IJG-08289; No of Pages 5 International Journal of Gynecology and Obstetrics xxx (2015) xxx–xxx

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International Journal of Gynecology and Obstetrics journal homepage: www.elsevier.com/locate/ijgo

CLINICAL ARTICLE

A double-blind randomized controlled trial of mifepristone or placebo before buccal misoprostol for abortion at 14–21 weeks of pregnancy Rasha Dabash a,⁎, Héla Chelli b, Selma Hajri c, Tara Shochet a, Sheila Raghavan a, Beverly Winikoff a a b c

Gynuity Health Projects, New York, NY, USA La Rabta Maternity Hospital, Tunis, Tunisia Groupe Tawhida, Tunis, Tunisia

a r t i c l e

i n f o

Article history: Received 3 October 2014 Received in revised form 27 January 2015 Accepted 27 March 2015 Keywords: Induced abortion Mifepristone Misoprostol Second trimester Tunisia

a b s t r a c t Objective: To assess differences in outcomes of misoprostol with or without mifepristone for second-trimester abortion. Methods: A randomized, double-blind, placebo-controlled trial of buccal misoprostol following placebo or 200 mg mifepristone was done in Tunisia among women presenting for abortions at 14–21 weeks of pregnancy between August 2009 and December 2011. Women with a live fetus, a closed cervical os, no cervical bleeding, and no contraindications to study drugs were eligible and underwent randomization (block size 10). Participants returned 24 hours later to receive 400 μg buccal misoprostol every 3 hours until complete fetal and placental expulsion (maximum 10 doses, five per 24-hour period). The primary outcomes were rates of complete uterine evacuation at 48 hours and time to expulsion. Results: A total of 120 women were evenly randomized to treatment. Complete uterine evacuation at 48 hours was recorded in 55 (91.7%) women in the combined group versus 43 (71.7%) in the misoprostol alone group (relative risk 1.28; 95% confidence interval 1.07–1.53). Mean time to complete abortion was 10.4 ± 6.6 hours in the group who received mifepristone versus 20.6 ± 9.7 hours in the misoprostol alone group (P b 0.001). Side effects were similar in both groups. Conclusion: Adding mifepristone before misoprostol can improve the quality of second-trimester abortion care by making the process faster. ClinicalTrials.gov: NCT00969982. © 2015 Published by Elsevier Ireland Ltd. on behalf of International Federation of Gynecology and Obstetrics.

1. Introduction Although only 10%–15% of abortion procedures worldwide occur in the second trimester, they account for more than two-thirds of major complications [1]. In many settings—including where surgical training and skills are limited—providers have increasingly resorted to medical methods, usually misoprostol, for second-trimester abortions [1,2]. Misoprostol is widely available and inexpensive, and is commonly used for other reproductive health indications [3]. Several studies [3–6] have shown that abortion efficacy is improved when mifepristone is used before misoprostol. For first-trimester abortions, this combination is already standard care [1,7,8]. However, despite recommendations that the combined regimen should be used in the second trimester [1,7,8], it is not yet standard protocol in many settings because of poor understanding of the relative benefit of adding mifepristone when misoprostol doses are continued beyond 24 hours. Because mifepristone is also becoming increasingly more affordable and available, establishing whether mifepristone continues to be beneficial when misoprostol dosing continues beyond 24 hours could help to convince providers—especially those in low-resource countries—to opt for combined protocols. ⁎ Corresponding author at: Gynuity Health Projects, 15 East 26th Street, Suite 801, New York, NY 10010, USA. Tel.: +1 212 448 1230; fax: +1 212 448 1260. E-mail address: [email protected] (R. Dabash).

In second-trimester procedures, repeat doses of misoprostol are typically administered without mifepristone until expulsion occurs, leading to successful completion in 26%–96% of women, depending on the dose, dosing interval, route, and allowed time to completion (many only document completion up to 15 hours after initiation of misoprostol) [9–15]. Regimens that include mifepristone before misoprostol have demonstrated completion rates of 63%–100% and typically result in shorter times to expulsion [6,16–21]. In Tunisia and other limited-resource settings, misoprostol is often still used alone in the second trimester, even when providers have experience using both drugs for first-trimester procedures. Even though mifepristone has been standard care in Tunisia for first-trimester abortion for over a decade, it is rarely used in the second trimester because of its limited availability outside the national family planning program that has supported its availability for first-trimester use. Because secondtrimester cases are legally more complex and limited to hospital settings, there has been little effort to advocate for the inclusion of mifepristone as part of second-trimester medical regimens. Difficulty obtaining mifepristone probably makes the combined regimen challenging to provide in many countries. In a study in Vietnam [6], 200 mg mifepristone or a placebo was followed 24 hours later by 400 μg buccal misoprostol every 3 hours (up to five doses with final assessment of success at 15 hours). It showed that adding mifepristone to misoprostol in second-trimester

http://dx.doi.org/10.1016/j.ijgo.2015.02.023 0020-7292/© 2015 Published by Elsevier Ireland Ltd. on behalf of International Federation of Gynecology and Obstetrics.

