Clinical Updates in Reproductive Health

Misoprostol only: Recommended regimen

Last reviewed: January 30, 2020

Recommended regimen for 13-24 weeks gestation:

  • Misoprostol 400mcg sublingually or vaginally every three hours until fetal and placental expulsion. Vaginal dosing is more effective than sublingual dosing for nulliparous women.
  • 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
  • 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), 2018).

Vaginal route

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, Saha, Ghoshroy, Bhowmik, & Barui, 2008; Koh et al., 2017; Tang, Lau, Chan, & Ho, 2004; von Hertzen et al., 2009). A 400mcg dose vaginally is more effective than a 200mcg dose (Koh et al., 2017).

Sublingual route

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.

Other routes

Buccal route: One trial randomized 130 women to misoprostol 400mcg every three hours either vaginally or buccally. Women 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, Kapp, Vragpvoc, & Borgatta, 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.

Oral route: 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, Mukherjee, Perhar, & Banerjee, 2015).

Dosing interval

In one randomized trial that examined two different regimens of vaginal misoprostol, lengthening the dosing interval from every three to every six hours decreases the efficacy of medical abortion (Wong, Ngai, Yeo, Tang, & Ho, 2000).

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 women 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 women with pregnancies over 20 weeks gestation.

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