Teratogen update: Azathioprine and 6-mercaptopurine

Maternal AZA or 6-MP treatment during pregnancy is clearly teratogenic in animals at doses similar to or greater than those used in humans, but information on the teratogenicity of these medications in human pregnancy is limited. Most available information is from single cases or clinical series of organ transplant recipients or women undergoing treatment for cancer. Less information is available on the use of AZA or 6-MP for treatment of other diseases in pregnant women. Without the benefit of well-controlled studies, it is difficult to determine if the risk of birth defects is higher among infants whose mothers are treated with AZA or 6-MP during pregnancy than in the general population. Given the animal and mechanistic data, however, one must assume that some risk exists with chemotherapeutic doses of 6-MP early in pregnancy. The available human data, although limited, suggest that this risk is not great. In addition, prenatal exposure to these drugs may cause bone marrow suppression in neonates. It is likely that women treated with AZA or 6-MP for malignancies have a higher risk of adverse pregnancy outcomes than women treated for other diseases because of the higher doses used to treat cancer. The evidence from clinical series suggests that the risk of congenital anomalies among infants of transplant recipients who are treated with AZA throughout pregnancy is minimal to small. One might expect a greater risk on the basis of the animal studies, but the poor bioavailability of AZA and 6-MP after oral administration may produce levels that are too low to have a substantial teratogenic effect. Both AZA and 6-MP are often used in conjunction with other medications. The teratogenic risks associated with polydrug therapy that includes AZA or 6-MP may be greater than the risks associated with maternal monotherapy with either drug. Genetic variations may influence the teratogenicity of AZA or 6-MP. Women with polymorphic variants that reduce the activity of TPMT may experience potentially toxic drug levels when treated with conventional doses of AZA or 6-MP. The occurrence of higher circulating concentrations of drug in women with such genetic variants seems likely to increase their risk of an adverse pregnancy outcome, but this has not been studied. It is important to remember that many of the women treated with cytotoxic immunosuppressants such as AZA and 6-MP have serious illnesses. Poor pregnancy outcomes are common among women with chronic illnesses, such as cancer and rheumatic diseases. Nevertheless, these medications may permit a woman to become pregnant who otherwise would be too ill to do so. These chronic diseases may pose very serious risks to both the mother and fetus during pregnancy. In many cases, the risk associated with effective treatment using AZA or 6-MP may be smaller than the risk that accompanies an untreated pregnancy in a seriously ill woman. Because AZA and 6-MP inhibit the synthesis of nucleic acids, it is possible that treatment with these drugs interfere with DNA replication in the germ cells. Although cytogenetic abnormalities and congenital anomalies have been described in a few of the offspring of patients treated with AZA or 6-MP before conception, too little information is available to draw any firm conclusions regarding the germ-cell mutagenicity of these drugs. Large populations are required to detect even a small increase in germ cell mutation (Byrne, '99). The limited available data suggest that the risk of birth defects associated with preconceptional treatment with these drugs is likely to be increased only slightly, if at all.