Association of Circulating miRNAs from the C19MC Cluster and IGF System with Macrosomia in Women with Gestational Diabetes Mellitus

Gestational diabetes mellitus (GDM) increases the risk of fetal overgrowth and macrosomia, yet the molecular mechanisms remain unclear. Emerging evidence implicates primate-specific placental microRNAs (miRNAs) from the C19MC cluster in modulating fetal growth via the insulin-like growth factor (IGF) axis. This study aimed to investigate the expression of circulating C19MC miRNAs in GDM pregnancies and their association with IGF axis biomarkers and birthweight outcomes. In this cross-sectional study, 158 pregnant women were stratified into normoglycemic pregnancies (<i>n</i> = 52), GDM with normal birthweight (<i>n</i> = 56), and GDM with large-for-gestational-age (LGA) newborns (<i>n</i> = 50). Plasma levels of 19 C19MC miRNAs and IGF-related proteins were measured. Associations between miRNAs, IGF axis components, and birthweight were analyzed using linear regression and correlation models adjusted for relevant covariates. Several miRNAs, including miR-516a-5p, miR-518d-3p, miR-521, and miR-525-3p, were differentially expressed in GDM, particularly in LGA cases. Strong correlations were observed, such as that of miR-516a-5p with IGFBP-5 (<i>r</i> = 0.705; <i>p</i> < 0.001). Inverse associations with birthweight were found for miR-519b-3p, miR-518d-5p, and miR-520a-5p. Circulating C19MC miRNAs are dysregulated in GDM and correlate with IGF signaling and fetal growth, supporting their potential as early biomarkers for macrosomia risk in GDM.