Methotrexate and misoprostol regimen

Overview and history

Since 1953, methotrexate has been available in the United States as a treatment for cancer. A chemotherapeutic agent, methotrexate has also been used since the 1980s to treat ectopic (extra-uterine) pregnancies. However, when the political environment in the US delayed the approval and availability of mifepristone as a medication abortion regimen, providers and researchers began to investigate the possibility of expanding the use of methotrexate to early pregnancy termination. In 1993, investigators initiated the first study using low-dose methotrexate in combination with misoprostol for early abortion. Subsequent studies have shown that the methotrexate/misoprostol regimen constitutes an effective method of terminating early pregnancies.

Methotrexate availability worldwide

As of 2009, methotrexate had been registered in more than 60 countries worldwide, as the following map indicates.

This map was originally created by the Population Council in 2002. In 2009, Ibis Reproductive Health conducted a follow-up assessment of global methotrexate registration and incorporated those findings accordingly.

In most countries, methotrexate is registered as a chemotherapeutic agent and/or for the treatment of ectopic pregnancies. Methotrexate may also be available in additional countries through the black market. The quality of methotrexate may vary considerably in unregulated markets and thus the reliability of the source should be examined.

Mechanism of action of methotrexate

Methotrexate is an anti-metabolite. By blocking the enzyme dihydrofolate reductase, methotrexate inhibits the production of thymidine, a requirement for DNA synthesis. Methotrexate interferes with cell growth and specifically interferes with rapidly dividing cells. Conditions that produce rapid cell division include neoplastic disease, autoimmune diseases, and pregnancy. Methotrexate primarily affects the cytotrophoblast and inhibits, rather than weakens, the implantation process [1].

Methotrexate is used in conjunction with misoprostol (brand name Cytotec® in the US). Misoprostol is an analog of prostaglandin E1. By interacting with prostaglandin receptors, misoprostol causes the cervix to soften and the uterus to contract, resulting in the expulsion of the uterine contents.

Methotrexate and misoprostol protocol

To date, there is no FDA approved protocol for the use of methotrexate and misoprostol to terminate an early pregnancy. However, a number of clinical trials have shown that the methotrexate and misoprostol is approximately 95% effective in terminating very early pregnancies (<49 days' gestation). Methotrexate is readily available to physicians in the US who are legally permitted to utilize the evidence-based protocol (called "off label" use). Professional organization guidelines also allow these practices.

The most common evidence-based regimen begins with either the intramuscular injection (50 mg/m²) or oral administration (50 mg) of methotrexate (Day 1). Three to seven days later the woman self-administers 800 µg (micrograms) of misoprostol vaginally at home. Follow-up with a provider occurs approximately one week after the methotrexate administration (Day 7). If the abortion has not occurred (as determined by vaginal ultrasound examination) the dose of misoprostol is repeated and the woman returns for final evaluation four weeks after the methotrexate administration (Day 28). However, if at the first follow-up visit (Day 7), embryonic cardiac activity is noted on ultrasound, the woman is given an additional dose of misoprostol and asked to return on Day 14. If the abortion is not complete on either the Day 28 or the Day 14 visit, vacuum aspiration should be performed.

Clinical studies conducted in the United States have shown that intramuscular and oral methotrexate administration result in similar completion rate. Although some protocols have instructed women to moisten the misoprostol before insertion, subsequent research has shown that this practice does not statistically improve efficacy [2].


Approximately 95% of women will have a complete abortion when using methotrexate/misoprostol up to 49 days' gestation. Medication abortion completion rates with the methotrexate and misoprostol regimen decline with increasing gestational age, with completion rates of approximately 95% up to 49 days' gestation compared to approximately 82% between 50 and 56 days' gestation [3].

Although the overall efficacy of the methotrexate/misoprostol regimen is similar to that of mifepristone and misoprostol within 49 days' gestation, timing of completion is quite different. For approximately one fifth of patients, the abortion will occur up to four weeks after the misoprostol administration. For women who do not experience a complete abortion an aspiration intervention may be required. Reasons for vacuum aspiration include prolonged or excessive bleeding, incomplete abortion (remnants of fetal tissue in the uterus), or an ongoing pregnancy. Ongoing pregnancy occurs in fewer than 1% of cases. An aspiration termination may also be performed at the request of the woman or the provider.


