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A randomized controlled trial of different buccal misoprostol doses in mifepristone medical abortion
Contraception 86 (2012) 251 – 256
Original research article
A randomized controlled trial of different buccal misoprostol doses in mifepristone medical abortion☆ Erica Chong a,⁎, Tamar Tsereteli b , Nhu Ngoc thi Nguyen c , Beverly Winikoff a a
Gynuity Health Projects, New York, NY 10010, USA b Gynuity Health Projects, Tbilisi 0108, Georgia c Center for Research and Consultancy in Reproductive Health, Ho Chi Minh City 70000, Vietnam Received 24 May 2011; revised 21 December 2011; accepted 21 December 2011
Abstract Background: An 800-mcg dose of buccal misoprostol following mifepristone has been shown to be highly effective in terminating pregnancies through 63 days since the last menstrual period (LMP) (B. Winikoff, I.G. Dzuba, M.D. Creinin, et al., Two distinct oral routes of misoprostol in mifepristone medical abortion: a randomized controlled trial. Obstet Gynecol 2008; 112: 1303–1310). However, a two 200mcg misoprostol pill option would simplify administration, and potentially reduce costs and increase women's satisfaction. This study compares a 400-mcg dose (Group I) to an 800-mcg dose (Group II) of buccal misoprostol. Study Design: Eligible and consenting women requesting medical termination of early pregnancy (n=1122) were randomized and instructed to take misoprostol 36 to 48 h after taking 200 mg mifepristone. Follow-up visits occurred 12 to 15 days after mifepristone administration. Results: Ninety-six percent of women in both groups had successful abortions. Women in Group I experienced significantly less vomiting and fever/chills than women in Group II. Ninety-six percent of women in both groups found the procedure very satisfactory or satisfactory. Conclusions: Four hundred micrograms of buccal misoprostol is as effective as the standard 800-mcg dose in terminating pregnancies up to 63 days LMP and reduces side effects. © 2012 Elsevier Inc. All rights reserved. Keywords: Medical abortion; Mifepristone; Misoprostol; Buccal
1. Introduction Since the introduction of mifepristone+misoprostol medical abortion, much research has been conducted to improve the regimen to make it more accessible and acceptable to both women and providers. One area of research has focused on finding doses and routes of misoprostol administration that are effective through 63 days since the last menstrual period (LMP). An 800-mcg dose of vaginal misoprostol following mifepristone is highly effective through 63 days LMP and is recommended by the World Health Organization [1]; however, some women express discomfort with this route and prefer in-the-mouth routes of administration [2,3]. Misoprostol taken orally ☆ Funds to carry out this study were provided by an anonymous donor without financial interests in the outcome of this study. ⁎ Corresponding author. Tel.: +1 212 448 1230; fax: +1 212 448 1260. E-mail address: [email protected] (E. Chong).
0010-7824/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.contraception.2011.12.012
(swallowed) after mifepristone offers the easiest administration, but the efficacies of an oral regimen using a 400-mcg dose [4,5] or an 800-mcg dose [5–7] both decline with increasing gestational age to as low as 77% and 85%, respectively, in the ninth week after LMP. Research has also looked at sublingual and buccal administration of misoprostol, in which the pills are held under the tongue or between the cheek and the gum until they dissolve. Initial studies with 800-mcg and 600-mcg doses of sublingual misoprostol after mifepristone found the regimens to be highly efficacious but also resulted in substantial levels of fever, chills, vomiting and diarrhea [8,9]. Subsequent studies suggest that the dose of misoprostol can be reduced to 400 mcg to minimize side effects, but still maintain a high success rate in the later gestational ages [10,11]. Clinical trials have shown an 800-mcg dose of buccal misoprostol after mifepristone to be highly effective through 56 and 63 days LMP [6,12]. A randomized controlled trial comparing 800 mcg oral to 800 mcg buccal misoprostol
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found that, in the ninth week LMP, the buccal regimen had a significantly higher success rate than the oral regimen (94.8% vs. 85.1%) and a significantly lower ongoing pregnancy rate (1.7% vs. 7.9%) [6]. Additionally, Planned Parenthood centers in the United States reported a 98% success rate with the buccal regimen in a 2006 audit in terminating pregnancies up to 59 days LMP [13]. Very little is known about the efficacy of a 400-mcg dose of buccal misoprostol after mifepristone; however, one study has been published that compared 400 mcg buccal misoprostol to 400 mcg sublingual misoprostol after mifepristone [14]. This study found comparable success rates between the two regimens (97.1% and 97.4%, respectively). Efficacy remained high at later gestational ages (100% and 94.6% among pregnancies 50–63 days LMP), although the sample size was small (38 and 37 women 50–63 days LMP). We were interested to see if, like misoprostol administered via the sublingual route, a reduced dose of buccal misoprostol after mifepristone would still be highly effective, yet reduce the side effects women experience. A two 200-mcg misoprostol pill option would simplify administration, substantially reduce the costs associated with the method in some settings and potentially increase women's satisfaction.
2. Materials and methods The study was conducted from May 2007 to September 2009 at three clinics in Tbilisi, the Republic of Georgia [Zhordania Institute of Human Reproduction (ZIHR), Mater-
nity House #2 and Maternity House #4), and at Hoc Mon Hospital, about 10 km outside Ho Chi Minh City, Vietnam. Two sites (ZIHR and Hoc Mon Hospital) had experience providing medical abortion prior to this study, while the other two sites were trained in medical abortion provision at the same time they were trained in the study procedures. Women who presented for termination of pregnancy with gestations up to 63 days since LMP were recruited to participate in the study. Exclusion criteria included concurrent anticoagulant therapy, concurrent long-term corticosteroid therapy, adrenal insufficiency, inherited porphyria, suspicion of ectopic pregnancy, and known allergy to mifepristone or misoprostol. Gestational age was determined by ultrasound in 98% of cases; LMP and clinical examination were also used. Ethical committees at the ZIHR and Hoc Mon Hospital reviewed and approved the study protocol. All women gave their informed consent to participate in the study. Women swallowed one 200-mg pill of mifepristone [in Georgia: Mirpharma or Pentcroft Pharma (Russia); in Vietnam: STADA (Vietnam)] at the clinic and were given the option of taking the misoprostol at the clinic or at home 36 to 48 h after taking mifepristone. After eligibility was confirmed, allocation to the 400-mcg or 800-mcg group was determined based on a random code generated in blocks of 10 by Gynuity Health Projects in New York, whose staff packed the pills and organized them in sequential, sealed envelopes. Randomization was stratified by study site. This study was double-blinded; women in the 400-mcg group received two 200-mcg misoprostol (U-miso; U-Liang Ltd, Taiwan) pills and two placebo pills, and women in the 800-mcg group received four 200-mcg misoprostol pills. The group
Enrollment N=1122
Randomization
Women allocated to 400 mcg buccal group (n=559) - Received allocated intervention (n=558) - Did not receive allocated intervention (n=1); woman did not follow protocol and never took misoprostol
In-clinic follow-up (n=553) Phone follow-up (n=2) Lost to follow-up (n=3); women did not return to clinic for follow-up and could not be contacted by phone
Analyzed for efficacy (n=555) - Excluded from analysis (n=0) Analyzed for side effects (diary) (n=526) Analyzed for acceptability (exit interview) (n=551)
Allocation
Women allocated to 800 mcg buccal group (n=563) - Received allocated intervention (n=563) - Did not receive allocated intervention (n=0).
