Methotrexate/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 United States 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

Methotrexate has been registered in more than 50 countries worldwide, for both abortifacient and non-abortifacient purposes, as the following map indicates.

Methotrexate availability map courtesy of the Population Council

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. [18]

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/misoprostol protocol

To date, there is no FDA approved protocol for the use of methotrexate/misoprostol to terminate an early pregnancy. However, a number of clinical trials have shown that the methotrexate/misoprostol is approximately 95% effective in terminating very early pregnancies (<49 days' gestation). Methotrexate is readily available to physicians in the United States and US physicians are legally permitted to utilize the evidence-based protocol and professional organization guidelines 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 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 rates of completion. Although some protocols have instructed women to moisten the misoprostol before insertion, subsequent research has shown that this practice does not statistically improve efficacy. [19]


Efficacy

Approximately 95% of women will have a complete abortion when using methotrexate/misoprostol up to 49 days' gestation. Medical abortion completion rates 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. [20]

Although the overall efficacy of the methotrexate/misoprostol regimen is similar to that of mifepristone/misoprostol within 49 days' gestation, timing of completion is quite different. For approximately one fifth of patients using methotrexate/misoprostol 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. An aspiration termination may also be performed at the request of the woman or the provider. Ongoing pregnancy occurs in fewer than 1% of cases.


Eligibility

Most women with an early pregnancy can use the methotrexate/misoprostol regimen. Evidence-based protocols used in the United States have demonstrated that medication abortion with methotrexate/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/misoprostol regimen safely and effectively. [21] Accurate dating of the pregnancy is crucial and can occur through either clinical assessment or ultrasound. Methotrexate has demonstrated efficacy in treating ectopic pregnancies and thus the methotrexate/misoprostol regimen is preferable for women with suspected extra-uterine pregnancies.

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

Contraindications

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. [22] 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

Some side effects, such as 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 be heavier than a heavy period and 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 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. Several case reports have associated misoprostol use with limb defects and Mobius syndrome. However, an absolute causal relationship between misoprostol use and fetal deformities has yet to be demonstrated through prospective trials. Women electing to use the methotrexate/misoprostol regimen should be informed of the possible teratogenic effects of these drugs and should be counseled on the importance of aspiration completion in the event that the medication abortion is unsuccessful.

Complications

On rare occasion, uterine bleeding can be extremely heavy or prolonged. Although this is the most serious side effect, less than 1% of women have required intervention for heavy bleeding. [23] 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.


Acceptability

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. [24]

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.


References:

[18] Pymar H, Creinin M. Alternatives to mifepristone regimens for medical abortion. Am J Obstet Gyncol. 2000; 183(2). S54-64.

[19] Creinin MD, Carbonell JL, Schwartz JL, Varela L, Tanda R. A randomized trial of the effect of moistening misoprostol before vaginal administration when used with methotrexate for abortion. Contraception. 1999; 59(1): 217-221.

[20] Creinin M, Pymar H. Medical abortion alternatives to mifepristone. JAMWA. 2000; 35(3): S127-132.

[21] National Abortion Federation. Early medical abortion with mifepristone and other agents: Overview and protocol recommendations. Washington, DC: NAF, 2002.

[22] National Abortion Federation. Early medical abortion with mifepristone and other agents: Overview and protocol recommendations. Washington, DC: NAF, 2002.

[23] Harvey SM, Sherman CA, Bird ST, Warren J. Understanding Medical Abortion: Policy, Politics, and Women's Health. Eugene, OR: Center for the Study of Women in Society, 2002.

[24] Creinin M, Pymar H. Medical abortion alternatives to mifepristone. JAMWA. 2000; 35(3): S127-132.


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