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ORIGINAL RESEARCH |
From the Department of Family Practice, University of British Columbia, Vancouver, BC; Department of Family and Community Medicine, University of Toronto, Toronto, Ontario; University of Laval, Laval, Quebec; Family Planning Clinic, University of Quebec, Quebec, Quebec; University of Sherbrooke, Sherbrooke, Quebec; and University of Manitoba, Winnipeg, Manitoba, Canada.
Address reprint requests to: Ellen Wiebe, MD, University of British Columbia, Department of Family Practice, 1013 - 750 West Broadway, Vancouver, British Columbia V5Z 1H9, Canada; E-mail: ewiebe{at}interchange.ubc.ca.
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ABSTRACT |
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 ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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METHODS: This was a multicenter, randomized, non-blinded, controlled trial comparing 50 mg/m2 of methotrexate followed 4–6 days later by 800 µg of vaginal misoprostol with 600 mg of oral mifepristone followed 36–48 hours by 400 µg of oral misoprostol.
RESULTS: There were 518 women in the methotrexate group and 524 women in the mifepristone group. In the methotrexate group, 21 women required suction curretage, two for continuing pregnancy, eight because of physician request (usually for excessive bleeding), and 11 because of patient request. In the mifepristone group, 22 women needed surgical termination, 17 because of physician request, and five because of patient request. By day 8, only 386 (74.5%) in the methotrexate group had completed the abortion compared with 474 (90.5%) in the mifepristone group, and the mean number of days from beginning to completion was 7.1 for methotrexate and 3.3 for mifepristone (P 
.001). There were no differences in complications, and side effects were similar. Acceptance was slightly higher with mifepristone (88.0%) than with methotrexate (83.2%).
CONCLUSION: Abortions induced with mifepristone completed faster than those induced with methotrexate, but the overall success rates, side effects, and complications were similar. Acceptance rates were slightly higher with mifepristone than methotrexate (P = .03).
Medical abortion (ie, abortion induced by pharmaceutical agents rather than surgical means) has evolved as an option for women wishing early pregnancy termination, and there is an increasing demand for this option. Mifepristone was approved for abortion in France in 1988, and now about one-third of all abortions in that country are performed medically with mifepristone in combination with a prostaglandin.1 In North America, where mifepristone was unavailable until 2000, medical abortion with methotrexate and misoprostol has been increasingly available and has been shown to be highly acceptable to women.2,3
Mifepristone is a 19-norsteroid, which induces abortion by blocking the action of progesterone, resulting in detachment of products of conception,4 increasing endogenous synthesis of prostaglandin,5 and increasing sensitivity to both endogenous and exogenous prostaglandins.6 Methotrexate is an antimetabolite, which causes inhibition of dihydrofolate reductase and interferes with the cytotrophoblast and the implantation of the pregnancy.7 It is currently approved for use in most countries for malignancy, psoriasis, and severe rheumatoid or seronegative arthritis.8 Misoprostol is a prostaglandin estrone analogue approved for use in most countries for the prevention of peptic ulcers. It acts to facilitate abortion by stimulating uterine activity and softening the cervix.9
Mifepristone, in combination with a number of different prostaglandins, has been shown to be 92–96% effective in causing a complete abortion in pregnancies up to 63 days’ gestation.10–13 Continuing pregnancy rates are less than 1% in most series.11–13 The most common regimen used is 200 or 600 mg of mifepristone orally followed 48 hours later by a prostaglandin given either orally or vaginally. One US study reported the acceptability of patients self-administering the misoprostol at home.14
Medical abortions induced with methotrexate and misoprostol were first reported by Creinin and Darney in 1993,15 and other reports followed.16–24 In 1996, The National Abortion Federation published guidelines for abortions using methotrexate and misoprostol.25 Similar ones were published by the Society of Obstetricians and Gynecologists of Canada in 1999.26 The usual dose of methotrexate is 50 mg/m2 intramuscularly followed 3–7 days later at home with vaginal misoprostol, which is repeated if the abortion does not occur.
