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Misoprostol administered 1–3 days after mifepristone for early abortion resulted in similarly high success rates
GYNECOLOGY
Misoprostol administered 1^3 days after mifepristone for early abortion resulted in similarly high success rates Schaff EA, Fielding SL, Westhoff C, Ellertson C, Eisinger SH, Stadalius LS, Fuller L.Vaginal misoprostol administered1, 2, or 3 days after mifepristone for early medical abortion: a randomized trial. JAMA 2000; 284: 1948 ^1953.
OBJECTIVE To determine the optimal time interval between administration of mifepristone and misoprostol for early medical abortion. DESIGN Multicentre, randomized, non-blinded, three-arm, controlled trial. Allocation was by drawing of concealed treatment assignment, strati¢ed by centre. The study had su⁄cient power to detect an absolute di¡erence of 2% in complete abortion rate. SETTING Sixteen centres (hospitals, abortion clinics, and family practice and gynecology o⁄ces) in the USA. SUBJECTS 2295 women, aged 18 (mean 28) years, who requested termination of pregnancy at gestational age 56 (mean 46) days. 50% of women had had a prior abortion and 46% had had a live birth. 2% of subjects were lost to follow-up and were excluded from the analysis. INTERVENTION All women were administered mifepristone 200 mg orally and received four 200-mg tablets of misoprostol to be inserted dry into the vagina at home between 7 am and midnight on the assigned day. 734 women were randomized to insert the misoprostol 1 day after mifepristone administration (after at least 24 h), 766 women after 2 days (standard practice), and 755 women after 3 days. If ultrasonography showed a gestational sac at the follow-up visit within 1 week of mifepristone administration, a second dose of misoprostol was given. Aspiration curettage was performed if indicated. MAIN OUTCOME MEASURES Complete abortion (no gestational sac on ultrasound), need for surgical intervention, side-e¡ects.
1361-259X/02/$ - see front matter & 2002 Published by Elsevier Science Ltd. doi:10.1054/ebog.4, available online at http://www.idealibrary.com.on
MAIN RESULTS The proportion of women who had a complete abortion was 98% (95% CI 97^99) in the day 1 group, 98% (CI 97^99) in the day 2 group and 96% (CI 95^97) in the day 3 group ( p for trend=0.02; day 1 vs day 2, p=0.69, relative risk [RR] 1.00, CI 0.99^1.02; day 3 vs day 2, p=0.07, RR 0.98, CI 0.96^1.00)*. In the day 1 group, 0.5% of women aborted prior to taking misoprostol, compared to 1.6% in the day 2 group and 5% in the day 3 group ( p for trend o0.0001*). Of women who took the misoprostol per protocol, the proportions requiring surgical intervention were 2.1, 1.8, and 3.5%, respectively ( p=0.09*). There was no signi¢cant di¡erence among groups in the time to start of bleeding after administering misoprostol (86% within 4 h) or frequency of side-e¡ects, such as cramping (94%), nausea (63%), fever/chills (36%), dizziness (34%), and vomiting (31%). More than 90% of women in each group found the overall procedure acceptable, but satisfaction with the waiting time was higher in the day 1 group (86%) than in the day 2 (79%) or day 3 (76%) groups ( p=0.001).
CONCLUSION In pregnancies up to 56 days gestation, administration of misoprostol 1 or 3 days following mifepristone resulted in high rates of complete abortion, similar to after a 2-day interval. Although there was a signi¢cant trend to decreasing e¡ectiveness with a longer interval, there was no signi¢cant increase in the need for surgical intervention. *Calculated from data in article.
