Clinical Updates in Reproductive Health

Mifepristone and misoprostol: Recommended regimen

Last reviewed: January 30, 2020

Recommended regimen for 13-24 weeks gestation:

  • Mifepristone 200mg orally followed 1-2 days later by misoprostol 400mcg buccally, sublingually or vaginally every three hours until fetal and placental expulsion.
  • If the woman is stable and it is convenient for her to do so, providers should allow her at least four hours after fetal expulsion to expel the placenta before intervening.

Strength of recommendation: Strong

Quality of evidence:

  • Up to 20 weeks gestation: Moderate
  • 21-24 weeks gestation: Low

Background

Mifepristone combined with misoprostol is the preferred regimen for medical abortion at or after 13 weeks gestation, as it is highly efficacious, resulting in a short induction-to-abortion interval with an excellent safety profile (Borgatta & Kapp, 2011; Wildschut et al., 2011; World Health Organization [WHO], 2018). Mifepristone combined with misoprostol has a consistently shorter induction-to-abortion interval and higher expulsion rate at 15 (Ngoc et al., 2011), 24 (Constant et al., 2016) and 48 hours when compared to misoprostol alone (Dabash et al., 2015).

Mifepristone timing

A 2013 systematic review evaluating the effect of dosing interval between mifepristone and misoprostol on induction-to-abortion interval included 20 randomized controlled trials and nine observational studies (Shaw, Topp, Shaw, & Blumenthal, 2013). Based on the results of three randomized controlled trials, the review found that when mifepristone was given 12-24 hours before misoprostol, the induction-to-abortion interval was slightly longer (median 7.3 hours, range 7 to 8.5) than when mifepristone was administered 36 to 48 hours before misoprostol initiation (6.8 hours, range 6.3 to 7.2), but the abortion rate at 12 and 24 hours was the same (Shaw et al., 2013). In studies examining simultaneous administration of mifepristone and misoprostol, median expulsion times in the simultaneous group ranged from 10 to 13 hours, compared to 5 to 8 hours in women who waited 24 to 36 hours between mifepristone and misoprostol; however, rates of expulsion at 48 hours were equivalent in the two groups (Abbas et al., 2016; Chai et al., 2009).

Misoprostol loading dose

Although an early, large case series used an initial loading dose of vaginal misoprostol (Ashok, Templeton, Wagaarachchi & Flett, 2004), a more recent small, randomized controlled trial assigned 77 women to receive a loading dose of misoprostol vaginally (600mcg, followed by 400mcg every six hours) and 80 women to receive a no-loading dose regimen (400mcg every six hours) (Pongsatha & Tongsong, 2014). Median induction-to-abortion intervals and rates of complete abortion at 24 and 48 hours did not differ between groups, but the loading dose group suffered significantly more misoprostol-related side effects. Recent clinical trials that did not use loading doses of misoprostol showed average induction-to-abortion intervals of 8-10 hours and similar or better success rates as studies with loading doses (Abbas et al., 2016; Dabash et al., 2015; Louie et al., 2017; Ngoc et al., 2011). Therefore, a high initial dose of misoprostol appears to confer no benefit on expulsion times.

Misoprostol dosing

Route: In clinical trials of medical abortion at or after 13 weeks, misoprostol 400mcg vaginally or sublingually has higher success and shorter induction-to-abortion intervals than oral dosing (Dickinson, Jennings & Doherty, 2014; Tang, Chang, Kan & Ho, 2005). Buccal misoprostol has not been directly compared to other routes in a combined regimen for medical abortion at or after 13 weeks, but has similar efficacy as other routes of administration in abortion before 13 weeks (Kulier et al., 2011; Raymond, Shannon, Weaver, & Winikoff, 2013). Studies that use buccal misoprostol as part of a combined mifepristone-misoprostol regimen show an average induction-to-abortion interval of 8-10 hours (Abbas et al., 2016; Dabash, 2015; Louie et al, 2017; Ngoc et al., 2011; Blum et al., 2019).