Please cite this article as: Dabash R, et al, A double-blind randomized controlled trial of mifepristone or placebo before buccal misoprostol for abortion at 14–21 weeks of pregnancy, Int J Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.02.023

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R. Dabash et al. / International Journal of Gynecology and Obstetrics xxx (2015) xxx–xxx

abortions leads to greater success and a shorter time to completion [6]. In the misoprostol alone group, only 36.9% of women had complete expulsion, compared with 79.8% of women who had before received mifepristone. The shorter interval to expulsion (8.1 vs 10.6 hours) is a key improvement because women prefer a quicker process [22–24], and a shorter hospital time can mean lower costs for both women and health systems. The Vietnamese study [6] also reiterated the promise of the buccal route of misoprostol administration in the second trimester and raised the question of whether the large advantage of adding mifepristone would hold with continued dosing beyond 24 hours or if the large gap between the two regimens might close significantly with only a few additional doses of misoprostol. Building on the Vietnam results, the aim of the present study was to assess the difference in outcomes with mifepristone plus buccal misoprostol versus buccal misoprostol alone, and to establish whether the inclusion of mifepristone confers clinical advantages even when additional misoprostol doses are given after 24 hours. 2. Materials and methods A randomized, double-blind, placebo-controlled trial was done among women presenting to La Rabta Maternity Hospital, Tunis, Tunisia, for a second-trimester abortion between August 26, 2009, and December 19, 2011. Eligible women were at 14–21 weeks of pregnancy with a live fetus, had a closed cervical os, had no vaginal bleeding, and had no known contraindications to the study drugs or to vaginal delivery. Women with known previous transmural uterine incision, with a parity greater than 5, or presenting in active labor were not eligible. The research was approved by the Research Ethics Committee of La Rabta Maternity Hospital and all participants gave written informed consent. Participants were randomly assigned to receive buccal misoprostol with or without mifepristone. Participants received 200 mg mifepristone (Mifegyn, Exelgyn, France) or a visually comparable placebo at the first hospital visit. The mifepristone and placebo had been packed in opaque sequentially numbered envelopes (randomized in blocks of 10 via a computerized randomization sequence) by Gynuity Health Projects staff in the USA. Each enrolled woman received the next sequential envelope; an equal number of women were allocated to each study group. Both participants and providers were masked to group assignment, and data remained blinded to researchers until study enrollment was complete. Participants were instructed to swallow the mifepristone or placebo at home and then to return to the hospital 24 hours later for treatment with misoprostol (Cytotec, Pfizer, USA). Participants were told to return sooner if they experienced strong contractions or heavy bleeding. On day 2, participants underwent a pelvic examination and received 400 μg misoprostol. Women were asked to hold one 200-μg tablet in each cheek (400 μg overall) for 20 minutes and then swallow any remaining fragments. This process was repeated every 3 hours until fetal and placental expulsion occurred, or for a maximum of five doses. After five misoprostol doses (12 hours from first dose), women were observed until 24 hours from first misoprostol dose had passed. If there was no complete expulsion by 24 hours, up to five additional doses were given, followed by a similar observation period for a total of another 24 hours. Analgesia was provided as needed per site protocol. Success was defined as complete expulsion (including fetus and placenta) within 48 hours without additional interventions. Women with no fetal expulsion by 48 hours were treated per the hospital’s standard of care (repeat doses of 400 μg vaginal misoprostol). If the fetus was expelled but the placenta was not, the protocol was continued to up to 48 hours. In case of failure to expel the placenta or heavy bleeding, additional interventions including manual removal or surgical aspiration were provided according to the hospital’s standard of care. Women were discharged per the provider's discretion and asked to respond to questions regarding their experience with the procedure and its acceptability.

