1 Department of Obstetrics and Gynecology, University of Southern California Keck School of Medicine, Women's and Children's Hospital, Los Angeles, CA 90033, 2 Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh School of Medicine, MageeWomen's Hospital, Pittsburgh, PA 15213 and 3 Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, San Francisco General Hospital, San Francisco, CA 94110, USA
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Abstract |
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Key words: abortion/medical abortion/mifepristone/misoprostol/pregnancy
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Introduction |
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Misoprostol has also been studied as a single agent for elective termination of pregnancy. This regimen has the potential to be easier to use, provide more rapid pregnancy termination, and is less expensive compared with the mifepristone and misoprostol regimen. A single agent regimen with misoprostol is also likely to be more accessible in areas where mifepristone is unavailable or difficult to obtain. Most published trials have evaluated a dose of 800 µg vaginal misoprostol, administered every 24 h, in gestations up to 70 days duration with reported success rates of 8593% (Carbonell et al., 1997a,b
; Esteve et al., 1999
; Jain et al., 1999
; Bugalho et al., 2000
; Ngai et al., 2000
; Jain et al., 2001
). In a study comparing women who received 800 µg of vaginally administered, saline-moistened misoprostol to a historical control group of women who received 600 mg mifepristone followed by 400 µg misoprostol orally as part of a large multicentre US trial, there was no statistically significant difference in efficacy between the two groups (Jain et al., 1999
). Abortion success occurred in 88% of subjects receiving vaginal misoprostol alone and 94% of the subjects receiving mifepristone and oral misoprostol in the non-concurrent control group. Therefore, this randomized, placebo-controlled, double-blinded study was designed to compare directly and prospectively the efficacy of mifepristone and vaginal misoprostol to vaginal misoprostol alone for elective termination of pregnancies
56 days gestation.
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Materials and methods |
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Immediately following confirmation of eligibility and consent, subjects were randomized to one of two groups. Women assigned to group 1 received mifepristone on study day 1, and women in group 2 received placebo medication. The assigned study medication was dispensed and ingested in the study clinic. The placebo medication used was a 500 mg tablet of vitamin C, similar in size, shape, and colour to the mifepristone tablets, but with a single score. Mifepristone was administered as a single 200 mg tablet, and was obtained from the Abortion Rights Mobilization Group. At the time subjects were enrolled, mifepristone was an investigational drug. Therefore, this study was performed and mifepristone studied under US Food and Drug Administration IND no. 58,204. At this enrolment visit, each subject was also given a diary to record uterine bleeding episodes, side-effects, and any medications used on each day until their final visit. Consents, diaries, and questionnaires were made available in both English and Spanish.
On day 3, the subjects returned and a repeat haemoglobin measurement was performed. For women reporting the presence of uterine bleeding, a pelvic ultrasound was performed. If a gestational sac was still present, or if no bleeding had occurred after the mifepristone or placebo tablets, four 200 µg tablets (800 µg) of misoprostol (Cytotec; Searle, Skokie, IL, USA) were placed vaginally under direct visualization with a speculum, followed by placement of 2 ml of normal saline to moisten the tablets. Prophylactic doses of loperamide (4 mg) and acetaminophen (1000 mg) were administered to each subject, as described in a previous protocol (Jain et al., 2001). Subjects then remained supine for at least 30 min before discharge to home.
On day 4, a repeat haemoglobin measurement and pelvic ultrasound examination were performed. If the gestational sac was absent, the subject was given a return appointment for study day 15, 2 weeks after the enrolment visit. If the gestational sac was still present, subjects were offered a repeat dose of 800 µg misoprostol, and women who received a second dose also received the same dose of prophylactic loperamide and acetaminophen. Only those subjects who required a second dose of vaginal misoprostol and had no subsequent bleeding returned for evaluation on day 5. On study day 5, subjects again were offered a repeat dose of 800 µg vaginal misoprostol if the gestational sac was visualized by pelvic ultrasound. Women were given the option to have a surgical evacuation to terminate the pregnancy at any time during the study, usually as an alternative to a repeat dose of misoprostol.
