Obstetrics & Gynecology:
Mifepristone and Misoprostol Compared With Misoprostol Alone for Second-Trimester Abortion: A Randomized Controlled Trial
Ngoc, Nguyen Thi Nhu MD, MSc; Shochet, Tara PhD, MPH; Raghavan, Sheila MSc; Blum, Jennifer MPH; Nga, Nguyen Thi Bach MD; Minh, Nguyen Thi Hong MD; Phan, Van Quy MD, MPH; Winikoff, Beverly MD, MPH
From the Center for Research and Consultancy in Reproductive Health and Hung Vuong Hospital, Ho Chi Minh City, Vietnam; Gynuity Health Projects, New York, New York; and the Vietnam National Ob-Gyn Hospital, Hanoi, Vietnam.
The authors thank the women and providers who participated in this trial and the anonymous donor who funded this research.
Corresponding author: Sheila Raghavan, MS, Gynuity Health Projects, 15 East 26th Street, Suite 801, New York, NY 10010; e-mail: firstname.lastname@example.org.
Financial Disclosure The authors did not report any potential conflicts of interest.
OBJECTIVE: To estimate the clinical benefit of pretreatment with mifepristone followed by misoprostol compared with misoprostol alone for second-trimester abortion.
METHODS: Two hundred sixty women with live fetuses of gestational ages 14–21 weeks were enrolled in a randomized, placebo-controlled, double-blind trial in Vietnam. Eligible consenting women received either mifepristone or placebo to take on their own at home and were scheduled to return to the hospital the next day. At the hospital, women were given 400 micrograms buccal misoprostol every 3 hours, up to five doses, until both the fetus and placenta were expelled. Efficacy was evaluated 15 hours after misoprostol dosing began and the procedure was considered complete if uterine evacuation was achieved without recourse to surgical evacuation.
RESULTS: Pretreatment with mifepristone resulted in more than twice the chance of complete uterine evacuation in 15 hours (79.8% compared with 36.9%, relative risk 2.16, 95% confidence interval 1.70–2.75). The mean induction-to-abortion interval for complete uterine evacuations was statistically significantly shorter among participants pretreated with mifepristone compared with those given misoprostol alone (8.1, standard deviation 2.8, range 2.5–14.8; and 10.6, standard deviation 2.5, range 6.5–15.5 hours, respectively; P<.001). The side-effect profiles for the two regimens did not differ significantly and acceptability of the treatments was high.
CONCLUSION: Mifepristone–misoprostol is more efficacious and faster than misoprostol alone. Services offering home administration of mifepristone as pretreatment could optimize efficacy and acceptability of medical abortions for women with gestations 14–21 weeks since the last menstrual period.
CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00784186.
LEVEL OF EVIDENCE: I
Although worldwide only 10–15% of all abortion procedures occur in the second trimester, these procedures account for more than two-thirds of major complications.1 Increasingly, health care providers are using medical methods such as misoprostol, a synthetic orally active E1 prostaglandin, as the standard agents for second-trimester abortion.2,3
Misoprostol can be used with or without mifepristone pretreatment for second-trimester abortion. Published reports suggest that misoprostol regimens are more effective and have fewer side effects and complications than other prostaglandins.4–12 Regimens using 200 or 600 mg of mifepristone as pretreatment followed by 200- to 800-microgram doses of misoprostol have also been reported in the literature.4–7,13 The Royal College of Obstetricians and Gynecologists and the International Federation of Gynecology and Obstetrics recommend 200 mg mifepristone followed by 800 microgram vaginal misoprostol 36–48 hours later and repeated doses of 400 micrograms oral misoprostol every 3 hours.14,15
The induction-to-abortion interval seems to affect acceptability, because women tend to prefer to complete the procedure as quickly as possible.16–21 In addition, shorter time intervals often correspond to shorter hospital stays, likely resulting in lower cost for treatment. Research suggests that with mifepristone pretreatment lower doses of misoprostol may be sufficient to achieve comparable efficacy with a shorter induction-to-abortion interval.22 Both of these factors argue for a regimen of mifepristone and misoprostol over misoprostol alone, where mifepristone is available. However, only two small trials have been published; one of the studies enrolled only women with intrauterine fetal death and the other only gestations with fetal anomalies.22,23 There is little information on optimal medical regimens using mifepristone and misoprostol for second-trimester inductions with a live fetus.
