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Mifepristone Versus Methotrexate Regimens
During the 1990s, when access to mifepristone was limited in the United States, researchers began to investigate the safety and efficacy of other medical abortion options. One of the main alternative regimens that emerged from this research was the combination of methotrexate and misoprostol.
Methotrexate is widely used in cancer chemotherapy and as treatment for autoimmune diseases such as rheumatoid arthritis. Since 1982, the drug has been used off-label to treat ectopic pregnancy.55 By interfering with the growth of rapidly dividing cells, methotrexate impairs the development of placental trophoblast cells.56
Because of its mechanism of action and proven ability to treat ectopic gestations, researchers hypothesized that methotrexate, although not FDA-labeled for this use, might be an effective abortifacient.
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Medical abortion regimens involving methotrexate followed by misoprostol have been studied in a number of clinical trials. The first pilot study exploring the efficacy of methotrexate/misoprostol for medical abortion was conducted by Creinin and Darney57 in 1993. Four subjects at ≤ 56 days gestation received methotrexate 50 mg/m2 intramuscularly (IM) followed 72 hours later by oral misoprostol 600 µg, and none aborted.
In contrast, all six patients who received the same dose of methotrexate IM followed by 800 µg of vaginal misoprostol aborted without the need for surgical intervention. In 1995, Hausknecht58 reported the results from a study of 178 women with gestations of ≤ 63 days. The protocol was methotrexate 50 mg/m2 IM, followed 5 to 7 days later by 800 µg of misoprostol vaginally.
Patients who did not abort within a week received a second dose of misoprostol. This protocol resulted in a 96% rate of complete abortion (success rate) by day 14. In a multicenter study involving 300 women with pregnancies of ≤ 56 days gestation, Creinin and colleagues59 used a similar regimen except that a second dose of misoprostol was administered 24 hours after the first dose when needed. Success rates in this group were 92% at ≤ 42 days gestation, 89% at 43 to 49 days, and 82% at 50 to 56 days.
In addition to these reports, Carbonell and colleagues60 published findings on the effect of intramuscular methotrexate followed by premoistened misoprostol administered intravaginally every 48 hours for up to three doses by women at 63 days gestation or less.
Overall success rates were 92% to 93%, regardless of gestational age. A randomized trial by Creinin and colleagues61 designed to determine if efficacy is enhanced by wetting misoprostol tablets before insertion found no significant effect.
Research suggests that methotrexate is also effective when administered orally. Creinin and colleagues62 used oral methotrexate 50 mg followed by intravaginal misoprostol in 300 women at ≤ 49 days gestation with a success rate of 91%.
In a randomized trial, Carbonell and colleagues63 found that 25 mg of oral methotrexate was as effective as 50 mg when followed by premoistened vaginal misoprostol. As with the mifepristone/misoprostol regimens, bleeding, cramping, and gastrointestinal side effects were the most commonly reported adverse effects in studies of methotrexate/misoprostol.
Although the FDA has not approved the use of methotrexate followed by misoprostol for medical abortion, the available evidence supports the use of this regimen to terminate pregnancies that are ≤ 49 days in duration. Methotrexate doses of 50 mg/m2 IM or 25 mg to 50 mg PO followed 3 to 7 days later by vaginal misoprostol 800 µg have proven to be safe and effective. Efficacy of medical abortion with methotrexate/misoprostol decreases after 49 days gestation, but is still acceptable up to 56 days gestation.64
Click here to view Figure 10.
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After reading this section, you should be able to answer the following question:
An alternative medical abortion protocol - not FDA-approved - uses methotrexate and misoprostol. What do comparisons of this and the standard mifepristone/misoprostol regimen through 49 days gestation show?
Mifepristone Versus Methotrexate Regimens
In a prospective, randomized trial65 comparing the FDA-approved mifepristone/misoprostol regimen with the widely used methotrexate/misoprostol regimen of 50 mg/m2 of methotrexate IM followed 4 to 6 days later by 800 µg vaginal misoprostol in women whose pregnancies were ≤ 49 days gestation, the two methods achieved similar overall success rates with comparable side effects and complications. However, complete abortion occurred significantly more quickly in women using the mifepristone regimen. By day 8, 90.5% of women in the mifepristone group had had a complete abortion compared to 74.5% of women in the methotrexate group. The mean number of days from administration of the first medication until completion of the abortion was significantly lower in the mifepristone group compared to the methotrexate group (3.3 vs. 7.1, p < 0.001). Patient acceptability was slightly higher among women who had received mifepristone/misoprostol, although both methods were highly acceptable; 88.0% and 83.2% of women receiving mifepristone/misoprostol and methotrexate/misoprostol, respectively, indicated that they would choose the same method again (p = 0.03).
