G348(P) Ursodeoxycholic acid improves metabolic outcomes in the fetus, placenta and offspring of hypercholanemic pregnancy

Aims Perturbations in the intrauterine environment can result in lifelong consequences for fetal metabolic health. We previously showed that in humans, intrahepatic cholestasis of pregnancy (ICP) can predispose offspring to metabolic disease, likely due to a combination of the effects of increased bile acids (BA), maternal dyslipidemia and deranged maternal and fetal lipid homeostasis. Ursodeoxycholic acid (UDCA) is a well-established treatment for maternal ICP. We aimed to address whether UDCA can also prevent the adverse metabolic effects of ICP in the offspring and fetoplacental unit. Methods Women with ICP±UDCA treatment and controls with uncomplicated pregnancy were recruited for epigenome wide association studies which were performed on maternal and venous umbilical cord blood. Animal studies were performed on aged-matched Harlan mice (C57BL/6) using a previously established model of hypercholanaemic pregnancy. Serum biochemical measurements, global DNA methylation studies and qPCR was performed on mothers and offspring at a defined stage of pregnancy (day 18) and post-natal life in offspring (week 18). Statistical analysis for multiple comparisons was performed by repeated measures of ANOVA and Newman-Keuls post-hoc testing (p Results We analysed the lipid profile of fetal serum from untreated ICP, UDCA-treated ICP and uncomplicated pregnancies and found that UDCA ameliorates ICP-associated fetal dyslipidemia. We then investigated the effects of UDCA in a mouse model of hypercholanemic pregnancy and showed that it induces hepatoprotective mechanisms in the fetal liver, reduces hepatic fatty acid synthase (Fas) expression and improves glucose tolerance in the adult offspring. Finally, we show that ICP leads to epigenetic changes in pathways of relevance to the offspring phenotype. Conclusion UDCA prevents adverse metabolic features in offspring exposed to hypercholanemia in pregnancy. In addition, the effects of ICP on the offspring appear to be mediated by epigenetic mechanisms.