors and pre-eclampsia in type 1 diabetic women

“…Recent evidence indicates that the long-sought 'circulating factors' from the placenta which mediate pre-eclampsia may include soluble fms-like tyrosine kinase 1 (sFlt1) (the extracellular fragment of the vascular endothelial growth factor [VEGF] receptor) and soluble endoglin (a co-receptor for TGFβ1) [6][7][8][9][10][11][12], both of which are anti-angiogenic. Specifically, sFlt1 binds to and sequesters pro-angiogenic placental growth factor (PlGF) and VEGF, while endoglin blocks normal TGFβ1 signals [9,12].…”

The change in concentrations of angiogenic and anti-angiogenic factors in maternal plasma between the first and second trimesters in risk assessment for the subsequent development of preeclampsia and small-for-gestational age

“…These studies have largely focused on one determination of the plasma/serum concentrations of angiogenic and/or anti-angiogenic factors. Recently, it has been proposed that serial determinations of the concentrations of sVEGFR-1 [38,39], PlGF [38], and s-Eng [39] are more informative in assessing the risk for PE than are single measurements in the first or second trimester. This is plausible because PlGF, s-Eng, and sVEGFR-1 are produced by the trophoblast [23,[39][40][41][42][43][44] and, therefore, maternal plasma concentrations can change with placental development from the first to the second trimester.…”