Risk Factor: BM
Class: Gastrointestinal agents/ Gallstone solubilizing agents
Fetal Risk Summary
Ursodiol (ursodeoxycholic acid) is a naturally occurring bile acid used orally to dissolve gallstones. The drug has also been used for the treatment of intrahepatic cholestasis of pregnancy.
No fetal adverse effects were observed when ursodiol (up to 200 mg/kg/day) was fed to pregnant rats (1). Embryotoxicity was observed in a rat study, but this was less than with another closely related bile acid, chenodiol, and no evidence of hepatotoxicity was observed at three dosage levels (2). As reported by the manufacturer, reproduction studies in rats (with doses up to 22 times the recommended maximum human dose based on body surface area [RMHD]) and rabbits (with doses up to 7 times the RMHD) revealed no evidence of impaired fertility or fetal harm (3).
Ursodiol is absorbed from the small intestine and is extracted and conjugated by the liver. Although 30%50% of a dose may enter the systemic circulation, continuous hepatic uptake keeps ursodiol blood levels low and uptake by tissues other than the liver are considered nil (4). These factors combined with tight binding to albumin probably indicate that placental passage to the fetus does not occur.
During clinical trials, inadvertent exposure during the 1st trimester to therapeutic doses of ursodiol in four women had no effect on their fetuses or newborns (3). Several reports, summarized below, have described the apparent safe use of ursodiol in the latter portion of human pregnancy for the treatment of intrahepatic cholestasis (5,6,7,8,9 and 10).
A brief 1991 report described the use of ursodiol in the treatment of late-onset intrahepatic cholestasis during pregnancy (5). A 30-year-old primigravida was given ursodiol 600 mg/day in two divided doses for 20 days starting at 34 weeks’ gestation. No signs of fetal distress were observed during treatment. Labor was induced at 37 weeks’ gestation and a 2670-g, healthy baby girl was delivered with Apgar scores of 9 and 10 at 1 and 5 minutes, respectively.
A second letter, published in 1992, briefly described the successful outcome of eight pregnant women with intrahepatic cholestasis treated with ursodiol, 1 g/day for 3 weeks (6). The full report of this study was also published in 1992 (7). Treatment began after 25 weeks’ gestation in the eight women, five receiving 1 g/day in divided dosage for 20 consecutive days and the other three receiving the same dose for two 20-day treatment courses, separated by a 14-day drug-free interval (7). The mean dose was 14 mg/kg/day (range 1217 mg/kg/day). All of the newborns had Apgar scores >7 (at 1 and 5 minutes) and all were progressing normally at a 5-month follow-up.
A 1994 report described the use of ursodiol, 450 mg/day, in three pregnancies (singleton, twin, and quintuplet) for intrahepatic cholestasis (8). Ursodiol was started because of unsuccessful attempts to control the disease with cholestyramine or ademetionine (S-adenosyl-L-methionine; SAMe). The singleton pregnancy was treated from 29 weeks’ gestation to delivery at 37 weeks, the twin pregnancy from 27 to 33 weeks, and the woman with quintuplets from 21 weeks to delivery at 30 weeks. No adverse effects were observed in the eight newborns.
A significant reduction in the perinatal mortality and morbidity associated with cholestasis of pregnancy following the use of ursodiol was described in a study published in 1995 (9). Eight women with a history of 13 pregnancies affected by the disease were referred to a specialty clinic before conception. Expectant management had been used in 12 of the 13 pregnancies, with adverse outcomes occurring in 11: 8 stillbirths, 2 premature deliveries with one death in the perinatal period, and 1 emergency cesarean section for fetal distress. Subsequently, three of the women became pregnant again and each suffered a recurrence of cholestasis. Therapy with ursodiol, 750 mg/day in two and 1000 mg/day in one, was initiated at 31, 33, and 37 weeks’ gestation, respectively. The first patient had been pretreated with ademetionine from 16 to 31 weeks in an unsuccessful attempt to prevent cholestasis. Each of the three women showed rapid clinical improvement and resolution of their abnormal liver tests following initiation of ursodiol. Normal infants, who were doing well, were delivered at 35, 35, and 38 weeks, respectively.
A double-blind, placebo-controlled trial in women with intrahepatic cholestasis of pregnancy compared the effect of ursodiol treatment (N=8) with placebo (N=8) (10). Significant decreases in the pruritus score and all liver biochemical parameters occurred in the ursodiol group, but only the pruritus score and alanine aminotransferase were significantly improved in controls. Moreover, the gestational age at delivery in the treated group was 38 weeks compared with 34 weeks in controls (p
Breast Feeding Summary
No reports have been located that described the use of ursodiol during lactation or measured the amount, if any, excreted into milk. Because only small amounts of ursodiol appear in the systemic circulation and these are tightly bound to albumin, it is doubtful if clinically significant amounts are excreted into human breast milk.
- Toyoshima S, Fujita H, Sakurai T, Sato R, Kashima M. Reproduction studies of ursodeoxycholic acid in rats. II. Teratogenicity study. Oyo Yakuri 1978;15:93145. As cited in Shepard TH. Catalog of Teratogenic Agents. 8th ed. Baltimore, MD: Johns Hopkins University Press, 1995:438.
- Celle G, Cavanna M, Bocchini R, Robbiano L. Chenodeoxycholic acid (CDCA) versus ursodeoxycholic acid (UDCA): a comparison of their effects in pregnant rats. Arch Int Pharmacodyn Ther 1980;246:14958.
- Product information. Urso. Axcan Pharma U.S., 2000.
- Bachrach WH, Hofmann AF. Ursodeoxycholic acid in the treatment of cholesterol cholelithiasis. Part I. Dig Dis Sci 1982;27:73761.
- Mazzella G, Rizzo N, Salzetta A, Iampieri R, Bovicelli L, Roda E. Management of intrahepatic cholestasis in pregnancy. Lancet 1991;338:15945.
- Palma J, Reyes H, Ribalta J, Iglesias J, Gonzalez M. Management of intrahepatic cholestasis in pregnancy. Lancet 1992;339:1478.
- Palma J, Reyes H, Ribalta J, Iglesias J, Gonzalez MC, Hernandez I, Alvarez C, Molina C, Danitz AM. Effects of ursodeoxycholic acid in patients with intrahepatic cholestasis of pregnancy. Hepatology 1992;15:10437.
- Floreani A, Paternoster D, Grella V, Sacco S, Gangemi M, Chiaramonte M. Ursodeoxycholic acid in intrahepatic cholestasis of pregnancy. Br J Obstet Gynaecol 1994;101:645.
- 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;37:5804.
- Diaferia A, Nicastri PL, Tartagni M, Loizzi P, Iacovizzi C, Di Leo A. Ursodeoxycholic acid therapy in pregnant women with cholestasis. Int J Gynecol Obstet 1996;52:13340.