Azathioprine (AZA) is a prodrug and is rapidly metabolised to its active metabolite mercaptopurine (6-MP), a purine analogue which interferes with DNA/RNA synthesis and has immunosuppressant properties. AZA is licensed to treat various auto-immune disorders such as inflammatory bowel disease, rheumatoid arthritis, and psoriasis, and for the prevention of allograft rejection. It is also used off-licence to treat severe refractory eczema. 6-MP is licensed to treat acute and chronic leukaemia, as maintenance therapy in acute lymphoblastic and myelogenous leukaemia, and is used off-license to treat severe ulcerative colitis and Crohn’s disease.
There are theoretical concerns that use of AZA/6-MP in males could cause genetic abnormalities in sperm, potentially affecting offspring conceived during ongoing use or within one sperm cycle (~74 days) of cessation. However, the available pregnancy outcome data relating to offspring conceived following periconceptual paternal AZA/6-MP use (~1,000 exposures) do not raise concerns of increased risks of congenital malformation, low infant birth weight, or preterm birth. While this is reassuring, studies of additional cohorts are ideally required to confirm these findings. Additionally, due to a lack of data, the rates of miscarriage, stillbirth, and other outcomes remain unquantified. Adverse effects cannot therefore be ruled out.
The manufacturers of AZA/6-MP advise that, as a precaution, couples where the male partner is undergoing or has recently completed treatment use reliable contraception and wait at least three months after cessation of treatment before attempting conception. However, there is currently no scientific evidence of adverse fetal effects relating to paternal use. UKTIS therefore recommends that where a couple wishes to attempt conception and the male partner’s condition is well-controlled with AZA/6-MP, an assessment and discussion of the potential benefits and risks of continuing paternal treatment vs. discontinuation should be undertaken as part of the shared decision-making process.
Paternal exposure to AZA/6-MP would not usually be regarded as medical grounds for termination of pregnancy or any additional fetal monitoring. However, other risk factors may be present in individual cases which may independently increase the risk of adverse pregnancy outcome. Clinicians are reminded of the importance of consideration of such factors when performing case-specific risk assessments.
This is a summary of the full UKTIS monograph for health care professionals and should not be used in isolation. The full UKTIS monograph and access to any hyperlinked related documents is available to NHS health care professionals who are logged in.
If you have a patient with exposure to a drug or chemical and require assistance in making a patient-specific risk assessment, please telephone UKTIS on 0344 892 0909 to discuss the case with a teratology specialist.
If you would like to report a pregnancy to UKTIS please click here to download our pregnancy reporting form. Please encourage all women to complete an online reporting form.