Trexall

THE SAFETY OF METHOTREXATE DURING PREGNANCY OR BREASTFEEDING

The information provided below is for readers based in the United States of America. Readers outside of the United States of America should seek the information from local sources.

THIS MEDICATION CAN CAUSE HARM TO YOUR BABY:

Methotrexate should not be used during pregnancy or breastfeeding due to an increased risk of miscarriage, death of the baby, and birth defects including methotrexate embryopathy or fetal aminopterin-methotrexate syndrome. The highest risk of fetal aminopterin-methotrexate syndrome is 6-8 weeks after conception (or 8-10 weeks after the first day of the last menstrual period) at a dose of more than 10 mg per week. It is recommended to use this medication during pregnancy only in cancerous and noncancerous neoplastic conditions after weighing the potential risks versus benefits of use during pregnancy or while breastfeeding.

What is methotrexate?

Methotrexate is a medication known as a folic acid antagonist that is used as an antineoplastic, immunosuppressant, and antirheumatic agent. Methotrexate is currently available as a generic or brand name medication and is available orally, for intravenous use, or injection into the spine, fat, or muscle. Brand names of methotrexate include Otrexup™, Rasuvo™, and Trexall™. Methotrexate is dosed based on body weight or body surface area, and is administered as an initial dose followed by maintenance doses for one or more cycles over several weeks, months, or years. Methotrexate is available by prescription only. 

What is methotrexate used to treat?

Methotrexate is used to treat acute lymphoblastic leukemia, breast cancer, gestational trophoblastic neoplasia, head and neck cancer, non-Hodgkin lymphoma, cutaneous T-cell lymphoma, osteosarcoma, rheumatoid arthritis, psoriasis, as well as many off-label uses. In children and adolescents, methotrexate is used for acute lymphoblastic leukemia, brain and spinal cord tumors, Crohn’s disease, dermatomyositis, graft-versus-host disease, juvenile idiopathic arthritis, non-Hodgkin lymphoma, osteosarcoma, psoriasis, scleroderma, uveitis, and meningeal leukemia. Methotrexate has also been used to treat ectopic pregnancy and for termination of pregnancy. 

You can read more about juvenile arthritis during pregnancy here. Additional information on rheumatoid arthritis and psoriasis during pregnancy is also available.

How does methotrexate work?

Methotrexate works by interfering with folate as well as DNA creation, replication, and repair, particularly in areas of the body that have high cell and tissue proliferation such as cancerous cells, hair follicles, the reproductive system, and bone marrow.

If I am taking methotrexate, can it harm my baby?

Available studies, primarily using methotrexate for cancer treatment or to terminate pregnancy, suggest methotrexate increases the risk of birth defects and death of the baby when used during pregnancy. Some studies suggest low dose methotrexate and folate supplementation during pregnancy doesn't increase the risk of birth defects; however, other studies have found the risk of birth defects remains higher than normal with low dose methotrexate use during pregnancy. Methotrexate should not be used during pregnancy unless possible benefits are expected to outweigh potential risks. Males or females of reproductive age should use an effective form of birth control during and for at least 6 months after the last treatment with methotrexate for females and at least 3 months for males. Some sources recommend that women wait at least one menstrual cycle after stopping methotrexate to try and conceive. Because folate (folic acid) can be depleted with methotrexate use, the use of folate supplementation and prenatal vitamins is important to prevent spinal cord defects in babies. Some resources suggest male use of methotrexate before conception does not increase the risk of birth defects. Methotrexate is not recommended in pregnant women with non-cancerous conditions such as rheumatoid arthritis, polyarticular-course juvenile idiopathic arthritis, or psoriasis. Methotrexate is associated with adverse effects including bone marrow suppression, kidney impairment, liver toxicity, lung disease, gastrointestinal toxicity, serious skin reactions, secondary cancer development, tumor lysis syndrome, infection, and tissue or bone cell death. It is important to consider the risks versus benefits of methotrexate administration to the mother for cancerous and noncancerous neoplastic conditions, and potential risks to the developing baby before administering this medication during pregnancy. 

