By Katherine Rivlin, MD, MSc
Assistant Professor, Obstetrics and Gynecology, The Ohio State University Medical Center, Columbus
SYNOPSIS: In this prospective, double-blind, randomized, placebo-controlled trial, pretreatment with 200 mg of mifepristone 24 to 48 hours before labor induction using misoprostol significantly reduced time to delivery among demised fetuses between 14 and 28 weeks of gestation. Maternal complications were equivalent in both groups.
SOURCE: Allanson ER, Copson S, Spilsbury K, et al. Pretreatment with mifepristone compared with misoprostol alone for delivery after fetal death between 14 and 28 weeks of gestation: A randomized controlled trial. Obstet Gynecol 2021;137:801-809.
Mifepristone, a progesterone antagonist, increases myometrial and cervical sensitivity to prostaglandins. A combination of mifepristone followed by misoprostol 24 to 48 hours later (when prostaglandin receptors have been primed) works well in both first- and second-trimester medication abortion. In the second trimester, this two-dose regimen shortens the length of labor induction and reduces the dose of misoprostol needed when compared to misoprostol alone for induced abortion.1
Less is known about the utility of mifepristone following a fetal demise, and whether blocking the progesterone receptor adds benefit. The authors hypothesized that pretreatment with 200 mg of mifepristone 24 to 48 hours before labor induction with misoprostol could significantly decrease the interval to delivery when compared to placebo among demised fetuses from 14 to 28 weeks of gestation. From 2013 to 2016, the study team screened patients with a demised fetus between 14 and 28 weeks of gestation admitted to King Edward Memorial Hospital in Perth, Western Australia, for enrollment. Initially, the authors designed the trial to include pregnancies between 14 and 24 weeks of gestation, but enrollment was slow. After eight months of recruitment, they expanded eligibility to include pregnancies 14 to 28 weeks of gestation. The primary aim of the study was to compare the time interval from initial misoprostol administration to delivery of the fetus between the mifepristone group and the placebo group. Secondary aims included the incidence of maternal side effects, such as postpartum blood loss, placental retention, need for manual placental extraction, blood transfusion, febrile illness, antiemetic and analgesic use, and patient satisfaction.
The investigators included patients with confirmed fetal demise between 14 0/7 and 28 6/7 weeks of gestation. If the gestational age was unknown, a crown rump length of 85 mm was the lower limit for inclusion. They excluded participants taking corticosteroids, with documented allergies to misoprostol or mifepristone, with a history of three or more cesarean deliveries, with ruptured membranes, in spontaneous labor, and participants who did not speak English or were unable to provide written consent. They randomized consenting participants in a 1:1 ratio to take 200 mg mifepristone or an identical placebo 24 to 48 hours before misoprostol administration. Investigators, participants, and study staff all were blinded to the randomization group. Then, participants left the hospital and returned at the time of their misoprostol induction. The protocol included administration of 400 mcg misoprostol vaginally every six hours for pregnancies between 14 and 24 weeks of gestation, and 200 mcg misoprostol vaginally every four hours for pregnancies between 24 and 28 weeks of gestation.
In the United States, the Society of Family Planning generally recommends labor induction in the second trimester using 400 mcg of misoprostol administered vaginally or sublingually every three hours or at higher doses than those used in this study.2 All participants received 10 units of oxytocin intramuscularly following delivery. Participant hemoglobin and hematocrit were checked before induction of labor and again 24 hours after delivery. The study staff recorded vital signs throughout labor induction and measured nausea and pain through a visual analogue scale. Upon discharge, all participants completed a satisfaction questionnaire about their experiences. Initially, the study team planned to enroll 232 participants, but after three years of slow recruitment, they made a pragmatic decision to end the study at 66 participants. This decision affected their power calculation in that they were unable to find differences in subgroups of participants.
Among the 66 participants randomized, the median time to delivery was shorter in the mifepristone group (6.5 hours) compared to the placebo group (10.5 hours) (hazard ratio, 2.41; 95% confidence interval, 1.39-4.17; P = 0.002). The mifepristone group received fewer doses of misoprostol compared to the placebo group (2.1 vs. 3.4; P = 0.002) and less total misoprostol (767.7 mcg vs. 1,181.8 mcg; P = 0.003). There were no significant differences between the two groups in length of the third stage of labor, estimated blood loss, hemoglobin and hematocrit before or after delivery, or in vital signs. Procedure complications and readmissions were the same in both groups. On a scale from 0 to 10 (where 0 is “much better than expected” and 10 is “much worse than expected”), participants in the placebo group rated the question “What did you think of the procedure?” worse than those in the mifepristone group (mean score, 7.8 vs. 6.3; P = 0.035). Participants in both groups answered all other questions similarly.
