The current “standard” regimen of mifepristone and a prostaglandin analogue for medical abortion is mifepristone 600 mg followed 2 days later by misoprostol 400 μg orally.1 Most commonly, patients are observed for 4 hours after misoprostol administration. Abortion rates by 24 hours after misoprostol administration range from 87%, in studies involving women at up to 49 days' gestation,2 to 75%, in women at up to 63 days' gestation.3 Overall, complete abortion rates with the standard regimen decrease with advancing gestational age; rates vary from 96% to 98% at up to 42 days' gestation,4,5 91% to 95% at 43–49 days' gestation,4,5 and less than 90% beyond 49 days' gestation.3
There is considerable evidence that regimens using 200-mg doses of mifepristone are safe and effective.6–11 However, the question of how low a dose of mifepristone is clinically effective remains. Mifepristone doses of 100 mg or more are associated with similar serum levels, unlike doses less than 100 mg.12–14 Comparative studies have demonstrated that the total serum concentration over 72 hours is similar for women administered 100 mg, 200 mg, or 600 mg in a single dose.15 Similar peak serum concentrations of 2.0–2.5 μg/mL occur in women given 100 mg, 400 mg, 600 mg, or 800 mg of mifepristone.16 This information indicates that regimens using single doses of mifepristone at a level of as little as 100 mg might have clinical efficacy comparable to that of regimens with 200 or 600 mg.
This trial was designed as a preliminary study of a 100-mg dose of mifepristone followed 2 days later by misoprostol for medical abortion at up to 49 days' gestation. The doses of misoprostol typically used in medical abortion regimens include 400 μg orally (in regimens using mifepristone 600 mg)2–4,17,18 and 800 μg vaginally (in regimens using mifepristone 200 mg).8–11,19 We conducted initial evaluations of women who used mifepristone 100 mg with one of these established doses and routes of administration of misoprostol.
MATERIALS AND METHODS
This clinical trial was approved by the Institutional Review Board of Magee-Womens Hospital of the University of Pittsburgh Health System. Entry criteria included 1) age at least 18 years, 2) a singleton intrauterine pregnancy not exceeding 49 days' gestation as documented by vaginal ultrasound, 3) request for an abortion, 4) willingness to comply with the visit schedule, 5) willingness to have a surgical abortion if indicated, 6) adequate venous access for multiple phlebotomies, and 7) access to a telephone.
Exclusion criteria included 1) contraindications for use of mifepristone, including chronic systemic corticosteroid administration or adrenal disease, 2) contraindications for use of misoprostol, including glaucoma, mitral stenosis, sickle cell anemia, poorly controlled seizure disorder, or known allergy to prostaglandin, 3) hemoglobin level less than 10 g/dL, 4) cardiovascular disease, including angina, valvular disease, arrhythmia, or cardiac failure, 5) known coagulopathy or treatment with anticoagulants, 6) pregnancy with an intrauterine device in utero, and 7) breast-feeding.
Women who enrolled gave written informed consent and agreed to have a suction abortion should the pregnancy be viable (defined as evidence of cardiac activity on vaginal ultrasound) at the second follow-up visit. Vaginal ultrasonography was performed, and gestational age was estimated as follows: gestational age (days) = mean sac diameter (mm) + 30 or embryonic pole (mm) + 42.20,21 Mean sac diameter ([length + width + depth]/3) was used to estimate gestational age only when no embryonic pole was present. Estimated gestational age was determined from the last menstrual period (LMP), but if the ultrasound estimate differed by 4 days or more from the gestational age determined from the LMP, the ultrasound estimate was used.
On the day consent was given, a history was obtained, a physical examination was performed, and baseline hemoglobin values and blood type were determined. At least 24 hours after giving consent (as required by the Pennsylvania Abortion Control Act), the subject swallowed a capsule containing 100 mg of mifepristone in the presence of a member of the research staff, if all entry criteria were met. The mifepristone was supplied by Abortion Rights Mobilization and was prepared by grinding a 200-mg tablet and then inserting 100 mg (by weight) into a gelatin capsule. Because we did not use a reformulated tablet, the dose of mifepristone was only approximately 100 mg. The day of this visit was considered study day 1. If the patient's blood type was Rh-negative, she also received Rh immune globulin 50 μg intramuscularly.
Subjects then were randomized to misoprostol, administered 48 hours later, at a dose of 400 μg orally (group 1) or 800 μg vaginally (group 2). Randomization was performed in blocks of ten using a random number table to create 50 subjects in each of the two groups. A person unrelated to the study performed the randomization sequence and prepared the envelopes. Women were assigned to groups by opening the next sequentially numbered, sealed opaque envelope. The researchers and staff were not blinded to group assignment. Randomization was performed solely to remove any potential recruitment bias.