Follow-Up
Analysis
Fig. 1. Treatment flowchart.
In-clinic follow-up (n=559) Phone follow-up (n=1) Lost to follow-up (n=3); women did not return to clinic for follow-up and could not be contacted by phone
Analyzed for efficacy (n=560) - Excluded from analysis (n=0) Analyzed for side effects (diary) (n=540) Analyzed for acceptability (exit interview) (n=555)
E. Chong et al. / Contraception 86 (2012) 251–256
253
Table 1 Participant characteristics
Age, years (mean, range) Highest educational level completed, % Primary High school University Currently married, % Gravidity, mean Parity, mean Previous abortion, % Gestational age, days (mean)
400 mcg
800 mcg
Georgia
Vietnam
27.4 (17–44)
27.9 (15–45)
27.9 (15–45)
26.4 (18–45)⁎⁎
13.5 29.4 57.1 81.2 3.9 1.2 58.3 48.0
13.3 28.6 58.0 81.7 4.2 1.2 61.8 48.2
0.9 27.6 71.5 78.6 4.5 1.2 65.9 46.6
63.2⁎⁎ 34.5 2.2 92.9⁎⁎ 2.5⁎⁎ 1.1⁎ 36.6⁎⁎ 54.3⁎⁎
All differences between 400-mcg and 800-mcg groups are not significant. For Georgia vs. Vietnam: ⁎ p≤.05. ⁎⁎ p≤.001.
assignments were maintained at the Gynuity office in New York and were not disclosed to the participants or the providers. For those women who elected to take misoprostol at the clinic, providers stapled assigned envelopes to the women's study forms at the initial visit, and those pills were taken at the next (misoprostol) visit. Women were instructed to place the pills between the cheek and gums and to hold them there for 30 min, after which they should swallow any remaining fragments. In Georgia, women were given a prescription for paracetamol (500 mg) and advised to take it as needed; in Vietnam, all women were given four tablets of paracetamol (500 mg) and similarly advised. Women were asked to fill out patient diaries documenting the level of bleeding and any side effects that occurred in the 14 days following mifepristone administration. If women forgot to bring the diary with them to the follow-up visit, they were asked to complete at new diary at that time. Follow-up visits were scheduled 12 to 15 days after the initial visit to determine abortion status. If the abortion was determined to be complete, women underwent an exit interview and were discharged from the study. Women with ongoing, viable pregnancies were offered a surgical completion. Women with incomplete abortions were offered the option of a surgical completion or waiting another week, with or without an additional dose of 800 mcg buccal misoprostol. If the abortion was still incomplete after the additional week, a surgical completion was recommended. Women could request a surgical completion at any time during the study.
The study had two primary objectives: (1) to compare the efficacy of the two regimens, especially among women with gestations N49 days LMP, and (2) to compare the incidence of side effects of each regimen. We assumed that the 800-mcg buccal misoprostol regimen would be 95% effective, and therefore, 334 women per group were needed to detect a 5% lower efficacy with 400 mcg misoprostol (α=0.05, 1−β=0.8, with a one-tailed test). An additional 10% was added to account for loss to follow-up, for a total sample size of 735. Initially, study enrollment occurred only at the three sites in the Republic of Georgia. An interim analysis of 383 women enrolled found too few women with gestational age N50 days LMP were being enrolled to permit comparison of efficacy at higher gestational ages once enrollment was complete. Based on the interim analysis, we assumed that efficacy in the 800-mcg group would be 93% for gestational ages 50–63 days LMP, requiring a sample of 303 women in each study arm to detect a 6% lower efficacy with 400 mcg (α=0.05, 1−β=0.8). Adding 5% to account for loss to follow-up, we sought a final sample of 640 women in this gestational age range. In Vietnam, enrollment was limited to women presenting at 50–63 days LMP. We stopped the study when 1115 women had been enrolled and followed up, including 570 women in the 50–63-day gestational age group, when efficacy in both groups substantially exceeded that hypothesized based on interim review.
Table 2 Treatment outcomes by study group and gestational age
Failure (total) Ongoing pregnancy 42 days or less 43–49 days 50–56 days 57–63 days Incomplete abortion Excessive/prolonged bleeding Provider/patient request
Success (total) 42 days or less 43–49 days 50–56 days 57–63 days
400 mcg
800 mcg
RR (95% CI)
96.4 (535/555) 98.8 (164/166) 97.2 (106/109) 94.3⁎ (182/193) 95.4 (83/87)
96.4 (540/560) 95.8 (159/166) 96.2 (100/104) 98.5⁎ (201/204) 93.0 (80/86)
1.00 (.98–1.02) 1.03 (.99–1.07) 1.01 (.96–1.06) .96 (.92–.99) 1.03 (.95–1.10)
⁎ pb.05, comparing 400-mcg and 800-mcg groups.
Table 3 Reasons for failure by study group and gestational age 400 mcg
800 mcg
RR (95% CI)
3.6 1.4 0.6 0.0 2.6 2.3 0.9 0.4 0.9
3.6 0.9 (5/560) 1.2 (2/166) 0.0 (0/104) 0.5 (1/204) 2.3 (2/86) 1.1 (6/560) 1.1 (6/560) 0.5 (3/560)
1.61 (.53–4.9) 0.5 (.05–5.46) – 5.28 (.62–44.8) .99 (.14–6.86) .84 (.26–2.74) .34 (.07–1.66) 1.68 (0.4–7.0)
(8/555) (1/166) (0/109) (5/193) (2/87) (5/555) (2/555) (5/555)
All differences between 400-mcg and 800-mcg groups are not significant.
