Concerns with 2019 study of efficacy of Ursodeoxycholic Acid

CONCERNS WITH 2019 STUDY OF EFFICACY OF URSODEOXYCHOLIC ACID

A study published in the Lancet in August of 2019 compared Ursodeoxycholic Acid to placebo in women with intrahepatic cholestasis of pregnancy. This study failed to find a significant difference between the study group and the control group.

Overall, the study was well-designed. However, there was one important issue that may have profoundly impacted the results.

“Women who were taking Ursodeoxycholic Acid at enrollment agreed to stop the medication at randomisation.”

This means that at least some of the women who were recruited to the trial had been taking the medication prior to enrolling. Ursodeoxycholic acid, being a bile acid, is a highly recycled substance in the body and has a half-life of 4-6 days. This means it can remain in the body for weeks after ceasing the medication. In other words, women were randomized into the control group (receiving a placebo), while still under the potential benefits of the medication.

This may be apparent in the results as well. Both the study and control groups saw decreased bile acid levels.The study was unable to find a difference in outcomes for the babies, but given that the control group may have been affected by Ursodeoxycholic acid, this is not surprising. The most troubling outcome, stillbirth, was not observed with sufficient frequency to analyze. Two stillbirths were recorded in the control group and one in the study group. It is problematic to make management decisions based on these results, given that stillbirth is the outcome we most want to protect against.

Previous studies and two meta-analyses have shown a significant decrease in bile acids when Ursodeoxycholic acid is used versus control groups1,2. With this in mind, ICP Care advocates strongly for use of this medicine during pregnancy.

A number of studies have shown benefits of Ursodeoxycholic acid therapy which may contribute to fetal well-being. UDCA appears to protect fetal heart cells from the changes which can be induced by bile acids,3 prevents changes to the placenta which may be induced by bile acids,4,5 and corrects the placenta’s ability to transport bile acids away from the fetus.6-8

At the time this article was written, the Society for Maternal-Fetal Medicine recommends treating Intrahepatic Cholestasis of Pregnancy with Ursodeoxycholic acid.9

 

1 Grand’Maison S, Durand M, Mohone M: The effects of Ursodeoxycholic acid treatment for intrahepatic cholestasis of pregnancy on maternal and fetal outcomes: a meta-analysis including non-randomized studies. J Obstet Gynaec Can 2014;36(7):632-641.

2 Bacq Y, Sentilhes L, Reyes HB, et al: Efficacy of ursodeoxycholic acid in treating intrahepatic cholestasis of pregnancy: a meta-analysis. Gastroenterology 2012;143:1492-1501.

3 Williamson C, Miragoli M, Kadir SSA et al: Bile acid signaling in fetal tissues: implications for intrahepatic cholestasis of pregnancy. Digestive Diseases 2011;29:58-61.

4 Shemer EW, Thorsell M, Ostlund E, et al: Stereological assessment of placental morphology in intrahepatic cholestasis of pregnancy. Placenta 2012;33:914-918.

5 Geenes VL, Lim YH, Bowman N, et al: A placental phenotype for intrahepatic cholestasis of pregnancy. Placenta 2011;32: 1026-1032.

6 Serrano MA, Brites D, Larena MG, et al: Beneficial effect of ursodeoxycholic acid on alterations induced by cholestasis of pregnancy in bile acid transport across the human placenta. J Hepatology 1998;28:829-839.

7 Geenes V, Lovgren-Sandblom A, Benthin L, et al: The reversed feto-maternal bile acid gradient in intrahepatic cholestasis of pregnancy is corrected by ursodeoxycholic acid. Plos One 2014;9(1):e83828.

8 Azzaroli F, Raspanti ME, Simoni P, et al: High doses of ursodeoxycholic acid up-regulate the expression of placental breast cancer resistance protein in patients affected by intrahepatic cholestasis of pregnancy. Plos One 2013;8:e64101.

9 Understanding Intrahepatic Cholestasis of Pregnancy – Publications SMFM.org – The Society for Maternal-Fetal Medicine. Smfmorg. 2015. Available at: https://www.smfm.org/publications/96-understanding-intrahepatic-cholestasis-of-pregnancy.