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.
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
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
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
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 .
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 .
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
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
regimen safely and effectively . 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
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 . 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
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 . 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
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.