The role of complement in normal pregnancy and preeclampsia

Abstract

Preeclampsia affects 3-4% of pregnancies with adverse effects for both mother and child. Minimal therapeutic options are available, and biomarkers are urgently needed to identify those at greatest risk early in the pregnancy. Both the innate and adaptive immune systems are well regulated during normal pregnancy including the complement system. A functioning complement system with some degree of complement activation participates in proper placental development, ensuring a healthy pregnancy and assisting with host defense. However, aberrant complement activation can lead to adverse pregnancy outcomes such as preeclampsia. An overview of the complement system will be presented, along with review of the pre-clinical literature in animal models providing evidence for complement involvement in maintaining a normal pregnancy and contributing to symptoms of preeclampsia. In addition, clinical studies with evaluation of complement biomarkers in plasma and urine implicate complement dysregulation in the pathophysiology of subtypes of preeclampsia including HELLP (hemolysis, elevated liver enzymes and low platelet count) syndrome. Recent studies on the genetics of complement dysregulation in preeclampsia will be reviewed, along with updates on use of recently developed complement therapeutics. The potential utility of evaluating complement activation or manipulating complement during pregnancy will be discussed in view of the successful use of complement therapeutics in pregnancy in other immune diseases.

Keywords: complement; fetal development; innate immunity; preeclampsia; pregnancy; pregnancy loss.

Figure 1

Extracellular pathways of complement activation. Complement activation via the canonical pathways (classical, lectin and alternative) are depicted with distinct initiation steps. The classical pathway is initiated by antigen interaction with specific antibody to activate the C1qr2s2 molecule (C1 esterase) cleaving C4 and C2 resulting in a bimolecular enzyme complex C4b2b, the classical pathway C3 convertase. The lectin pathway is initiated by carbohydrates on invader surfaces binding to MBL (Mannose binding lectin) and engaging of Mannose associated serine proteases (MASP 1 & 2) to generate the identical bimolecular enzyme complex C4b2b. The alternative pathway can be activated by foreign surfaces in conjunction with the constant low level C3 tickover [C3 to C3(H₂0)]. In addition, cleavage of C3, C5 and Factor B can occur in the extracellular environment by extrinsic proteases such as trypsin, thrombin, and kallikrein – non-canonical activation (dotted boxes). Fragments generated from the action of extrinsic proteases can result in effector functions or continued pathway activation from that point. Depicted in red are select regulators of the complement pathway; fluid phase (Factor H, C1 INH, and C4BP) or membrane bound (CR1, CD46, CD55, CSMD and CD59, rodent specific Crry) that limit complement activation at the crucial C3 or C5 convertases or other points in the pathway. Created in BioRender. (2025) https://BioRender.com/ad285s3.

Figure 2

The non-canonical intracellular complement system. Complement components C3 and C5 are synthesized within the cell or shuttled into the cell in some cases. Lysosomal proteases such as cathepsin can then cleave the molecule yielding C3a/C3b or C5a/C5b, respectively, within the cell. C3a and C5a receptors have been identified within the cell on lysosomes and mitochondria. Alternatively, there is some evidence that C3a/C5a generated intracellularly can then act in an autocrine fashion on plasma membrane C3a/C5a receptors. Intracellular complement has been identified and characterized in T cells, Beta cells of the pancreas and the CNS. Ongoing research is identifying complement components operative in autophagy, metabolism, pathogen clearance and immune priming of cells in many different systems and cell types. Created in BioRender. (2025) https://BioRender.com/u1u2zs3.

Figure 3

Flow diagram for proposed evaluation of preeclampsia with severe features and HELLP syndrome. Ab, Antibody; AH50, alternative complement pathway activity; CBC, complete blood count; CFB, complement factor B; CFH, complement factor H; CFI, complement factor I; CH50, total complement activity; CMP, complete metabolic panel; Cr, creatinine; HELLP, hemolysis elevated liver enzymes low platelet count; INR, international normalized ratio; LDH, lactate dehydrogenase; Plt, platelet count; PT, prothrombin; PTT, partial thromboplastin time; TMA, thrombotic microangiopathy; UA, urinalysis.