COMMENTARY
This study adds to a growing body of literature supporting mifepristone as an adjunct to misoprostol for pregnancy termination.1,3 Time and again, the two-dose regimen is superior to misoprostol alone, almost regardless of context — in the first trimester, the second trimester, for medication abortion, for miscarriage management, or for fetal demise.4-6 Although this study ended before the team could recruit even a third of planned participants, they achieved their intended outcome of a 30% reduction in median duration of labor.
One negative consequence of ending enrollment early was insufficient power to show a difference in adverse events. The team did show improved satisfaction in the mifepristone group, even with a small sample size. Perhaps with sufficient power, they could have shown more. This lack of power to detect differences in adverse events matters because the serious adverse risk profile of mifepristone is important. In 2000, the Food and Drug Administration approved mifepristone for use as part of a two-dose regimen with misoprostol for first-trimester medication abortion. This approval came in conjunction with the Risk Evaluation and Mitigation Strategy (REMS) requirements, whose purpose was to mitigate the serious risks associated with the drug. To comply with the REMS, prescribers must review the patient agreement form with the patient and provide them with a medication guide, which details the safe use of mifepristone. Then patients must sign the patient agreement form in the presence of the provider and indicate that they have received risk counseling. The REMS also specifically restricts the use of mifepristone to “clinics, medical offices, and hospitals” and bars its dispensing from retail pharmacies.7 The American College of Obstetricians and Gynecologists calls the REMS requirements “outdated” as they “substantially limit access to this safe, effective medication.”8 This study, and countless others like it, indicates that not only does mifepristone bring minimal risk, it may actually prevent harm — in this case it lowers the dose of misoprostol required, shortens labor, and improves patient satisfaction. In clinical practice, when mifepristone is easily available, this study clearly supports its use when inducing labor for fetal demise between 14 and 28 weeks. It shortens labor induction intervals and improves patient satisfaction. Yet whether mifepristone is easily available, unfortunately, has everything to do with burdens created by the REMS and little to do with the risk profile of the medication.
REFERENCES
- Ngoc NT, Shochet T, Raghavan S, et al. Mifepristone and misoprostol compared with misoprostol alone for second-trimester abortion: A randomized controlled trial. Obstet Gynecol 2011;118:601-608.
- Borgatta L, Kapp N, Society of Family Planning. Clinical guidelines. Labor induction in the second trimester. Contraception 2011;84:4-18.
- Kulier R, Kapp N, Gülmezoglu AM, et al. Medical methods for first trimester abortion. Cochrane Database Syst Rev 2011;2011:CD002855.
- Schreiber CA, Creinin MD, Atrio J, et al. Mifepristone pretreatment for the medical management of early pregnancy loss. N Engl J Med 2018;378:2161-2170.
- Chaudhuri P, Datta S. Mifepristone and misoprostol compared with misoprostol alone for induction of labor in intrauterine fetal death: A randomized trial. J Obstet Gynaecol Res 2015;41:1884-1890.
- Bracken H, Ngoc NT, Ha DQ, et al. Mifepristone pretreatment followed by misoprostol 200 mcg buccal for the medical management of intrauterine fetal death at 14-28 weeks: A randomized, placebo-controlled, double blind trial. Contraception 2020;102:7-12.
- Risk Evaluation and Mitigation Strategy (REMS) Single Shared System for Mifepristone 200mg 2019. https://www.accessdata.fda.gov/drugsatfda_docs/rems/Mifeprex_2011-06-08_Full.pdf
- The American College of Obstetricians and Gynecologists. Improving access to mifepristone for reproductive health indications. Published June 2018. https://www.acog.org/clinical-information/policy-and-position-statements/position-statements/2018/improving-access-to-mifepristone-for-reproductive-health-indications
In this prospective, double-blind, randomized, placebo-controlled trial, pretreatment with 200 mg of mifepristone 24 to 48 hours before labor induction using misoprostol significantly reduced time to delivery among demised fetuses between 14 and 28 weeks of gestation. Maternal complications were equivalent in both groups.
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