By Rebecca H. Allen, MD, MPH
Associate Professor, Department of Obstetrics and Gynecology, Warren Alpert Medical School of Brown University, Women and Infants Hospital, Providence, RI
Dr. Allen reports she is a Nexplanon trainer for Merck.
In a recent trial, researchers found that pretreatment with mifepristone followed by treatment with misoprostol resulted in a higher likelihood of successful management of first-trimester pregnancy loss than treatment with misoprostol alone. The rate of surgical evacuation also was reduced in the mifepristone pretreatment arm compared to the misoprostol-alone arm.
Schreiber CA, Creinin MD, Atrio J, et al. Mifepristone pretreatment for the medical management of early pregnancy loss. N Engl J Med 2018;378:2162-2170.
In this multicenter, randomized trial, researchers compared the efficacy of pretreatment with mifepristone followed by treatment with misoprostol vs. treatment with misoprostol use alone for managing anembryonic gestation and embryonic or fetal death. Women had to be between five and 12 completed weeks of gestation with a documented intrauterine pregnancy, clinically stable with a closed cervical os, and with a hemoglobin level of at least 9.5 g/dL. Participants received either pretreatment with 200 mg of mifepristone administered orally followed by 800 mcg of misoprostol administered vaginally approximately 24 hours later (mifepristone group), or standard therapy with 800 mcg of misoprostol alone administered vaginally (misoprostol-only group) 24 hours after randomization. The primary outcome was gestational sac expulsion by the first follow-up visit with one dose of misoprostol and no additional surgical or medical intervention within 30 days after treatment. Participants were scheduled for a follow-up visit from 48 hours up to four days after randomization. A transvaginal ultrasound was performed by a blinded investigator. If the gestational sac was absent, the participants were followed for 30 days after treatment. If the gestational sac was present, women were offered a second dose of misoprostol, expectant management, or surgical management. Participants who chose expectant management or a second dose of misoprostol returned for an additional follow-up visit approximately eight days after randomization for evaluation by a blinded investigator and then were followed for a total of 30 days. Other data collected included bleeding, pain, and acceptability of the treatment.
Between May 2014 and April 2017, researchers enrolled 300 women, with 149 assigned to mifepristone pretreatment and 151 to misoprostol only. The treatment was successful by the first follow-up visit, with no additional need for intervention in 124 of 148 women (83.8%; 95% confidence interval [CI], 76.8-89.3) in the mifepristone group and in 100 of 149 women (67.1%; 95% CI, 59.0-74.6) in the misoprostol-only group. For those women who still had a gestational sac, 41% chose expectant management, 27% chose a second dose of misoprostol, and 31% underwent surgical evacuation. Thirty days after randomization, the cumulative rate of gestational sac expulsion with up to two doses of misoprostol was 91.2% (95% CI, 85.4-95.2) in the mifepristone group and 75.8% (95% CI, 68.2-82.5) in the misoprostol-alone group. Thirteen women (8.8%) in the mifepristone group and 35 women (23.5) in the misoprostol-only group underwent surgical evacuation (relative risk, 0.37; 95% CI, 0.21-0.68). There was no difference in the effect of the intervention when stratified by gestation, gravidity, parity, or type of missed abortion. There were no significant differences in mean scores for bleeding intensity or pain between the two groups, and both groups found the treatment acceptable (89.4% mifepristone group vs. 87.4% misoprostol-only group). The number of serious adverse events was no different between the two groups. Three women in the mifepristone group and one woman in the misoprostol-only group required a blood transfusion, and two women in each group were diagnosed with pelvic infection.
COMMENTARY
Early pregnancy loss, also known as missed abortion, typically is defined as an intrauterine pregnancy in the first trimester that is not viable, whether because the gestational sac is empty or because the embryo has no cardiac activity.1 Most commonly, diagnosis is made by ultrasound and the patient may or may not be symptomatic. For women who are stable without hemorrhage or infection, the three main options for the management of early pregnancy failure are expectant management, medical management with misoprostol, and surgical management.
