Summary
Azathioprine and its active metabolite mercaptopurine are purine analogues which interfere with the synthesis of DNA and RNA precursors. Azathioprine is used either alone or in combination with other immunosuppressive medications in the prevention of organ rejection following renal, cardiac or hepatic transplantation, and in the treatment of various autoimmune disorders. Mercaptopurine is licensed for the treatment of leukaemia.
Due to the anti-metabolite effects of azathioprine/mercaptopurine (AZA/MP), there are theoretical concerns that periconceptual paternal use could result in genetic abnormalities in the sperm and disorders in subsequent offspring. As such, the manufacturers of both azathioprine and mercaptopurine advise use of adequate contraceptive precautions in cases where either partner is undergoing AZA/MP treatment.
The available data concerning pregnancy outcomes following periconceptual paternal AZA/MP exposure are currently limited (<500 fathered pregnancies). Although isolated case reports have described adverse pregnancy outcomes, overall the data do not currently provide evidence that paternal use of AZA/MP is associated with an increased risk of spontaneous abortion, congenital malformation, low birth weight or preterm delivery. Single cases of impaired motor development and carcinogenicity (Wilms tumour) in the offspring following paternal AZA/MP use have been reported in the literature. Epidemiological studies assessing the risk of these specific outcomes or the risk of stillbirth following paternal AZA/MP exposure are currently unavailable.
The available evidence base is currently too limited to accurately assess whether the risk of adverse pregnancy outcomes differs with paternal periconceptual use in comparison with discontinued use prior to conception. It is therefore not possible to state whether paternal use of AZA/MP should be discontinued prior to attempting conception. As spermatogenesis takes approximately three months to complete, it is often advised that male patients exposed to medication for which there may be theoretical mutagenic concerns should wait six months (approximately two sperm cycles) after exposure cessation before attempting conception. However, the lack of evidence of adverse effects and the need for continued control of the paternal condition should be considered when discussing preconception discontinuation with patients.
Paternal exposure to AZA/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.
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