The complement system and adverse pregnancy outcomes

Abstract

Adverse pregnancy outcomes significantly contribute to morbidity and mortality for mother and child, with lifelong health consequences for both. The innate and adaptive immune system must be regulated to insure survival of the fetal allograft, and the complement system is no exception. An intact complement system optimizes placental development and function and is essential to maintain host defense and fetal survival. Complement regulation is apparent at the placental interface from early pregnancy with some degree of complement activation occurring normally throughout gestation. However, a number of pregnancy complications including early pregnancy loss, fetal growth restriction, hypertensive disorders of pregnancy and preterm birth are associated with excessive or misdirected complement activation, and are more frequent in women with inherited or acquired complement system disorders or complement gene mutations. Clinical studies employing complement biomarkers in plasma and urine implicate dysregulated complement activation in components of each of the adverse pregnancy outcomes. In addition, mechanistic studies in rat and mouse models of adverse pregnancy outcomes address the complement pathways or activation products of importance and allow critical analysis of the pathophysiology. Targeted complement therapeutics are already in use to control adverse pregnancy outcomes in select situations. A clearer understanding of the role of the complement system in both normal pregnancy and complicated or failed pregnancy will allow a rational approach to future therapeutic strategies for manipulating complement with the goal of mitigating adverse pregnancy outcomes, preserving host defense, and improving long term outcomes for both mother and child.

Keywords: Complement system; Fetal growth restriction; Miscarriage; Placenta; Preeclampsia; Pregnancy; Preterm birth.

Figure 1. Complement System

Three activation pathways of complement are depicted with regulators of complement activation in red text. Blue boxes highlight products of complement activation of interest in normal pregnancy or associated with adverse pregnancy outcomes. The C3 convertase is a molecular complex generated from the classical or lectin pathway (C4bC2a) and the alternative pathway (C3bBb) that cleaves C3 generating the C5 convertase (C4bC2aC3b or C3bBbC3b). Once activated, C3b and C4b can be further degraded to smaller fragments C3d and C4d that are still covalently bound to target and maintain many biological activities but do not participate as components of the C3 and C5 convertase to propagate activation of the pathway. The rodent specific regulator of complement activation Crry (CR-1 related gene y) is not included but has CD46/CD55 like activities. C1-INH, C1 inhibitor; MCP, membrane cofactor protein; C4BP, C4 binding protein; CR1, complement receptor 1; DAF, decay accelerating factor; MASP, mannose associated serine protease; MBL, mannose binding lectin

Figure 2

Figure 2A. Schematic of a portion of a hemochorial placenta depicting comparable zones in human and rodent. Portion enclosed by dashed line is expanded in Figure 2B to illustrate in more detail the villous structure and maternal spiral artery with subtypes of trophoblasts and complement components/regulators of most interest. Figure 2B. Schematic of hemochorial placenta illustrating subtypes of trophoblasts and associated selective complement components/regulators of interest that participate in normal placental development and protection of the trophoblast subpopulations from maternal complement attack. Intervillous space and maternal spiral artery is illustrated with maternal blood and plasma complement proteins bathing the villous structure for exchange of nutrients and oxygen with the fetal blood supply within the villous structure.

Figure 2

Figure 2A. Schematic of a portion of a hemochorial placenta depicting comparable zones in human and rodent. Portion enclosed by dashed line is expanded in Figure 2B to illustrate in more detail the villous structure and maternal spiral artery with subtypes of trophoblasts and complement components/regulators of most interest. Figure 2B. Schematic of hemochorial placenta illustrating subtypes of trophoblasts and associated selective complement components/regulators of interest that participate in normal placental development and protection of the trophoblast subpopulations from maternal complement attack. Intervillous space and maternal spiral artery is illustrated with maternal blood and plasma complement proteins bathing the villous structure for exchange of nutrients and oxygen with the fetal blood supply within the villous structure.