Women’s preferences should guide treatment decisions, given that all three options are medically safe. Overall, the success rates of each method depend on the time allowed for completion. With misoprostol management, the authors of a large U.S. randomized, controlled trial reported success rates of 71% by day 3 with 800 mcg of vaginal misoprostol.2 The success rate was increased to 84% when women took a second dose of 800 mcg of vaginal misoprostol, if needed. Given its efficacy in inducing abortion with misoprostol,3 mifepristone has been researched as a supplementary drug for the treatment of early pregnancy failure to improve patient experience and success rates.4 This is the largest trial to date evaluating the efficacy of combining mifepristone with misoprostol for medical treatment of missed abortion.
The important findings from this study are that pretreatment with mifepristone increased the success of complete evacuation of the uterus without the need for additional medication or surgery. The number of mifepristone doses needed for one additional treatment success (i.e., the number needed to treat) was six. This was true across gestational age categories. Critically, the investigators kept the study population relatively homogeneous in that all women had to have a missed abortion, either an anembryonic pregnancy or embryonic fetal demise. The authors did not include incomplete abortions or inevitable abortions, which have higher success rates with misoprostol alone. The use of mifepristone as a pretreatment to misoprostol certainly will decrease the need for additional visits, ultrasounds, and interventions for those women opting for medical management of their early pregnancy loss.
However, mifepristone is a medication that has carried a U.S. Food and Drug Administration (FDA) Risk Evaluation and Mitigation Strategy (REMS) requirement since its approval in 2000. Typically, REMS requirements are used for drugs associated with the risk of serious complications that cannot be addressed by labeling information alone, and the requirements often limit drug supply. Because of the REMS, mifepristone is not permitted to be sold in retail pharmacies. The medication must be stocked in physician offices or hospitals, and it must be dispensed by a certified prescriber. To become a certified prescriber, the provider must attest to the drug distributor that they can date a pregnancy, diagnose ectopic pregnancy, and provide or refer for surgical evacuation of the uterus if needed. Finally, under the REMS requirement, women must be given an FDA-approved medication guide and sign an FDA-approved patient agreement form outlining the instructions for use and potential risks. Nevertheless, the safety of mifepristone and misoprostol for induced abortion has been well established since 2000. Only 19 deaths have been reported to the FDA out of more than 3 million women who have used mifepristone, and, as in this trial, the rate of hospital admission, blood transfusion, or serious infection is rare.5 Therefore, the REMS restrictions are unnecessary and only make mifepristone more difficult to access for both patients and providers. Mifepristone has many uses in obstetrics and gynecology, having been shown to work for induced abortion with misoprostol, cervical ripening for surgical abortion, and to shorten the duration of labor for induction abortions. With this new indication for the use of mifepristone now established, hopefully we can work on improving the availability of mifepristone across the United States.
REFERENCES
- Committee on Practice Bulletins—Gynecology. The American College of Obstetricians and Gynecologists Practice Bulletin no. 150. Early pregnancy loss. 2015;125:1258-1267.
- Zhang J, Gilles JM, Barnhart K, et al. A comparison of medical management with misoprostol and surgical management for early pregnancy failure. N Engl J Med 2005;353:761-769.
- Schaff EA, Fielding SL, Westhoff C, et al. Vaginal misoprostol administered 1, 2, or 3 days after mifepristone for early medical abortion: A randomized trial. JAMA 2000;284:1948-1953.
- Van den Berg J, Gordon BB, Snijders MP, et al. The added value of mifepristone to non-surgical treatment regimens for uterine evacuation in case of early pregnancy failure: A systematic review of the literature. Eur J Obstet Gynecol Reprod Biol 2015;195:18-26.
- Mifeprex REMS Study Group, Raymond EG, Blanchard K, et al. Sixteen years of overregulation: Time to unburden Mifeprex. N Engl J Med 2017;376:790-794.