The primary outcomes were the differences between study groups in the proportion of women with a complete uterine evacuation by 48 hours and time to completion among successes. The secondary outcomes were side effects and acceptability. A sample size of 110 women was necessary to determine whether there were significant differences between the two regimens for each of the two primary outcomes, with 90% power and precision (95% confidence level). On the basis of the findings from the Vietnam [6], success rates of 83% and 98%, and mean expulsion times of 32 and 10 hours were assumed for the misoprostol alone group and the combined group, respectively. A 15% difference in efficacy/expulsion time was deemed to be acceptable. The sample size was calculated to be 55 per group; it was rounded up to 120 to account for possible loss to follow-up. Data on total dose of misoprostol, time to fetal and placental expulsion, additional interventions needed, side effects, and acceptability were collected and compared between study groups. Participants who received the assigned intervention and completed the study were included in analyses. Wilcoxon rank-sum tests, Pearson χ2 tests, Fisher exact tests, t tests, and relative risks were used as appropriate to compare frequencies, medians, and means. P b 0.05 was considered to be statistically significant. Linear and logistic regression analyses were used to control for the possible effect of parity on the primary outcomes. All analyses were conducted with Stata version 11 (StataCorp, College Station, TX, USA). 3. Results A total of 120 women were enrolled in the study; none were lost to follow-up, so all were included in analysis (Fig. 1). Participant characteristics were similar in the two groups (Table 1). Complete uterine evacuation within 48 hours was recorded for more women in the combined group than in the misoprostol alone group (relative risk 1.28; 95% confidence interval 1.07–1.53) (Table 2). Although the numbers of participants in the subgroups divided by length of pregnancy are quite small, significant differences in completion rate between the two study groups were found among women at 14–15 and 16–17 weeks of pregnancy (Table 2). When the length of pregnancy was greater than 17 weeks, the efficacy of the combined regimen was similar to that of misoprostol alone. Among women in the combined group, the overall efficacy at 48 hours was higher between 14–17 weeks (complete expulsion in 38 [97.4%] of 39 women) than between 18–21 weeks (17 [81.0%] of 21; P = 0.05). The greater efficacy at earlier gestational ages was not observed in the misoprostol alone group. The mean time to complete uterine evacuation among women with successful induction was significantly shorter among women in the combined group than among those who only took misoprostol (P b 0.001) (Table 2). Survival curves for time to completion further demonstrate the difference between the two study groups (Fig. 2). Additionally, the mean number of misoprostol doses needed for

Randomization (n=120)

Mifepristone and misoprostol (n=60)

Misoprostol alone (n=60)

Received assigned intervention (n=60)

Received assigned intervention (n=60)

Analyzed (n=60)

Analyzed (n=60)

Fig. 1. Flow of participants through the study.

Please cite this article as: Dabash R, et al, A double-blind randomized controlled trial of mifepristone or placebo before buccal misoprostol for abortion at 14–21 weeks of pregnancy, Int J Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.02.023

a b

23 (17–40) 17.3 (14.0–21.0) 1 (1–7) 0 (0–4) 33 (55.0) 20 (33.3)

Values are given as median (range) or number (percentage). P = 0.003.

complete abortion was significantly lower in the combined group than in the misoprostol alone group (P b 0.001) (Table 2). Fourteen women (7 [11.7%] in each group) achieved fetal expulsion with the study drug alone but required additional care for placental expulsion. Successful completion was achieved in eight of these women after an additional dose of misoprostol and/or manual removal of expelled products from the vaginal canal. Logistic and linear regression models were run to assess the potential confounding of parity on the two primary outcomes. After controlling for parity, both the rate of complete uterine evacuation and time to completion remained significantly better among women in the combined group than among those in the misoprostol alone group (P = 0.007 and P = 0.001, respectively). Side effects as reported by women in the two groups were similar (Table 3). Pain was the most commonly reported, with all but two women reporting some degree of pain. The mean pain score was significantly higher among women who received mifepristone and misoprostol than among those who received misoprostol alone (P = 0.04) (Table 3); however, significant differences in reported pain might or might not be clinically significant. Mean pain level was not statistically different between the study groups among women who had complete abortion (P = 0.25). Severity of the other side effects did not differ significantly between the two groups (data not shown). Acceptability of treatment was very high in both study groups, with most participants reporting satisfaction with the overall experience

1.00 0.75

26 (13–42) 16.2 (14.0–21.3) 2 (1–6) 1 (0–5) 24 (40.0) 16 (26.7)

0.50

Misoprostol alone (n = 60)

0.25

Maternal age, y Length of pregnancy, wk Gravidity Parityb Primigravida Previous induced abortion

Mifepristone plus misoprostol (n = 60)

3

0.00

Table 1 Participants’ characteristics.a

Proportion without complete uterine evacuation

R. Dabash et al. / International Journal of Gynecology and Obstetrics xxx (2015) xxx–xxx

0

10 20 30 Time to complete uterine evacuation, h arm = Mifepristone plus misoprostol

40

arm = Misoprostol alone

Fig. 2. Survival curves demonstrating the rates of complete uterine evacuation over 48 hours.

