Integrated First-Trimester Assessment of Placental Biomarkers, Metabolic Indices, and IGF-1/IGFBP-5 in Relation to Subsequent Gestational Diabetes Mellitus: A Prospective Cohort Study.

Background and Objectives: Gestational diabetes mellitus (GDM) is usually diagnosed at 24-28 gestational weeks, although metabolic and placental alterations may emerge considerably earlier. This study evaluated whether routinely available first-trimester placental biomarkers, metabolic indices, and insulin-like growth factor (IGF)-axis components are associated with GDM diagnosed later in pregnancy and whether these markers provide complementary information across distinct biological domains. Materials and Methods: Of 200 women completing the 75-g OGTT (34 with GDM and 166 normoglycemic), deferred IGF-1 and IGFBP-5 assays were performed in a complete-biomarker analytic cohort of 90 participants with complete clinical follow-up and available stored specimens (30 GDM and 60 controls). At 11+0-13+6 weeks, pregnancy-associated plasma protein-A (PAPP-A), free β-human chorionic gonadotropin (free β-hCG), IGF-1, IGF-binding protein-5 (IGFBP-5), fasting glucose, insulin, and lipid parameters were assessed. HOMA-IR, the triglyceride-glucose (TyG) index, TG/HDL-C, and LDL/HDL-C were calculated. GDM was diagnosed using a 75-g oral glucose tolerance test at 24-28 weeks. Group comparisons, correlation analyses, and logistic regression were performed. Results: Compared with controls, women who later developed GDM had higher first-trimester insulin, HOMA-IR, triglycerides, VLDL-C, TyG, and TG/HDL-C and lower HDL-C, free β-hCG, PAPP-A, PAPP-A MoM, and IGF-1 (all p < 0.05). Birth weight was also higher in the GDM group. Correlation patterns differed between groups, suggesting distinct relationships among placental, metabolic, and IGF-related markers. In the four-variable adjusted model, higher HOMA-IR (OR 2.123, 95% CI 1.089-4.137; p = 0.027) and TyG (OR 3.747, 95% CI 1.010-13.894; p = 0.048) were associated with increased GDM odds, whereas free β-hCG MoM (OR 0.325, 95% CI 0.115-0.920; p = 0.034) and IGF-1 (OR 0.856, 95% CI 0.748-0.980; p = 0.024) showed inverse associations. Conclusions: Pregnancies that subsequently developed GDM showed detectable first-trimester differences across metabolic, placental, and IGF-related pathways. The combined pattern supports further evaluation of multidomain early-risk assessment, although clinical predictive utility requires validation in larger independent cohorts.