Evidence from animal studies with methotrexate:

Animal studies in rats, rabbits, mice, and chicks have noted an increased incidence of negative developmental effects including defects of the brain, spinal cord, and nose/mouth with methotrexate exposure during pregnancy. Animal studies in dogs and monkeys have shown no association between methotrexate exposure during pregnancy and birth defects at methotrexate doses similar to those used in rats, rabbits, mice, and chicks.

Evidence for the risks of methotrexate in human babies:

Exposure to methotrexate during the period of pregnancy known as organogenesis during the first trimester where the baby’s organs are formed is associated with the development of methotrexate embryopathy or fetal aminopterin-methotrexate syndrome. This syndrome is characterized by the presence of the following characteristics: 

  • Intrauterine growth restriction
  • Decreased bone formation in the skull
  • Decreased size of the brow bones
  • Small, low-set ears
  • Undersized jaw
  • Limb abnormalities
  • Mental retardation

Case reports as well as data from the Organization of Teratology Information Services (OTIS) and the European Network of Teratology Information Services (ENTIS) suggest the critical time period for fetal aminopterin-methotrexate syndrome to develop is with methotrexate exposure  6-8 weeks after conception (or 8-10 weeks after the first day of the last menstrual period). Doses of methotrexate over 10 mg per week are thought to be associated with a greater risk of fetal aminopterin-methotrexate syndrome. 

The National Birth Defects Prevention Study reviewed data on 27,623 women who delivered babies with birth defects and 10,113 women who delivered babies without birth defects (control group) to determine the risk of birth defects with exposure to methotrexate at any time 3 months before pregnancy to the end of pregnancy. Of the 27,623 women delivering babies with birth defects, 16 (0.06%) were exposed to methotrexate during pregnancy. Of the 10,113 women in the control group, 4 (0.04%) were exposed to methotrexate during pregnancy. Of the 16 babies born with birth defects, 11 (68.8%) had heart defects. The authors suggest there is an a
ssociation between methotrexate exposure in early pregnancy and the development of heart defects in the baby. One study reported a 42.5% rate of miscarriage and a 6.6% rate of birth defects in babies exposed to methotrexate in early pregnancy or before conception. Case reports suggest the risk of birth defects with methotrexate exposure during pregnancy is 10/42 (24%). 

Additional birth defects that can accompany characteristics of fetal aminopterin-methotrexate syndrome include spine and heart defects, decreased muscle tone, seizures, increased distance between the eyes, nasal defects, and a small head. There are reports of defects of the face, skull, brain, spinal cord, heart and limb. Intrauterine growth restriction and impairments in function and intelligence have also been reported.

Exposure to methotrexate during the second and third trimesters of pregnancy is also associated with an increased risk of toxicity and death of the baby. Women who become pregnant after stopping methotrexate therapy are expected to have the same risk of birth defects as the general population. However, one study suggested a possible link between retention of methotrexate in the maternal tissues after stopping therapy before pregnancy and a lung disorder known as desquamating fibrosing alveolitis. No correlation has been proven. One study reported on low dose methotrexate exposure during the first trimester in 8 infants, and all infants were born healthy without birth defects. 

There have been reports of bone marrow suppression and low birth weight in infants exposed to methotrexate during pregnancy. One case report suggested methotrexate may cause genetic damage and an increased possibility for cancer development in infants exposed to the medication during pregnancy. Occupational exposure of pregnant women to methotrexate is considered a serious risk. 

Bottom line:  Methotrexate should not be used during pregnancy due to an increased risk of miscarriage, birth defects, and death of the baby. Methotrexate should not be used to treat non-cancerous conditions such as rheumatoid arthritis or psoriasis during pregnancy. It is important to consider possible benefits to the mother and risks to the baby before using this medication before conception or during pregnancy.

If I am taking methotrexate and become pregnant, what should I do?

If you are taking methotrexate and become pregnant, you should contact your doctor immediately. Your doctor will determine if your medication is medically necessary, or if it should be discontinued until after the birth of your baby. In women desiring to continue pregnancy after exposure to methotrexate, folic acid supplementation for a minimum of 5 months as well as counseling should be suggested. In women who conceive less than 6 months after discontinuation of methotrexate, counseling and monitoring of the baby during pregnancy are suggested. 

