Clinical Updates in Reproductive Health

Mifepristone and misoprostol: Recommended regimen

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Last reviewed: September 29, 2022

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.
  • The combined regimen is safe and effective, with fetal expulsion rates of over 90% at 24 hours and major complication rates around 1%.
  • The median time to abortion is 6-10 hours after beginning misoprostol, although some individuals will require more time to successfully abort.

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; Shay et al., 2021) and 48 hours when compared to misoprostol alone (Dabash et al., 2015).

Combined regimen with mifepristone and misoprostol

Expulsion rates

Studies using the recommended regimen of mifepristone and misoprostol show fetal expulsion rates of 94% at 24 hours and 97% at 48 hours (Abbas et al., 2016), and fetal and placental expulsion rates of 88% at 24 hours and 92% at 48 hours (Dabash et al., 2015). When individuals continue misoprostol until expulsion with no cut off time, 99% of people eventually have a successful abortion (Ashok et al., 2004; Louie et al., 2017).

Induction-to-abortion interval

In studies using the recommended mifepristone and misoprostol regimen, the median times to fetal expulsion were from 6-10 hours, with a wide range of times until complete expulsion (Abbas et al., 2016; Dabash et al., 2015; Louie et al., 2017; Ngoc et al., 2011; Prodan et al., 2019; Shaw et al., 2013). The induction-to-abortion interval is longer in nulliparous people, older people, and those with pregnancies at a later gestational age (Abbas et al., 2016; Ashok et al., 2004; Dabash et al., 2015; Louie et al., 2017; Platais et al., 2019). The addition of mifepristone to a misoprostol medical abortion regimen consistently reduces the induction-to-abortion interval (Constant et al., 2016; Dabash et al., 2015; Kapp et al., 2007; Ngoc et al., 2011; Prodan et al., 2019).

Complication rates

The rate of major complications from mifepristone and misoprostol medical abortion at or after 13 weeks gestation is low, although minor complications—such as needing a procedure for bleeding or retained products of conception—are more frequent than for dilatation and evacuation (Autry et al., 2002). The largest related cohort study of medical abortion with mifepristone and misoprostol included 1,002 women between 13-21 weeks gestation (Ashok et al., 2004).  Eighty-one women (8.1%) needed a uterine evacuation procedure, the majority of which were needed for retained placenta; only two women needed an evacuation to terminate the pregnancy. In this study, serious complications such as hemorrhage, blood transfusion, or unanticipated surgery occurred in eight women (less than 1%). In a more recent but smaller prospective cohort study of mifepristone and misoprostol abortion between 13-18 gestational weeks conducted in Nepal, 35 out of 230 women required placental removal (15%) and three women experienced hemorrhage, for a serious adverse event rate of 1.3% (Blum et al., 2019). In a 2017 cohort study in which 120 women between 13-22 weeks gestation received mifepristone followed by unlimited dosing of misoprostol until fetal and placental expulsion, 99% of women evacuated the uterus without any additional intervention (Louie et al., 2017). No serious adverse events were reported in this study and only one woman failed to abort with the combined regimen.

In a meta-analysis of data from medical abortion studies at or after 13 weeks gestation using either the combined regimen or a misoprostol-only regimen, the overall rate of uterine rupture was 0.08%, with a rate of 0.28% in women with a previous cesarean section (Goyal, 2009).

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 et al., 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). A 2020 systematic review which included three randomized controlled trials, two of which were included in the Shaw, 2013 review, found no significant differences in the induction-to-abortion interval or successful abortion rate when misoprostol was started one day, or two days, after mifepristone (Wu et al., 2021). 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 et al., 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 et al., 2000).

Number of doses: A prospective cohort study of 120 people 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 people between 13-22 weeks, 90.2% required five or fewer doses of misoprostol (Platais et al., 2019).

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 those managed expectantly during this time frame.

Who can provide medical abortion at or after 13 weeks gestation?

The World Health Organization (WHO) makes service delivery recommendations for the provision of medical abortion at or after 13 weeks gestation, which includes assessment of medical abortion eligibility (determining pregnancy duration and assessing for contraindications to abortion medications), administration of abortion medications, management of the abortion process, and assessment of abortion success (WHO, 2022). WHO recommends the provision of medical abortion at or after 13 weeks by specialty and general medical practitioners, and suggests that in contexts where established and easy access to appropriate surgical backup and other infrastructure necessary to address possible complications exists, associate and advanced associate clinicians, midwives, nurses, auxiliary nurses and auxiliary nurse midwives, and traditional and complementary medicine professionals can also safely and effectively provide this service based on the expected competencies for these health workers (WHO, 2022). For further information about health worker roles in abortion care, see Appendix C: World Health Organization recommendations for health worker roles in abortion care.

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.

Autry, A. M., Hayes, E. C., Jacobson, G. F., & Kirby, R. S. (2002). A comparison of medical induction and dilation and evacuation for second-trimester abortion. American Journal of Obstetrics & Gynecology, 187(2), 393-397.

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.

Goyal, V. (2009). Uterine rupture in second-trimester misoprostol-induced abortion after cesarean delivery: A systematic review. Obstetrics & Gynecology, 113(5), 1117-1123.

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.

Prodan, N., Breisch, J., Hoopmann, M., Abele, H., Wagner, P., & Kagan, K.O. (2019). Dosing interval between mifepristone and misoprostol in second and third trimester termination. Archives of Gynecology and Obstetrics, 99(3), 675-679.

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. (2022). Abortion Care Guideline. Geneva: World Health Organization.

Wu, L., Xiong, W., Zeng, M., Yan, A., Song, L., Chen, M., Wei, T., Zu, Q. & Zhang, J. (2021). Different dosing intervals of mifepristone-misoprostol for second-trimester termination of pregnancy: A meta-analysis and systematic review. International Journal of Gynaecology and Obstetrics, 154(2), 195-203.

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