International Journal of Gynecology and Obstetrics 118 (2012) 166–171 Contents lists available at SciVerse ScienceDirect International Journal of Gynecology and Obstetrics journal homepage: www.elsevier.com/locate/ijgo CLINICAL ARTICLE Comparison of misoprostol-only and combined mifepristone–misoprostol regimens for home-based early medical abortion in Tunisia and Vietnam Jennifer Blum a,⁎, Sheila Raghavan a, Rasha Dabash a, Nguyen thi Nhu Ngoc b, Héla Chelli c, Selma Hajri d, Kathryn Conkling a, Beverly Winikoff a a Gynuity Health Projects, New York, USA Center for Research and Consultancy in Reproductive Health, Ho Chi Minh City, Vietnam Maternity and Neonatology Center Rabta El Jaberi, Tunis, Tunisia d Medical Consultant, Tunis, Tunisia b c a r t i c l e i n f o Article history: Received 31 October 2011 Received in revised form 20 March 2012 Accepted 10 May 2012 Keywords: Medical abortion Mifepristone Misoprostol a b s t r a c t Objective: To assess the potential advantages of combined mifepristone–misoprostol versus misoprostol-only for early medical abortion Methods: A double-blind randomized placebo controlled study was conducted that enrolled 441 pregnant women (b 63 days since last menstrual period) at hospitals in Tunisia and Vietnam The mifepristone–misoprostol group (n = 220) received 200 mg of mifepristone on day and 800 μg buccal misoprostol followed by placebo hours later on day The misoprostol-only group (n = 221) received placebo on day and 1600 μg of misoprostol (2 doses of 800 μg, given hours apart) on day All medications were self-administered at home with follow-up week later The primary outcome was complete uterine evacuation without surgical intervention Results: Successful uterine evacuation occurred for 78.0% (n = 170) of women with misoprostol only versus 92.9% (n = 195) of women with mifepristone–misoprostol (relative risk 0.84, 95% CI, 0.78–0.91; P b 0.001) Ongoing pregnancy occurred for 13.8% (n = 30) of women given misoprostol-only and 1.4% (n = 3) of women given mifepristone–misoprostol (relative risk 9.63, 95% CI 2.98–31.09; P b 0.001) Conclusion: Mifepristone plus misoprostol is significantly more effective than misoprostol-only for early medical abortion Clinical trials.gov registration number: NCT00680394 © 2012 International Federation of Gynecology and Obstetrics Published by Elsevier Ireland Ltd All rights reserved Introduction Medical abortion provides an alternative to surgical evacuation for women seeking non-invasive pregnancy termination Medical methods have the potential to reduce system costs, help meet demand for abortion services, and increase access to care in settings where skilled providers and supplies are limited Mifepristone followed by misoprostol is considered the gold standard regimen for medical abortion [1] However, mifepristone can be expensive and is not as widely available as misoprostol, which has led to widespread use of misoprostol-only regimens With the emergence of more affordable mifepristone and misoprostol products, the introduction of the combined regimen in new settings is increasingly feasible [2,3] One study hypothesized that the actual cost differential between misoprostol-only and mifepristone–misoprostol regimens is small [4] Thus, it is important to better understand the ⁎ Corresponding author at: Gynuity Health Projects, 15 E 26th Street, Suite 801, New York, NY 10012, USA Tel.: + 212 448 1230 E-mail address: jblum@gynuity.org (J Blum) advantage of adding mifepristone to misoprostol-only regimens in terms of efficacy, cost, and type of service delivery In resourcelimited settings, policymakers and healthcare providers often struggle to decide whether adding mifepristone to misoprostol-only regimens is likely to be more beneficial than simply expanding access to misoprostol-only services In Tunisia, for instance, the mifepristonemisoprostol regimen is limited to the public sector The safety and efficacy of mifepristone–misoprostol for medical abortion is well established [5–7] A frequently used regimen is 200 mg of mifepristone followed 1–2 days later by 800 μg of buccal misoprostol [5] Research has documented an efficacy of 64%–92% with misoprostol-only regimens [8–12]; these studies have examined a number of factors, including the dose, route and intervals of misoprostol