Confined Placental Mosaicism, Cell-free DNA Discordance, and the Continuum of Reproductive Failure: A Systematic Review Integrating Recurrent Pregnancy Loss, Aneuploid Rescue, and Placenta-driven Obstetric Disease

Confined placental mosaicism (CPM) has traditionally been framed as a technical explanation for discordant noninvasive prenatal testing results, yet its broader biological relevance across pregnancy remains only partially integrated. In day-to-day practice, however, the pattern feels familiar – early loss attributed to chromosomal abnormality, a continuing pregnancy marked by unexpected cell-free DNA (cfDNA) signals, and, later, a shift toward fetal growth restriction or hypertensive disease. This review set out to examine whether such observations may be related rather than coincidental, drawing on a systematic search conducted in line with Preferred Reporting Items for Systematic reviews and Meta-Analyses 2020 guidance. Major biomedical databases were screened for studies published between 2016 and 2025 addressing CPM, cfDNA discordance, recurrent pregnancy loss, and placenta-mediated complications. After stepwise selection, 38 studies were included for qualitative synthesis. Across these reports, chromosomal instability arising early in development appears, in some cases, to undergo partial resolution, resulting in mosaicism that is disproportionately represented in placental tissues. Because circulating cfDNA reflects trophoblastic turnover, this process can generate discordant screening signals while also being associated with altered placental structure and function. Taken together, these findings suggest – but do not establish – a possible continuum, linking early pregnancy loss, discordant cfDNA results, and later obstetric complications. Importantly, this interpretation remains hypothesis-generating and grounded largely in observational evidence, with limited direct longitudinal validation. Rather than defining a causal pathway, the framework offers a way to reconsider how seemingly separate clinical events might intersect. Such a perspective may support more integrated interpretation of cfDNA findings and reproductive outcomes, while underscoring the need for prospective studies to clarify biological mechanisms and clinical relevance.