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Updated March 07, 2014.
Methotrexate is a disease-modifying anti-rheumatic drug (DMARD) used to treat rheumatoid arthritis and certain other rheumatic diseases. The dose used for rheumatoid arthritis is considered low. Comparatively, methotrexate is also used as a high-dose cancer therapy and at high doses to terminate ectopic pregnancy.
Technically-speaking, methotrexate is a dihydrofolate reductase inhibitor that impairs purine metabolism.
That said, it can lead to abnormalities in ribonucleic acid and deoxyribonucleic acid synthesis. Methotrexate is a known teratogen, which is defined as any substance, organism, or process that causes malformations in a fetus. Methotrexate can cause dysmorphic facial features, abnormalities of the skull and limbs, growth deficiency, developmental delays, and mental retardation.
The potential for fetal complications makes the drug a concern for those of childbearing age, those planning to become pregnant, and especially those who become pregnant while being treated with methotrexate.
Fetal Anomalies and Pregnancy Loss Associated With Methotrexate
Women must be made aware of the risk of fetal anomalies and pregnancy loss associated with methotrexate, even though the rate of fetal anomalies is considered low. In a French study (2004), women with chronic inflammatory disorders who were treated with low-dose methotrexate during the first trimester were assessed. Of the 28 cases analyzed, methotrexate exposure ended prior to 8 weeks gestation in 26 women.
Four women had miscarriages, while 5 opted for termination of the pregnancy. There were 19 live births, of which 3 were premature. Researchers concluded that their results support the idea that there is not a strong teratogenic risk with low-dose methotrexate, providing the drug is stopped as early in a pregnancy as possible.
Another study looked at 8 methotrexate-exposed pregnancies. There was one case of typical methotrexate embryopathy identified. It is the first such case found among people taking the lower once-weekly dose of methotrexate (the usual dose for rheumatic diseases). Even though it was only one case, researchers concluded that the assumption of methotrexate safety at low doses is premature.
What About the Men?
According to Drugs.com, pregnancy should be avoided by either spouse or partner who is being treated with methotrexate. Pregnancy should be avoided during treatment and for a minimum of 3 months after treatment for male patients, and during treatment and for at least one ovulatory cycle after treatment for female patients.
There is a theoretical risk of sperm mutation in men taking methotrexate, but it has not been proven. Also, according to the Journal of Rheumatology, paternal methotrexate exposure at the time of conception does not seem to raise concerns or issues for the fetus.
The Bottom Line
There is no 100% safe period of gestational exposure to methotrexate. The effect of methotrexate seems unpredictable, in part due to genetic differences in placental and fetal response to toxins. Following exposure to methotrexate during the first trimester, a mother choosing to continue with the pregnancy should know that there is about a 10/42 chance of abnormality in the fetus (QJM: An International Journal of Medicine).
According to Kelley's Textbook of Rheumatology, women are advised to discontinue methotrexate at least 3 months prior to conceiving. Folic acid supplementation should be continued through the pregnancy. The American College of Rheumatology recommends the use of effective contraception while taking methotrexate and for 3 months after stopping methotrexate.
Sources:
Methotrexate (Rheumatrex, Trexall). American College of Rheumatology. Michael Cannon, M.D. May 2012.
http://www.rheumatology.org/Practice/Clinical/Patients/Medications/Methotrexate_%28Rheumatrex,_Trexall%29/
Low dose methotrexate in the first trimester of pregnancy: results of a French collaborative study. Lewden B et al. Journal of Rheumatology. December 2004.
http://www.ncbi.nlm.nih.gov/pubmed/15570635
Methotrexate Embryopathy After Exposure to Low Weekly Doses in Early Pregnancy. Martin MC, et al. Reproductive Toxicology. October 26, 2013.
http://www.ncbi.nlm.nih.gov/pubmed/24513926
Methotrexate Pregnancy and Breastfeeding Warnings. Drugs.com. Accessed 2/22/14.
http://www.drugs.com/pregnancy/methotrexate.html
Paternal Exposure to Methotrexate and Pregnancy Outcomes. Journal of Rheumatology. Beghin, et al. January 15, 2011.
http://www.jrheum.org/content/early/2011/01/11/jrheum.100600.abstract
The effects of methotrexate on pregnancy, fertility and lactation. QJM: An International Journal of Medicine. 1999.
http://qjmed.oxfordjournals.org/content/92/10/551.long
Kelley's Textbook of Rheumatology. Elsevier Saunders. Volume I. Pregnancy in the Rheumatic Diseases. Chapter 39. Page 552.
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