Abstract More than half of U.S. mothers entered pregnancy with overweight or obesity (OWO); maternal obesity is considered a major determinant of the next generations' OWO risk.7 A similar inter-generational link was observed for maternal hypertensive disorders before and during pregnancy. This inter-generational link may originate in utero and amplify the cardio- metabolic risk in current and future generations. However, questions remain about what the underlying mechanisms are and what can be done to mitigate the adverse effects of maternal cardio-metabolic disorders on offspring health. We propose to leverage the exceptional resources of the Boston Birth Cohort (BBC), one of the largest and longest U.S. high-risk urban low-income minority birth cohorts, to investigate the inter-generational link of cardio-metabolic outcomes and the role of maternal folate/B12 nutrition (modifiable early life factors), and to explore plausible epigenetic underpinnings. Furthermore, by combining fetal multi-omics data (genome, epigenome, and metabolome) with maternal and fetal epidemiological and clinical data, we seek to more precisely characterize newborns' future risk for the development of adverse cardio-metabolic outcomes up to age 21 years. Our proposal has a strong scientific premise. Both animal models and human studies implicate the intrauterine period as a critical time for the establishment of epigenetic variability. Epigenetic regulation has been implicated in a range of important biological functions, including adipogenesis, glucose homeostasis, inflammation, and insulin signaling. As such, fetal epigenetic mechanisms are critical for understanding an inter-generational link of cardio- metabolic disorders. However, currently there is no adequately powered prospective birth cohort study to assess the role of the fetal epigenome (using the latest profiling technology) along with maternal folate/B12 status in inter-generational cardio-metabolic risk in U.S. populations. Our proposal is also supported by promising preliminary data from the BBC, indicating that maternal folate status influences offspring DNA methylation and cardio-metabolic outcomes and mitigates the adverse effects of maternal cardio-metabolic disorders on offspring health. Successful completion of this study will improve our understanding of inter-generational cardio-metabolic risk and lead to a new paradigm for early prediction and prevention to halt or reverse the vicious inter-generational cycle, beginning at critical developmental windows when interventions may have the greatest impact on improving life-long health and reducing health disparities in current and future generations.