Abortion failure was defined as a need for evacuation of the uterus by a surgical technique for any reason, including the presence of a persistent gestational sac seen sonographically, excessive or prolonged uterine bleeding, incomplete abortion, or subject request. Surgical evacuation was performed by electric or manual vacuum aspiration after informed consent.
All subjects were contacted on study day 8 by telephone to evaluate symptoms and all subjects were scheduled to return on study day 15 (or for women who required surgical evacuation, a week or more following the procedure) for a follow-up visit. At that time, subjects underwent a repeat pelvic ultrasound and haemoglobin measurement. The subjects also returned their symptom diaries detailing uterine bleeding patterns (none, spotting, moderate or heavy), and incidence of pain, nausea, vomiting or diarrhoea for each day during the study protocol. All subjects returning for the final visit completed a questionnaire concerning acceptability of the method.
Assignment
Randomization was based on a computer-generated random number table; from this, a study coordinator who was not involved in patient care created the randomization list assigning treatment group. Subjects assigned to group 1 received mifepristone orally on day 1 of the protocol, and subjects assigned to group 2 received placebo.
Masking
An investigator placed single 200 mg mifepristone tablets into 125 unlabelled opaque vials, and single tablets of placebo into another identical, unlabelled 125 opaque vials. A study coordinator not involved with this protocol labelled the vials with subject numbers (1250) using the randomization list, and placed the vials in sequential order. Each vial was then distributed in sequential numerical order to assign randomization to treatment. At the time of the administration of study medication on day 1, an investigator or a study coordinator witnessed the subjects swallowing the study medication, but did not see the individual tablets. In this manner both the providers and subjects remained blinded to group assignment. For each abortion failure, two separate investigators independently verified the outcome and reason for surgical evacuation: one at the time of the subject's clinic visit and another at the time of data entry and chart review.
Statistical analysis
Based on published rates of abortion success at the time of protocol development of 95% with mifepristone and misoprostol and of 85% with misoprostol alone, a sample size of 125 subjects in each group was needed to determine significance at an alpha of 0.05 with a power of 80%. Statistical analyses were performed using Pearson's 2-test for comparison of proportions, and Student's t-test for comparison of means.
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Results |
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In the mifepristone and misoprostol treatment group, there were five surgical evacuations performed only for subject request, without a medical indication. The reasons for the surgical procedure were mild persistent bleeding (n = 3), or refusal to take a third dose of misoprostol with presence of a gestational sac (n = 2). Reasons for surgical evacuation in the 15 women who received placebo and misoprostol were presence of an ongoing pregnancy (n = 6), incomplete uterine evacuation of gestational tissue with no visible gestational sac (n = 5), clinical indication due to an allergic reaction to misoprostol (n = 1), or due to subject request (n = 3). The reasons for requesting surgical evacuation were mild, irregular, but persistent uterine bleeding without evidence of a gestational sac (range of bleeding 3 weeks to 2 months) (n = 2), or refusal to take a third dose of misoprostol with presence of a gestational sac (n = 1).
Side-effects were recorded by the subjects on each day during the study protocol, and included yes or no marks in columns designated `nausea', `vomiting', `diarrhoea', and `fever/chills'. For most subjective symptoms, side-effects between the two groups were similar (Table III). There was a significantly higher frequency of nausea and vomiting after administration of mifepristone compared with placebo (P = 0.009, P < 0.001). A total of 24% (34/140) of subjects in the combined groups reported a recorded maximum temperature
100.5°F (combined median 99.8, range 96.5104). Pain requiring use of opiate analgesics (acetaminophen with codeine) was reported by 27 women in group 1, and 29 women in group 2 (P = not significant). No severe complications occurred in any subjects, including transfusion, emergent surgery for haemorrhage, or sepsis.
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Bleeding patterns among the subjects having a successful medical abortion by either regimen were analysed, and there were no statistically significant differences between the two groups. By the final visit, women in group 1 reported a mean of 8.3 days of moderate or heavy bleeding, compared with 9.8 days in group 2 (P = not significant). The total number of bleeding days including days of spotting in group 1 was a mean of 12.4 days, and in group 2 was a mean of 13.0 days (P = not significant).