Dose: Misoprostol 400mcg has higher expulsion rates, shorter induction-to-abortion intervals and similar side effects compared to 200mcg, regardless of route of administration (Brouns, van Wely, Burger, & van Wijngaarden, 2010; Shaw et al., 2013).

Timing: In one randomized trial examining two regimens of misoprostol-only medical abortion at or after 13 weeks gestation, the induction-to-abortion interval was shorter and the expulsion rate at 24 hours was higher when misoprostol was given every three hours compared to every six hours; rates of adverse events were similar (Wong, Ngai, Yeo, Tang, & Ho, 2000).

Number of doses: A prospective cohort study of 120 women between 13 and 22 weeks gestation who received mifepristone followed 24 hours later by misoprostol 400mcg buccally every 3 hours until fetal and placental expulsion reported a complete abortion rate of 99% without additional intervention (Louie et al., 2017). The median number of misoprostol doses necessary was four (range 2 to 6) and no adverse events were reported. In a similar prospective study of 306 women between 13-22 weeks, 90.2% required five or fewer doses of misoprostol (Platais et al., 2019).

Quality of evidence: The recommendation is based on multiple randomized clinical trials and a Cochrane meta-analysis comparing different mifepristone and misoprostol doses, dosing intervals and routes of administration in the second trimester (Wildschut et al., 2011). Most randomized controlled trials of medical abortion at or after 13 weeks do not include women with pregnancies greater than 21 weeks gestation.

Placental expulsion

In a prospective study of women between 13-18 weeks gestation utilizing mifepristone and misoprostol, most women expelled the fetus and placenta at about the same time, with a median time between fetal and placental expulsion of 15 minutes (range 0-4.5 hours) and 15.5% requiring a manual removal of the placenta (Blum et al., 2019). One retrospective cohort study measured intervention rates for placental removal in 233 women receiving a feticidal agent and repeated doses of misoprostol to induce abortion for pregnancies between 18-23 weeks gestation (Green et al., 2007). Following fetal expulsion, the placenta was allowed to expel spontaneously; operative intervention was performed only for excessive bleeding following fetal expulsion or to expedite hospital discharge after a minimum of four hours had elapsed since fetal expulsion. The overall intervention rate for retained placenta was 6%, and most removals were to expedite discharge. The study found no increase in morbidity for women managed expectantly during this time frame.

Resources

Protocols for Medical Abortion (dosage card)

References

Abbas, D.F., Blum, J., Ngoc, N.T., Nga, N.T., Chi, H.T., Martin, R., & Winikoff, B. (2016) Simultaneous administration compared with a 24-hour mifepristone-misoprostol interval in second-trimester abortion. Obstetrics & Gynecology128,(5), 1077-1083.

Ashok, P. W., Templeton, A., Wagaarachchi, P. T., & Flett, G. M. (2004). Midtrimester medical termination of pregnancy: A review of 1002 consecutive cases. Contraception, 69(1), 51-58.

Blum, J., Karki, C., Tamang, A., et al. (2019). Feasibility of a hospital outpatient day procedure for medication abortion at 13-18 weeks gestation: Findings from Nepal. Contraception, 100(6), 451-456.

Borgatta, L., & Kapp, N. (2011). Society of Family Planning Clinical Guideline 20111: Labor induction in the second trimester. Contraception, 84(1), 4-18.

Brouns, J. F., van Wely, M., Burger, M. P., & van Wijngaarden, W. J. (2010). Comparison of two dose regimens of misoprostol for second-trimester pregnancy termination. Contraception82(3), 266-275.

Chai, J., Tang, O. S., Hong, Q. Q., Chen, Q. F., Cheng, L. N., Ng, E., & Ho, P. C. (2009). A randomized trial to compare two dosing intervals of misoprostol following mifepristone administration in second trimester medical abortion. Human Reproduction24(2), 320-324.