Evidence-based Obstetrics and Gynecology (2002) 4,19^20
19
Commentary In the United Kingdom, mifepristone in combination with a prostaglandin analogue was licensed in 1991 for the termination of pregnancy up to 9 weeks gestation, and since 1995 has also been available for termination of pregnancy beyond 13 weeks. At present, surgical methods (vacuum aspiration) are used at 10 ^13 weeks gestation, although studies have shown the feasibility of medical abortion at these gestational ages.1 The manufacturer’s recommended regimen for early medical abortion comprises mifepristone 600 mg in combination with the prostaglandin analogue gemeprost. A number of published studies have shown that a 200 mg dose of mifepristone is as effective as a 600 mg dose for early medical abortion.2 Additionally, the synthetic prostaglandin E1analogue, misoprostol, has several advantages over gemeprost, in that it is easily stored and transported and of very low cost. Published regimens, consisting of a reduced dose of mifepristone (200 mg) and the vaginal use of misoprostol, have demonstrated efficacy rates up to 97%.3 Current regimens for medical abortion recommend that gemeprost or misoprostol be administered 36 ^ 48 hours following mifepristone. The present study was a multicentre, randomised controlled trial to determine the appropriate timing of misoprostol administration following mifepristone for medical abortion of pregnancies up to 56 days gestation.The results of this study suggest that vaginal misoprostol can be administered between 1 and 3 days following administration of mifepristone without loss of e¡icacy. This was a well-conducted study with sound methodology, the findings of which have important implications for clinical practice. In addition to this study, another study from the USA showed the feasibility of home administration of misoprostol with high patient acceptability.4 In the UK, however, abortion can be carried out only in a licensed facility and, hence, women are usually admitted as day cases for the procedure. Flexibility of administration of misoprostol has a clear advantage, both in a hospital setting and for home use, although, in this study, the ac-
20
Evidence-based Obstetrics and Gynecology (2002) 4,19^20
ceptability of the procedure was not affected by the day of administration of misoprostol. Mifepristone has also been licensed in a 600 mg dose for use for cervical priming 48 hours prior to vacuum aspiration, but has been shown to be effective in a 200 mg dose for this purpose. However, the optimal time interval for priming is 48 hours prior to surgical evacuation.5 In summary, vaginal administration of misoprostol between 1 and 3 days following mifepristone administration increases the flexibility of the regimen for both the woman and the clinician. This study also confirms the findings of previous published studies regarding the safety and acceptability of home administration of misoprostol. Premila W. Ashok, MB University of Aberdeen, Aberdeen, UK
Literature cited 1. Ashok PW, Kidd A, Flett GM et al. A randomized comparison of medical abortion and surgical vacuum aspiration at 10 ^13 weeks gestation. Hum Reprod 2002; 17: 92^98. 2. World Health Organisation Task Force on Post-ovulatory Methods of Fertility Regulation. Comparison of two doses of mifepristone in combination with misoprostol for early medical abortion: a randomised trial. Br J Obstet Gynaecol 2000; 107: 524 ^530. 3. Ashok PW, Penney GC, Flett GM, Templeton A. An effective regimen for early medical abortion: a report of 2000 consecutive cases. Hum Reprod 1998; 13: 2962^2965. 4. Schaff EA, Stadalius LS, Eisinger SH, Franks P. Vaginal misoprostol administered at home after mifepristone (RU486) for abortion. J Fam Pract 1997; 44: 353^360. 5. Ashok PW, Flett GM, Templeton A. Mifepristone versus vaginally administered misoprostol for cervical priming before first-trimester termination of pregnancy: a randomized, controlled study. Am J Obstet Gynecol 2000; 183: 998 ^1002.
Misoprostol administered 1^3 days after mifepristone for early abortion resulted in similarly high success rates Schaff EA, Fielding SL, Westhoff C, Ellertson C, Eisinger SH, Stadalius LS, Fuller L.Vaginal misoprostol administered1, 2, or 3 days after mifepristone for early medical abortion: a randomized trial. JAMA 2000; 284: 1948 ^1953.
OBJECTIVE To determine the optimal time interval between administration of mifepristone and misoprostol for early medical abortion. DESIGN Multicentre, randomized, non-blinded, three-arm, controlled trial. Allocation was by drawing of concealed treatment assignment, strati¢ed by centre. The study had su⁄cient power to detect an absolute di¡erence of 2% in complete abortion rate. SETTING Sixteen centres (hospitals, abortion clinics, and family practice and gynecology o⁄ces) in the USA. SUBJECTS 2295 women, aged 18 (mean 28) years, who requested termination of pregnancy at gestational age 56 (mean 46) days. 50% of women had had a prior abortion and 46% had had a live birth. 2% of subjects were lost to follow-up and were excluded from the analysis. INTERVENTION All women were administered mifepristone 200 mg orally and received four 200-mg tablets of misoprostol to be inserted dry into the vagina at home between 7 am and midnight on the assigned day. 734 women were randomized to insert the misoprostol 1 day after mifepristone administration (after at least 24 h), 766 women after 2 days (standard practice), and 755 women after 3 days. If ultrasonography showed a gestational sac at the follow-up visit within 1 week of mifepristone administration, a second dose of misoprostol was given. Aspiration curettage was performed if indicated. MAIN OUTCOME MEASURES Complete abortion (no gestational sac on ultrasound), need for surgical intervention, side-e¡ects.
