Abstract Fetal growth restriction (FGR) remains one of the most complex and unresolved challenges in perinatal medicine, with mounting evidence suggesting that its origins extend beyond placental insufficiency alone. Increasingly, genomic and epigenomic alterations within the fetal–placental unit appear to shape the trajectory of impaired growth; however, the diversity and fragmentation of current studies have hindered a unified understanding of these mechanisms. This systematic review synthesizes multi-omic evidence to clarify how fetal and placental genomic architecture, DNA methylation, imprinting networks, and noncoding RNA signaling converge to influence FGR. A comprehensive search of major databases and registers was conducted in alignment with Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines, yielding 560 records. After screening and eligibility assessment, 37 studies met the inclusion criteria, of which 20 were identified as low-risk core literature based on Risk of Bias in Systematic Reviews appraisal. Across studies, consistent patterns emerged: dysregulation of imprinted genes such as pleomorphic adenoma gene-like 1 ( PLAGL1 ) and IGF2; broad methylation disturbances involving growth and metabolic pathways; sex-dimorphic expression of long noncoding RNAs; and microRNA-driven disruption of angiogenic signaling. Evidence from confined placental mosaicism and fetal genetic variants further underscores the role of genomic instability in modifying placental development. Collectively, these findings reveal a coordinated network of fetal–placental genomic and epigenomic interactions that precede the classical physiological features of placental insufficiency. Understanding these molecular intersections not only reframes the pathophysiology of FGR but also highlights emerging opportunities for integrative biomarker panels, early diagnostic strategies, and precision obstetric interventions. This review provides an updated, mechanistically anchored synthesis intended to guide future translational and clinical research in the field.
Andonotopo et al. (Wed,) studied this question.