Subjects were given two (group 1) or four (group 2) tablets of misoprostol 200 μg to take home, along with appropriate instructions for administration. All participants were instructed to call the research office if vaginal bleeding resulted in more than two soaked sanitary maxipads in 1 hour for 2 consecutive hours. Subjects were given a prescription for 20 tablets of codeine phosphate 30 mg or oxycodone 5 mg. The women were instructed to use ibuprofen or acetaminophen initially and to use the prescribed narcotic only if necessary.
All subjects returned 24 ± 1 hours after using the misoprostol, at which time they were questioned regarding side effects occurring during the interval between mifepristone and misoprostol administration and after misoprostol administration as well as at the time of misoprostol administration. Vaginal ultrasonography was performed.
A second follow-up visit was performed between days 14 and 20. A history of events since the prior visit was obtained. Vaginal ultrasonography was repeated if the prior examination did not demonstrate absence of the gestational sac. If the gestational sac and embryonic cardiac activity were present, a surgical abortion was performed. If the gestational sac was still present and there was no cardiac activity, the patient returned in 3 weeks (approximately day 36), at which time an interim history was obtained and vaginal ultrasonography was performed. If the gestational sac was still present, the woman was offered a surgical abortion. If she declined intervention, she was observed at 1- to 2-week intervals until she either aborted or requested a surgical abortion. All subjects were permitted to request a surgical procedure at any time rather than continue to wait for expulsion.
The total number of participants was selected so that the sample size would be adequate for a preliminary investigation. Given an expected 90% complete abortion rate within 24 hours of misoprostol administration,2 the sample size was selected to give a lower 95% confidence interval (CI) of no less than 80%, which is 10% lower than the hypothesized efficacy rate. A sample size of 40 subjects with a 90% rate of complete abortion yields 95% CIs of 81% and 99%, using a normal approximation. Thus, to obtain a sample of 40 subjects per treatment group, a total of 80 subjects were enrolled. The procedure was considered successful if complete abortion occurred without the need for suction aspiration. Body surface area was calculated using a body surface area table.22 Statistical analyses were performed using the Fisher exact test, Wilcoxon rank-sum tests, and χ2 analysis with a Yates correction when appropriate. Because of the small numbers in some subgroup analyses, exact confidence limits for outcome variables could not be calculated using a normal approximation and were estimated using a graph for binomial distribution.23 Data are presented as mean ± standard deviation.
Patient characteristics are presented in Table 1. All 80 subjects used the misoprostol, although histories obtained at first follow-up suggested that two women in group 1 and one woman in group 2 might have aborted before using the misoprostol. All but one of the women in group 1 (98%) and 38 (95%) of the women in group 2 used the misoprostol 48 hours ± 30 minutes after administration of mifepristone. The three women who did not use misoprostol during this time inserted the misoprostol tablets 2.25, 2.5, and 3.0 hours after the 48-hour mark; all of these women had complete expulsion at the first follow-up visit.
By the first follow-up visit (scheduled 24 hours after misoprostol was to be administered), 34 (85%; 95% CI 71%, 94%) of the 40 women in group 1 and 38 (95%; 95% CI 85%, 99%) of the 40 women in group 2 had aborted (P = .26). By follow-up 2 weeks after administration of mifepristone, 35 (88%; 95% CI 75%, 96%) of the women in group 1 and 40 (100%; 95% CI 91%, 100%) of the women in group 2 had aborted (P = .06). All five of the subjects who had not aborted by the second follow-up visit were in group 1. Four (10%; 95% CI 4%, 23%) of these women still had gestational cardiac activity and had surgical abortions. The other subject did not have gestational cardiac activity and returned for a follow-up visit on study day 35, at which time a suction aspiration was performed because the patient had not expelled the gestational sac. One subject in group 1 who had expelled the gestational sac by the first follow-up visit presented on study day 42 with persistent bleeding. Vaginal ultrasonography demonstrated an intrauterine heterogeneous fluid collection 1.2 cm in diameter consistent with an incomplete abortion; a suction aspiration was performed. Thus, the overall complete abortion rates were 85% (95% CI 71%, 94%) for women in group 1 (34 of 40) and 100% (95% CI 91%, 100%) for women in group 2 (40 of 40; P = .03). The pathology reports for all women who had surgical completion of their abortions demonstrated chorionic villi.
Information on cramping and bleeding after the first dose of misoprostol is presented in Table 2. Twenty-five women in group 1 and 15 women in group 2 did not provide final information about the total length of bleeding. No patients reported bleeding that resulted in more than two soaked maxipads in 1 hour for 2 consecutive hours, and no women required transfusions.
