Phenotype-stratified Targeted Therapy for Preeclampsia: A Biomarker-guided, Mechanism-driven Systematic Review Integrating Oxidative Stress, Metabolic Dysfunction, Immune Injury, and Placental Vasculopathy

Preeclampsia remains one of the most consequential and conceptually unresolved syndromes in perinatal medicine. Despite decades of research, clinical management continues to rely on broadly applied preventive strategies and supportive care, reflecting an implicit assumption of disease uniformity that is increasingly difficult to justify. Accumulating molecular, metabolic, and immunovascular data instead point toward a heterogeneous disorder driven by distinct, and sometimes overlapping, pathophysiological pathways. Against this background, we conducted a systematic review to reframe preeclampsia as a phenotype-stratified condition amenable to mechanism-targeted intervention rather than a single entity managed by uniform protocols. Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020-aligned methods, we synthesized evidence from experimental studies, observational cohorts, randomized trials, and systematic reviews evaluating oxidative stress, metabolic dysfunction, immune maladaptation, angiogenic imbalance, and placental vasculopathy, alongside therapeutic strategies targeting these mechanisms. Thirty-six studies met predefined inclusion criteria. The evidence consistently supports a placenta-initiated cascade that diverges into distinct molecular phenotypes, each associated with differential biomarker profiles and therapeutic responsiveness. Antiplatelet and anticoagulant strategies appear most effective in thrombo-placental phenotypes, while metabolic modulators such as metformin show benefit in subsets characterized by endothelial and metabolic stress. Statins and antioxidant approaches demonstrate biologic plausibility and biomarker modulation, although clinical efficacy remains phenotype-dependent and incompletely resolved. This review advances a unifying yet flexible framework that integrates biomarkers with mechanism-driven drug selection, moving beyond risk-based prophylaxis toward precision-guided prevention and treatment. By aligning therapy with underlying biology, this approach challenges current paradigms and opens a path toward individualized management strategies capable of improving both maternal and fetal outcomes.