Access to these drugs varies widely throughout the world because of availability and cost. Methotrexate and misoprostol are widely available and inexpensive. Mifepristone is marketed in the United States at a cost of $270 for 600 mg compared with methotrexate, which costs approximately $5 per 100-mg dose. Mifepristone is not approved for use in Canada and many other countries. It is important to compare the two regimens so that women and their physicians can make informed choices about using methotrexate when mifepristone is not affordable or available. The purpose of this study was to compare the effectiveness, side effects, and acceptability of medical abortions induced by methotrexate and misoprostol with abortions induced by mifepristone and misoprostol. The regimens studied were chosen to reflect the ones most commonly used in Europe and North America and those approved by the United States Food and Drug Administration, the National Abortion Federation, and the Society of Obstetricians and Gynecologists of Canada.
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MATERIALS AND METHODS |
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Participants were recruited from women equal or less than 49 days’ gestation presenting for elective abortion at five study clinics situated across Canada. The study protocol, risks, benefits, and visit schedules were reviewed. Inclusion criteria included ability to understand consent form, willingness to consent and comply with visit schedule, endovaginal ultrasound evidence of a singleton intrauterine pregnancy of less than 7 weeks’ gestation, agreement to undergo aspiration abortion in case of failure of the medical abortion, telephone access, and age 16 and over. Exclusion criteria included hemoglobin less than 95 g/L, active hepatic disease or aspartate transaminase twice normal, active renal disease or creatinine more than 120 µmol/L, unstable insulin-dependent diabetes mellitus, adrenal insufficiency, glaucoma, sickle cell anemia, allergy or intolerance to any of the three medications, coagulopathy, uncontrolled seizure disorder, severe cardiovascular disease, chronic oral steroid medications or anticoagulants such as warfarin, and any medical condition which in the opinion of the investigator would compromise the patient during the procedure. Women were asked to stop folate and nonsteroidal anti-inflammatory drugs for 24 hours.
The women were randomized to receive either mifepristone and misoprostol or methotrexate and misoprostol. Randomization was stratified by center. A research assistant not doing any clinical work prepared sequentially numbered opaque envelopes with group membership assigned using a table of random numbers. After signing the consent form, a relevant history and physical including an endovaginal ultrasound were done. Gestational dating was by last menstrual period confirmed by ultrasound using Rossavik et al27 and Goldstein and Wolfson dating.28 Hemoglobin and Rh testing were done. If there was concern by history or physical about liver or renal function, blood was sent for aspartate transaminase and serum creatinine.
The mifepristone group received 600 mg of mifepristone orally with water under supervision and was given two packages of two 200-µg misoprostol tablets with instructions to take orally at home, the first set 36–48 hours after the mifepristone and the second 24 hours later if the bleeding was less than the usual period. The methotrexate group received methotrexate 50 mg/m2 intramuscularly in one site and was given two packages of four 200-µg misoprostol tablets with instructions to insert the first four vaginally 4–6 days later at home and the second dose 24 hours after the first if the bleeding was less than during a period. The women were asked to wet the tablets by placing a few drops of water on each tablet before inserting them. We chose to use wet tablets based on the information of a previous study.29 Rh immunoglobulin was given to Rh-negative women. Each woman was provided two dimenhydrinate 50-mg tablets for nausea, six ibuprofen 400-mg tablets for pain, and ten tablets of acetaminophen 325 mg with codeine 30 mg for pain. They received written and verbal information on the medications and emergency contact numbers. They were given a symptom diary to record the bleeding, pain, and symptoms.
