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 to 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 patients 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.

Figure 1

Profile of plasma soluble endoglin (sEng) concentrations (ng/ml) in relation to gestational age in normal pregnant women and patients with spontaneous preterm labor and delivery (PTL). Patients destined to developed PTL had a significantly different profile (plasma concentration over time) of plasma sEng concentration from patients with normal pregnancies after adjusting for gestational age at blood sampling, maternal age, body mass index, nulliparity, a history of preterm delivery, smoking and duration of sample storage (p=0.04). Plasma sEng concentration was higher in patients destined to develop PTL than in normal pregnant women from 15-20 weeks of gestation. The difference became statistical significance at 27.7 weeks and was more pronounce as delivery approached.

Figure 2

Profile of plasma sVEGFR-1 concentrations (pg/ml) in relation to gestational age in normal pregnant women and patients with spontaneous preterm labor (PTL) and delivery. Patients destined to developed PTL had a significantly different profile (plasma concentration over time) of plasma sVEGFR-1 concentration from patients with normal pregnancies after adjusting for gestational age at blood sampling, maternal age, body mass index, nulliparity, a history of preterm delivery, smoking and duration of sample storage (p=0.003). Plasma sVEGFR-1 concentrations in patients with PTL were slightly lower than those in normal pregnant women from 10-28 weeks of gestation. After this gestational age, plasma sVEGFR-1 concentrations became higher until delivery.

Figure 3

Profile of plasma placenta growth factor (PlGF) concentrations (pg/ml) in relation to gestational age in normal pregnant women and patients with spontaneous preterm labor (PTL) and delivery. There was no significant difference in the profile (plasma concentration over time) of plasma PlGF concentration between patients with PTL and normal pregnant women after adjusting for gestational age at blood sampling, maternal age, body mass index, nulliparity, a history of preterm delivery, smoking and duration of sample storage (p=0.3).

Figure 4

Profile of plasma sVEGFR-2 concentrations (ng/ml) in relation to gestational age in normal pregnant women and patients with spontaneous preterm labor (PTL) and delivery. There was no significant difference in the profile (plasma concentration over time) of plasma sVEGFR-2 concentration between patients with PTL and normal pregnant women after adjusting for gestational age at blood sampling, maternal age, body mass index, nulliparity, a history of preterm delivery, smoking and duration of sample storage (p=0.1).

Figure 5

Individual changes in maternal plasma concentration (Log10 (conc+1)) of soluble endoglin (sEng) and soluble vascular endothelial growth factor receptor-2 (sVEGFR-2) in normal pregnant women (control; n= 208) and patients destined to develop preterm labor and delivery (PTL; n=52) in relation to gestational age (GA).

Figure 6

Individual changes in maternal plasma concentration (Log10 (conc+1)) of soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) and placental growth factor (PlGF) in normal pregnant women (control; n= 208) and patients destined to develop preterm labor and delivery (PTL; n=52) in relation to gestational age (GA).