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Table 4 Probability of failure, unadjusted and adjusted analyses Unadjusted
Treatment group Country Age Gestational age b 43–49 days 50–56 days 57–63 days Highest education completed c High school University Married Parity # of previous abortions a b c
Adjusted, full model
Adjusted, backward stepwise Wald model a
OR (95% CI)
p
OR (95% CI)
p
OR (95% CI)
p
1.01 (.54–1.90)
.98
1.04 (.55–1.96) .86 (.22–3.34) 1.01 (.95–1.08)
.92 .82 .74
1.03 (.55–1.94)
.94
1.30 (.47–3.55) 1.74 (.71–4.28) 2.91 (1.12–7.58)
.62 .23 .03
1.97 (.41–9.55) 3.10 (.54–17.81) .91 (.36–2.28) .99 (.65–1.51) 1.05 (.96–1.15)
.40 .20 .84 .96 .25
1.07 (.99–1.15)
.10
Treatment group was force entered into the model as the initial term; all other variables were entered with PIN=0.05, POUT=0.10. Compared with ≤42 days. Compared with primary school.
Data were entered in Georgia and Vietnam, merged in New York and analyzed using SPSS 14.0 (SPSS Inc., Chicago, IL, USA) and EpiInfo™ Version 3.4.3 (Centers for Disease Control, Atlanta, GA, USA). The χ 2 with Fisher's Exact Test was used as appropriate for independent nominal data, and independent t tests were used for continuous variables. Statistical significance was defined as a p value of b.05. Hierarchical logistic regression analyses were conducted to adjust for possible confounders and the effects of including women solely with later gestation abortions in Vietnam, with forced entry of the term for treatment group and using both forced entry and, separately, the backwards stepwise Wald method with probability of score statistic for variable entry (PIN)=0.05 and probability of the Wald statistic to remove a variable (POUT)=0.10 for all covariates (age, gestational age, country, completion of high school, completion of university, marital status, parity, and number of previous abortions). Success was defined as a complete abortion using mifepristone and misoprostol without any surgical intervention. In the few cases where the woman did not return for follow-up, telephone follow-up was deemed
acceptable to determine the abortion outcome. Per-protocol analysis was used since there was only one woman who did not follow the protocol (she took mifepristone but not misoprostol). The analyses excluded six women who were lost to follow-up and one woman who did not take misoprostol (Fig. 1). Data on adverse effects were stratified by country to illustrate cultural differences in experiencing and reporting of these symptoms.
3. Results One thousand one hundred twenty-two women were enrolled in the study, of which 559 were randomized to the 400-mcg buccal group of misoprostol and 563 to the 800mcg buccal group. Three women did not return to the clinic for follow-up but confirmed by phone that they received surgery elsewhere (Fig. 1). There were no statistically significant differences between the two study arms with respect to mean age, education, marital status, gravidity and parity, abortion history and gestational age (Table 1). In general, participants in this suburban area of Vietnam
Table 5 Adverse effects (% reporting ever experiencing) Adverse effect
Total 400 mcg
800 mcg
RR (95% CI)
400 mcg
Georgia 800 mcg
RR (95% CI)
400 mcg
800 mcg
RR (95% CI)
Nausea Vomiting Pain/cramps Fever/chills Headache Dizziness Weakness
44 16⁎⁎ 77 26⁎⁎ 32 26 38
47 22⁎⁎ 81 33⁎⁎ 33 24 42
.93 (.81–1.06) .72 (.56–.92) .96 (.9–1.02) .78 (.65–.94) .97 (.82–1.16) 1.08 (.88–1.33) .88 (.76–1.02)
42 16⁎ 81 31⁎⁎ 32 24 44
48 22⁎ 83 41⁎⁎ 33 25 48
.88 (.75–1.02) .72 (.54–.95) .96 (.91–1.03) .75 (.63–.91) .97 (.8–1.18) .98 (.78–1.25) .92 (.8–1.07)
49 15 64 9 32 33⁎ 13
42 21 70 5 32 22⁎ 21
1.16 (.87–1.55) .71 (.41–1.26) .92 (.76–1.11) 1.68 (.63–4.47) .98 (.67–1.44) 1.49 (.97–2.31) .59 (.32–1.08)
⁎ pb.05, comparing 400-mcg and 800-mcg groups. ⁎⁎ pb.01, comparing 400-mcg and 800-mcg groups.
Vietnam
E. Chong et al. / Contraception 86 (2012) 251–256
tended to be less educated, less likely to have had a previous abortion and more likely to be married than women in Georgia. Ninety-five percent of Georgian participants decided to take the misoprostol at home, whereas only two women in Vietnam availed themselves of this option. Ultrasound use at the follow-up visit varied widely by site, ranging from 37% at Maternity House #4 to 90% at Hoc Mon Hospital. Eightyfour women had incomplete abortions at follow-up, and 83 decided to wait an additional week (47 taking an additional dose of misoprostol/oxytocin and 36 opting for expectant management). Ninety-two percent of women who took additional misoprostol and 78% of women using expectant management had complete abortions at the extended followup visit [relative risk (RR)=1.18, 95% confidence interval (CI) 0.97–1.43]. Overall, the efficacy of the two regimens was identical, with 96.4% of women having a successful abortion in each arm (Table 2). The two regimens maintained a high success rate at the later gestational ages as well, with 95.4% of the 400-mcg group and 93.0% of the 800-mcg group successfully aborting in the ninth week of gestation. The ongoing pregnancy rate was slightly, but not significantly, higher in the 400-mcg study arm than the 800-mcg study arm (1.4% vs. 0.9%, RR 1.61, 95% CI .53–4.9) (Table 3). However, the ongoing pregnancy rate was the same in both arms in the ninth week of gestation (2.3%). No significant differences were seen in the rates of incomplete abortion, heavy or prolonged bleeding, or provider preference/patient request. Adjustment for covariates including country did not influence the difference in rates of success [fully adjusted model odds ratio (OR)=1.03, 95% CI 0.55–1.94; unadjusted model OR=1.01, 95% CI 0.54–1.90] (Table 4). Since side effects are experienced and reported differently in different cultures, Georgia and Vietnam data are reported separately as well as in aggregate (Table 5). In general, Georgian women tended to report side effects at a higher rate than Vietnamese women. In Georgia, women in the 800-mcg group were significantly more likely than women in the 400-
255
mcg group to report experiencing nausea (48% vs. 42%, RR=.88, 95% CI 0.75–1.02), vomiting (22% vs. 16%, RR=.72, 95% CI 0.54–0.95) and fever/chills (41% vs. 31%, RR=.75, 95% CI 0.63–0.91). In Vietnam, the only significant difference in the side effects reported actually occurred in the opposite direction, with 33% of women in the 400-mcg group and 22% of women in the 800-mcg group reporting dizziness (RR=1.49, 95% CI 0.97–2.31). No serious adverse events occurred. Nearly all women reported feeling very satisfied or satisfied with their abortions, regardless of study group allocation (Table 6). Women in the 800-mcg group were slightly less likely than women in the 400-mcg group to say that buccal administration of misoprostol was very acceptable or acceptable (88% vs. 92%, RR=1.05, 95% CI 1.01–1.09). Ninety-six percent of women in both groups would choose to have a medical abortion in the future should the need arise, and 98% would recommend the method to a friend.
