From Pages to Practice

By MaryAnn Wilbur, MD, MPH, MHS

Published May 18, 2022


Women who present with vaginal bleeding during a desired early pregnancy often fear that the bleeding represents the beginning of a miscarriage. A miscarriage — or spontaneous abortion (SAB) — is often preceded by vaginal bleeding or spotting. When a patient presents in this manner and the ultrasound findings are reassuring for an early intrauterine pregnancy (cavitary gestational sac, yolk sac, embryo and a heartbeat, if timing is applicable), she is diagnosed with a threatened SAB. Then what? We check her Rh status, give her Rhogam if indicated, and send her on her way. However, this management is often unsatisfying for both patient and provider. The patient may look at you and ask, “Isn’t there anything that you can do?”

We know that progesterone is important for maintaining an early pregnancy, at least until approximately 8–10 weeks of gestation, when the early placenta takes over. Data also suggest that progesterone, either administered vaginal or intramuscularly (IM), can prevent preterm delivery in patients with a history of preterm birth. However, few data address treatment with progesterone among women with bleeding in early pregnancy. At Johns Hopkins Hospital, we do not give IM progesterone to such patients. However, some providers prescribe vaginal progesterone.

In a large randomized, placebo-controlled trial published in NEJM, researchers evaluated vaginal progesterone in 4153 women with vaginal bleeding in early pregnancy. Participants received either standard care (observation alone) or vaginal progesterone (400-mg vaginal suppository twice daily) from the time bleeding started until 16 weeks of gestation. The primary outcome — the incidence of live births at 34 weeks or later — did not differ significantly between the two groups.

Sadly, the appropriate but uncomfortable response to such patients remains, “No, I’m sorry. Currently, there is nothing we can do to reduce the risk of miscarriage.” On a positive note, you can now feel more confident in this response.

The following NEJM Journal Watch summary provides more details of the trial and findings.


Progesterone Was Ineffective Against Threatened Miscarriage

In a large randomized trial, vaginal progesterone was no better than placebo for bolstering live birth rates.

Some 20% of pregnancies end in miscarriage (spontaneous loss after recognition of a clinical pregnancy and before 20 weeks' gestation), and exogenous progesterone has produced inconsistent results. To test whether vaginal progesterone could increase the likelihood of live birth in the setting of threatened miscarriage, U.K. investigators randomized 4153 women (age range, 16–39) with vaginal bleeding before 12 weeks' gestation and a sonographically identified intrauterine gestational sac to progesterone (400-mg vaginal suppository twice daily) or placebo through 16 completed weeks.

Rates of live birth after ≥34 weeks' gestation did not differ between the progesterone and placebo groups (75% and 72%; relative rate, 1.03; P=0.08). Likelihood of maternal obstetric adverse events and neonatal congenital anomalies was also similar between groups.

Comment: Several small clinical trials with methodologic limitations have indicated that progestogen supplementation increases live birth rates in women with threatened miscarriage (Cochrane Database Syst Rev 2018 Aug 6; [e-pub]). By contrast, this large trial showed that vaginal progesterone through 16 weeks' gestation did not raise live birth rates by ≥5%. Furthermore, in a large trial involving women with ≥3 recurrent miscarriages, vaginal progesterone was similar to placebo (NEJM JW Womens Health Dec 2015 and N Engl J Med 2015; 373:2141). Taken together, these findings indicate that, if progesterone is beneficial, its effect size is relatively small. Accordingly, I do not recommend progesterone treatment for women with threatened or recurrent miscarriage.

Browse more From Pages to Practice 

MaryAnn Wilbur was a 2015-2016 NEJM Editorial Fellow. She is now a clinical fellow in Gynecologic Oncology at Johns Hopkins Hospital. MaryAnn graduated with a combined MD/MPH from Boston University in 2011 and completed residency training in Gynecology & Obstetrics at Johns Hopkins Hospital in June 2015. Her areas of interest include women’s health issues and health outcome disparities.