Does methotrexate (Disease-Modifying Antirheumatic Drug, DMARD) affect reproductive health?

Impact of Methotrexate on Reproductive Health

Methotrexate significantly affects reproductive health in both women and men, with absolute contraindication during pregnancy due to its teratogenic effects, and requires discontinuation at least 3 months before conception attempts in both sexes. 1

Effects on Female Reproduction

Pregnancy Risks

• Methotrexate is an FDA pregnancy category X medication and a known teratogen 1, 2
• Contraindicated in women attempting to conceive 1
• Causes serious fetal abnormalities including:
  • Cardiac defects
  • Skeletal abnormalities
  • Central nervous system defects 1, 3
• Serves as an abortifacient (can cause pregnancy loss) 1

Recommendations for Women

• Must use effective contraception while taking methotrexate 1
• Should discontinue methotrexate at least 3 months before attempting conception 1
• If pregnancy occurs while on methotrexate:
  • Immediately discontinue the medication
  • Seek urgent obstetric consultation 1
  • Begin folic acid supplementation 1
• Breastfeeding is contraindicated during methotrexate therapy 1, 4

Pregnancy Outcomes After Exposure

• 23% miscarriage rate reported in women exposed to methotrexate during pregnancy 1, 4

• 5% rate of congenital anomalies 4, 3

• A recent German study found that among 184 methotrexate-exposed pregnancies:
  • 53% resulted in live births (21% preterm)
  • 11% ended in induced abortion
  • 6% of live-born children had relevant malformations 3

Effects on Male Reproduction

Spermatogenesis

• Controversy exists regarding methotrexate's effects on male fertility 1
• Some studies suggest methotrexate may cause:
  • Severe but reversible oligospermia 1
  • Potential toxicity to dividing cells in spermatogenesis 1, 5
• Other studies show no changes in sperm counts or spermatogenesis 1, 6

Paternal Exposure and Pregnancy Outcomes

• Limited evidence regarding teratogenicity in pregnancies fathered by men on methotrexate 1, 6
• A review of 284 pregnancies with paternal methotrexate exposure reported:
  • 248 live births
  • 13 malformations, with no clear pattern of methotrexate embryopathy 6
• Risk of direct fetal toxicity through methotrexate-contaminated seminal fluid appears negligible 6

Recommendations for Men

• Men should wait 3 months after discontinuing methotrexate before attempting to conceive a child 1
• This recommendation is based on the 74-day cycle of spermatogenesis rather than clear evidence of harm 1, 5
• The American College of Rheumatology strongly recommends discontinuing methotrexate 3 months prior to conception attempts 1

Clinical Implications and Management

Pre-Treatment Counseling

• Discuss reproductive risks with all patients of childbearing potential 1, 2
• Emphasize need for contraception during treatment 1
• Consider sperm cryopreservation for men concerned about fertility 5

Monitoring and Follow-up

• Regular pregnancy tests for women of childbearing potential 1
• Discuss family planning well in advance of conception attempts 1

Common Pitfalls to Avoid

• Failure to counsel patients about reproductive risks before starting treatment
• Inadequate contraception during methotrexate therapy
• Not allowing sufficient washout period (3 months) before conception attempts
• Continuing methotrexate after pregnancy is detected
• Overlooking the need for folic acid supplementation if pregnancy occurs during treatment

Methotrexate's effects on reproduction must be taken seriously, with appropriate counseling and management strategies to prevent adverse outcomes. The 3-month washout period before conception attempts is recommended for both women and men to minimize risks to fertility and fetal development.