Acceptability of the regimens was estimated by analysis of the exit questionnaires. There were no statistically significant differences between the two groups for any of the parameters analysed. For the combined groups, the overall satisfaction with both regimens was high, with 91% (200/220) of the women rating their medical abortion experience as satisfactory or very satisfactory. Seventy-nine per cent of the respondents would choose to have a medical abortion again if they needed a subsequent abortion, and 89.6% would recommend the method to a friend if she needed an early abortion. Of those who had a prior surgical abortion, 64% thought that the medical abortion was `better'. Subjects also rated the overall side-effects as `tolerable' or `very tolerable' in 83% of the cases. Women commonly wrote down the benefit of `no surgery' as one of the best features of the method, while `cramping' or `pain,' `bleeding,' and `nausea' or `vomiting' were some of the worst features of the method.
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Discussion |
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El-Rafaey et al. published one of the first reports demonstrating that vaginal administration of 800 µg misoprostol 48 h after mifepristone was more effective and better tolerated than 800 µg oral misoprostol (el-Refaey et al., 1995). This clinical finding was supported by pharmacokinetic studies that demonstrated prolonged serum levels of misoprostol and a greater area under the curve after vaginal administration compared with oral administration of the same dose (Zieman et al., 1997
). Another large trial in the USA using a regimen of 200 mg mifepristone and 800 µg of vaginal misoprostol was effective in terminating 95% of pregnancies up to 63 days gestation (Schaff et al., 1999
). Currently, many providers of medical abortion have adapted this specific regimen for its lower cost, increased effectiveness at later gestational ages, and more tolerable side-effect profile compared with use of higher doses of mifepristone and oral administration of misoprostol.
However, due to concerns that mifepristone would not be approved in the USA, investigators also developed medical abortion regimens without mifepristone. One of these regimens uses methotrexate, an anti-metabolite, in combination with vaginal misoprostol for early pregnancy termination. Trials evaluating methotrexate and misoprostol reported successful abortion rates of 9296% for pregnancies up to 63 days gestation, but with an interval of as long as 2 or 3 weeks between administration of methotrexate and occurrence of abortion (Hausknecht, 1995; Creinin et al., 1996
).
Another alternative to the mifepristone and misoprostol regimen, based on the successful experience of investigators outside the USA (Carbonell et al., 1997a,b
) is the use of misoprostol as a single agent for termination of pregnancies of 56 days gestation or less. A non-concurrent cohort trial compared 800 µg of vaginally administered misoprostol, given every 24 h up to two doses, to the standard regimen of 600 mg mifepristone and 400 µg oral misoprostol, and found no statistically significant difference in efficacy (Jain et al., 1999
). A subsequent trial reported the efficacy of 800 µg vaginal misoprostol given with oral loperamide and acetaminophen to be 93% overall (Jain et al., 2001
). Comparing these efficacy rates with the mifepristone and misoprostol regimen is problematic, however, due to risk of bias in selection of subjects, and the non-blinded administration of medications. Therefore, the current study was designed to compare the two regimens directly using a more rigorous randomized clinical trial. This study is the first randomized, placebo-controlled trial directly comparing mifepristone and misoprostol with misoprostol alone for medical termination of early pregnancy.
Our results confirm that a regimen of mifepristone and vaginal misoprostol is more effective compared with a regimen of misoprostol alone for termination of pregnancies of 56 days gestation. These findings also support the conclusion that mifepristone provides a small but significant contribution to the overall efficacy of a combined mifepristone and misoprostol regimen. The abortifacient action of mifepristone is supported by the documentation of four successful abortions in this trial that occurred after only mifepristone was administered. A recent report (Creinin et al., 2001
) demonstrated an abortion rate of 95% using mifepristone 100 mg and a single dose of misoprostol 800 µg vaginally. They concluded that even a very low dose of mifepristone is clinically active, and that the combined regimen still had a higher efficacy compared with most trials using multiple doses of vaginal misoprostol alone.