4. Discussion This study demonstrates that both 400-mcg and 800mcg doses of buccal misoprostol after 200 mg mifepristone are highly effective at terminating pregnancy through 63 days LMP. Our results on the performance of the 800-mcg buccal regimen are consistent with the only previous study in the literature that looked at buccal misoprostol through 63 days LMP with an interval of at least 24 h between mifepristone and misoprostol [6]. The high success rate of the 400-mcg buccal regimen, even at later gestational ages, corroborates a study conducted in Moldova by Raghavan et al. [14] that found a 97% success rate overall, with no decline in efficacy at gestations 50 to 63 days LMP. Halving the dose of misoprostol resulted in significantly fewer reports of vomiting and fever or chills in the Georgia sites, but not in the Vietnam site. Women in Georgia reported fewer side effects with the 400-mcg misoprostol regimen and found buccal administration of misoprostol to
Table 6 Women's satisfaction with the procedure
Satisfied with procedure Buccal administration acceptable⁎ Side effects acceptable Pain medication adequate Yes a No Did not take pain medication If in need of another abortion, would choose: Surgical Medical No preference Would recommend method to friend Excluded ‘did not take medication’ to compare treatments. ⁎ pb.05, comparing 400-mcg and 800-mcg groups.
a
400 mcg (n=551)
800 mcg (n=555)
RR (95% CI)
95.6 (527) 92.0 (507) 86.0 (474)
96.2 (534) 87.9 (488) 84.7 (470)
.99 (.97–1.02) 1.05 (1.01–1.09) 1.02 (.97–1.07)
72.1 (397) 6.4 (35) 21.6 (119)
76.2 (423) 5.9 (33) 17.8 (99)
.99 (.95–1.03) 1.12 (.71–1.77) 1.21 (.95–1.54)
1.5 (8) 96.2 (530) 2.4 (13) 98.4 (542)
1.4 (8) 96.2 (534) 2.3 (13) 97.8 (543)
1.01 (.38–2.66) 1.00 (.98–1.02) 1.01 (.47–2.15) 1.01 (.99–1.02)
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E. Chong et al. / Contraception 86 (2012) 251–256
be slightly more acceptable than women in the 800-mcg arm, despite the fact that both groups were instructed to hold four pills in their cheeks. This study has very few limitations. As the study was double-blinded, the effects of provider bias should be minimal. Abortion outcomes were confirmed for nearly all participants, as less than 1% of women were lost to followup. However, we are limited in the trend analyses we can conduct on success rates by gestational age due to the uneven distribution of patients in the two countries. Also, because the study was powered to detect differences in efficacy between the two arms at later gestational ages, it was perhaps overpowered to detect differences in other outcomes, such as side effects. Thus, a six-percentage point difference in reporting of nausea in Georgia is statistically significant, but perhaps less important in clinical terms. The findings of our research indicate that a regimen of 400 mcg buccal misoprostol after mifepristone is as safe and effective as a regimen of 800 mcg buccal misoprostol and results in fewer side effects. While 800 mcg vaginal misoprostol and 800 mcg buccal misoprostol remain excellent options for abortion through 63 days LMP, 400 mcg buccal misoprostol is highly efficacious as well. Clinicians interested in a two-pill in-the-mouth misoprostol regimen for ease of administration, decreased cost and increased acceptability may consider this method.
Acknowledgments George Tsertsvadze, M.D.; George Tevdorashvili, M.D.; Nikoloz Manjgaladze, M.D.; Le van Thanh, M.D.; Archil Khomassuridze, M.D., Ph.D.; study site staff. References [1] World Health Organization. Safe abortion: technical and policy guidance for health systems. Geneva: World Health Organization; 2003.
