An increasing number of women of reproductive age are being treated with azathioprine (Imuran) for inflammatory bowel disease (IBD) because the peak incidence of the disease is among women in this age group. The immunosuppressant, also used to treat other autoimmune diseases and renal transplant patients, is a pro-drug that is metabolized to 6-mercaptopurine (6-MP); 6-MP is available and is used to a lesser extent to treat IBD.
Dr. Gideon Koren
Concerns about the safety of the drug during pregnancy are reflected in the many calls we receive at Motherisk from women with IBD who are worried about the risks of exposure – and numerous queries from women on Internet message boards and IBD patient websites. Many clinicians also choose not to prescribe azathioprine during early pregnancy or in the third trimester. Contributing to this anxiety are warnings in the drug’s label that it "can cause fetal harm" when used in pregnancy, and the fact that azathioprine and 6-MP are purine antimetabolites. Moreover, studies of animals exposed to very high doses found an increased risk of congenital malformations, although the doses used to treat women and others are orders of magnitude smaller than those used in the animal studies.
Addressing these concerns, we recently conducted a meta-analysis of studies of women treated with azathioprine, and to a lesser extent, 6-MP, during pregnancy. A search of the medical literature found nine studies of about 500 women with IBD treated with these drugs during any stage of pregnancy and a group of disease-matched controls who were not treated with either drug, who were included to avoid the confounding effects of other diseases on outcomes measured in the studies, which included congenital malformations, spontaneous abortions, low birth weight, and prematurity.
The incidence of prematurity was about 70% higher among the women treated with azathioprine or 6-MP, compared with another control group of healthy women who were not treated with the drug. This was a trend that we believe is due in large part to the disease because other autoimmune diseases also are associated with an increased risk of prematurity.
When compared with the group of healthy women who did not have IBD, the risk of congenital malformations was increased by about 45% among women with IBD who were treated with azathioprine or 6-MP. But when the women on azathioprine or 6-MP were compared with women with IBD who were not on one of the purines, there was no increased risk in malformation – which indicates that it is not prenatal exposure to azathioprine or 6-MP but the condition itself that may increase the risk of malformations to some extent.
We concluded that the previously reported association of thiopurines with congenital malformations is likely due to the confounding effects of disease activity. The results of the study, which was recently completed, supports the use of azathioprine during pregnancy because the benefits of the treatment outweigh any minimal theoretical risks that may exist.
At the time a new drug enters the marketplace, there are typically case reports of malformations following drug exposure in pregnant women. Yet since azathioprine became available, there have been no case reports of malformations associated with prenatal exposure. This trend further supports our recent meta-analysis that it is not associated with an increased risk for malformations.
Other reassuring reproductive safety information includes evidence that levels of maternal 6-MP found in cord blood and the placenta are very low, which possibly means the placenta blocks some of the passage of 6-MP from the mother to the fetus. A study we published in August, which involved perfusing term placentas obtained after cesarean section in healthy women with 6-MP, showed transfer is limited from the mother to the fetus (Reprod. Toxicol. 2011 [doi:10.1016/j.reprotox.2011.8.008]).
Both studies provide helpful information for counseling patients with IBD who are doing well on azathioprine. These results also provide some reassurance regarding the relative safety of azathioprine during pregnancy for other conditions as well – although the effects of the underlying maternal disease on pregnancy must always be considered as an important factor.
Dr. Koren is professor of pediatrics, pharmacology, pharmacy, medicine, and medical genetics at the University of Toronto. He heads the Research Leadership for Better Pharmacotherapy During Pregnancy and Lactation at the Hospital for Sick Children, Toronto, where he is director of the Motherisk program. He also holds the Ivey Chair in Molecular Toxicology at the department of medicine, University of Western Ontario, London. Dr. Koren said he had no relevant financial disclosures.