Dynamic TyG–inflammation–endothelial trajectories and placental histopathology synergistically define a maternal–fetal vascular risk phenotype

Background: Maternal dysmetabolism and low-grade inflammation accelerate fetal aortic wall thickening. Whether concomitant placental vascular or inflammatory lesions amplify this risk is unknown. Participants, Materials and Methods: 88 women with singleton, anatomically normal pregnancies were phenotyped at 24–26 weeks (visit 1, V1) and 32–34 weeks (visit 2, V2). Dynamic maternal markers [(Δ triglyceride–glucose (TyG) index, Δ interleukin-6 (IL-6), Δ high-sensitivity C-reactive protein (hsCRP), Δ flow-mediated dilation (FMD)] again generated three metabolic inflammatory response phenotypes (MIRP-1/-2/-3). Placentas were examined by pathologists. A placental malperfusion–inflammation composite (PMIC) score (0–10) summed semiquantitative grades of maternal vascular malperfusion (MVM), distal villous immaturity, chronic villitis of unknown etiology (CVUE) and acute chorioamnionitis. Results: Adequate placental tissue was obtained from 84 (95%) dyads. Median PMIC rose step wise from MIRP-1 = 2 [interquartile range (IQR) 1–3] to MIRP-2 = 5 [IQR 3–6] and MIRP-3 = 7 [IQR 6–9] (p 0.001). In mixed effects modelling, PMIC independently predicted fetal abdominal aorta intima–media thickness (IMT) progression [β=+0.012 mm per PMIC point; 95% confidence interval (CI): 0.007–0.017; p 0.001] alongside Δ TyG and Δ IL-6 (R2 conditional = 0.61). Mothers in the high risk combined phenotype (MIRP-3 + PMIC ≥7; n=25) exhibited a mean IMT increment of +0.21±0.05 mm vs. +0.06±0.03 mm in the double low reference group (MIRP-1 + PMIC ≤3; n=22; p 0.001). A five variable XGBoost model [Δ TyG, Δ IL-6, Δ FMD, PMIC, baseline body mass index (BMI)] identified fetuses with late gestation high IMT (≥90th percentile) with area under the receiver operating characteristic (AUROC) 0.91, outperforming the parent model lacking PMIC (AUROC 0.88). Conclusions: Placental vascular and inflammatory lesions potentiate the impact of adverse maternal metabolic inflammatory trajectories on fetal arterial remodeling. Integrating rapid placental histology with dynamic TyG inflammation endothelial indices could refine perinatal risk stratification and guide both ante and postpartum surveillance.