[2] Arvidsson C, Hellborg M, Gemzell-Danielsson K. Preference and acceptability of oral versus vaginal administration of misoprostol in medical abortion with mifepristone. Eur J Obstet Gynecol Reprod Biol 2005;123:87–91. [3] Ho PC, Ngai SW, Liu KL, Wong GCY, Lee SWH. Vaginal misoprostol compared with oral misoprostol in termination of second trimester pregnancy. Obstet Gynecol 1997;90:735–8. [4] Spitz IM, Bardin CW, Benton L, Robbins A. Early pregnancy termination with mifepristone and misoprostol in the United States. N Engl J Med 1998;338:1241–7. [5] Schaff EA, Fielding SL, Westhoff C. Randomized trial of oral versus vaginal misoprostol 2 days after mifepristone 200 mg for abortion up to 63 days of pregnancy. Contraception 2002;66:247–50. [6] Winikoff B, Dzuba IG, Creinin MD, et al. Two distinct oral routes of misoprostol in mifepristone medical abortion: a randomized controlled trial. Obstet Gynecol 2008;112:1303–10. [7] von Hertzen H, Honkanen H, Piaggio G, et al. WHO multinational study of three misoprostol regimens after mifepristone for early medical abortion. I: efficacy. BJOG 2003;110:808–18. [8] Tang OS, Chan CC, Ng EH, Lee SW, Ho PC. A prospective, randomized, placebo-controlled trial on the use of mifepristone with sublingual or vaginal misoprostol for medical abortions of less than 9 weeks gestation. Hum Reprod 2003;18:2315–8. [9] Hamoda H, Ashok PW, Dow J, Flett GM, Templeton A. A pilot study of mifepristone in combination with sublingual or vaginal misoprostol for medical termination of pregnancy up to 63 days gestation. Contraception 2003;68:335–8. [10] Mundle S, Elul B, Anand A, Kalyanwala S, Ughade S. Increasing access to safe abortion services in rural India: experiences with medical abortion in a primary health center. Contraception 2007;76: 66–70. [11] Raghavan S, Comendant R, Digol I, et al. Two-pill regimens of misoprostol after mifepristone medical abortion through 63 days' gestational age: a randomized controlled trial of sublingual and oral misoprostol. Contraception 2009;79:84–90. [12] Middleton T, Schaff E, Fielding SL, et al. Randomized trial of mifepristone and buccal or vaginal misoprostol for abortion through 56 days of last menstrual period. Contraception 2005;72: 328–32. [13] Fjerstad M, Sivin I, Lichtenberg ES, Trussell J, Cleland K, Cullins V. Effectiveness of medical abortion with mifepristone and buccal misoprostol through 59 gestational days. Contraception 2009;80: 282–6. [14] Raghavan S, Comendant R, Digol I, et al. Comparison of 400 mcg buccal and 400 mcg sublingual misoprostol after mifepristone medical abortion through 63 days' LMP: a randomized controlled trial. Contraception 2010;82:513–9.
Original research article
A randomized controlled trial of different buccal misoprostol doses in mifepristone medical abortion☆ Erica Chong a,⁎, Tamar Tsereteli b , Nhu Ngoc thi Nguyen c , Beverly Winikoff a a
Gynuity Health Projects, New York, NY 10010, USA b Gynuity Health Projects, Tbilisi 0108, Georgia c Center for Research and Consultancy in Reproductive Health, Ho Chi Minh City 70000, Vietnam Received 24 May 2011; revised 21 December 2011; accepted 21 December 2011
Abstract Background: An 800-mcg dose of buccal misoprostol following mifepristone has been shown to be highly effective in terminating pregnancies through 63 days since the last menstrual period (LMP) (B. Winikoff, I.G. Dzuba, M.D. Creinin, et al., Two distinct oral routes of misoprostol in mifepristone medical abortion: a randomized controlled trial. Obstet Gynecol 2008; 112: 1303–1310). However, a two 200mcg misoprostol pill option would simplify administration, and potentially reduce costs and increase women's satisfaction. This study compares a 400-mcg dose (Group I) to an 800-mcg dose (Group II) of buccal misoprostol. Study Design: Eligible and consenting women requesting medical termination of early pregnancy (n=1122) were randomized and instructed to take misoprostol 36 to 48 h after taking 200 mg mifepristone. Follow-up visits occurred 12 to 15 days after mifepristone administration. Results: Ninety-six percent of women in both groups had successful abortions. Women in Group I experienced significantly less vomiting and fever/chills than women in Group II. Ninety-six percent of women in both groups found the procedure very satisfactory or satisfactory. Conclusions: Four hundred micrograms of buccal misoprostol is as effective as the standard 800-mcg dose in terminating pregnancies up to 63 days LMP and reduces side effects. © 2012 Elsevier Inc. All rights reserved. Keywords: Medical abortion; Mifepristone; Misoprostol; Buccal
1. Introduction Since the introduction of mifepristone+misoprostol medical abortion, much research has been conducted to improve the regimen to make it more accessible and acceptable to both women and providers. One area of research has focused on finding doses and routes of misoprostol administration that are effective through 63 days since the last menstrual period (LMP). An 800-mcg dose of vaginal misoprostol following mifepristone is highly effective through 63 days LMP and is recommended by the World Health Organization [1]; however, some women express discomfort with this route and prefer in-the-mouth routes of administration [2,3]. Misoprostol taken orally ☆ Funds to carry out this study were provided by an anonymous donor without financial interests in the outcome of this study. ⁎ Corresponding author. Tel.: +1 212 448 1230; fax: +1 212 448 1260. E-mail address: [email protected] (E. Chong).
0010-7824/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.contraception.2011.12.012
(swallowed) after mifepristone offers the easiest administration, but the efficacies of an oral regimen using a 400-mcg dose [4,5] or an 800-mcg dose [5–7] both decline with increasing gestational age to as low as 77% and 85%, respectively, in the ninth week after LMP. Research has also looked at sublingual and buccal administration of misoprostol, in which the pills are held under the tongue or between the cheek and the gum until they dissolve. Initial studies with 800-mcg and 600-mcg doses of sublingual misoprostol after mifepristone found the regimens to be highly efficacious but also resulted in substantial levels of fever, chills, vomiting and diarrhea [8,9]. Subsequent studies suggest that the dose of misoprostol can be reduced to 400 mcg to minimize side effects, but still maintain a high success rate in the later gestational ages [10,11]. Clinical trials have shown an 800-mcg dose of buccal misoprostol after mifepristone to be highly effective through 56 and 63 days LMP [6,12]. A randomized controlled trial comparing 800 mcg oral to 800 mcg buccal misoprostol
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found that, in the ninth week LMP, the buccal regimen had a significantly higher success rate than the oral regimen (94.8% vs. 85.1%) and a significantly lower ongoing pregnancy rate (1.7% vs. 7.9%) [6]. Additionally, Planned Parenthood centers in the United States reported a 98% success rate with the buccal regimen in a 2006 audit in terminating pregnancies up to 59 days LMP [13]. Very little is known about the efficacy of a 400-mcg dose of buccal misoprostol after mifepristone; however, one study has been published that compared 400 mcg buccal misoprostol to 400 mcg sublingual misoprostol after mifepristone [14]. This study found comparable success rates between the two regimens (97.1% and 97.4%, respectively). Efficacy remained high at later gestational ages (100% and 94.6% among pregnancies 50–63 days LMP), although the sample size was small (38 and 37 women 50–63 days LMP). We were interested to see if, like misoprostol administered via the sublingual route, a reduced dose of buccal misoprostol after mifepristone would still be highly effective, yet reduce the side effects women experience. A two 200-mcg misoprostol pill option would simplify administration, substantially reduce the costs associated with the method in some settings and potentially increase women's satisfaction.
