Placental calcineurin/NFATc1 expression and angiogenic profiles in isolated fetal growth restriction: A prospective longitudinal study.

INTRODUCTION: The calcineurin/nuclear factor of activated T-cells (NFAT) signaling pathway regulates soluble fms-like tyrosine kinase-1 (sFlt-1) expression in placental tissue; however, its role in isolated fetal growth restriction (FGR) has not been investigated. METHODS: This prospective longitudinal cohort study enrolled 39 women with isolated FGR (15 early-onset <32 weeks, 24 late-onset ≥32 weeks). Placental calcineurin and NFATc1 were quantified by ELISA at delivery. Serum sFlt-1, placental growth factor (PlGF), and vascular endothelial growth factor (VEGF), together with urinary sFlt-1 and PlGF, were measured at antepartum presentation (T1) and 24 ± 2 h postpartum (T3). RESULTS: Placental calcineurin was significantly higher in early-onset versus late-onset FGR (3.23 ± 0.93 vs. 2.63 ± 0.85 ng/mg protein, p = 0.038). A significant positive correlation was observed between placental calcineurin and NFATc1 (r = 0.409, 95% CI [0.107-0.642], p = 0.010). Early-onset FGR exhibited markedly elevated serum sFlt-1/PlGF ratios (151.4 ± 55.6 vs. 86.1 ± 46.2, p < 0.001; Cohen's d = 1.28), higher placental sFlt-1 (p = 0.036), and lower placental PlGF (p = 0.014). Following delivery, serum sFlt-1 declined by 78% in both groups (p < 0.001), while VEGF remained stable. Urinary biomarkers did not discriminate between phenotypes at antepartum presentation. CONCLUSIONS: Placental calcineurin is elevated in early-onset FGR and positively correlates with NFATc1, suggesting coordinated pathway involvement in placental insufficiency. Postpartum normalization of sFlt-1 and PlGF confirms the predominantly placental origin of the angiogenic imbalance. The serum sFlt-1/PlGF ratio discriminates between FGR phenotypes and may complement clinical decision-making.