The thiopurines – 6-mercaptopurine and azathioprine, which is metabolized to 6-mercaptopurine – are highly effective medications for treating inflammatory bowel disease, a diagnosis with a peak incidence during childbearing age. IBD, therefore, is quite common among pregnant women and is associated with an increased risk of miscarriage, prematurity, and low birth weight.
The use of these drugs during pregnancy has been a concern, because they are cytotoxic antimetabolites that are also used as anticancer drugs, albeit at higher doses than those used for IBD. Moreover, animal studies have consistently found an increased risk of malformations with exposure to high doses of these drugs.
As early as 20 years ago in J.L. Schardein’s book, "Chemically Induced Birth Defects" (New York: Marcel Dekker, Inc, 1993) on the safety of drugs in pregnancy, the author noted that while published case reports typically report adverse outcomes, he had collected over 90 cases of babies exposed to thiopurines during the first trimester with no evidence of malformations. This raised the question of whether reports of malformations associated with prenatal exposure had been missed, or whether prenatal exposure to the drug – at the levels used to treat IBD – is not associated with an increased malformation rate.
Nevertheless, over the past 2 decades, the inclination has been not to use these two drugs during pregnancy if possible, and human studies evaluating their reproductive safety have been limited and have produced conflicting results. However half of all pregnancies are unplanned, and for some women, physicians feel that it is important to continue treatment, despite the uncertainty about potential fetal risks. Hence the need for authoritative data on fetal safety is paramount.
At Motherisk, we receive many calls from women with IBD and their health care providers about the safety of these two drugs in pregnancy, so we embarked on a systematic review of the available studies.
The meta-analysis of all available observational cohort studies included studies that compared women with IBD who were treated with a thiopurine vs. disease-matched controls who were not on a thiopurine; studies that compared women who were treated with a thiopurine for any diagnosis; and studies that included both comparisons.
One of the main findings was that women with IBD who continued treatment with azathioprine (Imuran) or 6-mercaptourine during pregnancy had a significantly greater risk of having a premature baby, compared with untreated disease-matched controls and disease-matched controls who were on other IBD treatments. The risk of preterm birth was also higher among women who were treated with a thiopurine for any indication, compared with the healthy controls.
Because a thiopurine is used to treat a woman with active disease, this finding is consistent with the fact that active disease is also associated with an increased risk for preterm birth, suggesting that it’s not necessarily the medicine but the condition itself that may result in preterm delivery.
There was no significant difference in the risk of congenital malformations or low birth weight among the women with IBD who were treated with a thiopurine and women with IBD who were not treated with these medications. But the risk of malformations or low birth weight was increased significantly among the women with IBD who were treated with a thiopurine, compared with healthy controls. These findings again suggest that the increased risk has more to do with the condition, and not with exposure to a thiopurine.
Because most of the studies in the meta-analysis did not include specific information on disease activity among the pregnant women with IBD, studies in the future should do so. The results of our analysis suggest that the benefits of treatment outweigh the possible risks during pregnancy.
Another consideration is that these are among the drugs used to treat IBD that have replaced corticosteroids, which have significant maternal side effects and an increased, established small risk of oral clefts with first trimester exposure.
The benefit of treatment with a thiopurine must be balanced against the risk of not treating the mother, keeping in mind that maintaining disease remission in pregnancy is critical for a positive outcome for the baby.
Dr. Koren is professor of pediatrics, pharmacology, pharmacy, 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 reported that he had no relevant financial disclosures. E-mail him at [email protected].