administration A previous trial compared 200-mg mifepristone followed by 800-μg buccal misoprostol day later or doses of 800-μg buccal misoprostolonly 24 hours apart among women with gestations up to 63 days since last menstrual period in Vietnam and found that mifepristone– misoprostol was associated with a significantly higher success rate (96.5% vs 76.2% for misoprostol-only) The study also revealed 10-fold greater (16.6% vs 1.5%) likelihood of ongoing pregnancy in the misoprostol-only group [12] 0020-7292/$ – see front matter © 2012 International Federation of Gynecology and Obstetrics Published by Elsevier Ireland Ltd All rights reserved doi:10.1016/j.ijgo.2012.03.039 J Blum et al / International Journal of Gynecology and Obstetrics 118 (2012) 166–171 The aim of the present study was to compare mifepristone plus buccal misoprostol with repeat doses of buccal misoprostol alone at hour intervals to determine whether this short dosing interval improved the success of treatment with misoprostol alone, thereby bringing it in line with the gold standard combined mifepristone– misoprostol regimens Materials and methods A double-blind randomized placebo-controlled trial was conducted From May 5, 2009, to July 20, 2010, pregnant women presenting for early medical abortion up to 63 days since their last menstrual period were recruited at two large maternity hospitals: either the Centre de Maternite et Neonatologie de la Rabta in Tunisia (n = 193) or Hung Vuong Hospital, Ho Chi Minh City, Vietnam (n = 248) Participants had to live or work within a reasonable distance from the study hospital, have an intrauterine pregnancy, no known contraindications to mifepristone and/or misoprostol, and present in general good health In addition, all participants had to be willing to provide informed consent and return for follow-up at the hospital Women with known allergy to misoprostol, those with gestations more than 63 days since last menstrual period, and those who did not give consent were excluded from the trial Treatment allocation was assigned in blocks of 10 using a computer-generated random sequence created by staff at Gynuity Health Projects (New York, USA) All medication packets were prepared by Gynuity Health Projects staff; providers and participants were blinded to study treatment Ethics approvals were obtained from the relevant Institutional Review Boards at the Centre de Maternite et Neonatologie de la Rabta in Tunisia and at Hung Vuong Hospital, Ho Chi Minh City, Vietnam Participant flow, randomization, and treatment assignment are presented in Fig Eligible participants were randomly allocated to of the treatment groups Women in the combined mifepristone– misoprostol group (n = 220) received 200 mg of mifepristone on day and 800 μg of buccal misoprostol followed by placebo hours later on day Women in the mifepristone-only group (n = 221) received placebo on day and 1600 μg of buccal misoprostol, administered as doses of 800 μg given hours apart, on day On study day 1, all participants received an envelope containing packets of pills and were instructed to swallow the tablet in study packet (either 200 mg of mifepristone or matching placebo) Participants were instructed to administer the tablets contained in study packet (800 μg of misoprostol as × 200-μg tablets) after 24 hours and to repeat hours later with the tablets contained in study packet (either placebo or 800 μg of misoprostol) Women were instructed to administer the pills contained in study packets and buccally (between the cheek and gum) for approximately 20 minutes and to swallow the remainder of the tablets afterwards They were told to take all of the medications even if they believed that the abortion was already complete Women were provided tablets of paracetamol (500 mg, with or without codeine) to manage any pain In addition, they were asked to record use of pain medication and the occurrence of any adverse effects in a diary card After this counseling, all participants were scheduled for a follow-up appointment week ± days later at the study hospital Women were instructed that they could return to the hospital or contact their healthcare providers at any time for any reason ENROLLED AND RANDOMIZED (n=441) MIFEPRISTONE–MISOPROSTOL (n=220) ALLOCATED (n=220) Received intervention (n=217) Did