This study confirmed earlier conclusions regarding the relative efficacy and time to completion of mifepristone/misoprostol and methotrexate/misoprostol that were based on comparisons of studies of the two regimens.18, 1, 66, 67
Data from two medical abortion studies conducted by Schaff and colleagues
show higher complete abortion rates with mifepristone than with methotrexate (both combined with vaginal misoprostol) at week 1 (95% vs. 65%, respectively) and week 3 (96% vs. 90%, respectively) but comparable complete abortion rates at week 4 (96% vs. 94%, respectively). Click here to view Figure 11.
Three studies published by Creinin and colleagues59,61,62 provide additional confirmation about the rates of complete abortion at various intervals following methotrexate (IM or PO) and intravaginal misoprostol in women with pregnancies of ≤ 49 days gestation.
By day 14, between 68% and 80% of women had aborted, and success rates did not approach 90% until 4 weeks after receiving methotrexate. Thus, although overall efficacy is comparable, the time to expulsion can be much longer for some women with methotrexate/misoprostol compared to mifepristone/misoprostol.
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Misoprostol as a single-agent abortifacient is an important pharmacologic option because many countries do not have access to mifepristone or methotrexate. Investigations by Carbonell and colleagues68-70 in Cuba examined the use of misoprostol 800 µg alone, using the strategy of repeated intravaginal dosing with premoistened tablets at regular intervals. While this regimen was inconvenient, success rates were as high as 94% - comparable to standard regimens using mifepristone or methotrexate combined with misoprostol.
These impressive results were reproduced in a study by Jain and colleagues.71 Reported rates of side effects are generally higher, however, with these multidose misoprostol-only protocols than with regimens combining misoprostol with mifepristone.
Reported regimens differ with respect to several factors, including the intervals between doses (three to 48 hours), the time point for assessing the outcome (a few days to several weeks), and the gestational age (Table 9.3). These multiple variables make it difficult to determine the most effective regimen. When misoprostol is used alone, the oral route is less effective than the vaginal route.72 Vaginal doses of 800 µg misoprostol are usually repeated several times at intervals from three to 48 hours if abortion has not occurred. Typical success rates range from 85% to 95%, with continuing pregnancies occurring in about 4% to 10% of women. One review concluded that the evidence supported a recommendation of using misoprostol 800 µg vaginally every six, 12 or 24 hours for a maximum of three doses.73
Although the interval for vaginal administration, ranging in studies from three to 24 hours, may not be critical, a recent WHO trial showed that the interval did matter for sublingual administration, with three hours being more effective than 12 hours.74 Investigators recorded complete abortion rates after two weeks of follow-up for 431 (84%) women in the sublingual group and 434 (85%) women in the vaginal group when misoprostol 800 µg was given at three-hour intervals. However, complete abortion occurred in 399 (78%) and 425 (83%), respectively, when the dosing occurred at 12-hour intervals. The rate of continuing pregnancy also was significantly higher for the 12-hour interval as compared with the three-hour interval when using sublingual misoprostol (difference 4%, 95% CI 0.4, 6.8%, p=0.03) but not for vaginal dosing (difference 1%, 95% CI -1.5, 3.5%, p = 0.44). The sublingual route was associated with more frequent gastrointestinal side effects (such as nausea, vomiting, shivering, and hyperthermia) than vaginal administration. In this large study, the efficacy was noted to decrease with advancing gestation regardless of route of misoprostol. The risk of failure was twice as high for women at 8 to 9 weeks' gestation compared with those at 7 weeks' gestation or less. This finding is similar to those of previous studies using misoprostol-only regimens.75
Misoprostol as a single agent has been used for higher gestational ages. Two early studies by Carbonell reported success rates of 89% and 84% using repeated vaginal doses of 800 µg for women with pregnancies from 9 to 13 weeks' gestation.76, 77 A 2012 study by Rodriguez concluded that, where mifepristone is not available, misoprostol only is acceptable to women in order to have a non-surgical option.78
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Proceed to Teratogenicity of Medications Used for Medical Abortion.
References for this module
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