(Table 3). Additionally, most women found the side effects to be acceptable or very acceptable and had no difficulty administering the misoprostol buccally (Table 3). The only significant difference in acceptability between the groups was regarding length of hospital stay: more women in the combined group than in the misoprostol alone group reported that their length of stay was acceptable or very acceptable (P = 0.04) (Table 3). Indeed, the mean length of stay among women in the combined group was shorter than among those who received misoprostol alone (1.3 ± 0.9 vs 2.0 ± 1.6 days; P = 0.002). 4. Discussion The present study is one of few double-blind research studies comparing misoprostol with or without mifepristone and reiterates the significant advantage conferred by the addition of mifepristone. The combined regimen had a higher rate of successful abortion within 48 hours and a much shorter time to expulsion of the fetus and placenta

Table 2 Complete uterine evacuation and time to expulsion.a

Complete uterine evacuation with initial study regimen By 15 h By 24 h By 48 h Length of pregnancy 14–15 wk 16–17 wk 18–19 wk 20–21 wk Median time to complete abortion, hc Mean time to complete abortion, hc Median number of misoprostol doses for complete abortionc Mean number of misoprostol doses for complete abortionc Complete fetal expulsion Median time to fetal expulsion, hc Mean time to fetal expulsion, hc Additional care given for placental expulsiond Massage Manual exploration/curettage with fingers Small forceps to remove debris from vaginal canal Additional 400 μg misoprostol Aspiration a b c d

Mifepristone plus misoprostol (n = 60)

Misoprostol alone (n = 60)

Relative risk (95% confidence interval)

P valueb

48 (78.3) 53 (88.3) 55 (91.7)

18 (30.0) 29 (48.3) 43 (71.7)

2.61 (1.73–3.93) 1.83 (1.38–2.41) 1.28 (1.07–1.53)

– – –

27/28 (96.4) 11/11 (100) 8/10 (80.0) 9/11 (81.8) 8.6 (2.1–41.4) 10.4 ± 6.6 3 (1–10) 3.4 ± 1.6 57 (95.0) 8.2 (2.0–40.3) 9.7 ± 6.4 7 (12.3) 0 (0) 3 (5.3) 2 (3.5) 5 (8.8) 0

19/25 (76.0) 5/10 (50.0) 11/15 (73.3) 8/10 (80.0) 18.2 (6.3–39.3) 20.6 ± 9.7 5 (3–10) 5.8 ± 1.9 47 (78.3) 18.0 (6.3–39.0) 20.0 ± 9.4 7 (14.9) 2 (4.3) 2 (4.3) 2 (4.3) 1 (2.1) 2 (4.3)

1.27 (1.01–1.60) 2.00 (1.08–3.72) 1.09 (0.71–1.69) 1.02 (0.67–1.55) – – – – 1.21 (1.05–1.40) – – – – – – – –

– – – – b0.001 b0.001 b0.001 b0.001 – b0.001 b0.001 – – – – – –

Values are given as number (percentage), number/total number (percentage), median (range), or mean ± SD, unless indicated otherwise. t test or Wilcoxon rank sum test. Among women with complete uterine evacuation with the assigned study regimen. Among women with complete fetal expulsion; complete uterine expulsion was achieved in 5 of the 7 women in combined group and 3 of the 7 in misoprostol alone group.

Please cite this article as: Dabash R, et al, A double-blind randomized controlled trial of mifepristone or placebo before buccal misoprostol for abortion at 14–21 weeks of pregnancy, Int J Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.02.023

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R. Dabash et al. / International Journal of Gynecology and Obstetrics xxx (2015) xxx–xxx

Table 3 Side effects and acceptability.a

Pain Nausea Vomiting Diarrhea Chills Headache Mean pain scoreb Among women with complete abortion Participants’ overall satisfaction with the assigned method Very satisfactory or satisfactory Neutral Unsatisfactory or very unsatisfactory Participants’ views of acceptability of side effects Very acceptable or acceptable Neutral Unacceptable Participant’s views on difficulty of buccal administration Not at all difficult Slightly difficult Moderately difficult or very difficult Participants’ views on acceptability of length of hospital stay Very acceptable or acceptable Neutral Unacceptable a b

