Complement as a driver of immune-vascular heterogeneity across preeclampsia subtypes: toward a precision medicine framework.

Preeclampsia (PE) is a leading cause of maternal and perinatal morbidity worldwide, traditionally defined as a hypertensive disorder of pregnancy but increasingly recognized as a heterogeneous syndrome with diverse biological origins. Emerging evidence indicates that distinct pathogenic pathways-including placental insufficiency, maternal cardiometabolic dysfunction, and intrinsic immune dysregulation-contribute to different clinical phenotypes of the disease. Among these, the complement system has gained attention as a central regulator of immune-vascular interactions during pregnancy. Recent studies demonstrate that tightly controlled complement activation is required for normal placental development, whereas dysregulation of this system contributes to endothelial injury, inflammation, and microvascular dysfunction characteristic of PE. Importantly, complement activation patterns differ across disease subtypes: classical pathway activation predominates in placental-driven early-onset PE, chronic low-grade alternative pathway activation is associated with maternal metabolic disease, and genetic or functional defects in complement regulation define a subset of severe, complement-mediated cases with overlap features of thrombotic microangiopathy. Despite these advances, current diagnostic and therapeutic approaches remain largely non-specific and fail to account for this biological heterogeneity. Here, we propose a subtype-based framework of PE centered on complement dysregulation, integrating mechanistic, genetic, and clinical evidence. This model links distinct complement activation patterns to disease trajectories and identifies corresponding biomarker signatures and therapeutic targets. By redefining PE as a spectrum of complement-stratified disorders, this Review provides a conceptual foundation for precision diagnostics and mechanism-guided therapy. Such an approach has the potential to improve risk stratification, enable earlier detection, and support the development of targeted interventions tailored to individual disease mechanisms.