Compared with the two earlier trials published by Jain et al., the efficacy rate in this placebo and misoprostol group was similar (88 versus 88 and 93%) (Jain et al., 1999, 2001
). All studies allowed subjects either to receive multiple doses of misoprostol (two or three), or to request a surgical evacuation in lieu of a repeat dose if desired. Comparing successful abortion rates after only two doses of vaginal misoprostol again reveals consistent findings: 85.6% in the current study, compared with 88 and 89% in the previous trials.
The analysis of self-reported side-effects demonstrates that subjects receiving mifepristone had a significantly higher incidence of nausea (P = 0.009) and vomiting (P < 0.001) on day 1 compared with subjects receiving placebo. There were no other significantly different rates of side-effects reported between the two groups. Forty-four to 52% of subjects reported nausea, and 2233% of subjects reported vomiting after the vaginal misoprostol insertion (on or after day 3). Despite the administration of prophylactic acetaminophen and loperamide before misoprostol, the rates of reported diarrhoea ranged from 11 to 16%, and subjective fever or chills was reported by 6172% of subjects. These rates of side-effects are all similar to rates of previous studies of both the mifepristone and misoprostol alone regimens. Despite these relatively high incidences of side-effects, an overwhelming majority of subjects still reported the method to be tolerable or very tolerable. The use of additional medication to treat any of these side-effects was rare among the study population (35%).
One limitation of the study is that five subjects were lost to follow-up in the mifepristone and misoprostol group. Subjects may have failed to return because they perceived the method to be successful, and did not want further examinations. Alternatively, subjects with heavy bleeding or severe side-effects requiring treatment may have chosen to seek care with another provider, rather than return to our clinics for further treatment. Assuming that these five cases had successful outcomes strengthens the statistical difference in efficacy between the two groups. If all five subjects with no or inadequate outcome data are assumed to have had abortion failures (an intention-to-treat analysis), then the statistically significant difference remains only between the groups receiving one dose of misoprostol (P = 0.005), but not between the groups when subjects receiving 2 or
3 doses of misoprostol were included (P = 0.109, P = 0.292 respectively).
Despite the lower efficacy of misoprostol as a single agent compared with mifepristone and misoprostol to effect abortion up to 8 weeks gestation, further investigation is needed to evaluate the efficacy of misoprostol alone for earlier gestations (49 or even
42 days gestation). Bugalho et al. have reported an abortion rate of 92.1% 1 week after vaginal administration of a single dose of 800 µg misoprostol in pregnancies of <6 weeks gestation (Bugalho et al., 2000
). It is possible that the regimen of up to three doses of misoprostol every 24 h used in this trial and others is unnecessary to achieve high efficacy rates, and that expectant management would allow a higher proportion of pregnancies to abort much later than 24 h after misoprostol administration.
Current research in medical abortifacient regimens is focused on altering the dose of both mifepristone and misoprostol in order to reduce side-effects and optimize efficacy, altering the timing of doses to reduce the necessary clinic appointments and follow-up, and addressing issues such as need for ultrasound examination or administration of Rh immune globulin in early pregnancy. This study and others (Winikoff, 1995; Beckman and Harvey, 1997
) confirm that subjects in medical abortion trials find the procedure highly acceptable. However, surgical termination of early pregnancy is also an effective and safe option for most women, and may be a preferred method when distance or resources limit the use of medical methods. Additional research is needed to identify the optimal regimens for specific populations of women.
In conclusion, mifepristone appears to have a small but clinically and statistically significant effect on the abortion success rate of the mifepristone and vaginal misoprostol regimen analysed in this randomized, double-blinded, placebo-controlled trial. However, use of misoprostol as a single agent for pregnancy termination remains of value in clinical situations where mifepristone is unavailable or contraindicated, especially due to the much lower cost of misoprostol compared with mifepristone. It is important to note that the expense of additional provider visits to determine the need for repeat doses of misoprostol may outweigh the expense saved by medication costs. The efficacy and convenience of medical abortion regimens, and the cost of each regimen, are important priorities for future research.
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Notes |
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References |
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Submitted on November 19, 2001; accepted on January 25, 2002.