The interrelationship of complement‐activation fragments and angiogenesis‐related factors in early pregnancy and their association with pre‐eclampsia

Abstract

Objective To determine the interrelationships during early pregnancy of complement-activation fragments Bb, C3a and sC5b-9, and angiogenesis-related factors placental growth factor (PiGF), soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng), and their associations with pre-eclampsia. Design Prospective cohort study. Setting Denver complement study (June 2005–June 2008). Population A total of 668 pregnant women with singleton gestations, recruited between 10 and 15 weeks of gestation. Methods Using univariable and multivariable logistic regression analysis, concentrations of complement-activation fragments and angiogenesis-related factors were compared between 10 and 15 weeks of gestation in women who subsequently did or did not develop pre-eclampsia. Interrelationships between these variables were tested using the non-parametric Spearman rank correlation coefficient. Main outcome measure Pre-eclampsia. The association of complement-activation fragments and angiogenesis-related factors with obesity was also examined. Results The mean (±SD) levels of complement Bb in early pregnancy among women who did and did not develop pre-eclampsia were 0.84 (±0.26) µg/ml and 0.69 (±0.2) µg/ml, respectively (P = 0.001). Concentrations of PiGF were significantly (P = 0.01) lower (31 ± 12 pg/ml) in early pregnancy in the pre-eclamptic group of women, as compared with the normotensive group (39 ± 32 pg/ml). The adjusted odds ratio (AOR) of Bb and PiGF were 2.1 (CI = 1.4–3.1, P < 0.0003) and 0.2 (CI = 0.07–0.7, P = 0.01), respectively. There was no significant difference in the levels of C3a, sC5b-9, sFlt-1 and sEng in early pregnancy among women who developed pre-eclampsia, compared with women who remained normotensive during pregnancy. Higher levels of Bb (P = 0.0001) and C3a (P = 0.03), and lower levels of sFlt-1 (P = 0.0002) and sEng (P = 0.0001) were found among women with obesity, compared with non-obese controls. No meaningful relationships were found between the complement-activation fragments and the angiogenesis-related factors. Conclusions In this cohort during early pregnancy, increased concentrations of complement-activation factor Bb and lower concentrations of PiGF were associated with the development of pre-eclampsia later in pregnancy.

Aspects of inflammation, angiogenesis and coagulation in preeclampsia

“…There was no correlation between local expression and plasma level for CCL18 (r=-0.15; p=0.47) or CXCL10 (r=-0.22; p=0.23). For CCL22 we did not find any placental expression in the third trimester 117 and CCL20 was not detectable in the majority of the plasma samples. Correlation tests were therefore not performed for these chemokines.…”

Maternal and Fetal Alternative Complement Pathway Activation in Early Severe Preeclampsia

“…In particular, obesity in conjunction with elevated Bb levels increases the risk of PE beyond elevated Bb alone. 21 This information may further elucidate specific groups of women at risk of severe preeclampsia related to abnormal alternative complement activation.…”

Innate Immune System at the Maternal–Fetal Interface: Mechanisms of Disease and Targets of Therapy in Pregnancy Syndromes

“…While not all related studies have been conclusive, both the classical and the alternative CS pathway have been recognized in the pathogenesis of PE. 10,37,38 Bb fragments may represent a sign of the exaggerated alternative CS pathway activation occurring in the early severe PE. 38 Clinical studies reported that CS is activated with increased terminal complex (C5b9) formation in the third trimester of normal human pregnancy, and further in PE.…”

“…49 Alterations in circulating sFlt-1 and placental growth factor (PlGF) appear to be involved in the pathogenesis of PE. 37 Authors identified elevated expression of sFlt-1 by gene expression profiling in placentas delivered from women with PE. 50 Moreover, several sFlt-1 variant isoforms have been identified and shown to be upregulated in PE.…”