2. Materials and methods The study was conducted from May 2007 to September 2009 at three clinics in Tbilisi, the Republic of Georgia [Zhordania Institute of Human Reproduction (ZIHR), Mater-
nity House #2 and Maternity House #4), and at Hoc Mon Hospital, about 10 km outside Ho Chi Minh City, Vietnam. Two sites (ZIHR and Hoc Mon Hospital) had experience providing medical abortion prior to this study, while the other two sites were trained in medical abortion provision at the same time they were trained in the study procedures. Women who presented for termination of pregnancy with gestations up to 63 days since LMP were recruited to participate in the study. Exclusion criteria included concurrent anticoagulant therapy, concurrent long-term corticosteroid therapy, adrenal insufficiency, inherited porphyria, suspicion of ectopic pregnancy, and known allergy to mifepristone or misoprostol. Gestational age was determined by ultrasound in 98% of cases; LMP and clinical examination were also used. Ethical committees at the ZIHR and Hoc Mon Hospital reviewed and approved the study protocol. All women gave their informed consent to participate in the study. Women swallowed one 200-mg pill of mifepristone [in Georgia: Mirpharma or Pentcroft Pharma (Russia); in Vietnam: STADA (Vietnam)] at the clinic and were given the option of taking the misoprostol at the clinic or at home 36 to 48 h after taking mifepristone. After eligibility was confirmed, allocation to the 400-mcg or 800-mcg group was determined based on a random code generated in blocks of 10 by Gynuity Health Projects in New York, whose staff packed the pills and organized them in sequential, sealed envelopes. Randomization was stratified by study site. This study was double-blinded; women in the 400-mcg group received two 200-mcg misoprostol (U-miso; U-Liang Ltd, Taiwan) pills and two placebo pills, and women in the 800-mcg group received four 200-mcg misoprostol pills. The group
Enrollment N=1122
Randomization
Women allocated to 400 mcg buccal group (n=559) - Received allocated intervention (n=558) - Did not receive allocated intervention (n=1); woman did not follow protocol and never took misoprostol
In-clinic follow-up (n=553) Phone follow-up (n=2) Lost to follow-up (n=3); women did not return to clinic for follow-up and could not be contacted by phone
Analyzed for efficacy (n=555) - Excluded from analysis (n=0) Analyzed for side effects (diary) (n=526) Analyzed for acceptability (exit interview) (n=551)
Allocation
Women allocated to 800 mcg buccal group (n=563) - Received allocated intervention (n=563) - Did not receive allocated intervention (n=0).
Follow-Up
Analysis
Fig. 1. Treatment flowchart.
In-clinic follow-up (n=559) Phone follow-up (n=1) Lost to follow-up (n=3); women did not return to clinic for follow-up and could not be contacted by phone
Analyzed for efficacy (n=560) - Excluded from analysis (n=0) Analyzed for side effects (diary) (n=540) Analyzed for acceptability (exit interview) (n=555)
E. Chong et al. / Contraception 86 (2012) 251–256
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Table 1 Participant characteristics
Age, years (mean, range) Highest educational level completed, % Primary High school University Currently married, % Gravidity, mean Parity, mean Previous abortion, % Gestational age, days (mean)
400 mcg
800 mcg
Georgia
Vietnam
27.4 (17–44)
27.9 (15–45)
27.9 (15–45)
26.4 (18–45)⁎⁎
13.5 29.4 57.1 81.2 3.9 1.2 58.3 48.0
13.3 28.6 58.0 81.7 4.2 1.2 61.8 48.2
0.9 27.6 71.5 78.6 4.5 1.2 65.9 46.6
63.2⁎⁎ 34.5 2.2 92.9⁎⁎ 2.5⁎⁎ 1.1⁎ 36.6⁎⁎ 54.3⁎⁎
All differences between 400-mcg and 800-mcg groups are not significant. For Georgia vs. Vietnam: ⁎ p≤.05. ⁎⁎ p≤.001.
assignments were maintained at the Gynuity office in New York and were not disclosed to the participants or the providers. For those women who elected to take misoprostol at the clinic, providers stapled assigned envelopes to the women's study forms at the initial visit, and those pills were taken at the next (misoprostol) visit. Women were instructed to place the pills between the cheek and gums and to hold them there for 30 min, after which they should swallow any remaining fragments. In Georgia, women were given a prescription for paracetamol (500 mg) and advised to take it as needed; in Vietnam, all women were given four tablets of paracetamol (500 mg) and similarly advised. Women were asked to fill out patient diaries documenting the level of bleeding and any side effects that occurred in the 14 days following mifepristone administration. If women forgot to bring the diary with them to the follow-up visit, they were asked to complete at new diary at that time. Follow-up visits were scheduled 12 to 15 days after the initial visit to determine abortion status. If the abortion was determined to be complete, women underwent an exit interview and were discharged from the study. Women with ongoing, viable pregnancies were offered a surgical completion. Women with incomplete abortions were offered the option of a surgical completion or waiting another week, with or without an additional dose of 800 mcg buccal misoprostol. If the abortion was still incomplete after the additional week, a surgical completion was recommended. Women could request a surgical completion at any time during the study.
The study had two primary objectives: (1) to compare the efficacy of the two regimens, especially among women with gestations N49 days LMP, and (2) to compare the incidence of side effects of each regimen. We assumed that the 800-mcg buccal misoprostol regimen would be 95% effective, and therefore, 334 women per group were needed to detect a 5% lower efficacy with 400 mcg misoprostol (α=0.05, 1−β=0.8, with a one-tailed test). An additional 10% was added to account for loss to follow-up, for a total sample size of 735. Initially, study enrollment occurred only at the three sites in the Republic of Georgia. An interim analysis of 383 women enrolled found too few women with gestational age N50 days LMP were being enrolled to permit comparison of efficacy at higher gestational ages once enrollment was complete. Based on the interim analysis, we assumed that efficacy in the 800-mcg group would be 93% for gestational ages 50–63 days LMP, requiring a sample of 303 women in each study arm to detect a 6% lower efficacy with 400 mcg (α=0.05, 1−β=0.8). Adding 5% to account for loss to follow-up, we sought a final sample of 640 women in this gestational age range. In Vietnam, enrollment was limited to women presenting at 50–63 days LMP. We stopped the study when 1115 women had been enrolled and followed up, including 570 women in the 50–63-day gestational age group, when efficacy in both groups substantially exceeded that hypothesized based on interim review.
