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

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