Side effects are presented in Table 3. There was no statistically significant difference in the incidence of side effects reported after either mifepristone or misoprostol administration. Pain medication was not used at any time by seven subjects (18%) in each group; all of these women aborted successfully within 24 hours of misoprostol administration. All of the remaining subjects used only oral medication; 23 women (58%) in each group used oral narcotics for pain relief. Most of the women using narcotic pain medication did so without first trying ibuprofen or acetaminophen as instructed. Of those women who used narcotics, only 12 (52%) in group 1 and five (22%) in group 2 used a nonnarcotic analgesic at any time during the study.
Mifepristone at doses less than the 600 mg, standardly used throughout most of the world, is known to be clinically effective. Two randomized studies demonstrated equal efficacy of regimens using either 200 or 600 mg of mifepristone followed in 48 hours by a misoprostol dose of 400 μg orally6 or 600 μg orally.7 In addition, a retrospective analysis by Ashok et al8 of data from 2000 women using mifepristone 200 mg followed in 48 hours by misoprostol 800 μg vaginally demonstrated complete abortion rates of 98% through 63 days' gestation. Prospective trials in which participants self-administered the misoprostol at home also demonstrated the effectiveness of mifepristone 200 mg followed in 48 hours by misoprostol 800 μg vaginally, through 56 days' gestation9,10 and 63 days' gestation.11 Moreover, complete abortion rates of 96% and 98% using mifepristone 200 mg and misoprostol 800 μg vaginally were reported when the interval between administration of the medications was 6–8 hours, through 49 days' gestation (Pymar HC, Creinin MD, Schwartz JL. Mifepristone followed on the same day by vaginal misoprostol for early abortion. Contraception. In press.), or 24 hours, through 56 days' gestation, respectively11; in both of these studies, the subjects self-administered the misoprostol at home.
Our current study demonstrates that mifepristone 100 mg in combination with misoprostol is also clinically effective for early medical abortion. The sample size of this study was not established with the objective of having a trial large enough to provide a definitive comparison of the two regimens used in this trial. The study simply created two groups of 40 women to provide information to guide future studies.
The 85% overall efficacy of the regimen in this study using misoprostol 400 μg orally is similar to the 93% rate recently reported in a World Health Organization study using mifepristone 200 or 600 mg with misoprostol 400 μg orally (P = .26) through 49 days' gestation.6 Moreover, the efficacy of the regimen using misoprostol 800 μg vaginally (100%) is similar to the 97–99% rate reported in larger trials using mifepristone 200 mg with misoprostol 800 μg vaginally through 49 days' gestation.8–11 Thus, our findings suggest that both regimens tested in this trial, using a mifepristone dose of 100 mg, provide clinical efficacy in the same range as regimens using higher doses.
The side effect profile for the lower dose of mifepristone is similar to that reported by Spitz et al3 in women at up to 49 days' gestation using the standard regimen of mifepristone and misoprostol. That study's rates of nausea (61%), vomiting (26%), and diarrhea (20%) are virtually identical to those reported in this study. However, Pymar et al (Mifepristone followed on the same day by vaginal misoprostol for early abortion. Contraception. In press.) reported lower rates of nausea, vomiting, and diarrhea with a regimen of mifepristone 200 mg followed 6–8 hours later by misoprostol 800 μg vaginally; other side effects occurred at similar rates. In general, such comparisons are limited because the results are from studies performed at different times using different populations. More importantly, the accuracy of the results from this current study is limited by the small sample size.
Carbonell et al24–26 and Jain et al27,28 reported complete abortion rates exceeding 85% among women at as much as 63 days' gestation, when moistened misoprostol was administered vaginally and mifepristone was not given. These studies included complex dosing regimens with repeated administration of misoprostol 800 μg. Only two of the studies reported abortion rates for the group of women at up to 49 days' gestation. Expulsion occurred within 24 hours after a single dose of misoprostol in 70% and 81% of women in studies by Carbonell et al24 and Jain et al,28 respectively. Both of these rates are significantly lower than the current study's 95% rate for use of nonmoistened vaginal misoprostol after administration of mifepristone 100 mg. Additionally, Jain et al28 reported vomiting, diarrhea, and fever or chills in 45%, 67%, and 89% of women, respectively, through 56 days' gestation. These rates are higher than in the current study. These findings support the concept that this very low dose of mifepristone is clinically active, because expulsion rates exceed those of treatment with misoprostol alone.
Thus, it appears that mifepristone 100 mg may effect abortion as well as 200 or 600 mg, in combination with misoprostol, through 49 days' gestation. The major advantage of using a lower dose of mifepristone is potentially lower cost. Prospective trials are needed to find the mifepristone-misoprostol regimen with the most acceptable side effect profile at different gestational ages. Variations requiring additional investigation include the optimal mifepristone dose, the dose and route of administration of misoprostol, and the interval between administration of the medications.
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