not receive intervention or changed mind about taking drugs (n=3) 167 MISOPROSTOL-ONLY (n=221) ALLOCATION ALLOCATED (n=221) Received intervention (n=218) Did not receive intervention or changed mind about taking drugs (n=3) One week in person or phone follow-up made (n=212) Did not have week in person or phone follow-up (n=5) Lost to follow-up after week in person or phone follow-up visit (n=2) Lost to follow-up after unscheduled visit (n=0) FOLLOW-UP One week in person or phone follow-up made (n=218) Did not have week in person or phone follow-up (n=0) Lost to follow-up after week in person or phone follow-up visit (n=0) Lost to follow-up after unscheduled visit (n=0) ANALYZED FOR PRIMARY OUTCOME (n=210) All available data included in the analysis ANALYSIS ANALYZED FOR PRIMARY OUTCOME (n=218) All available data included in the analysis Fig Participant flow, randomization, and treatment assignment 168 J Blum et al / International Journal of Gynecology and Obstetrics 118 (2012) 166–171 At the follow-up appointment, the study protocol stipulated that each woman's abortion status would be assessed by clinical examination and/or transvaginal ultrasonography as the provider deemed necessary If an ongoing pregnancy was diagnosed, immediate surgical evacuation was offered (manual vacuum aspiration in Vietnam and electric vacuum aspiration in Tunisia) Women with a persistent non-viable pregnancy or gestational sac were given the choice of either administering an additional 800 μg of misoprostol buccally and waiting another week to see if the products would evacuate spontaneously or immediate surgical completion All women presenting with retained products of conception at the second follow-up visit underwent a vacuum aspiration After the abortion was completed, participants were interviewed about their experience and satisfaction with the procedure The primary outcome measure was complete uterine evacuation without surgical evacuation for any reason The study design assumed that mifepristone plus buccal misoprostol would be 95% effective and it was hypothesized that doses of buccal misoprostol administered hours apart would be approximately 88% effective A 7% difference in efficacy between the treatment regimens was considered to be clinically meaningful; as a consequence, enrollment of 376 participants was sought to provide for a α value of 0.05, a one-sided test and 80% power The estimated efficacy of misoprostol-only was based on results shown with other routes of administration at 3hour time intervals (approximately 83%) [10] To allow for a lost-tofollow-up rate of approximately 15%, the intention was to enroll 432 women (216 per treatment arm) Ultimately, 441 women were enrolled as recruitment was ongoing in countries concurrently Data entry and analysis were performed using SPSS version 15.0 (IBM, Armonk, NY, USA) Study data were entered separately in each of the countries and clean datasets merged for analysis by the investigators in New York The treatment regimens were compared using t tests or the Mann–Whitney U test for continuous variables and χ or Fisher exact tests for categoric variables The main study outcomes were compared using relative risk (RR), 95% confidence interval (CI), and P value A P value below 0.05 was considered statistically significant Results The participants' baseline characteristics are presented in Table 1; there were no significant differences detected between the groups In all, 441 women were randomly allocated to treatment with either misoprostol-only (n = 221) or combined mifepristone–misoprostol Table Baseline characteristics of the study participants (n = 441)a Age, y Level of education None Primary Secondary University or higher Married Gravidity Primigravida Number of previous surgical abortions ≥1 Number of previous medical abortions ≥1 a b Misoprostol-only (n = 221) Mifepristone–misoprostol (n = 220) 29 ± 6.5 (15–45) 29 ± 6.2 (18–46) (3.2) 36 (16.3) 128 (57.9) 50 (22.6) 170 (76.9) 2.74 ± 1.6 (1–9) 60/218 (27.5) (0.9) 34 (15.4) 139 (63.2) 45 (20.5) 178 (80.9) 2.98 ± 1.6 (1–9) 46/217 (21.2) 173 (78.3) 48 (21.7) 168 (76.4) 52 (23.6) 186 (84.2) 35 (15.8) 180 (82.6) b 38 (17.4) b Values are given as mean ± SD (range) or number (percentage) Data missing for participants (n = 220) The findings of the present study are reported