The reversed feto-maternal bile acid gradient in intrahepatic cholestasis of pregnancy is corrected by ursodeoxycholic acid

Abstract

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder associated with an increased risk of adverse fetal outcomes. It is characterised by raised maternal serum bile acids, which are believed to cause the adverse outcomes. ICP is commonly treated with ursodeoxycholic acid (UDCA). This study aimed to determine the fetal and maternal bile acid profiles in normal and ICP pregnancies, and to examine the effect of UDCA treatment. Matched maternal and umbilical cord serum samples were collected from untreated ICP (n = 18), UDCA-treated ICP (n = 46) and uncomplicated pregnancy (n = 15) cases at the time of delivery. Nineteen individual bile acids were measured using HPLC-MS/MS. Maternal and fetal serum bile acids are significantly raised in ICP compared with normal pregnancy (p = <0.0001 and <0.05, respectively), predominantly due to increased levels of conjugated cholic and chenodeoxycholic acid. There are no differences between the umbilical cord artery and cord vein levels of the major bile acid species. The feto-maternal gradient of bile acids is reversed in ICP. Treatment with UDCA significantly reduces serum bile acids in the maternal compartment (p = <0.0001), thereby reducing the feto-maternal transplacental gradient. UDCA-treatment does not cause a clinically important increase in lithocholic acid (LCA) concentrations. ICP is associated with significant quantitative and qualitative changes in the maternal and fetal bile acid pools. Treatment with UDCA reduces the level of bile acids in both compartments and reverses the qualitative changes. We have not found evidence to support the suggestion that UDCA treatment increases fetal LCA concentrations to deleterious levels.

Figure 1. Total serum bile acids and HPLC-MS/MS analysis of bile acid profiles in maternal serum.

Total serum bile acids in control, untreated ICP and UDCA-treated ICP maternal serum (A). Maternal serum bile acid profiles in normal (B), untreated ICP (C) and UDCA-treated ICP pregnancies (D). In panels B–D, the serum bile acid level is shown using equivalent Y-axes in each group. However, given the significantly lower levels of bile acids in control serum the inset panel demonstrates these data using a smaller scale. * p = <0.05, ** p = <0.001, *** p = <0.0001. Panel C comparisons vs. control, panel D comparisons vs. untreated ICP.

Figure 2. Total serum bile acids and HPLC-MS/MS analysis of bile acid profiles in umbilical cord serum.

Total serum bile acids in control, untreated ICP and UDCA-treated ICP umbilical cord serum (A). Umbilical cord serum bile acid profiles in normal (B), untreated ICP (C) and UDCA-treated ICP pregnancies (D). In panels B–D, the serum bile acid level is shown using equivalent Y-axes in each group. However, given the significantly lower levels of bile acids in control serum the inset panel demonstrates these data using a smaller scale. * p = <0.05, ** p = <0.001, *** p = <0.0001. Panel C comparisons vs. control, panel D comparisons vs. untreated ICP.

Figure 3. The distribution of unconjugated, taurine and glycine conjugated bile acids in maternal and cord serum.

Upper panel shows data from maternal samples from normal (A), untreated ICP (B) and treated ICP (C) pregnancies and lower panel shows data from umbilical cord blood samples from normal (D), untreated ICP (E) and treated ICP (F) pregnancies.

Figure 4. Transplacental total bile acid gradients in ICP cases and controls.

Graphs representing the differences in the levels of total bile acids between maternal, umbilical cord artery and vein serum samples from normal (A) (n = 15), untreated ICP (B) (n = 7) and treated ICP (C) (n = 5) pregnancies. Black bars = maternal samples, grey bars = umbilical cord vein samples, white bars = umbilical cord artery samples. * p = <0.05, maternal total bile acid vs. cord artery total bile acid and cord vein total bile acid. ** p = <0.005, maternal total bile acid vs. cord artery total bile acid and cord vein total bile acid. ns = not significant.