Complement System Dynamics in Pregnancy and Preeclampsia

The complement system, a proteolytic cascade within innate immunity, is tightly regulated during healthy gestation to support implantation, placental development and parturition while preventing excessive inflammation at the maternal–fetal interface. Activation proceeds via three arms—the classical, lectin and alternative pathways—converging on the central component C3 and culminating in formation of the membrane attack complex. Soluble and membrane-bound regulators, including factor H and C4b‐binding protein, safeguard the placenta from collateral damage. In preeclampsia, dysregulated complement activity—marked by elevated anaphylatoxins (C3a, C5a) and terminal complexes (C5b-9)—drives endothelial dysfunction, placental insufficiency and systemic inflammation. Genetic variants in regulatory proteins can further compromise complement control, predisposing to severe disease. Circulating complement split products and regulatory factor levels are under active investigation as predictive biomarkers and potential therapeutic targets, offering a route to personalised interventions and improved maternal-fetal outcomes.

Research from Nature Portfolio

Maternal plasma proteomics in early-onset severe preeclampsia has revealed a distinct signature dominated by complement and coagulation cascade activation. Unsupervised principal component analysis separated disease from control samples, while supervised multivariate modelling identified 17 differentially abundant proteins at 5% false discovery rate. Pathway enrichment ranked complement and coagulation cascades as the most significantly perturbed. Functional validation using independent plasma samples showed increased endothelial deposition of the C5b-9 complex and von Willebrand factor in preeclampsia, underscoring complement’s role in vascular injury and highlighting novel targets for therapy.

Complement System Dynamics in Pregnancy and Preeclampsia publication trend

The graph below shows the total number of articles in complement system dynamics in pregnancy and preeclampsia across all publications each year (not limited to Nature Index journals).

Technical terms

Complement system: A sequence of proteolytic activations in innate immunity that labels pathogens and damaged cells for clearance and promotes inflammation.

Classical pathway: Complement activation initiated by antibody–antigen complexes, leading to C4 and C2 cleavage.

Lectin pathway: Activation triggered by carbohydrate recognition on microbial or stressed cell surfaces via mannose-binding lectin.

Alternative pathway: A continuously low-level activation loop amplifying complement responses independently of antibodies.

Membrane attack complex (MAC): A terminal assembly of C5b‐9 that forms pores in target cell membranes, causing lysis.

Complement regulators: Soluble or membrane proteins (e.g., factor H, C4b-binding protein) that restrict complement activation to prevent host tissue damage.

References

1. Essential Role of Complement in Pregnancy: From Implantation to Parturition and Beyond. Frontiers in Immunology (2020).
2. Complement and coagulation cascades activation is the main pathophysiological pathway in early-onset severe preeclampsia revealed by maternal proteomics. Scientific Reports (2021).
3. Systematic review of the complement components as potential biomarkers of pre-eclampsia: pitfalls and opportunities. Frontiers in Immunology (2024).
4. Identification of complement factor H variants that predispose to pre‐eclampsia: A genetic and functional study. BJOG An International Journal of Obstetrics & Gynaecology (2023).
5. Is the Complement System Dysregulated in Preeclampsia Comorbid with HIV Infection?. International Journal of Molecular Sciences (2024).