Progesterone Does Not Prevent Recurrent Miscarriage

Troy Brown, RN

November 25, 2015

Vaginal progesterone during the first trimester of pregnancy in women with unexplained recurrent miscarriages did not increase the rate of live births or improve newborn survival, according to a new multicenter, double-blind, placebo-controlled, randomized trial.

"Unexplained recurrent miscarriage is associated with substantial adverse clinical and psychological consequences for the women and their families," the researchers write. "Various therapeutic strategies to increase the rate of live births among these women have been evaluated, but no effective treatment has been identified."

Arri Coomarasamy, MB, ChB, MD, from the College of Medical and Dental Sciences, University of Birmingham, United Kingdom, and colleagues report their findings in an article published in the November 26 issue of the New England Journal of Medicine.

The researchers defined recurrent miscarriages as three or more consecutive or nonconsecutive pregnancy losses in the first trimester. The Progesterone in Recurrent Miscarriages (PROMISE) study included a total of 836 women who conceived naturally within 1 year of recruitment to the study. The researchers randomly assigned the women to receive micronized progesterone 400 mg (n = 404) or placebo (n = 432) by vaginal suppository twice daily, beginning no later than 6 weeks' gestational age and ending at 12 weeks' gestational age.

The study's primary outcome was live births after 24 completed weeks of gestation. The rate of live births after 24 weeks of gestation was 65.8% (262 of 398 pregnancies) in the group that received progesterone and 63.3% (271 of 428 pregnancies) in the group that received placebo (relative rate, 1.04; 95% confidence interval [CI], 0.94 - 1.15; absolute rate difference, 2.5 percentage points; 95% CI, −4.0 to 9.0).

The rates of clinical pregnancy (at 6 - 8 weeks), ongoing pregnancy (at 12 weeks), ectopic pregnancy, miscarriage, stillbirth, and neonatal outcomes did not differ significantly between the groups, nor did the median gestational age at miscarriage.

In the two groups combined, 533 pregnancies advanced to live birth after 24 weeks, and 10 (3.8%) of 262 pregnancies in the progesterone group and 10 (3.7%) of 271 pregnancies in the placebo group were delivered before 34 weeks (relative risk, 1.03; 95% CI, 0.44 - 2.45).

The rate of adverse events did not differ significantly between the two groups.

"[O]ur trial showed no significant increase in the rate of live births with the use of vaginal progesterone in the first trimester of pregnancy among women with recurrent miscarriages," the authors conclude. "Our results do not support the earlier findings of a Cochrane review that suggested a benefit of progesterone therapy in the first trimester among women with recurrent miscarriages."

"Interventions Not Targeting an Abnormality Are Rarely Helpful"

"[T]here are three key lessons that we can learn from this study," Zev Williams, MD, PhD, director, Program for Early and Recurrent Pregnancy Loss, assistant professor, Department of Obstetrics & Gynecology and Women's Health, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York, told Medscape Medical News. Dr Williams was not involved in the study.

"The first is that in a low-risk and properly screened and monitored population, even after two losses, the chances of having a successful pregnancy are very good, greater than 60%. The second important point is that in this low-risk and monitored population, providing supplemental vaginal progesterone does not appear to confer...protection against future miscarriage," he said.

"The final point is that this study is a reminder of how easy it is to mistakenly come to believe that a therapy has benefit, as over 60% of those women who had three or more miscarriages went on to have a healthy pregnancy, and therefore we need to be cautious to practice evidence-based treatments and avoid interventions, particularly ones that can be potentially dangerous, that have only anecdotal reports of success," Dr Williams explained.

"In general, we find that when it comes to recurrent miscarriage management, there is 'normal' and 'abnormal,' but no 'super normal.' If an abnormality is identified, such as thyroid disease or a uterine anomaly, it should be corrected, but interventions not targeting an abnormality are rarely helpful and may be harmful," he added.

"The study highlights the critical importance of genetic testing of miscarriage tissue for aneuploidy. If aneuploidy is found in the miscarriage sample and the parents carry no cytogenetic abnormalities, the prognosis for future pregnancies is excellent, while if the miscarriages are euploid, a careful evaluation for other causes of miscarriage is warranted," Dr. Williams concluded.

One author reports grant support from Ferring BV and ZoNMW, and grant support and personal fees from Merck Sharp & Dohme outside the submitted work. The remaining authors and Dr Williams have disclosed no relevant financial relationships.

N Engl J Med. 2015;373:2141-2148. Abstract

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