The Placental Epigenome in Preterm Birth: From Cellular Heterogeneity to Liquid Biopsy Biomarkers

Preterm birth (PTB) remains a leading cause of neonatal morbidity and mortality worldwide, with limited tools for early prediction or targeted prevention. Increasing evidence identifies the placenta as a central regulator of gestational duration, and alterations in placental gene regulatory programs have been associated with PTB. This review synthesizes recent advances in placental genomics and epigenomics, emphasizing how cell-type-specific regulatory landscapes shape PTB risk. We describe how DNA methylation, chromatin accessibility, and transcriptional heterogeneity across trophoblasts, Hofbauer cells, endothelial cells, Natural Killer (NK) cells, and mesenchymal stromal cells integrate maternal, fetal, immune, and environmental signals. We further evaluate emerging liquid biopsy approaches, focusing on circulating cell-free placental DNA (cfpDNA) methylation as a minimally invasive strategy to detect placental dysfunction. Single-cell and long-read sequencing technologies have enabled high-resolution mapping of placental regulatory architecture, revealing cell-type-specific pathways underlying inflammation, impaired trophoblast differentiation, and aberrant vascular remodeling. These studies support the investigation of placental epigenetic alterations as potential contributors to PTB-associated biology, although their causal roles and consistency across PTB subtypes remain uncertain. Circulating cfpDNA methylation profiles are being investigated as minimally invasive indicators of placental biology, but their accuracy and clinical utility for PTB prediction require further validation. Together, these findings suggest that epigenomic alterations may be associated with biological pathways implicated in PTB and may also provide measurable molecular signatures in maternal circulation.