A subset of patients destined to develop spontaneous preterm labor has an abnormal angiogenic/anti-angiogenic profile in maternal plasma: Evidence in support of pathophysiologic heterogeneity of preterm labor derived from a longitudinal study

Abstract

OBJECTIVE An imbalance between angiogenic and anti-angiogenic factors in maternal blood has been observed in several obstetrical syndromes including preeclampsia, pregnancies with fetal growth restriction, and fetal death. Vascular lesions have been identified in a subset of patients with spontaneous preterm labor (PTL). It is possible that PTL may be one of the manifestations of an anti-angiogenic state. The aim of this study was to determine if patients prior to the clinical diagnosis of PTL leading to preterm delivery had plasma concentrations of angiogenic and anti-angiogenic factors different from normal pregnant women. STUDY DESIGN This longitudinal nested case-control study included normal pregnant women (n=208) and patients with PTL leading to preterm delivery (n=52). Maternal blood samples were collected at 6 gestational age intervals from 6-36.9 weeks of gestation. The end point (time of diagnosis) of the study, “True PTL”, was defined as patients presenting with PTL and delivered within 1 day. Plasma concentrations of sVEGFR-1, sVEGFR-2, sEng and PlGF were determined by ELISA. Analysis was performed with both cross-sectional and longitudinal (mixed effects model) approaches. RESULTS 1) Plasma sEng concentration in patients destined to develop PTL was higher than that in normal pregnant women from 15-20 weeks of gestation. The difference became statistical significant at 28 weeks of gestation, or approximately 5-10 weeks prior to the diagnosis of “true PTL”. 2) Backward analysis suggests that plasma concentrations of PlGF and sVEGFR-2 were lower, and those of sVEGFR-1 were higher in patients with PTL than in normal pregnant women less than 5 weeks prior to the diagnosis of “true PTL”; and 3) Plasma concentrations of sEng and sVEGFR-1 were higher and those of PlGF and sVEGFR-2 were lower in patents diagnosed with PTL and delivery within 1 day than in normal pregnant women who delivered at term. CONCLUSION The changes in sEng are demonstrable several weeks prior to the onset of preterm parturition. In contrast, the changes in the other angiogenic proteins are present close to the onset of PTL and delivery. This observation supports the view that an imbalance of angiogenic factors participates in the pathophysiology of spontaneous preterm parturition.

Novel biomarkers for the prediction of the spontaneous preterm birth phenotype: a systematic review and meta-analysis

“…66,85 The number of case participants enrolled in case-control studies ranged from 5 to 882, 55,91 and the corresponding number of controls ranged from 5 to 1372. 55,91 Thirty-nine studies (n = 18 368 women) reported on 18 inflammation-related biomarkers, 21-59 28 (n = 71 609 women) reported on eight placental proteins/ hormone-related biomarkers, three (n = 359 women) reported on two angiogenesis-related biomarkers, [88][89][90] two (n = 971 women) reported on one coagulation-related biomarker, 58,91 and one (n = 10 women) reported on proteomics-related biomarkers. 92 Eleven studies evaluated more than one test.…”

“…90 The predictive accuracy of these biomarkers for preterm birth before 34 and 37 weeks of gestation was minimal to moderate (positive and negative LRs between 1.1 and 6.7, and between 0.4 and 1.0, respectively).…”

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

“…Preeclampsia [63][64][65][66][67]69,70,72,[92][93][94][95][96][97][98][99][100][101][102][103], as well as other obstetrical syndromes [46,[104][105][106][107][108][109][110][111][112][113][114][115][116][117][118], is characterized by an anti-angiogenic state. 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]…”

Angiogenesis-related biomarkers (sFlt-1/PlGF) in placental mesenchymal dysplasia

“…The anti-angiogenic state in the maternal circulation has been widely related to the development of pregnancy complications due to placental insufficiency [4,5] and has been associated with a shorter remaining time to delivery [6]. Preeclampsia (PE) [3] and a broad spectrum of other pregnancy disorders linked to placental insufficiency such as IUGR, placental abruption and mirror syndrome have been related to an imbalance of the angiogenesis-related biomarkers [7].…”