according to the Consolidated Standards of Reporting Trials (CONSORT) guidelines [13] Of the 441 participants, from each group withdrew from the study before administering any study medication and were last seen at their initial visit (Fig 1) No women in the misoprostol group were lost to follow-up; however, treatment outcomes were unknown for women in the mifepristone–misoprostol group The data analysis is presented for 428 women with known final outcomes The outcome measures are presented in Table A significantly higher proportion of women in the mifepristone–misoprostol group (n = 195; 92.9%) experienced complete abortion without surgical evacuation compared with the misoprostol-only group (n = 170; 78.0%) The RR was 0.84 (95% CI, 0.78–0.91; P b 0.001) Women receiving misoprostol-only were significantly more likely to experience ongoing pregnancy compared with women treated with mifepristone– misoprostol (13.8% [n = 30] versus 1.4% [n = 3]) The RR was 9.63 (95% CI 2.98–31.09; P b 0.001) The proportion of women with ongoing pregnancy in each gestational age group was also significantly higher with misoprostol-only Multivariable logistic regression controlling for gestational age revealed that there was a greater likelihood of ongoing pregnancy in Vietnam than in Tunisia (odds ratio 2.482; P = 0.042) among women randomized to misoprostol-only Reasons for surgical intervention were also similar in the groups No serious adverse events were reported (Table 3) The majority of women in each treatment group indicated that they experienced diarrhea; however, diarrhea was reported more frequently in the misoprostol-only group (P b 0.001) No other significant differences were detected in the adverse effect profiles The participants' experiences of bleeding and pain were not significantly different between the groups, although bleeding was commonly reported to be “less than expected” in misoprostol-only group The RR was 1.41 (95% CI, 1.09–1.83; P = 0.008) The majority of women reported that the adverse effects experienced were “acceptable” or “very acceptable.” Reports that the time required for the procedure was “less than expected” was significantly more frequent among the women who received mifepristone–misoprostol (Table 4) The RR was 0.76 (95% CI, 0.61–0.95; P = 0.015) Overall, participants' characterization of the procedure was not different between the groups, and 66.3% (n= 283) characterized the procedure as “not difficult.” Generally, women reported that they were “satisfied” or “very satisfied” with their medical abortion experience Significantly more women reported being “very satisfied” in the mifepristone–misoprostol group than in the misoprostol-only group The RR was 0.75 (95% CI, 0.59–0.96; P = 0.020) Satisfaction rates were similar among women with successful uterine evacuations regardless of the medical abortion regimen they received A characterization of “satisfied or very satisfied” was reported by 94.7% (161/170) in the misoprostol-only group and by 96.4% (187/ 194) in the mifepristone–misoprostol group The RR was 0.98 (95% CI, 0.94–1.03; P = 0.613) Although most women said they would opt for medical abortion over surgery if required in the future, significantly more women in the mifepristone–misoprostol group indicated this preference Discussion Medical abortion using mifepristone–misoprostol or misoprostolonly has an important role in safe abortion care for women globally In some settings, women have access to both mifepristone and misoprostol, and the results of this study corroborate previous conclusions that, where available, mifepristone regimens should be offered In other settings, due to legal restrictions on abortion and wide availability of misoprostol, the use of misoprostol-only will continue to be the only medical abortion method available for the foreseeable future J Blum et al / International Journal of Gynecology and Obstetrics 118 (2012) 166–171 169 Table Outcomes following medical abortion.a Outcome Misoprostol-only (n = 221) Mifepristone–misoprostol (n = 220) Relative risk (95% confidence interval) P value Lost to follow-up Withdrew from study Complete abortion without surgical evacuation b Reasons for surgical intervention b Ongoing pregnancy Non-viable pregnancy or gestational sac Incomplete abortion Woman's request