Unraveling the complex web: pathogenesis and prevention of gestational diabetes mellitus-related fetal overgrowth

Fetal overgrowth, manifesting as large for gestational age or macrosomia, remains a common complication of gestational diabetes mellitus (GDM) with neonatal and long-term metabolic implications. While maternal hyperglycemia is a key driver, evidence describes the role of dysregulated placental nutrient transport involving glucose, amino acids, and lipids mediated by signaling hubs like mTOR, IGF, and AMPK. Beyond traditional metabolic axes, this review explores emerging contributors, including gut microbiota dysbiosis and extracellular vesicle mediated communication, which modulate the environment. We synthesize evidence on fetal vascular adaptations and epigenetic programming underpinning accelerated growth. Clinically, achieving euglycemia often fails to eliminate residual overgrowth risks completely. Management is evolving to integrate advanced ultrasonic markers, such as fetal abdominal fat layer thickness, and pharmacotherapeutic candidates like metformin or pravastatin. However, addressing critical knowledge gaps requires robust longitudinal cohorts and rigorous causal inference to validate complex mechanisms. Furthermore, implementing standardized biomarker protocols remains essential for clinical translation. This review provides a comprehensive framework for precision-based strategies to manage GDM-related fetal overgrowth effectively. Search Strategy. A systematic search of PubMed, Web of Science, and Google Scholar was conducted for literature published up to 2025. The search utilized a combination of the following keywords and their variants: "gestational diabetes mellitus," "fetal overgrowth," "macrosomia," "placental transport," "insulin resistance," "mTOR," "extracellular vesicles," "microbiome," and "epigenetics." Boolean operators (AND, OR) were applied. Priority was given to human clinical studies, meta-analyses, and large cohort studies, with animal and <i>in vitro</i> experiments included as mechanistic supplements.