Studies on the risk factors for intrahepatic cholestasis of pregnancy (ICP) in a population-based cohort are lacking. We assess the prevalence and risk factors of ICP in a Chinese population. In this study, a cohort study was conducted that included 12,200 eligible pregnant women. The overall incidence of ICP in this cohort was 6.06%. With increasing maternal age, the incidence of ICP decreased in women younger than 30 years of age but increased in those older than 30. With increasing pre-pregnancy BMI, the incidence of ICP decreased if the pre-pregnancy BMI was less than 23 kg/m2 but increased if it was 23 kg/m2 or higher. Further analysis showed that the risk of ICP increased when maternal age was < 25 years (Adjusted RR  2.01; 95% CI 1.64–2.47) or ≥ 35 years (Adjusted RR  1.34; 95% CI 1.02–1.76). Furthermore, an increased risk of ICP was associated with pre-pregnancy underweight (adjusted RR  1.27; 95% CI 1.04–1.56), inadequate gestational weight gain (GWG) (adjusted RR  1.58; 95% CI 1.28–1.96), lower maternal education (adjusted RR  2.96; 95% CI 2.35–3.74), multiparity (adjusted RR  1.54; 95% CI 1.23–1.93), and twin/multiple pregnancies (adjusted RR  2.12; 95% CI 1.25–3.58). Maternal age (< 25 or ≥ 35 years), underweight, inadequate GWG, lower maternal education, multiparity, and twin/multiple pregnancies were identified as risk factors of ICP.

Epidemiological studies suggest that fetal growth restriction (FGR) caused by gestational cholestasis is associated with elevated serum cholic acid (CA).Here, we explore the mechanism by which CA induces FGR. Pregnant mice except controls were orally administered with CA daily from gestational day 13 (GD13) to GD17. Results found that CA exposure decreased fetal weight and crown-rump length, and increased the incidence of FGR in a dose-dependent manner. Furthermore, CA caused placental glucocorticoid (GC) barrier dysfunction via down-regulating the protein but not the mRNA level of placental 11β-Hydroxysteroid dehydrogenase-2 (11β-HSD2). Additionally, CA activated placental GCN2/eIF2α pathway. GCN2iB, an inhibitor of GCN2, significantly inhibited CA-induced down-regulation of 11β-HSD2 protein. We further found that CA caused excessive reactive oxygen species (ROS) production and oxidative stress in mouse placentas and human trophoblasts. NAC significantly rescued CA-induced placental barrier dysfunction by inhibiting activation of GCN2/ eIF2α pathway and subsequent down-regulation of 11β-HSD2 protein in placental trophoblasts. Importantly, NAC rescued CA-induced FGR in mice. Overall, our results suggest that CA exposure during late pregnancy induces placental GC barrier dysfunction and subsequent FGR may be via ROS-mediated placental GCN2/eIF2α activation. This study provides valuable insight for understanding How to cite this article: Lin S, Ye M-Y, Fu Q-Y, et al. Cholic acid exposure during late pregnancy causes placental dysfunction and fetal growth restriction by reactive oxygen species-mediated activation of placental GCN2/eIF2α pathway. The