At follow-up, 7 days after receiving the first medication, an ultrasound was done to determine the status of the pregnancy. Women who still had a gestational sac in the uterus received another dose of 800 µg of misoprostol vaginally and were asked to return in 1 week. At the 2-week visit (day 15), those with continuing pregnancies (embryonic cardiac activity on ultrasound) were scheduled for surgery and those with delayed reactions, defined as persistent gestational sac with no embryonic cardiac activity, were asked to return for further follow-up on day 36. At the 5-week visit, they were offered surgery if still delayed or followed until they aborted. Women were seen or contacted by telephone at day 36. Anyone wishing to terminate the study before 5 weeks had a surgical aspiration scheduled. At each visit, they were asked about pain, bleeding, side effects, and any medications used, and at the last visit (or phone call), they were asked about satisfaction. Pain was measured by an 11-point pain scale, asking the question "On a scale of 0 to 10 where 0 is no pain and 10 is pain as bad as it can be, what was the worst pain like for you?" This has been used in other abortion studies,18,30 and is validated against other pain scales.31 Bleeding was assessed by number of days of bleeding. Satisfaction was assessed by a question, "If you were faced with the choice again, would you choose a medical or surgical abortion?" The staff asking these questions was not blinded as to treatment. Complications such as infection and hemorrhage were recorded. Infection was defined as anyone treated with antibiotics for fever, pain, or tenderness. Hemorrhage was defined as bleeding requiring treatment with methergine, surgery, or intravenous fluids, or bleeding resulting in a drop of hemoglobin of more than 20 g/L to hemoglobin of less than 90 g/L. Reasons for surgery were coded by the physician as because of patient request, physician request, or continuing pregnancy. Physician request meant that the patient was experiencing enough symptoms of bleeding and pain to warrant surgery. Patient request was usually related to travel or work plans. A patient was called "lost to follow-up" if she had not been contacted by the end of the study. The day of abortion (expulsion) was determined by history only after ultrasound determination of a uterus with no gestational sac. Therefore, the day 8 expulsion rate is an objective outcome, but the day of expulsion only a subjective one.
The sample size was calculated on an anticipated success rate of 90% in the methotrexate group and 95% in the mifepristone group, and a sample size of 474 subjects was required in each group to provide a study power of 80% and a probability of a type 1 error of 0.05. Data were sent to the main site and entered into SPSS (Statistical Package for the Social Sciences). The proportions of successful abortions in each group were compared using a 
2 test. The proportions of women going on to surgery in each group were estimated, and the difference between the two groups presented with 95% confidence limits to denote the limits of the true difference. For each group, a Kaplan-Meier survival curve was used to show time (number of days) to abort, and median day to abort was compared using a Mann-Whitney test. Complications and adverse events are presented in tabular form by allocation. The number of days of bleeding are shown as means and standard deviations for each group, and patient satisfaction is expressed as a categoric outcome.
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RESULTS |
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).
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. The rates of surgery were not significantly different between the two groups: 4.0% for methotrexate and 3.9% for mifepristone. The reasons doctors requested surgery were either prolonged or excessive bleeding. The reasons patients requested surgery included being unable to tolerate delayed reactions because of emotional upset, pregnancy symptoms, or travel plans. The mean number of days from taking the medication to having surgery was 21.6 in the methotrexate group and 24.2 in the mifepristone group. Abortions induced with methotrexate took longer to complete than those induced with mifepristone: 74.5% of the women in the methotrexate group had completed the abortion by the day 8 visit compared with 90.5% in the mifepristone group. The mean day of abortion was 7.1 days in the methotrexate group compared with 3.3 days in the mifepristone group. The medians were 5 days and 3 days, respectively (P .001). The bleeding began a mean of 4.6 hours after taking the misoprostol in the methotrexate group compared with 3.0 hours in the mifepristone group. There was no significant difference in outcome with respect to ethnicity, weight, investigational site, gravidity, gestational age, or maternal age. Women who had surgery had a higher mean parity (1.05 compared with 0.71) (P = .027).
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. This analysis confirmed the difference in outcome between the two study groups and showed that the number of previous births (parity) was a predictor of outcome.
Side effects were similar between the two groups except that women experienced more headaches after mifepristone and more diarrhea after methotrexate (Table 3). After misoprostol, there was significantly more fever, chills, and diarrhea in the methotrexate group who had taken 800 µg vaginally than in the mifepristone group who had taken 400 µg orally. There was no difference in the quantity of analgesics (acetaminophen with codeine or ibuprofen) or antinauseant (dimenhydrinate) taken. Nausea and tiredness were very common with about 40% in each group complaining of each of these side effects after each medication. Vomiting occurred in about 12% of the women taking the first medication and 15% of the women taking misoprostol in both groups.