Mifepristone plus misoprostol (n = 60)

Misoprostol alone (n = 60)

P value

59 (98.3) 28 (46.7) 26 (43.3) 25 (41.7) 23 (38.3) 14 (23.3) 5.0 ± 1.7 5.0 ± 1.6

59 (98.3) 36 (60.0) 29 (48.3) 33 (55.0) 22 (36.7) 12 (20.0) 4.4 ± 1.7 4.7 ± 1.5

N0.99 0.14 0.58 0.14 0.85 0.66 0.04 0.25 0.40

54 (90.0) 2 (3.3) 4 (6.7)

49 (81.7) 5 (8.3) 6 (10.0) 0.59

54 (90.0) 4 (6.7) 2 (3.3)

50 (83.3) 7 (11.7) 3 (5.0) 0.74

52 (86.7) 5 (8.3) 3 (5.0)

54 (90.0) 5 (8.3) 1 (1.7)

Acknowledgments 0.04

55 (91.7) 4 (6.7) 1 (1.7)

24 hours, as well as mean number of doses) are comparable with those documented with sublingual misoprostol in the second trimester [6,13,19,20]. Because the buccal and sublingual routes have never been directly compared, future research should assess if one confers an advantage. Although assessing pain is important in second-trimester care, it can also be rather complex given differences in pain control measures and women’s and providers’ preferences. Because pain control was not standardized in the present study, one limitation is the extent to which experiences of pain can be compared between regimens. In conclusion, given the clear benefit of adding mifepristone to misoprostol in abortion regimens early in the second trimester, future efforts should advocate for its availability and use in the second trimester globally. The combined mifepristone–misoprostol regimen could also potentially be cost-effective for systems; the financial impact should be explored in future research. Where mifepristone is not available, this indication could make an important case for its registration. In Tunisia and other settings where mifepristone is already available for first-trimester abortion but is rarely used in second-trimester abortion, its inclusion as a norm through the second trimester could greatly improve the quality of care for women.

47 (78.3) 4 (6.8) 8 (13.6)

Values are given as number (percentage) or mean ± SD, unless indicated otherwise. Scale of 1–7.

This study was funded by a grant from an anonymous donor. Conflict of interest The authors have no conflicts of interest.

References than did misoprostol alone. These results are in line with the findings of other studies of induced abortion in the second trimester [3,5,6,16–21]. As expected, with additional doses of misoprostol, complete abortion rates in both groups were markedly higher than in the Vietnam study [6] (combined regimen 91.7% vs 79.8%; misoprostol alone: 71.7% vs 36.9%). This confirms that misoprostol alone can eventually achieve higher efficacy with continued dosing, but the advantage of mifepristone remains substantial even at 10 doses and 48 hours. The additional doses did more to improve completion rates for the misoprostol alone group, possibly because they had greater room for improvement. But even with the additional doses/time, the failure rate of the misoprostol alone group remains relatively high compared with standards of efficacy. Additionally, the mean time is dramatically higher in the absence of mifepristone (20.6 vs 10.4 hours). The relatively short time to completion with mifepristone has important service delivery implications. The rarity of complications requiring surgical intervention coupled with the high likelihood of expulsion within 10 hours (60.0%) with a combined regimen suggest its potential in an outpatient or non-hospital based service. The feasibility of such a service delivery model, at least early in the second trimester, should be explored in future research. Extending the dosing to 48 hours perhaps more closely reflects what providers, including providers at this site, do in practice (continuous dosing until expulsion). However, assessing outcomes at 10 doses— although a necessary research endpoint—is by no means meant to imply a dosing “maximum” as has been interpreted by some guidelines. In reality, discontinuing doses leaves providers with few options and potentially increases the complication rate for women still trying to reach completion. The route of misoprostol administration is another area that warrants future exploration. The present study builds on the limited data regarding the buccal route in view of its increasing use in the first trimester. Indeed, the present findings (both efficacy at 15 and

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Please cite this article as: Dabash R, et al, A double-blind randomized controlled trial of mifepristone or placebo before buccal misoprostol for abortion at 14–21 weeks of pregnancy, Int J Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.02.023

A double-blind randomized controlled trial of mifepristone or placebo before buccal misoprostol for abortion at 14-21 weeks of pregnancy.

To assess differences in outcomes of misoprostol with or without mifepristone for second-trimester abortion...
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