Methotrexate does not appear to cause lasting infertility in most people. The drug can temporarily affect egg and sperm production while you’re taking it, but these effects are generally reversible once you stop. The bigger concern is that methotrexate is highly toxic to a developing embryo, which is why timing around conception matters so much.
How Methotrexate Affects Female Fertility
Methotrexate works by blocking a key step in DNA synthesis, which means it targets any cells that divide rapidly. Egg cells go through a period of rapid division during their final maturation, making them temporarily vulnerable to the drug. A study of women undergoing fertility treatment found that when IVF cycles were performed within six months of methotrexate exposure, doctors retrieved significantly fewer eggs. But cycles performed more than six months after stopping the drug showed no decline in egg production at all, pointing to a time-limited, reversible effect.
Broader reviews of ovarian reserve markers, including follicle-stimulating hormone levels and antral follicle counts, have found no differences between pre- and post-methotrexate cycles. The number of eggs retrieved, fertilization rates, and stimulation duration all remained comparable. In short, the drug doesn’t appear to permanently deplete your egg supply.
How Methotrexate Affects Male Fertility
The picture for men is similarly reassuring. A study of men with psoriasis taking methotrexate found no statistically significant changes in sperm count, motility, morphology, or semen volume after treatment. Sperm concentration actually trended upward by about 22%, though this didn’t reach statistical significance. The percentage of normally shaped sperm and overall sperm movement stayed essentially the same.
Perhaps more important for men wondering whether they need to worry: a systematic review and meta-analysis of pregnancy outcomes following paternal methotrexate exposure found no increased risk of birth defects (adjusted odds ratio of 1.00), stillbirth, or preterm birth. No consistent or recurring pattern of malformations appeared in case reports either. These findings offer meaningful reassurance that fathering a child while on or recently off methotrexate does not carry the same risks as maternal exposure.
The Real Risk: Pregnancy While Taking It
The serious danger with methotrexate isn’t infertility. It’s what happens if conception occurs while the drug is still active in the body. Methotrexate is classified as a known teratogen, meaning it can cause severe birth defects when a developing embryo is exposed during early pregnancy. The resulting pattern of malformations, sometimes called fetal methotrexate syndrome, includes an abnormally small skull, premature fusion of skull bones, heart defects (particularly certain structural heart malformations), limb reduction defects, and fused fingers or toes. These abnormalities occur at statistically significant rates compared to unexposed pregnancies.
This is why the drug carries an absolute requirement to avoid pregnancy while using it and for a defined period afterward.
How Long to Wait Before Trying to Conceive
Current guidelines from the American College of Rheumatology recommend stopping methotrexate at least three months before planned conception. This applies to women taking the drug for conditions like rheumatoid arthritis, psoriasis, or lupus. The three-month window allows the drug to fully clear the body and gives eggs time to mature without exposure. For women using assisted reproductive technology, guidelines also recommend achieving at least six months of stable, low-level disease before starting fertility procedures.
The evidence on timing aligns with this guidance. The study showing reduced egg retrieval within six months of exposure, combined with normal results after that window, suggests that waiting at least three to six months provides a comfortable margin. Your rheumatologist will typically switch you to a pregnancy-compatible medication during this period so your underlying condition stays managed.
Fertility After Methotrexate for Ectopic Pregnancy
Many women encounter methotrexate not as a long-term medication but as a one-time treatment for ectopic pregnancy, where a fertilized egg implants outside the uterus. This is a common source of anxiety about future fertility, and the data here is encouraging.
In a randomized trial comparing single-dose methotrexate to laparoscopic surgery for tubal ectopic pregnancies, 73% of women treated with methotrexate went on to have a spontaneous intrauterine pregnancy afterward, compared to 62% in the surgery group. The rate of repeat ectopic pregnancy was also lower in the methotrexate group (9.6% versus 17.3%), though neither difference reached statistical significance. The takeaway: methotrexate treatment for ectopic pregnancy preserves future fertility at least as well as surgical options, and likely better, since it avoids any structural damage to the fallopian tube.
The Role of Folic Acid
Because methotrexate works by blocking the enzyme that converts folic acid into its active form, folic acid supplementation is standard practice for anyone taking the drug long-term. This helps reduce side effects like mouth sores, fatigue, and liver stress. There’s also evidence from developmental toxicity studies that adequate folate can counteract some of methotrexate’s harmful effects on rapidly dividing cells. In one experiment, co-administering a sufficient dose of the active form of folic acid completely eliminated the developmental abnormalities caused by methotrexate, while also significantly reducing mortality.
For women planning pregnancy after stopping methotrexate, continuing folic acid supplementation during the washout period and into early pregnancy is standard practice. This serves double duty: replenishing folate stores that methotrexate depleted and providing the neural tube protection that all prenatal folic acid supplementation aims for.