Complement activation fragment Bb in early pregnancy and spontaneous preterm birth

Abstract

Objective: The objective of this study was to determine whether an elevated level of the complement activation fragment Bb in early pregnancy was associated with spontaneous preterm birth (SPTB) at less than 34 weeks' gestation or SPTB between 34 and 37 weeks' gestation (late SPTB).

Study design: This was a prospective study of 784 women enrolled at less than 20 weeks' gestation.

Results: Following exclusions, 13 women (1.7%) had a SPTB at less than 34 weeks' gestation and 25 (3.2%) a SPTB between 34 and 37 weeks' gestation. Women with Bb in the top quartile were 4.7 times more likely to have an SPTB less than 34 weeks' gestation as compared with women who had levels of Bb in the lower 3 quartiles (95% confidence interval [CI] 1.5-14, P = .003). There was no association between Bb and late SPTB (relative risk 0.8, 95% CI 0.3-2).

Conclusion: A significant relationship was found between an elevated Bb in early pregnancy and SPTB less than 34 weeks' gestation. These results suggest that inflammatory events in early pregnancy are part of the pathogenic mechanisms of this condition.

Figure 1. Classical, Lectin and Alternative Complement Pathways

Complement has three initiating mechanisms known as the classical, lectin, and alternative pathways. The triggers for these pathways include: immune complexes, apoptotic bodies, mitochondrial membranes, mitochondrial cardiolipin, C-reactive protein, endothelial neoepitopes in ischemic tissue (classical pathway), carbohydrates on pathogens (lectin pathway) and “tickover, ”, polysaccharides, endotoxin, IgA immune complexes, C3 nephritic factor, absence or interference with regulatory proteins (alternative pathway) . Biological functions of the complement system are achieved through the production of activation fragments (e.g. C3a, C5a, C5b-9). The classical, lectin and alternative complement pathways converge to generate enzymes called C3 convertases which cleave C3 into C3b and C3a. C3b is a major effector molecule of the complement system. C3b binds to the surface of foreign cells and opsonizes the cells for phagocytosis. Through a series of reactions the membrane attack complex (MAC) is formed. This complex can insert into membranes and has the potential to damage cells. Factors B, D and Properdin initiate activation of C3 directly through the alternative pathway initiation complex or through the amplification loop when C3b is formed. The Bb activation product is derived from factor B and serves as a protease that is able to cleave additional C3 molecules. In the absence of Bb generation, no alternative pathway activation is possible. The production of C3b, triggered from engagement of the classical or lectin pathways is augmented through the alternative pathway amplification loop that is essential to generate pathogenic pro-inflammatory mediators in vivo .

Figure 2. Distribution of Bb levels by gestational age delivery

The figure demonstrates the levels of Bb in women who had an SPTB (< 34 weeks gestation n = 13), a SPTB (34-37 weeks gestation, n = 25) and a term delivery (after 37 weeks gestation, n = 746). The upper and lower ends of the box are the 75^th and 25^th percentiles. The line across the middle of the box represents the median level of Bb (μg/ml) in each group. The P value for the difference in the median levels of Bb between the SPTB < 34 weeks gestation and the term deliveries was 0.01. The P value for the difference in the median Bb levels between the SPTB < 34 weeks and the late SPTB was 0.09 (Wilcoxon rank-sum) and the P value for differences in Bb levels across the 3 categories of birth was 0.047 (Kruskal-Wallis test).