The toxicity of methotrexate in male fertility and paternal teratogenicity

ABSTRACT

Introduction: There is a high prevalence of methotrexate (MTX) use in males of reproductive age. The scope of this paper reviews what is known regarding risks to fertility and partners’ pregnancy outcomes with regard to MTX use in men.

Areas covered: This paper reviews the evidence for current recommendations for MTX use and male fertility and aims to educate professionals regarding MTX use in reproducing males so that patients may be counseled appropriately. A literature search included peer-reviewed sources from PubMed searches and the literature referenced within.

Expert opinion: There is a lack of evidence regarding effects of MTX on male fertility. The recommendation to stop MTX three months prior to conception is safe, but is not evidenced by an understanding of the impact of MTX on spermatogenesis or paternal-mediated teratogenicity but rather the timeframe of spermatogenesis. Given the unclear evidence, patients treated with MTX must be counseled on the likelihood of adverse effects of MTX and role of sperm cryopreservation. Future studies are needed to help elucidate the unclear evidence of MTX effects on male fertility and pregnancy outcomes.

KEYWORDS:

• Male infertility
• methotrexate
• spermatogenesis
• psoriasis
• rheumatoid arthritis

Article highlights

• A number of investigators have recommended to delay conception until after therapy with MTX.

• There are various proposed mechanisms in which paternal exposure may influence pregnancy outcomes, including mutagenic, teratogenic, and cytotoxic activity.

• Evidence includes small studies, case reports, and animal models, that demonstrate a cytotoxic potential of MTX on sperm and mutagenic changes in germline cells, however the risk of inheritance of chromosomal changes or point mutations appears minimal.

• There are clear limitations in the current literature and future studies are required to better quantify risk.

• The recommendation of cessation of MTX three months before conception appears safe, but is based on the timeframe of spermatogenesis rather than quality evidence of germline mutations resulting in clinically significant changes in offspring.

• Recommendation should be based on a discussion between the patient and provider, rather than a strict recommendation, and take into consideration the disease state of the patient and risk-benefit ratio of continuing treatment of MTX.

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Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

The authors were supported by Brown University.