Table 2 Treatment outcomes by study group and gestational age
Failure (total) Ongoing pregnancy 42 days or less 43–49 days 50–56 days 57–63 days Incomplete abortion Excessive/prolonged bleeding Provider/patient request
Success (total) 42 days or less 43–49 days 50–56 days 57–63 days
400 mcg
800 mcg
RR (95% CI)
96.4 (535/555) 98.8 (164/166) 97.2 (106/109) 94.3⁎ (182/193) 95.4 (83/87)
96.4 (540/560) 95.8 (159/166) 96.2 (100/104) 98.5⁎ (201/204) 93.0 (80/86)
1.00 (.98–1.02) 1.03 (.99–1.07) 1.01 (.96–1.06) .96 (.92–.99) 1.03 (.95–1.10)
⁎ pb.05, comparing 400-mcg and 800-mcg groups.
Table 3 Reasons for failure by study group and gestational age 400 mcg
800 mcg
RR (95% CI)
3.6 1.4 0.6 0.0 2.6 2.3 0.9 0.4 0.9
3.6 0.9 (5/560) 1.2 (2/166) 0.0 (0/104) 0.5 (1/204) 2.3 (2/86) 1.1 (6/560) 1.1 (6/560) 0.5 (3/560)
1.61 (.53–4.9) 0.5 (.05–5.46) – 5.28 (.62–44.8) .99 (.14–6.86) .84 (.26–2.74) .34 (.07–1.66) 1.68 (0.4–7.0)
(8/555) (1/166) (0/109) (5/193) (2/87) (5/555) (2/555) (5/555)
All differences between 400-mcg and 800-mcg groups are not significant.
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Table 4 Probability of failure, unadjusted and adjusted analyses Unadjusted
Treatment group Country Age Gestational age b 43–49 days 50–56 days 57–63 days Highest education completed c High school University Married Parity # of previous abortions a b c
Adjusted, full model
Adjusted, backward stepwise Wald model a
OR (95% CI)
p
OR (95% CI)
p
OR (95% CI)
p
1.01 (.54–1.90)
.98
1.04 (.55–1.96) .86 (.22–3.34) 1.01 (.95–1.08)
.92 .82 .74
1.03 (.55–1.94)
.94
1.30 (.47–3.55) 1.74 (.71–4.28) 2.91 (1.12–7.58)
.62 .23 .03
1.97 (.41–9.55) 3.10 (.54–17.81) .91 (.36–2.28) .99 (.65–1.51) 1.05 (.96–1.15)
.40 .20 .84 .96 .25
1.07 (.99–1.15)
.10
Treatment group was force entered into the model as the initial term; all other variables were entered with PIN=0.05, POUT=0.10. Compared with ≤42 days. Compared with primary school.
Data were entered in Georgia and Vietnam, merged in New York and analyzed using SPSS 14.0 (SPSS Inc., Chicago, IL, USA) and EpiInfo™ Version 3.4.3 (Centers for Disease Control, Atlanta, GA, USA). The χ 2 with Fisher's Exact Test was used as appropriate for independent nominal data, and independent t tests were used for continuous variables. Statistical significance was defined as a p value of b.05. Hierarchical logistic regression analyses were conducted to adjust for possible confounders and the effects of including women solely with later gestation abortions in Vietnam, with forced entry of the term for treatment group and using both forced entry and, separately, the backwards stepwise Wald method with probability of score statistic for variable entry (PIN)=0.05 and probability of the Wald statistic to remove a variable (POUT)=0.10 for all covariates (age, gestational age, country, completion of high school, completion of university, marital status, parity, and number of previous abortions). Success was defined as a complete abortion using mifepristone and misoprostol without any surgical intervention. In the few cases where the woman did not return for follow-up, telephone follow-up was deemed
acceptable to determine the abortion outcome. Per-protocol analysis was used since there was only one woman who did not follow the protocol (she took mifepristone but not misoprostol). The analyses excluded six women who were lost to follow-up and one woman who did not take misoprostol (Fig. 1). Data on adverse effects were stratified by country to illustrate cultural differences in experiencing and reporting of these symptoms.
3. Results One thousand one hundred twenty-two women were enrolled in the study, of which 559 were randomized to the 400-mcg buccal group of misoprostol and 563 to the 800mcg buccal group. Three women did not return to the clinic for follow-up but confirmed by phone that they received surgery elsewhere (Fig. 1). There were no statistically significant differences between the two study arms with respect to mean age, education, marital status, gravidity and parity, abortion history and gestational age (Table 1). In general, participants in this suburban area of Vietnam
Table 5 Adverse effects (% reporting ever experiencing) Adverse effect
Total 400 mcg
800 mcg
RR (95% CI)
400 mcg
Georgia 800 mcg
RR (95% CI)
400 mcg
800 mcg
RR (95% CI)
Nausea Vomiting Pain/cramps Fever/chills Headache Dizziness Weakness
44 16⁎⁎ 77 26⁎⁎ 32 26 38
47 22⁎⁎ 81 33⁎⁎ 33 24 42
.93 (.81–1.06) .72 (.56–.92) .96 (.9–1.02) .78 (.65–.94) .97 (.82–1.16) 1.08 (.88–1.33) .88 (.76–1.02)
42 16⁎ 81 31⁎⁎ 32 24 44
48 22⁎ 83 41⁎⁎ 33 25 48
.88 (.75–1.02) .72 (.54–.95) .96 (.91–1.03) .75 (.63–.91) .97 (.8–1.18) .98 (.78–1.25) .92 (.8–1.07)
49 15 64 9 32 33⁎ 13
42 21 70 5 32 22⁎ 21
1.16 (.87–1.55) .71 (.41–1.26) .92 (.76–1.11) 1.68 (.63–4.47) .98 (.67–1.44) 1.49 (.97–2.31) .59 (.32–1.08)
⁎ pb.05, comparing 400-mcg and 800-mcg groups. ⁎⁎ pb.01, comparing 400-mcg and 800-mcg groups.