Medically indicated for hemorrhage Complete abortion without surgical evacuation, by gestational age group ≤49 days LMP 50–56 days LMP 57–63 days LMP Ongoing pregnancy, by gestational age group ≤49 days LMP 50–56 days LMP 57–63 days LMP Non-viable pregnancy or gestational sac, by gestational age group ≤49 days LMP 50–56 days LMP 57–63 days LMP Incomplete abortion, by gestational age group ≤49 days LMP 50–56 days LMP 57–63 days LMP 00 (0.0) (1.4) 170/218 (78.0) 48/218 (22.0) 30/218 (13.8) 9/218 (4.1) 6/218 (2.8) 3/218 (1.4) 0/218 (0.0) (3.2) (1.4) 195/210 (92.9) 15/210 (7.1) 3/210 (1.4) 0/210 (0.0) 7/210 (3.3) 3/210 (1.4) 2/210 (1.0) 0.84 (0.78–0.91) b0.001 9.63 (2.98–31.09) b0.001 95/121 (78.5) 53/70 (75.7) 22/27 (81.5) 105/109 (96.3) 64/74 (86.5) 26/27 (96.3) 0.82 (0.74–0.90) 0.88 (0.75–1.03) 0.85 (0.70–1.03) b0.001 0.098 0.083 16/121 (13.2) 11/70 (15.7) 3/27 (11.1) 1/109 (0.9) 2/74 (2.7) 0/27 (0.0) 14.41 (1.94–106.89) 5.81 (1.34–25.31) — b0.001 0.006 0.118 5/121 (4.1) 3/70 (4.3) 1/27 (3.7) 0/109 (0.0) 0/74 (0.0) 0/27 (0.0) — — — 0.038 0.112 0.500 3/121 (2.5) 3/70 (4.3) 00 (0.0) 2/109 (1.8) 5/74 (6.8) 00 (0.0) 1.35 (0.23–7.94) 0.63 (0.16–2.56) — 0.738 0.518 — b,c Abbreviation: LMP, last menstrual period a Values are given as number (percentage) unless otherwise indicated b Does not include women lost to follow-up in the mifepristone–misoprostol group and women who withdrew from study and did not take any study medication (3 in the mifepristone–misoprostol group; in the misoprostol-only group) c Breakdown by gestational age does not show interventions for providers' or women's choice, which were evenly distributed across strata Table Participants' characterization of adverse effects and experiences of the procedure.a,b Adverse effect or experience Nausea Mild Moderate Severe Vomiting Mild Moderate Severe Diarrhea Mild Moderate Severe Fever Mild Moderate Severe Chills Mild Moderate Severe Experience of bleeding More than expected Same as expected Less than expected Experience of pain More than expected Same as expected Less than expected Overall experience with adverse effects Very acceptable Acceptable Neutral Unacceptable Very unacceptable a b Misoprostol-only (n = 218) Mifepristone–misoprostol (n = 209) 0.303 — 0.655 — b0.001 — 0.283 — 0.086 70/206 (34.0) 73/206 (35.4) 63/206 (30.6) 0.79 (0.58–1.06) 0.85 (0.64–1.12) 1.41 (1.09–1.83) 0.108 0.248 0.008 65/204 (31.9) 51/204 (25.0) 88/204 (43.1) 1.04 (0.79–1.38) 0.90 (0.64–1.28) 1.03 (0.82–1.28) 0.777 0.567 0.823 0.89 (0.70–1.12) 0.314 96 (45.9) 73 (34.9) 17 (8.1) (2.9) 79 (37.8) 56 (26.8) 15 (7.2) (3.3) 128 (61.2) 85 (40.7) 30 (14.4) 13 (6.2) 59 (28.2) 39 (18.7) 14 (6.7) (2.9) 64 (30.6) 39 (18.7) 16 (7.7) (4.3) 55/206 (26.7) 62/206 (30.1) 89/206 (43.2) 69/208 (33.2) 47/208 (22.6) 92/208 (44.2) Values are given as number (percentage) unless otherwise indicated Some data missing as not all participants responded to all questions P value — 111 (50.9) 83 (38.1) 23 (10.6) (2.3) 87 (39.9) 67 (30.7) 15 (6.9) (2.3) 183 (83.9) 112 (51.4) 53 (24.3) 18 (8.3) 72 (33.0) 61 (28.0) (2.8) (2.3) 84 (38.5) 61 (28.0) (4.1) 14 (6.4) 36.9 (80/217) 58.1 (126/217) 0.5 (1/217) 4.6 (10/217) 0.0 (0/217) Relative risk (95% confidence interval) 87/209 114/209 2/209 5/209 1/209 (41.6) (54.5) (1.0) (2.4) (0.5) 170 J Blum et al / International Journal of Gynecology and Obstetrics 118 (2012) 166–171 Table Participants' characterization of the procedure and reports of satisfaction.a,b Misoprostol-only (n = 218) Time required for procedure More than expected Same than expected Less than expected Overall characterization of the procedure Not difficult Slightly difficult Moderately difficult Very difficult Overall satisfaction Very satisfied Satisfied Neutral Unsatisfied Very unsatisfied Method of abortion selected in future Medical Surgical a b 61/190 (32.1) 54/190 (28.4) 75/190 (39.5) Mifepristone–misoprostol (n = 209) Relative risk (95% confidence interval) P value 44/203 (21.6) 54/203 (26.6) 105/203 (51.7) 1.48 (1.06–2.07) 1.07 (0.77–1.47) 0.76 (0.61–0.95) 0.020 0.686 0.015 141/214 51/214 17/214 5/214 (65.9) (23.8) (7.9) (2.3) 142/208 53/208 10/208 3/208 (68.3) (25.5) (4.8) (1.4) 0.97 0.94 1.65 1.62 (0.84–1.10) (0.67–1.31) (0.77–3.52) (0.39–6.69) 0.603 0.694 0.188 0.501 71 95 37 13 (32.6) (43.6) (17.0) (6.0) (0.9) 91 97 16 00 (43.5) (46.4) (7.7) (2.4) (0.0) 0.75 0.94 2.22 2.49 — (0.59–0.96) (0.76–1.16) (1.27–3.86) (0.90–6.87) 0.020 0.556 0.003 0.066 0.165 0.85 (0.79–0.92) 2.95 (1.67–5.21) b0.001 b0.001 166/210 (79.1) 44/210 (20.9) 183/197 (92.9) 14/197 (7.1) Values are given as number (percentage) unless otherwise indicated Some data missing as not all participants responded to all questions The present study shows that treatment with 200 mg of mifepristone plus 800 μg of buccal misoprostol results in complete abortion for more than out of 10 women By contrast, repeat doses of 800 μg of buccal misoprostol, given hours apart, resulted in complete abortion for out of 10 women These complete abortion rates —92.9% for mifepristone–misoprostol and 78.0% for misoprostolonly—is within the range of previous reports [5,12] Indeed, the present findings closely match those from the largest randomized controlled trial of misoprostol-only, which recorded success rates of 78%–85% with vaginal and sublingual misoprostol administered at hour and 12 hour intervals [10] The ongoing pregnancy rate in the misoprostol-only arm of the present study (13.8%) is similar to the 17% rate of ongoing pregnancy reported by Ngoc et al [12] with 800-μg buccal misoprostol repeated 24 h later Likewise, the observed outcomes with the mifepristone–misoprostol regimen were not dissimilar to those previously reported in the USA and in Vietnam [5,12] The outcomes with the misoprostol-only regimen used in this study cannot be generalized to all misoprostol-only regimens The present study tested a regimen of doses of 800 μg of buccal misoprostol Although pharmacokinetic data show the buccal route this promising [14,15], it is possible that outcomes may improve slightly with other routes of administration, possibly with reduced time intervals between doses In our study, if the pregnancy was confirmed as ongoing at the 1-week follow-up, additional misoprostol doses were not offered and instead standard surgical termination was provided In other settings, repeat doses of misoprostol are increasingly becoming the standard of care—an approach that should result in fewer surgical interventions While the randomization procedure used in the present study was successful (Table 1), some limitations exist given that the countries contributed differently to the gestational age groups and that few women with gestations beyond 57 days of their last menstrual period were enrolled There was a greater likelihood of ongoing pregnancy in Vietnam than in Tunisia (odds ratio 2.482; P = 0.042) among women randomized to misoprostol-only Future research exploring misoprostol-only regimens might investigate the reasons for these country-level differences Looking forward, it is critical to bear in mind that while a need for medical abortion regimens with and without mifepristone will continue, service delivery should account for the potential differences in outcomes In the present study, it was shown that women can safely and effectively self-administer all of their medical abortion drugs at home In terms of service delivery, women given misoprostol-only should be counseled and prepared for a higher incidence of ongoing pregnancy and incomplete abortion Service delivery with the inclusion of at-home self-checkup mechanisms, such as symptom checklists and semi-quantitative pregnancy tests, may prove beneficial Future research should address the cost-effectiveness of these methods of medical abortion However, programmatic activities should not curtail global efforts to make mifepristone available to all women in all settings Ensuring that the safest and most efficacious methods are made universally available should continue to be a priority for women's health Acknowledgments The present study was funded by an anonymous donor Conflict of interest The authors have no conflicts of interest References [1] ACOG ACOG practice bulletin Clinical management guidelines of obstetriciangynecologists Number 67, October 2005 Medical management of abortion Obstet Gynecol 2005;106(4):871–82 [2] Concept Foundation Medabon® for Medical Abortion http://www.medabon.info Updated August 17, 2009 [3] Fernandez MM, Coeytaux F, de León RG, Harrison DL Assessing the global availability of misoprostol Int J Gynecol Obstet 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