A first‐trimester mechanistic framework integrating three Physiopathologic biomarker domains for pre‐eclampsia classification

Abstract Objective To develop and internally validate a mechanistic, three‐domain framework for early classification and prediction of pre‐eclampsia (PE) using first‐trimester angiogenic, uteroplacental, and maternal vascular biomarkers. Methods In a prospective cohort of 1925 singleton pregnancies screened at 11 to 13.6 weeks, placental growth factor (PGF), uterine artery pulsatility index (UtA‐PI), and mean arterial pressure (MAP) were log‐transformed and standardized to gestational age–adjusted multiples of the median. Prespecified percentile thresholds (PGF 95th; MAP >95th) defined domain abnormalities and mechanistic phenotypes. Associations with PE, fetal growth restriction (FGR), and the composite of PE or FGR were assessed using logistic regression. Discrimination (area under the receiver operating characteristic curve AUC), calibration, and clinical utility were evaluated; bootstrap internal validation was used for optimism correction; and decision‐curve analysis quantified net clinical benefit. Results PE occurred in 104 of 1925 pregnancies (5.4%). Phenotypes were distributed as normo (81.7%), molecular (7.6%), hemodynamic (3.2%), tensional (5.1%), dual (≥2 domains; 2.1%), and triple (3/3; 0.3%). The risk of PE increased stepwise from 3.9% (normo) to 80.0% (triple) ( P for trend <0.001). The three‐domain model improved discrimination to an AUC of 0.81 (95% confidence interval CI, 0.77–0.86) versus the clinical model (AUC, 0.68; P < 0.001), achieved good discrimination for isolated FGR (AUC, 0.75 95% CI, 0.70–0.81), and provided higher net clinical benefit among 5% to 30% thresholds. In early‐onset PE (n = 14), discrimination was high (AUC, 0.99 95% CI, 0.98–1.00); estimates should be interpreted cautiously given the small number of events. Conclusion A first‐trimester, mechanistic three‐domain framework captures the pathophysiologic continuum of placental insufficiency and supports accurate, clinically meaningful early risk stratification for PE. Findings were internally validated; external validation—particularly for early‐onset PE—is warranted.