The Mosaic Placenta: Somatic Genomic Variation as a Hidden Driver of Placental Dysfunction and Adverse Pregnancy Outcomes—A Systematic Review and Translational Framework for Precision Maternal–Fetal Medicine

Placental mosaicism is increasingly recognized as an intrinsic biological feature of the placenta, although its contribution to placental dysfunction remains uncertain. This systematic review synthesized studies published between 2015 and 2026 examining somatic genomic variation, clonal placental architecture, pregnancy outcomes, and emerging molecular surveillance, following PRISMA 2020 principles. Of 783 records screened, 35 studies met the inclusion criteria. Across studies, placentas exhibited extensive copy-number variation, chromosomal instability, somatic mutations, and spatially restricted clonal populations. Confined placental mosaicism showed the strongest clinical association with fetal growth restriction and discordant cell-free DNA screening results. In contrast, evidence directly linking sequence-level somatic variation with preeclampsia, pregnancy loss, or stillbirth remains limited. Advances in single-cell profiling, transcriptomics, methylomics, and circulating nucleic-acid analysis may enable non-invasive placental phenotyping. Current evidence supports prospective validation of integrated placental genomic and liquid-biopsy approaches for longitudinal maternal–fetal surveillance and improved identification of clinically informative genomic signals.