1361-259X/02/$ - see front matter & 2002 Published by Elsevier Science Ltd. doi:10.1054/ebog.4, available online at http://www.idealibrary.com.on
MAIN RESULTS The proportion of women who had a complete abortion was 98% (95% CI 97^99) in the day 1 group, 98% (CI 97^99) in the day 2 group and 96% (CI 95^97) in the day 3 group ( p for trend=0.02; day 1 vs day 2, p=0.69, relative risk [RR] 1.00, CI 0.99^1.02; day 3 vs day 2, p=0.07, RR 0.98, CI 0.96^1.00)*. In the day 1 group, 0.5% of women aborted prior to taking misoprostol, compared to 1.6% in the day 2 group and 5% in the day 3 group ( p for trend o0.0001*). Of women who took the misoprostol per protocol, the proportions requiring surgical intervention were 2.1, 1.8, and 3.5%, respectively ( p=0.09*). There was no signi¢cant di¡erence among groups in the time to start of bleeding after administering misoprostol (86% within 4 h) or frequency of side-e¡ects, such as cramping (94%), nausea (63%), fever/chills (36%), dizziness (34%), and vomiting (31%). More than 90% of women in each group found the overall procedure acceptable, but satisfaction with the waiting time was higher in the day 1 group (86%) than in the day 2 (79%) or day 3 (76%) groups ( p=0.001).
CONCLUSION In pregnancies up to 56 days gestation, administration of misoprostol 1 or 3 days following mifepristone resulted in high rates of complete abortion, similar to after a 2-day interval. Although there was a signi¢cant trend to decreasing e¡ectiveness with a longer interval, there was no signi¢cant increase in the need for surgical intervention. *Calculated from data in article.
Evidence-based Obstetrics and Gynecology (2002) 4,19^20
19
Commentary In the United Kingdom, mifepristone in combination with a prostaglandin analogue was licensed in 1991 for the termination of pregnancy up to 9 weeks gestation, and since 1995 has also been available for termination of pregnancy beyond 13 weeks. At present, surgical methods (vacuum aspiration) are used at 10 ^13 weeks gestation, although studies have shown the feasibility of medical abortion at these gestational ages.1 The manufacturer’s recommended regimen for early medical abortion comprises mifepristone 600 mg in combination with the prostaglandin analogue gemeprost. A number of published studies have shown that a 200 mg dose of mifepristone is as effective as a 600 mg dose for early medical abortion.2 Additionally, the synthetic prostaglandin E1analogue, misoprostol, has several advantages over gemeprost, in that it is easily stored and transported and of very low cost. Published regimens, consisting of a reduced dose of mifepristone (200 mg) and the vaginal use of misoprostol, have demonstrated efficacy rates up to 97%.3 Current regimens for medical abortion recommend that gemeprost or misoprostol be administered 36 ^ 48 hours following mifepristone. The present study was a multicentre, randomised controlled trial to determine the appropriate timing of misoprostol administration following mifepristone for medical abortion of pregnancies up to 56 days gestation.The results of this study suggest that vaginal misoprostol can be administered between 1 and 3 days following administration of mifepristone without loss of e¡icacy. This was a well-conducted study with sound methodology, the findings of which have important implications for clinical practice. In addition to this study, another study from the USA showed the feasibility of home administration of misoprostol with high patient acceptability.4 In the UK, however, abortion can be carried out only in a licensed facility and, hence, women are usually admitted as day cases for the procedure. Flexibility of administration of misoprostol has a clear advantage, both in a hospital setting and for home use, although, in this study, the ac-
20
Evidence-based Obstetrics and Gynecology (2002) 4,19^20
ceptability of the procedure was not affected by the day of administration of misoprostol. Mifepristone has also been licensed in a 600 mg dose for use for cervical priming 48 hours prior to vacuum aspiration, but has been shown to be effective in a 200 mg dose for this purpose. However, the optimal time interval for priming is 48 hours prior to surgical evacuation.5 In summary, vaginal administration of misoprostol between 1 and 3 days following mifepristone administration increases the flexibility of the regimen for both the woman and the clinician. This study also confirms the findings of previous published studies regarding the safety and acceptability of home administration of misoprostol. Premila W. Ashok, MB University of Aberdeen, Aberdeen, UK
Literature cited 1. Ashok PW, Kidd A, Flett GM et al. A randomized comparison of medical abortion and surgical vacuum aspiration at 10 ^13 weeks gestation. Hum Reprod 2002; 17: 92^98. 2. World Health Organisation Task Force on Post-ovulatory Methods of Fertility Regulation. Comparison of two doses of mifepristone in combination with misoprostol for early medical abortion: a randomised trial. Br J Obstet Gynaecol 2000; 107: 524 ^530. 3. Ashok PW, Penney GC, Flett GM, Templeton A. An effective regimen for early medical abortion: a report of 2000 consecutive cases. Hum Reprod 1998; 13: 2962^2965. 4. Schaff EA, Stadalius LS, Eisinger SH, Franks P. Vaginal misoprostol administered at home after mifepristone (RU486) for abortion. J Fam Pract 1997; 44: 353^360. 5. Ashok PW, Flett GM, Templeton A. Mifepristone versus vaginally administered misoprostol for cervical priming before first-trimester termination of pregnancy: a randomized, controlled study. Am J Obstet Gynecol 2000; 183: 998 ^1002.