Nonalcoholic fatty liver disease (NAFLD), and its progressive form, nonalcoholic steatohepatitis (NASH), is the leading cause of cirrhosis and liver transplantation in women, yet it is often undiagnosed until overt complications have developed. Non-invasive tests can now identify “at-risk” NASH, defined as having the highest risk for liver disease progression. Women of reproductive age commonly engage with healthcare systems during their pregnancy care, providing a unique opportunity to identify “at-risk” NASH early, particularly because metabolic changes in pregnancy may initiate and/ or worsen NAFLD progression. As such, we first conducted a multidisciplinary protocol to screen for NAFLD in pregnant individuals, Fatty Liver in Pregnancy (FLIP) I, in which we identified 1) a 14% overall prevalence of NAFLD in pregnant individuals, 2) Hispanic ethnicity and pre-pregnancy weight as key predictors of NAFLD in pregnancy, and 3) in a pilot study of postpartum assessment, found that 83% of individuals had worsening NAFLD grade post-delivery. Given that hepatic lipid metabolism dysregulation plays a central role in NAFLD initiation and progression, in a preliminary lipidomics analysis in FLIP I participants, we identified distinct lipidomic profiles in individuals with NAFLD in pregnancy (compared to non-pregnant individuals with NAFLD), and clustering of polyunsaturated fatty acid-derived oxidized fatty acids in individuals with NAFLD, gestational hypertension and preeclampsia, emphasizing the potential shared role of these lipid pathways in the pathogenesis of NAFLD and these adverse pregnancy outcomes (APOs). With our findings from FLIP I, we are now poised to study the longitudinal influence of NAFLD in pregnancy, and associated lipid parameters, on women's health. In the proposed FLIP II study, we seek to evaluate the evolution of NAFLD in pregnancy and its influence on pregnancy outcomes, identify predictors for the development of “at-risk” NASH after pregnancy, and evaluate the NAFLD driven lipid based mechanisms that predict these events. We will prospectively screen 1540 pregnant individuals for NAFLD (by ultrasound and Fibroscan) in early pregnancy and enroll them for longitudinal follow up for up to one year postpartum. We will administer detailed questionnaires collecting sociodemographic, dietary, and clinical data and collect and bank serum specimens for analysis. Our specific aims are 1) To determine the association between NAFLD in pregnancy and APOs; 2) To evaluate antepartum factors that predispose to “at-risk” NASH post-pregnancy; and 3) To investigate the lipidomics-based mechanisms underlying NAFLD in pregnancy and its association with post-delivery “at-risk” NASH. By uncovering novel insights into the natural history of NAFLD/ NASH in women in the pregnancy/ postpartum period, our study will help stratify risk factors for NASH progression and provide valuable information for future targeted interventions in this subgroup. Ultimate...