If I am taking methotrexate, can I safely breastfeed my baby?

Methotrexate is present in breast milk in low concentrations. However, methotrexate can accumulate in the tissues of the nursing infant, so the American Academy of Pediatrics considers methotrexate as a cytotoxic drug. Breastfeeding is not recommended in women who take methotrexate. The World Health Organization recommends against breastfeeding while taking methotrexate. Potential complications in nursing infants exposed to methotrexate in the mother’s breast milk include immune system suppression, delayed growth, and development of cancer. Although lower doses of methotrexate are considered to have less risk compared to higher doses, other medications are recommended while breastfeeding. A minimum period of one week is recommended between last dose of methotrexate and resuming breastfeeding. A weekly, low methotrexate dose may only require 24 hours to decrease infant methotrexate exposure by 40%. Longer term, low methotrexate doses may require closer monitoring of infant blood cell counts. High doses of chemotherapy for the treatment of cancer may require the mother discard her breast milk for at least one week after finishing the last dose of methotrexate. 

Bottom line: Methotrexate should not be used if you are breastfeeding. Potential complications in nursing infants exposed to methotrexate in the mother’s breast milk include immune system suppression, delayed growth, and development of cancer.

If I am taking methotrexate, will it be more difficult to get pregnant?

Methotrexate has been associated with ovary, sperm, and testicle dysfunction, reducing fertility; however, these effects may potentially be reversed when methotrexate is stopped. 

If I am taking methotrexate, what should I know?

Methotrexate has been associated with an increased risk of miscarriage, birth defects, and death of the baby with use during pregnancy. Methotrexate should not be used while pregnant or breastfeeding due to the risk of serious adverse effects on the baby. It is recommended to use this medication only after weighing the potential risks versus benefits.

If I am taking any medication, what should I know?

This report provides a summary of the available information about the use of methotrexate during pregnancy and breastfeeding. Content is from the product label unless otherwise indicated.

You may find Pregistry's expert report about cancer here, Crohn’s disease here, ulcerative colitis here, rheumatoid arthritis here and reports about the individual medications used to treat immune disorders here.   Additional information can also be found in the resources below. 

For more information about methotrexate during and after pregnancy, contact http://www.womenshealth.gov/ (800-994-9662 [TDD: 888-220-5446]) or check the following links:

U.S. National Library of Medicine: LACTMED: METHOTREXATE

U.S. Food and Drug Administration:  Methotrexate Prescribing Information

Read the whole report
General information

It is very common for women to worry about having a miscarriage or giving birth to a child with a birth defect while they are pregnant. Many decisions that women make about their health during pregnancy are made with these concerns in mind.

For many women these concerns are very real. As many as 1 in 5 pregnancies end in a miscarriage, and 1 in 33 babies are born with a birth defect. These rates are considered the background population risk, which means they do not take into consideration anything about the health of the mom, the medications she is taking, or the family history of the mom or the baby’s dad. A number of different things can increase these risks, including taking certain medications during pregnancy.

It is known that most medications, including over-the-counter medications, taken during pregnancy do get passed on to the baby. Fortunately, most medicines are not harmful to the baby and can be safely taken during pregnancy. But there are some that are known to be harmful to a baby’s normal development and growth, especially when they are taken during certain times of the pregnancy. Because of this, it is important to talk with your doctor or midwife about any medications you are taking, ideally before you even try to get pregnant.

If a doctor other than the one caring for your pregnancy recommends that you start a new medicine while you are pregnant, it is important that you let them know you are pregnant.

If you do need to take a new medication while pregnant, it is important to discuss the possible risks the medicine may pose on your pregnancy with your doctor or midwife. They can help you understand the benefits and the risks of taking the medicine.

Ultimately, the decision to start, stop, or change medications during pregnancy is up to you to make, along with input from your doctor or midwife. If you do take medications during pregnancy, be sure to keep track of all the medications you are taking.