Clinical Updates in Reproductive Health

Misoprostol only: Recommended regimen

Last reviewed: September 29, 2022

Recommended regimen for 13-24 weeks gestation:

  • Misoprostol 400mcg buccally, sublingually or vaginally every three hours until fetal and placental expulsion. Vaginal dosing is more effective than other routes.
  • Misoprostol-only medical abortion is safe and effective, with fetal expulsion rates of 72-91% at 24 hours and major complication rates of less than 1%.
  • The average time to abortion is 10-15 hours after beginning misoprostol, although some individuals will require multiple days to successfully abort.

In practice:

  • A combined mifepristone and misoprostol regimen is more effective than misoprostol used alone and is recommended for medical abortion at or after 13 weeks; where mifepristone is unavailable the misoprostol-only regimen can be used.
  • If the individual is stable and it is convenient to do so, providers should allow 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
  • 20-24 weeks gestation: Low

Background

A combination regimen with mifepristone and misoprostol has shorter induction-to-abortion intervals and higher success rates than misoprostol only for medical abortion at or after 13 weeks gestation (Wildschut et al., 2011). If mifepristone is not available, a misoprostol-only regimen with dosing every three hours is an acceptable alternative (Wildschut et al., 2011; World Health Organization (WHO), 2022).

Misoprostol-only regimen

Expulsion rates

The largest international randomized controlled trial of medical abortion at or after 13 weeks gestation, with the recommended vaginal or sublingual misoprostol-only regimen, included 681 women between 13-20 weeks gestation (von Hertzen et al., 2009). The fetal expulsion rate was 84.8% at 24 hours and 94.3% at 48 hours. Smaller randomized trials using vaginal or sublingual misoprostol every three hours showed fetal expulsion rates of 72-91% at 24 hours and 91-95% at 48 hours (Bhattacharjee et al., Saha, Ghoshroy, Bhowmik, & Barui, 2008; Tang et al., Lau, Chan, & Ho, 2004), and fetal and placental expulsion rates of 62-64% at 24 hours and 79-82% at 48 hours (Bhattacharjee et al., 2008). 

Induction-to-abortion interval

In the von Hertzen trial, the median time to fetal expulsion was 12 hours (range 4.1-61.8 hours), with parous women having faster induction-to-abortion times than nulliparous women (von Hertzen et al., 2009). In smaller randomized trials, time to expulsion ranges from 10-15 hours (Bhattacharjee et al., 2008; Tang et al., 2004). Lengthening the dosing interval of misoprostol from every three to every six hours increases the induction-to-abortion time (Wong et al., Ngai, Yeo, Tang, & Ho, 2000).

 Complication rates

The rate of major complications from misoprostol-only abortion at or after 13 weeks is low. In the trial cited above, 12 adverse events (0.02%) were reported;  10 women required blood transfusions (von Hertzen et al., 2009).  

Routes of misoprostol administration

In randomized controlled clinical trials, misoprostol 400mcg vaginally every three hours is associated with a median induction-to-abortion interval of 10-15 hours and a 48-hour successful abortion rate of 90-95% (Bhattacharjee et al., 2008; Koh et al., 2017; Tang et al., 2004; von Hertzen et al., 2009). A 400mcg dose vaginally is more effective than a 200mcg dose (Koh et al., 2017).

In a meta-analysis of 1,178 women from three randomized controlled trials, misoprostol 400mcg sublingually is similar (Bhattacharjee et al., 2008) or slightly inferior to vaginal dosing when given every three hours (Tang et al., 2004; von Hertzen et al., 2009; Wildschut et al., 2011). In the trials that showed reduced efficacy, the difference was driven by an inferior response to sublingual misoprostol in nulliparous women only. Of note: all of these studies found that women prefer the sublingual route to vaginal administration by health care workers.