Most women with an early pregnancy can use the methotrexate and misoprostol regimen. Evidence-based protocols used in the United States have demonstrated that medication abortion with methotrexate and misoprostol is most effective in terminating pregnancies up to 49 days' gestation. However, women with pregnancies of 50-56 days' gestation may still use the methotrexate and misoprostol regimen safely and effectively [4]. Accurate dating of the pregnancy is critical and can occur through either clinical assessment or ultrasound. Methotrexate has demonstrated efficacy in treating ectopic pregnancies and thus the methotrexate and misoprostol regimen is preferable for women with suspected extra-uterine pregnancies.

If the use of methotrexate and misoprostol results in an incomplete abortion, aspiration intervention may be necessary. Women considering the methotrexate and misoprostol regimen should we willing to undergo a vacuum aspiration, if indicated.


There are a number of contraindications to methotrexate/misoprostol use. These include: a history of allergy or intolerance to either methotrexate or misoprostol; coagulopathy or current severe anemia; acute or chronic renal or hepatic disease; acute inflammatory bowel disease; or uncontrolled seizure disorders. Further, if an intrauterine device (IUD) is present, the device must be removed before a methotrexate/misoprostol termination can be performed.

To date, no data is available on the effect of folate supplementation on the efficacy of the methotrexate/misoprostol regimen. Generally, patients are advised to discontinue the use of folate supplements for one week after methotrexate administration [5]. Women may also be advised to discontinue consumption of leafy green vegetables, beans, and organ meats for two weeks after methotrexate administration. However, no studies have evaluated the necessity of dietary modifications.

Side Effects and Complications

Abdominal cramping and bleeding, are hallmarks of the abortion process itself. Many women and clinicians report cramps and abdominal pain similar to those associated with a heavy menstrual period. Vaginal bleeding can vary significantly in both duration and severity, and many report that the bleeding resembles a heavy period or a spontaneous miscarriage. Bleeding can last for weeks; the mean duration of bleeding is approximately 14 to 21 days.

Side effects of methotrexate include nausea, vomiting, diarrhea, fever or chills, headache, dizziness, and oral ulcers. Side effects of the misoprostol include nausea, vomiting, diarrhea, fever, and chills. In most cases, side effects can be managed with appropriate counseling and symptomatic treatments, such as oral analgesics for pain.

In the high doses used in the chemotherapy regimen, methotrexate exposure during pregnancy has been associated with numerous fetal malformations. Several case reports indicate that methotrexate may have teratogenic effects in cases of incomplete abortion. Women electing to use the methotrexate/misoprostol regimen should be informed of the teratogenic effects of methortrexate and should be counseled on the importance of aspiration completion in the event that the medication abortion is unsuccessful.


On rare occasion, uterine bleeding can be extremely heavy or prolonged; less than 1% of women have required intervention for heavy bleeding [6]. In approximately 5% of cases, the medication abortion is incomplete. Typically, patients will require vacuum aspiration, to resolve an incomplete abortion, end a continuing pregnancy, or control bleeding.


Studies on the acceptability of the methotrexate/misoprostol regimen have found that the majority of women found the method satisfactory. Further, the majority of women reported that they would both choose the methotrexate/misoprostol method again and recommend the method to others [7]

Additional uses of methotrexate

Methotrexate is commonly used to treat neoplastic diseases, rheumatoid arthritis, and psoriasis. Methotrexate is also used to treat ectopic pregnancies, Crohn's disease, systemic lupus, and severe asthma.

Citations in this section
[1] Pymar H and Creinin M, 2000.
[2] Creinin M et al, 1999.
[3] Creinin M and Pymar H, 2000.
[4] National Abortion Federation, 2002.
[5] National Abortion Federation, 2002.
[6] Harvey S, Sherman C, Bird S and Warren J, 2002.
[7] Creinin M and Pymar, 2000.

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