First-Trimester Maternal Serum Growth Arrest-Specific Protein 6 (Gas6) Levels for the Prediction of Preeclampsia.

Objective: Preeclampsia (PE) is a leading cause of maternal and perinatal morbidity; however, reliable first-trimester biomarkers are limited. Growth arrest-specific protein 6 (Gas6), a vitamin K-dependent ligand for the TAM receptor family (Tyro3, AXL, and MerTK), is crucial for trophoblast invasion and placental remodeling. This study evaluated whether first-trimester serum Gas6 levels differed between women with PE and controls and assessed the predictive utility across phenotypes. Methods: Participants were enrolled prospectively during routine first-trimester screening at 11 + 0 to 13 + 6 weeks, and cases and controls were selected using a nested case-control design after pregnancy outcomes were known. ROC-derived cut-off values for Gas6 were selected retrospectively using the Youden index and were considered exploratory. The PE group was divided into early (n = 15, <34 weeks) and late onset (n = 65, ≥34 weeks) subgroups. ELISA measured serum Gas6. Mann-Whitney U, Kruskal-Wallis, Spearman's correlation, ROC analysis, and multivariate logistic regression were applied. Results: Gas6 levels were significantly lower in PE than controls (15.73 vs. 38.08 ng/mL, p < 0.001); control reference median (38.08 ng/mL, IQR 27.62 to 49.14), decreasing progressively to late (20.07 ng/mL) and early onset PE (6.45 ng/mL; all p < 0.001). ROC analysis showed the highest exploratory discrimination for early onset preeclampsia (AUC = 0.959, 95% CI: 0.923-0.995; sensitivity 93.3%, specificity 84.1% at a retrospectively selected cut-off of ≤13.82 ng/mL), with more modest discrimination for overall PE (AUC = 0.762) and late onset PE (AUC = 0.708). Lower first-trimester Gas6 levels remained significantly associated with early onset PE after adjustment for maternal age and BMI (OR = 0.555, 95% CI: 0.412-0.748, p < 0.001). Conclusions: Serum Gas6 levels in the first trimester are lower in PE, particularly in cases of early onset disease, highlighting its potential as a candidate biomarker that requires further prospective and external validation before any screening application can be considered.