Constant, D., Harries, J., Malaba, T., Myer, L., Patel, M., Petro, G., & Grossman, D. (2016). Clinical outcomes and women’s experiences before and after the introduction of mifepristone into second-trimester medical abortion services in South Africa. PLoS ONE, 11(9), e0161843. DOI: 10.1371/journal.pone.0161843.

Dabash, R., Chelli, H., Hajri, S., Shochet, T., Raghavan, S., & Winikoff, B. (2015). A double-blind randomized controlled trial of mifepristone or placebo before buccal misoprostol for abortion at 14-21 weeks of pregnancy. International Journal of Gynecology & Obstetrics130(1), 40-44.

Dickinson, J. E., Jennings, B. G., & Doherty, D. A. (2014). Mifepristone and oral, vaginal, or sublingual misoprostol for second-trimester abortion. Obstetrics & Gynecology, 123(6), 1162-1168.

Green, J., Borgatta, L., Sia, M., Kapp, N., Saia, K., Carr-Ellis, S., & Vragovic, O. (2007). Intervention rates for placental removal following inducaiton abortion with misoprostol. Contraception, 76, 310-313.

Kulier, R., Kapp, N., Gulmezolglu, A. M., Hofmeyr, G. J., Cheng, L., & Campana, A. (2011). Medical methods for first trimester abortion. The Cochrane Database of Systematic Reviews, 11, CD002855.

Louie, K. S., Chong, E., Tsereteli, T., Avagyan, G., Abrahamyan, R., & Winikoff, B. (2017). Second trimester medical abortion with mifepristone followed by unlimited dosing of buccal misoprostol in Armenia. European Journal of Contraception & Reproductive Health Care, 22(1), 76-80.

Ngoc, N. T. N., Shochet, T., Raghavan, S., Blum, J., Nga, N. T. B., Minh, N. T. H., … Winikoff, B. (2011). Mifepristone and misoprostol compared with misoprostol alone for second-trimester abortion: A randomized controlled trial. Obstetrics & Gynecology, 118 (3), 601-8. DOI:10.1097/AOG.0b013e318227214e.

Platais, I., Tsereteli, T., Maystruk, G., Kurbanbekova, D., & Winikoff, B. (2019). A prospective study of mifepristone and unlimited dosing of sublingual misoprostol for termination of second-trimester pregnancy in Uzbekistan and Ukraine. BMJ Sexual & Reproductive Health, 45, 177-182.

Pongsatha, S., & Tongsong, T. (2014). Randomized controlled trial comparing efficacy between a vaginal misoprostol loading and non-loading dose regimen for second-trimester pregnancy termination. The Journal of Obstetrics and Gynaecology Research40(1), 155-160.

Raymond, E. G., Shannon, C., Weaver, M. A., & Winikoff, B. (2013). First-trimester medical abortion with mifepristone 200 mg and misoprostol: A systematic review. Contraception, 87(1), 26-37.

Shaw, K., Topp, N. J., Shaw, J. G., & Blumenthal, P. D. (2013). Mifepristone-misoprostol dosing interval and effect on induction abortion times: A systematic review. Obstetrics & Gynecology121(6), 1335-1347.

Tang, O. S., Chan, C. C., Kan, A. S., & Ho, P. C. (2005). A prospective randomized comparison of sublingual and oral misoprostol when combined with mifepristone for medical abortion at 12-20 weeks gestation. Human Reproduction20(11), 3062-3066.

Wildschut, H., Both, M. I., Medema, S., Thomee, E., Wildhagen, M. F., & Kapp, N. (2011). Medical methods for mid-trimester termination of pregnancy. The Cochrane Database of Systematic Reviews, 1, CD005216.

Wong, K. S., Ngai, C. S., Yeo, E. L., Tang, L. C., & Ho, P. C. (2000). A comparison of two regimens of intravaginal misoprostol for termination of second trimester pregnancy: A randomized comparative trial. Human Reproduction15(3), 709-712.

World Health Organization. (2018). Medical management of abortion. Geneva: World Health Organization Press.