Serum sPD-L1 Levels in Early Pregnancy Predict Fetal Growth Restriction and Its Subtypes: A Prospective Nested...

Fetal growth restriction (FGR) is a leading cause of perinatal morbidity and mortality, yet reliable first-trimester biomarkers for early prediction remain lacking. Growing evidence suggests that placental dysfunction is a central pathological driver of FGR. Therefore, placenta-derived proteins in maternal circulation may serve as mechanistically informative biomarkers for early detection. Here, we aimed to evaluate several placenta-relevant molecules as biomarkers for predicting isolated FGR and its subtypes. In this prospective nested case-control study, we included singleton pregnancies that underwent Down screening in the first trimester and were subsequently diagnosed with FGR (n = 50, including early-onset FGR [EFGR] and late-onset FGR [LFGR]) and healthy pregnancies (n = 100). Pregnancies with maternal comorbidities or fetal anomalies were excluded. Maternal serum protein concentrations were measured using ELISA kits. There were no significant differences in placenta-specific protein 1 (PLAC1) or netrin-1 between the two groups. By contrast, maternal soluble programmed death-ligand 1 (sPD-L1) levels were significantly lower in overall FGR (p < 0.001) and FGR subtypes (p = 0.002) than in controls. Circulating sPD-L1 levels were positively correlated with gestational age at delivery and birth weight Z score. Each one-unit increase in sPD-L1 was associated with lower odds of overall FGR (Odd ratio, OR 0.33), EFGR (OR 0.17), LFGR (OR 0.43), birth weight Z score 3-10% (OR 0.30), and neonatal intensive care unit (NICU) admission (OR 0.38). Moreover, first-trimester sPD-L1 predicted overall FGR (area under the receiver operating characteristic curve, AUC 0.75), EFGR (AUC 0.84), LFGR (AUC 0.70), birth weight Z score 3-10% (AUC 0.75), and NICU admission (AUC 0.67). Collectively, decreased maternal circulating sPD-L1 in early pregnancy may serve as a potential biomarker for isolated FGR, warranting validation in larger multicenter mechanistic studies.