Although there is only one published report on the efficacy of buccal misoprostol alone for second-trimester abortion,22 this route has become increasingly popular with mifepristone medical abortion regimens and is now recommended as standard care of early abortions at U.S. Planned Parenthood clinics.24 Although the buccal route produces lower serum levels than the vaginal route, uterine tone and activity are similar.25 A trial comparing buccal and oral misoprostol after mifepristone administration for medical abortion up to 63 days since the last menstrual period recorded complete abortion in 96.2% of women receiving buccal misoprostol.26
The primary goal of the current study was to estimate the clinical advantage of pretreatment with mifepristone in second-trimester misoprostol abortion. The study also documented whether women could safely administer mifepristone (or placebo) at home.
MATERIALS AND METHODS
This randomized, placebo-controlled, double-blind trial compared two methods of second-trimester medical abortion. All women presenting for termination of pregnancy at Hung Vuong Hospital (Ho Chi Minh City) and the National Ob-Gyn Hospital (Hanoi) and who met the study criteria were invited to participate. Requirements for eligibility included being 14–21 weeks of gestation with a live fetus based on menstrual history and clinical examination (with or without ultrasonography), presenting with a closed cervical os and no vaginal bleeding, and being willing to follow the study protocol and provide informed consent. Women with known previous transmural uterine incision, contraindications to using misoprostol or mifepristone (a history of allergy to either drug; chronic systemic use of corticosteroids; chronic adrenal failure; coagulopathy or current therapy with anticoagulants; or inherited porphyria) or to having a vaginal delivery, or who presented in active labor were not eligible. The study was approved by the Hung Vuong Hospital and National Ob-Gyn Hospital ethics committees and all participants gave written, informed consent. All forms were translated into Vietnamese and data collection occurred in Vietnamese.
Participants were randomized to one of two study groups; women in the first group received pretreatment of 200 mg Mifestad (Stada; mifepristone) to take orally at home; those in the second group received placebo (identical in size, shape, and color). All women were asked to return to the hospital the next day to begin treatment with Cytotec (Pfizer; misoprostol). Participants were instructed to return to the hospital at any time if they experienced strong contractions or heavy bleeding. On return, all participants were asked to confirm that they administered the first study medication (either mifepristone or placebo) at home. They were then admitted and received the first dose of 400 micrograms misoprostol buccally. Doses were repeated every 3 hours, up to five doses, until the expulsion of the fetus and the placenta occurred. After administration of the first misoprostol dose, blood pressure, temperature, side effects, and bleeding were monitored every 3 hours. Oral or parenteral analgesia was provided as needed.
If the products of conception were passed and appeared complete (including the placenta) within 15 hours of the first misoprostol dose, the procedure was considered complete and no further interventions were given. If fetal expulsion did not occur within 15 hours from the first misoprostol dose (3 hours after the final dose), the induction was considered a failure and the woman was offered standard evacuation. However, if the fetus was expelled but the placenta remained in the uterus after an additional 30 minutes, the woman could be given an additional 400 micrograms of misoprostol buccally to help evacuate the placenta and wait an additional 6 hours for expulsion (21.5 hours after the first misoprostol dose). If placental expulsion still did not occur, the health care provider was instructed to remove any remaining products either surgically or medically. Midlevel health care providers consented and enrolled women into the study, offered the mifepristone or placebo for home administration, administered misoprostol doses to women the next day at the hospital, and monitored the women regularly. Physician providers were responsible for determining whether the evacuation was complete and for providing any additional interventions to complete the evacuation. Before discharge, participants were asked to respond to a series of questions regarding their overall experience with the procedure and its acceptability. Women were advised to call or visit the hospital with any concerns after discharge.
Opaque, sealed envelopes contained the treatment allocation (either mifepristone plus misoprostol doses or placebo plus misoprostol doses) and were opened in strict numeric sequence. Both health care providers and women were masked to treatment assignment. A computer-generated random code in blocks of 10 was derived by Gynuity Health Projects in New York. Staff at Gynuity prepared the envelopes and treatment assignment was not revealed until data collection and cleaning were completed. Periodic monitoring ensured that hospitals followed the numeric sequence of the treatment allocation and that masking was successful.
Two hundred sixty participants were sought to detect a significant difference of 98% compared with 86% of complete fetal expulsion within 15 hours (and placental expulsion in 21.5 hours) in the mifepristone–misoprostol compared with misoprostol alone groups, respectively, with 80% power and a 95% confidence interval (CI). The sample size sought to detect a significant difference in the induction-to-abortion interval (estimated as 7 hours with mifepristone–misoprostol and 11 hours with misoprostol alone). Data on total dose of misoprostol administered, time to fetal and placental expulsion, documentation of any interventions needed, side effects, and women's satisfaction were collected and compared between the two study groups using chi-square or independent t tests, as appropriate. Data were entered in Vietnam using SPSS 15 software. All analyses were conducted with Stata 11 and SPSS 19 software.