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There was no significant difference in complications between the two groups (Table 4). There was one hospitalization in the methotrexate group in a woman who required intravenous antibiotics for endometritis after a surgical evacuation. There were no hemorrhages leading to blood transfusion. The emergency room visits were usually for uncontrolled bleeding or pain.
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) with 83.2% of the methotrexate group and 88.0% of the mifepristone group saying that they would choose the same method again (P = .03). The pain and time/waiting involved were more acceptable to the mifepristone group (P = .001 and P < .001, respectively).
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DISCUSSION |
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It is notable that the success rates for the regimens were equivalent. We had anticipated that the mifepristone group might have a higher success rate. Although the rate of surgery was not different between the two groups (4.0% compared with 3.9%), there were more women who chose to have surgery in the methotrexate group (11 compared with five) because of the long delays to complete abortion, and there were more surgical aspirations requested by the doctors in the mifepristone group (17 compared with eight) because of excessive bleeding. The surgery rate in US studies using the same mifepristone/misoprostol regimen was 8%13 and using the same methotrexate/misoprostol regimen was 9%.22 It is likely that the lower surgery rates in this study reflected our greater experience with medical abortions. Although there was no difference in total numbers of complications in the two groups, there were more women treated for bleeding (22 compared with 11) in the mifepristone group. It is possible that this is due to the lower dose of misoprostol or the route of administration. The lack of serious complications is similar to previous studies.13,18,32
The pain scores were statistically greater in the methotrexate group (P = .001), but the difference was less than 0.6 on an 11-point pain scale. Usually, a clinically significant difference is considered to be between 1.0 and 3.0 on such a scale.38 This small difference appears to have been significant to these women, however, because in the mifepristone group, the acceptance of the pain was 86.0% compared with 77.7% in the methotrexate group (P = .001). Despite the higher number of days of bleeding and rate of excessive bleeding in the mifepristone group, the acceptance of the bleeding was similar (93.1% compared with 90.1%, P = .09). The amount of bleeding was similar to previous studies.11–13,16,20
The overall level of side effects was the same for the two groups for all the drugs and similar to previous studies.2,3,18–21,32 The mifepristone group had more headaches both after mifepristone and after misoprostol. The methotrexate group had more diarrhea after methotrexate and more fever, chills, and diarrhea after misoprostol. It is possible that the difference in the side effects after misoprostol is purely due to the dose of misoprostol (800 µg for the methotrexate and 400 µg for the mifepristone group) rather than the first drug.
There are several limitations to this study. Neither participants nor investigators were blinded to the regimen used. The drug regimens were chosen so that the formally recommended regimen for each drug could be compared, but the different doses and routes of administration of the misoprostol may have accounted for some of the differences in outcomes. The study, therefore, compares two regimens rather than two drugs.
Abortions induced by methotrexate followed by misoprostol and those induced by mifepristone followed by misoprostol were both highly successful and acceptable to most women. The main difference was speed of action with mifepristone causing abortions to be completed more quickly than with methotrexate. There were minor differences in side effects. Mifepristone abortions were more acceptable to women than methotrexate abortions. Based on this information, we believe that clinicians and patients will be likely to choose mifepristone unless availability or cost is a factor.
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Footnotes |
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We gratefully acknowledge the assistance of Drs. Ludek Podhradsky, Inna Tcherenkova, and Jonathan Berkowitz.
Received September 17, 2001. Received in revised form November 29, 2001. Accepted December 26, 2001.
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REFERENCES |
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2. Creinin MD, Vittinghoff E, Galbraith S, Klaisle C. Methotrexate and misoprostol for early abortion: A randomized trial comparing misoprostol 3 days and 7 days following methotrexate. Am J Obstet Gynecol 1995;173:137–43.
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