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E. Chong et al. / Contraception 86 (2012) 251–256
tended to be less educated, less likely to have had a previous abortion and more likely to be married than women in Georgia. Ninety-five percent of Georgian participants decided to take the misoprostol at home, whereas only two women in Vietnam availed themselves of this option. Ultrasound use at the follow-up visit varied widely by site, ranging from 37% at Maternity House #4 to 90% at Hoc Mon Hospital. Eightyfour women had incomplete abortions at follow-up, and 83 decided to wait an additional week (47 taking an additional dose of misoprostol/oxytocin and 36 opting for expectant management). Ninety-two percent of women who took additional misoprostol and 78% of women using expectant management had complete abortions at the extended followup visit [relative risk (RR)=1.18, 95% confidence interval (CI) 0.97–1.43]. Overall, the efficacy of the two regimens was identical, with 96.4% of women having a successful abortion in each arm (Table 2). The two regimens maintained a high success rate at the later gestational ages as well, with 95.4% of the 400-mcg group and 93.0% of the 800-mcg group successfully aborting in the ninth week of gestation. The ongoing pregnancy rate was slightly, but not significantly, higher in the 400-mcg study arm than the 800-mcg study arm (1.4% vs. 0.9%, RR 1.61, 95% CI .53–4.9) (Table 3). However, the ongoing pregnancy rate was the same in both arms in the ninth week of gestation (2.3%). No significant differences were seen in the rates of incomplete abortion, heavy or prolonged bleeding, or provider preference/patient request. Adjustment for covariates including country did not influence the difference in rates of success [fully adjusted model odds ratio (OR)=1.03, 95% CI 0.55–1.94; unadjusted model OR=1.01, 95% CI 0.54–1.90] (Table 4). Since side effects are experienced and reported differently in different cultures, Georgia and Vietnam data are reported separately as well as in aggregate (Table 5). In general, Georgian women tended to report side effects at a higher rate than Vietnamese women. In Georgia, women in the 800-mcg group were significantly more likely than women in the 400-
255
mcg group to report experiencing nausea (48% vs. 42%, RR=.88, 95% CI 0.75–1.02), vomiting (22% vs. 16%, RR=.72, 95% CI 0.54–0.95) and fever/chills (41% vs. 31%, RR=.75, 95% CI 0.63–0.91). In Vietnam, the only significant difference in the side effects reported actually occurred in the opposite direction, with 33% of women in the 400-mcg group and 22% of women in the 800-mcg group reporting dizziness (RR=1.49, 95% CI 0.97–2.31). No serious adverse events occurred. Nearly all women reported feeling very satisfied or satisfied with their abortions, regardless of study group allocation (Table 6). Women in the 800-mcg group were slightly less likely than women in the 400-mcg group to say that buccal administration of misoprostol was very acceptable or acceptable (88% vs. 92%, RR=1.05, 95% CI 1.01–1.09). Ninety-six percent of women in both groups would choose to have a medical abortion in the future should the need arise, and 98% would recommend the method to a friend.
4. Discussion This study demonstrates that both 400-mcg and 800mcg doses of buccal misoprostol after 200 mg mifepristone are highly effective at terminating pregnancy through 63 days LMP. Our results on the performance of the 800-mcg buccal regimen are consistent with the only previous study in the literature that looked at buccal misoprostol through 63 days LMP with an interval of at least 24 h between mifepristone and misoprostol [6]. The high success rate of the 400-mcg buccal regimen, even at later gestational ages, corroborates a study conducted in Moldova by Raghavan et al. [14] that found a 97% success rate overall, with no decline in efficacy at gestations 50 to 63 days LMP. Halving the dose of misoprostol resulted in significantly fewer reports of vomiting and fever or chills in the Georgia sites, but not in the Vietnam site. Women in Georgia reported fewer side effects with the 400-mcg misoprostol regimen and found buccal administration of misoprostol to
Table 6 Women's satisfaction with the procedure
Satisfied with procedure Buccal administration acceptable⁎ Side effects acceptable Pain medication adequate Yes a No Did not take pain medication If in need of another abortion, would choose: Surgical Medical No preference Would recommend method to friend Excluded ‘did not take medication’ to compare treatments. ⁎ pb.05, comparing 400-mcg and 800-mcg groups.
a
400 mcg (n=551)
800 mcg (n=555)
RR (95% CI)
95.6 (527) 92.0 (507) 86.0 (474)
96.2 (534) 87.9 (488) 84.7 (470)
.99 (.97–1.02) 1.05 (1.01–1.09) 1.02 (.97–1.07)
72.1 (397) 6.4 (35) 21.6 (119)
76.2 (423) 5.9 (33) 17.8 (99)
.99 (.95–1.03) 1.12 (.71–1.77) 1.21 (.95–1.54)
1.5 (8) 96.2 (530) 2.4 (13) 98.4 (542)
1.4 (8) 96.2 (534) 2.3 (13) 97.8 (543)
1.01 (.38–2.66) 1.00 (.98–1.02) 1.01 (.47–2.15) 1.01 (.99–1.02)
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be slightly more acceptable than women in the 800-mcg arm, despite the fact that both groups were instructed to hold four pills in their cheeks. This study has very few limitations. As the study was double-blinded, the effects of provider bias should be minimal. Abortion outcomes were confirmed for nearly all participants, as less than 1% of women were lost to followup. However, we are limited in the trend analyses we can conduct on success rates by gestational age due to the uneven distribution of patients in the two countries. Also, because the study was powered to detect differences in efficacy between the two arms at later gestational ages, it was perhaps overpowered to detect differences in other outcomes, such as side effects. Thus, a six-percentage point difference in reporting of nausea in Georgia is statistically significant, but perhaps less important in clinical terms. The findings of our research indicate that a regimen of 400 mcg buccal misoprostol after mifepristone is as safe and effective as a regimen of 800 mcg buccal misoprostol and results in fewer side effects. While 800 mcg vaginal misoprostol and 800 mcg buccal misoprostol remain excellent options for abortion through 63 days LMP, 400 mcg buccal misoprostol is highly efficacious as well. Clinicians interested in a two-pill in-the-mouth misoprostol regimen for ease of administration, decreased cost and increased acceptability may consider this method.
Acknowledgments George Tsertsvadze, M.D.; George Tevdorashvili, M.D.; Nikoloz Manjgaladze, M.D.; Le van Thanh, M.D.; Archil Khomassuridze, M.D., Ph.D.; study site staff. References [1] World Health Organization. Safe abortion: technical and policy guidance for health systems. Geneva: World Health Organization; 2003.
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