Two hundred sixty women were enrolled from August 2008 to August 2009 (see Fig. 1). Participants were equally randomized between the two study groups. Analysis does not include one woman in the mifepristone–misoprostol group for whom no information is available beyond initial enrollment as she was lost to follow-up after this initial visit.
We examined the characteristics of the participants, including maternal age, gestational age, education, marital status, and pregnancy, and abortion history. The average age of participants was 25 years. More than half (57%) were married, and the majority (63%) had completed secondary school as their highest level of education (data not shown). These characteristics were compared by study group (Table 1). The only statistically significant difference between arms 1 and 2 was mean gestational age (16.6 and 17.2 weeks, respectively; P<.03).
Pretreatment with mifepristone resulted in more than twice the chance of a complete uterine evacuation compared with misoprostol alone (relative risk 2.16, 95% CI 1.70–2.75). Approximately 80% (79.8%) of the mifepristone–misoprostol group had complete abortions compared with 36.9% of the misoprostol-alone group (Table 2). As seen in Fig. 2, time to completion demonstrates the difference in duration between the two study arms and the percent of women in each group who achieved complete evacuation throughout the 15-hour period (Fig. 2; log-rank test: P<.001). For instance, by 10 hours, almost 60% of women in the mifepristone–misoprostol group had complete uterine evacuation compared with fewer than 20% in the misoprostol-only group. Of note, some women experienced complete uterine evacuation after the 15 hours stipulated in the protocol but before any additional interventions were provided. If we reclassify these women, we achieve moderately higher efficacy rates: 81.4% with mifepristone–misoprostol and 41.5% with misoprostol alone. Gestational age did not appear to affect evacuation rates among women pretreated with mifepristone; however, the rate of complete evacuation did vary by gestational age among women given misoprostol only (13.0–56.3%) resulting in a wide range of risk ratios between the two regimens (relative risk 1.42–6.13, 95% CI 1.01–2.00 and 2.07–18.15, respectively).
Fetal expulsion occurred for 86.1% of the mifepristone–misoprostol participants and for 39.2% of misoprosol-alone recipients (relative risk 2.19; 95% CI 1.75–2.75). The mean times to fetal expulsion among participants who had a complete uterine evacuation were similar to the mean times to complete evacuation for both study regimens (Table 2). Additional care given to women who expelled the fetus but not the placenta included administration of oxytocin, removal with sponge forceps, dilation and curettage, and additional doses of misoprostol (Table 2).
The mean induction-to-abortion interval for complete uterine evacuation was statistically significantly shorter among participants who were pretreated with mifepristone compared with those who took misoprostol alone (8.1 and 10.6 hours, respectively; P<.001). Among participants who experienced complete uterine evacuation with the study regimen, the median number of doses of misoprostol received was significantly lower among the mifepristone–misoprostol group (three) as compared with the misoprostol-alone group (four) (P<.001; Table 2). The side-effect profiles for the two study regimens did not differ significantly (Table 3). Pain was the most commonly reported side effect, with all but one woman reporting some degree of pain throughout the process. The mean pain score (range 1–7) reported was 4.4±1.4 with mifepristone–misoprostol and 4.0±1.4 with misoprostol alone (P=.048) with the majority of participants reporting that the pain medication received was adequate (90.7% mifepristone–misoprostol, 89.9% misoprostol alone; P>.99) (data not shown). Other reported side effects included nausea, vomiting, diarrhea, chills, and headache. Women were also asked about severity of their side effects; the only statistically significant differences in severity between the two groups were diarrhea and chills, both milder in the mifepristone plus misoprostol arm (mild diarrhea: 75.9% compared with 53.2%, P=.01; mild chills: 90.5% compared with 60.0%, P=.03; data not shown).
Acceptability was high for both study regimens. More than 90% of women in both the mifepristone–misoprostol and misoprostol-alone groups indicated that they were either “satisfied” or “very satisfied” with their overall experience (97.7% and 93.0%, respectively; not statistically significant) and found the side-effects profile and length of hospital stay to be “acceptable” or “very acceptable” (side effects: 96.1% for both groups; length of stay: 96.9% and 92.3%, respectively; not statistically significant; Table 3). In addition, the vast majority of women (86.8% in the mifepristone-misoprostol and 85.3% in the misoprostol-alone group; not statistically significant) did not find the buccal administration to be at all difficult. Participants reported that the most positive aspects of the process were speed of the procedure (73.6% in the mifepristone–misoprostol and 53.5% in the misoprostol-alone group; P<.01), comfort level (43.4% in the mifepristone–misoprostol and 39.5% in the misoprostol-alone group; not statistically significant), and the attitude of the staff and physician (32.6% in the former and 40.3% in the latter group; not statistically significant). However, speed was reported as a positive feature by significantly more women in the mifepristone–misoprostol group (73.6%) than in the misoprostol-alone group (53.5%) (P<.01). Regardless of regimen, the worst features noted were pain (39.5% in the mifepristone–misoprostol group and 31.0% in the misoprostol-alone group; not statistically significant) and fear (20.9% in the former and 27.1% in the latter group; not statistically significant).
