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 <10th; UtA-PI >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.