Maternal Serum Isthmin-1 as a Novel Biomarker for Late-Onset Fetal Growth Restriction

Background/Objectives: To investigate maternal serum Isthmin-1 (ISM1) levels in pregnancies complicated by fetal growth restriction (FGR) and to evaluate its potential discriminatory performance for FGR. Methods: This prospective cross-sectional study included 44 pregnant women with late-onset FGR and 43 gestational age-matched healthy controls. FGR was diagnosed according to one of two criteria: (1) estimated fetal weight (EFW) below the 3rd percentile, or (2) EFW between the 3rd and 10th percentile with at least one abnormal Doppler finding (Umbilical Artery Pulsatility Index (UA-PI), Middle Cerebral Artery Pulsatility Index (MCA-PI), or Cerebroplacental Ratio (CPR). Maternal serum ISM1 concentrations were measured using enzyme-linked immunosorbent assay (ELISA). Ultrasonographic parameters, Doppler indices, and perinatal outcomes were compared between groups. Correlation and receiver operating characteristic (ROC) analyses were performed to assess diagnostic performance. Results: Maternal ISM1 levels were significantly lower in the FGR group compared with controls [10.63 (9.95-12.10) vs. 12.40 (10.75-13.25) ng/mL, p = 0.003]. ISM1 correlated negatively with FGR presence (r = -0.318, p = 0.003) and positively with EFW percentile (r = 0.235, p = 0.028). ROC analysis showed moderate diagnostic accuracy Area Under the Curve (AUC) = 0.684, 95% CI: 0.575-0.779) with 70.5% sensitivity and 72.1% specificity at a cut-off ≤11.5 ng/mL. No significant association was found between ISM1 and composite adverse perinatal outcomes. Conclusions: Levels of ISM1 in maternal serum were found to be significantly lower in pregnancies complicated by FGR, supporting a potential association between ISM1 and impaired fetal growth. However, its moderate diagnostic performance and lack of association with adverse perinatal outcomes indicate that ISM1 should currently be regarded as a promising exploratory biomarker rather than a standalone diagnostic or prognostic marker. Further studies are needed to validate these findings and to determine whether ISM1 provides additional value when combined with established Doppler and angiogenic markers.