This placebo-controlled randomized trial compared misoprostol with or without mifepristone pretreatment for medical abortion with a live fetus in the second trimester. Unlike many previously published second-trimester studies, feticide was not part of the protocol; the trial enrolled only those women with live fetuses. In addition, the cutoff time for success was considerably stricter than in other protocols. Finally, no other treatments (including laminaria) were permitted. This approach demonstrates the true efficacy of misoprostol, both with and without mifepristone pretreatment, without additional interventions and perhaps offers more accurate estimates of complete evacuation rates for clinicians interested in using medical abortion in limited resource settings where preliminary feticide and/or use of laminaria are either not available or not preferred. These data also offer further evidence of the potential of buccally administered misoprostol for this indication. The buccal route was effective and considered easy to use by participants.
These results confirm that pretreatment with mifepristone leads to a higher completion rate as well as a shorter time-to-abortion interval while maintaining similar side-effect and acceptability profiles. As demonstrated in this study, mifepristone can be successfully taken at home by women. Where available, mifepristone should be included in second-trimester abortion regimens. Indeed, even with mifepristone pretreatment, efficacy rates were notably lower than in other second-trimester studies that used the same drugs.8 Again, we believe that this may be the result of the absence of feticide before the initiation of mifepristone, misoprostol, or both. Although there are insufficient data to support the effect of induced fetal death on outcomes in second-trimester abortion, a small retrospective study as well as anecdotal evidence suggested that feticide may reduce the induction-to-abortion interval.27,28 In addition, our study had a strict limit on time to expulsion, thus limiting the length of time the health care provider could continue to administer the medications to the woman and consider the procedure complete. Future research should explore whether shorter intervals between misoprostol dosages and additional doses would increase the likelihood that both study regimens would result in complete uterine evacuation for women presenting with live fetuses.
This study had several limitations. The cutoff time for outcome assessment (15 hours after the first misoprostol dose) is significantly shorter than cutoff times reported in other studies (24–48 hours).5,6,9,10,21,22 A majority of women with successful fetal expulsion within 15 hours also expelled their placenta within this time. Although our protocol allowed for an additional dose of misoprostol (and additional time of 6 hours) for placental expulsion to avoid additional intervention, there were few women who expelled their placenta more than 30 minutes after fetal expulsion. Indeed, had we instituted a 24-hour outcome assessment, results with both regimens could have conceivably been higher and would have allowed for easier comparison of our outcomes to those previously reported in the literature. Additionally, we elected to classify only participants with both fetal and placental expulsion in the prescribed time as a “success,” eg, complete uterine evacuation, whereas previous reports opted to classify fetal expulsion alone as a final outcome.21,22
It is possible that given its superior efficacy and shorter time-to-abortion interval, regimens with mifepristone pretreatment could be less expensive for future service delivery. Although mifepristone itself is currently more expensive than misoprostol, women given the combined regimen appear to complete their abortion sooner and could benefit from a shorter duration of hospitalization, thus reducing the overall cost for both the woman and the health care system.
This experience also paves the way for simplified service delivery of second-trimester procedures because we have shown that women can self-administer mifepristone at home as pretreatment and then, in lieu of being admitted for a second-trimester procedure, could present at the facility the next morning for care at an in-patient day clinic with a bulk of their care provided by midlevel health care providers. In the U.S. context, midlevel health care providers could conceivably manage the procedure. As we show in this study, 8 of 10 women receiving the mifepristone–misoprostol regimen can expect to complete their abortion in approximately 8 hours, making it a feasible outpatient day procedure.
As regimens continue to be refined, medical abortion could conceivably replace surgical procedures in the second trimester. Medical abortions may foster quality of care by eliminating the need for surgery for many women. In so doing, medical methods would provide a remedy for the practical difficulty of maintaining a cadre of skilled, equipped, and experienced surgical providers in places where such procedures are infrequent.
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© 2011 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.
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