Mifepristone-Misoprostol More Effective Than Misoprostol in Pregnancy Loss

Troy Brown, RN

June 06, 2018

Mifepristone pretreatment followed by misoprostol therapy was more likely to result in expulsion of the gestational sac in women who experienced early miscarriage compared with misoprostol alone, a new study has found.

Medical management of early pregnancy loss is an alternative to uterine aspiration but standard medical treatment with misoprostol commonly results in treatment failure, explain Courtney A. Schreiber, MD, MPH, from the Pregnancy Early Access Center, Division of Family Planning, and the Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, and colleagues.

So they decided to compare the efficacy and safety of pretreatment with mifepristone followed by treatment with misoprostol vs misoprostol use alone for the management of early pregnancy loss. The work is published online June 6 in the New England Journal of Medicine.

"For too many women, misoprostol alone just leads to frustration. I have seen my patients suffer from the insult of the treatment failure added to the injury of the initial loss," said Schreiber in a press release from her institution. "As physicians, we have to do better for these patients, and our new study shows that by combining mifepristone with misoprostol, we can."

Writing in an accompanying editorial, Carolyn L. Westhoff, MD, Columbia University Medical Center, New York City, agrees.

"These results provide strong evidence that the sequential regimen of mifepristone followed by misoprostol is safe and is superior to misoprostol alone in attaining quick treatment success and avoiding an aspiration procedure," she asserts.

"These results support the use of the sequential regimen as the standard of care," she adds.

However, she notes that the US Food and Drug Administration's requirement of a Risk Evaluation and Mitigation Strategy (REMS) for mifepristone unnecessarily limits the drug's availability by preventing retail pharmacies from selling it. Therefore, women who experience a miscarriage "must find a clinician who stocks mifepristone in the office," and therefore timely availability of sequential treatment with mifepristone and misoprostol is not "as simple as it should be," she points out.

NNT With Mifepristone for Additional Success Was 6

The study included 300 women aged 18 years or older with a nonviable intrauterine pregnancy between 5 and 12 completed weeks of gestation diagnosed by ultrasound.

The researchers randomly assigned the participants to receive mifepristone 200 mg by mouth in the office followed by 800 μg of misoprostol, administered vaginally 24 hours later (n = 149) or 800 μg of misoprostol alone on the day of randomization (n = 151). Women in both groups self-administered the misoprostol at home.

Study patients returned for an initial follow-up appointment between 24 hours and 4 days after misoprostol use (trial day 3), at which time they underwent endovaginal ultrasonography and assessment by an investigator who was unaware of the treatment-group assignments.

At an average of 3 days after misoprostol treatment, the rate of treatment success (defined as 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) was 67.1% with misoprostol alone (100 of 149 women) compared with 83.8% (124 of 148) in women with mifepristone pretreatment followed by misoprostol.

Women in whom the gestational sac was not expelled were offered the option of a second dose of misoprostol, expectant management, or surgical management. Of these, 41% desired expectant management, 27% preferred a second dose of misoprostol, and 31% underwent uterine aspiration.

Women who chose expectant management or a second dose of misoprostol returned for another follow-up visit approximately 8 days after randomization.

The number of mifepristone doses needed for one additional treatment success (ie, the number needed to treat) was 6.

By 30 days, 8.8% of the women who had received mifepristone pretreatment underwent uterine aspiration compared with 23.5% of the women who had received misoprostol alone (relative risk, 0.37).

Most Women Satisfied, Would Use Medical Management Again

The researchers telephoned all participants approximately 30 days after randomization to inquire about additional treatments or adverse events.

On a scale of 1 to 3, mean scores for bleeding intensity (1.8 in both groups) and pain (2.7 in both groups) did not differ significantly between the groups.

Serious adverse events occurred rarely and other side effects were similar in the two treatment groups, with the exception of more vomiting reported among women who received mifepristone pretreatment than among those who received misoprostol alone (27% vs 15%).

At the trial's end, close to 90% of women in both groups said their overall experience had been "good" or "neutral"; 87.0% of those in the mifepristone-pretreatment group said they would recommend their treatment method to a friend, compared with 89.6% of women in the misoprostol-alone group.

Most of the women (>65% in both cases) said they would use medical management if they experienced another pregnancy loss.

The researchers say their results are likely generalizable because the study population was diverse in terms of sociodemographic status and pregnancy diagnosis;  in addition, the assessing investigator was not aware of the treatment-group assignments, so they don't believe the lack of a placebo group introduced bias.

REMS Not Needed With Mifepristone, Will Decrease Use of Effective Regimen

Medical management should never be the only treatment for women with miscarriage, Westhoff writes in her editorial. Women who are bleeding heavily and women who prefer surgical management should have prompt access to aspiration, she notes — either in the emergency department for symptomatic women or in the clinic for asymptomatic women.

But for women who prefer it, this trial "supports a better approach for women who want medical management for miscarriage," she observes.  

However, the REMS restriction on mifepristone places "a burden on both women and clinicians that would delay care and surely decrease the use of this safer, more effective treatment regimen," she observes, noting that REMS restrictions are intended for drugs shown to have serious adverse effects.

"But extensive clinical experience with mifepristone indicates that there is no need for such restrictions," she contends.

One coauthor reports receiving personal fees from Danco Laboratories, outside the submitted work. The remaining coauthors have disclosed no relevant financial relationships. Westhoff reports receiving personal fees from Planned Parenthood, personal fees and nonfinancial support from Merck, personal fees from Bayer, personal fees from Agile Therapeutics, personal fees from Cooper Surgical, personal fees from Allergan, and personal fees from Elsevier, outside the submitted work. Westhoff reports Columbia University receives and manages research funding from Leon Farma, Mithra, Medicines360, and ContraMed for phase 3 trials and says none of these companies have products related to the drugs in this study.

N Engl J Med. Published online June 6, 2018. Abstract, Editorial

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