Methotrexate and Birth Defects: What Are the Risks?

Methotrexate is a medication used to treat a variety of medical conditions. It functions as an antimetabolite, specifically a folate antagonist, which interferes with how cells use folic acid. This mechanism makes it effective but also introduces significant risks, particularly concerning pregnancy. Since the medication is often used for long-term diseases, people of childbearing age may be prescribed it, making an understanding of its effects on fetal development important.

Common Uses for Methotrexate

Methotrexate is prescribed for a range of conditions, falling into two main categories: autoimmune diseases and cancer. For autoimmune disorders such as rheumatoid arthritis, severe psoriasis, and Crohn’s disease, it works as an immunosuppressant to lower inflammation. In these cases, it is administered in low doses to manage chronic symptoms and modify the disease’s progression.

The medication is also a chemotherapy agent used to treat certain cancers, including leukemia, lymphoma, and breast cancer. When used for cancer, the doses are significantly higher and are aimed at stopping the rapid growth of malignant cells.

Methotrexate’s Impact on Fetal Development

Methotrexate is classified as a teratogen, a substance that can cause developmental abnormalities in a fetus. Its primary mechanism of harm is the disruption of folic acid metabolism. Folic acid is a B vitamin that plays a direct role in the synthesis of DNA and the division of cells, processes fundamental to the rapid growth of an embryo. By inhibiting a key enzyme, methotrexate blocks the availability of folate, which can lead to cell death and interfere with the formation of vital structures.

Exposure during pregnancy can lead to a pattern of birth defects known as methotrexate embryopathy. Common developmental anomalies include:

• Craniofacial abnormalities, such as widely spaced eyes (hypertelorism), a small jaw (micrognathia), and an incompletely formed skull.
• Limb defects, including shortened limbs, missing fingers or toes (hypodactyly), and webbed digits (syndactyly).
• Central nervous system issues, like neural tube defects (malformations of the brain and spinal cord), hydrocephalus (fluid in the brain), and an absent corpus callosum.
• Cardiac defects, such as Tetralogy of Fallot.

The risk of these outcomes is highest during the first trimester of pregnancy. This period, specifically between 6 and 8 weeks after conception, is when the foundational structures of the fetus are developing. Exposure during this window corresponds with the highest likelihood of severe malformations. While the risk is dose-dependent, even the low doses used for autoimmune conditions are associated with adverse outcomes.

Safe Conception Guidelines After Methotrexate Use

For women planning a pregnancy, it is recommended to discontinue methotrexate use well before attempting to conceive. This waiting period, often called a “washout period,” allows the body to eliminate the drug. The U.S. Food and Drug Administration (FDA) advises waiting for at least one ovulatory cycle after the final dose before trying to become pregnant. Other health organizations and providers may recommend a longer waiting period of one to three months to minimize any lingering effects.

Following the discontinuation of methotrexate, supplementing with high-dose folic acid is a common recommendation. Because the drug depletes the body’s folate stores, replenishing these levels is important for supporting a future pregnancy. Patients should consult their healthcare provider for personalized advice based on their treatment history.

Managing Accidental Exposure During Pregnancy

Discovering a pregnancy while taking methotrexate or shortly after stopping requires immediate action. The first step is to contact the prescribing physician and an obstetrician right away. A healthcare team can then assess the situation based on the specific dosage and the timing of the exposure.

Medical management following accidental exposure involves careful monitoring. A physician may recommend high-resolution ultrasounds to closely examine fetal anatomy for any signs of the abnormalities associated with methotrexate embryopathy.

In addition to advanced imaging, a consultation with a maternal-fetal medicine specialist or a genetic counselor may be offered. These specialists can provide a detailed understanding of the specific risks and help patients make informed decisions.

Risks Associated with Paternal Methotrexate Use

Considerations for methotrexate and pregnancy also extend to prospective fathers. The primary concern is the theoretical risk that the drug could affect sperm cells. Because methotrexate interferes with DNA replication, it could potentially cause genetic changes in sperm that might impact fertilization or lead to early pregnancy loss.

Due to these risks, it is recommended that men wait a period of time after their final dose before trying to conceive. The FDA and drug manufacturers recommend that male patients use effective contraception during treatment and for a minimum of three months after their last dose. This timeframe accounts for the cycle of sperm production, ensuring that sperm present at conception were not exposed to the medication.

While the guidance is cautious, studies on pregnancies fathered by men taking methotrexate have not found a definitive link to an increased risk of birth defects or miscarriage. Despite these reassuring findings, consulting with a healthcare provider for personalized advice remains the standard recommendation.