Is there any documentation concerning the safety of ursodeoxycholic acid treatment for cholestasis

Fråga: Is there any documentation concerning the safety of ursodeoxycholic acid treatment for cholestasis during the first trimester of pregnancy?

Background: a woman with a history of pruritus gravidarum during early pregnancy is now pregnant in week 10. She again is suffering from severe pruritus. Some time after the first pregnancy, the patient developed a hepatotoxic reaction after treatment with Heracillin. However, her liver values have normalized since then.

Sammanfattning: There is no documentation on the use of ursodeoxycholic acid during the first trimester of pregnancy, except for a few case reports. Most reports describe its use during the latter portion of human pregnancy, where the drug is considered to be effective and safe. In the unusual event of severe pruritus in early pregnancy, it may be justified to administer the drug, if other alternatives with documented safety have proven ineffective.

Svar: Cholestasis of pregnancy typically develops during the third trimester of pregnancy, but occasionally presents before 20 weeks. Severe cholestasis is associated with significant fetal morbidity and mortality. Most patients are not jaundiced and serum alanine transaminase (ALAT) is the most sensitive of conventional liver function tests, although serum bile acids are invariably increased (1). Treatment tends to be supportive, sometimes in combination with dietary recommendations and antihistamines. Also, an earlier Drugline document (2) evaluated the use of cholestyramine likely to be safe during pregnancy, although reports of its use during early pregnancy seem scarce. However, antihistamines or cholestyramine may not be sufficiently effective. In (1), it is stressed that cholestasis of pregnancy is under-recognized and undertreated.

According to (3), in reproductive studies reported by the manufacturer, doses up to 100 times the human dose in rats and up to 5 times the human dose in rabbits revealed no evidence of impaired fertility or fetal harm. Lithocholic acid, a product of intestinal bacterial dehydroxylation of ursodeoxycholic acid may be associated with embryotoxicity in the rat, although it is not known whether this is of relevance to the human fetus (4). Human fetal liver, despite its inability to detoxify lithocholic acid by sulfatation, is able to rapidly change lithocholic acid into hyodeoxycholic acid by hydroxylation (5).

Concerning the treatment of cholestasis of pregnancy with ursodeoxycholic acid, most reports describe its use during the latter portion of human pregnancy, where the drug is considered to be effective and safe. However, inadvertent exposure in four women during the first trimester had no adverse effect on their fetuses or newborns (3).

A 41-year-old woman with primary biliary cirrhosis had been treated with ursodeoxycholic acid 750 mg/day for 3 years (6). At the time of diagnosis of pregnancy (5th gestational week), the drug was withdrawn, but needed to be re-introduced because of severe pruritus. A normal infant was delivered at the 34th week of pregnancy after Caesarean section for placental insufficiency. Another case report (7) concerned a 23-year-old woman with primary sclerosing cholangitis treated with ursodeoxycholic acid. When pregnancy was diagnosed, she was already through the first trimester. It was not possible to discontinue the drug treatment and she delivered a healthy baby at term. 1 Davies MH. da Silva RCMA, Jones SR, Weaver JB, Elias E: Fetal mortality associated with cholestasis of pregnancy and the potential benefit of therapy with ursodeoxycholic acid. Gut 1995; 37: 580-581 2 Drugline no 10604 (year 1993) 3 Briggs GB, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation. 5th ed. Baltimore: Williams & Wilkins; 1998 4 Dubner H, Fromm H: Ursodeoxycholic acid treatment of intrahepatic cholestasis of pregnancy: observations on efficacy and safety. Gastroenterology 1993; 104: 660-661 5 Diaferia A, Nicastri PL, Tartagni M, Loizzi P, Iacovizzi C, Di Leo A: Ursodeoxycholic acid therapy in pregnant women with cholestasis. Int J Gynaecol Obstet 1996; 52: 133-140 6 Rudi J, Schönig T, Stremmel W: Therapie mit Ursodeoxycholsäure bei primär biliärer Zirrhose während der Schwangerschaft. Z Gastroenterol 1996; 34: 188-191 7 Lodberg Christensen K, Nyboe Andersen B, Vilstrup H: Primaer skleroserende cholangitis med kloe behandlet under graviditet med ursodeoxykolsyre. Ugeskr Laeger 1997; 159: 7151-7153