One trial randomized 130 women to misoprostol 400mcg every three hours either vaginally or buccally. Those in the vaginal group had a shorter mean induction-to-fetal expulsion interval (25 compared to 40 hours, p=0.001) and higher rates of fetal expulsion at both 24 hours (63% compared to 42%, p=0.014) and 48 hours (91% compared to 68%, p=0.001) (Al & Yapca, 2015). A smaller trial of 64 women showed buccal misoprostol was as effective as vaginal; however, all of the women received an initial loading dose of misoprostol 400mcg vaginally and were randomized to 200mcg buccally or vaginally every six hours thereafter (Ellis et al., 2010). Finally, a trial including a cohort of 60 women who received misoprostol 400mcg buccally every three hours until fetal and placental expulsion found a complete abortion rate of 71% at 48 hours (Dabash et al., 2015). Based on these studies, vaginal and sublingual administration appear to be superior to buccal misoprostol dosing in this gestational age range.

In multiple randomized clinical trials, oral dosing has been shown to be less effective with longer time-to-abortion intervals than vaginal or sublingual dosing (Akoury et al., 2004; Bebbington et al., 2002; Behrashi & Mahdian, 2008; Nautiyal et al., 2015).

Placental expulsion

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.

Quality of evidence

The recommendation is based on multiple randomized clinical trials and a Cochrane meta-analysis comparing different misoprostol doses, dosing intervals and routes of administration at or after 13 weeks gestation (Wildschut et al., 2011). This body of evidence is limited by the fact that most randomized controlled trials of medical abortion do not include people with pregnancies over 20 weeks gestation.

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

Akoury, H. A., Hannah, M. E., Chitayat, D., Thomas, M., Winsor, E., Ferris, L. E., & Windrim, R. (2004). Randomized controlled trial of misoprostol for second-trimester pregnancy termination associated with fetal malformation. American Journal of Obstetrics & Gynecology190(3), 755-762.

Al, R. A., & Yapca, O. E. (2015). Vaginal misoprostol compared with buccal misoprostol for termination of second-trimester pregnancy: A randomized controlled trial. Obstetrics & Gynecology126(3), 593-8.

Bebbington, M. W., Kent, N., Lim, K., Gagnon, A., Delisle, M. F., Tessier, F., & Wilson, R. D. (2002). A randomized controlled trial comparing two protocols for the use of misoprostol in midtrimester pregnancy termination. American Journal of Obstetrics & Gynecology187(4), 853-857.

Behrashi, M., & Mahdian, M. (2008). Vaginal versus oral misoprostol for second-trimester pregnancy termination: A randomized trial. Pakistan Journal of Biological Sciences, 11(21), 2505-2508.

Bhattacharjee, N., Saha, S. P., Ghoshroy, S. C., Bhowmik, S., & Barui, G. (2008). A randomised comparative study on sublingual versus vaginal administration of misoprostol for termination of pregnancy between 13 to 20 weeks. Australian and New Zealand Journal of Obstetrics and Gynaecology48(2), 165-171.

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 & Obstetrics, 130, 40-44.

Ellis, S. C., Kapp, N., Vragovic, O., & Borgatta, L. (2010). Randomized trial of buccal versus vaginal misoprostol for induction of second trimester abortion. Contraception81(5), 441-445.

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.

Koh, D. S. C., Ang, E. P. J., Coyuco, J. C., Teo, H. Z., Huang, X., Wei, X., … Tan, K. H. (2017). Comparing two regimens of intravaginal misoprostol with intravaginal gemprost for second-trimester pregnancy termination: A randomised controlled trial. Journal of Family Planning and Reproductive Health Care, DOI: 10.1136/jfprhc-2016-101652.

Nautiyal, D., Mukherjee, K., Perhar, I., & Banerjee, N. (2015). Comparative study of misoprostol in first and second trimester abortions by oral, sublingual and vaginal routes. Journal of Obstetrics and Gynecology of India65(4), 246-50.

Tang, O. S., Lau, W. N., Chan, C. C., & Ho, P. C. (2004). A prospective randomised comparison of sublingual and vaginal misoprostol in second trimester termination of pregnancy. BJOG: An International Journal of Obstetrics & Gynecology111(9), 1001-1005.

von Hertzen, H., Piaggio, G., Wojdyla, D., Nguyen, T. M., Marions, L., Okoev, G., & Peregoudov, A. (2009). Comparison of vaginal and sublingual misoprostol for second trimester abortion: Randomized controlled equivalence trial. Human Reproduction24(1), 106-112.

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.

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