Navigating the epigenetic landscape of gestational age

Accurate estimation of gestational age is essential for clinical decision-making during pregnancy and is a critical indicator of both fetal development and maternal health. While traditional methods relying on the last menstrual period or ultrasound imaging provide varying levels of precision, emerging evidence suggests that DNA methylation patterns offer a powerful molecular approach for estimating gestational age at birth. Epigenetic gestational age clocks, developed using machine learning models trained on DNA methylation data from neonatal blood samples, have demonstrated high accuracy and are increasingly used in epidemiological research. However, despite the growing interest in these tools, their biological significance is only partially understood. In this review, we synthesize current evidence on the relationship between DNA methylation and gestational age, with a particular focus on the development and interpretation of epigenetic gestational age clocks. We explore potential biological pathways linking DNA methylation to gestational age, discuss key methodological considerations, and compare these clocks with established DNA methylation-based aging clocks. Finally, we outline future research directions to clarify the utility of epigenetic gestational age measures in understanding prenatal development, perinatal health, and early-life risk factors.