Exploratory Urinary Proteomic Profiling in Pregnancies with Fetal Aneuploidies: Molecular Insights into Maternal–Fetal Metabolic Communication

Maternal-fetal communication involves complex molecular exchanges that can be perturbed by chromosomal abnormalities. Despite the growing use of omics approaches in prenatal research, maternal urine remains underexplored as a non-invasive source of molecular information reflecting both systemic and pregnancy-specific processes. This study performed an exploratory, label-free mass spectrometry-based proteomic analysis of maternal urine from pregnancies with normal karyotype (<i>n</i> = 15) and those affected by fetal aneuploidy (<i>n</i> = 9; trisomy 21, 18, 13, or monosomy X). A total of 861 proteins were identified across all samples, of which 42 significantly differed between groups (<i>p</i> ≤ 0.05, |fold change| ≥ 1.2). Ten proteins, including TFF1, TFF3, KRT76, CD300, PVR, VWA1, FBLN1, FGA, AZGP1, and MAT1, were more abundant in aneuploid pregnancies, suggesting roles in immune modulation, epithelial restitution, metabolic control, and extracellular matrix remodeling. Conversely, 32 proteins with lower abundance were primarily involved in immune regulation, structural organization, and energy metabolism, consistent with impaired placental and vascular adaptation. These findings reveal distinct urinary proteomic signatures associated with fetal aneuploidy, highlighting biologically relevant pathways that may advance understanding of maternal-fetal metabolic communication.