Preterm birth represents a significant cause of morbidity and mortality, disproportionately impacting percentage of preterm births among Black pregnant people (14.8%) compared to white (9.5%) or Hispanic (10.2%) pregnant people in the U.S. Progesterone has been used for the last 20 years to reduce the risk of preterm birth. However, the FDA recently withdrew 17-hydroxyprogesterone caproate (17-OHPC or Makena) from the market for lack of efficacy, prompting the maternal-fetal medicine specialists at Northwest Perinatal Center (NWP) to review treatment options.


In patients with a history of a spontaneous preterm birth (either due to preterm labor or PPROM), progesterone therapy was historically recommended to start between 16-20 weeks. The FDA granted 17-OHPC accelerated approval in 2011 based on a trial published by Meis et al in 2003, and it has been the progesterone of choice. That trial showed a 30% reduction in risk of recurrent preterm birth. Subsequent studies failed to replicate the initial success rates found in the Meis trial for 17-OHPC. A more recent study, the PROLONG trial, found that 17-OHPC was not effective at all in prevention of preterm birth or reduction in neonatal morbidity. The lack of benefit found in the PROLONG trial called into question the efficacy of 17-OHPC in prevention of preterm birth.

In October of 2020, the FDA advisory panel recommended withdrawal of 17-OHPC from the market. In October of 2022, the FDA voted to approve the advisory panel’s recommendation 14-1. As of April 5, 2023, the FDA issued a final decision to remove approval of 17-OHPC and required its withdrawal from the market, effective immediately.

Studies using alternative forms of progesterone, including vaginal progesterone in pill or capsule form (Prometrium) and gel form (Crinone), demonstrated mixed results. A meta-analysis published in 2021 failed to show a benefit when using vaginal progesterone for preterm birth prevention in the absence of cervical shortening. For this reason, ACOG no longer recommends the use of vaginal progesterone for the prevention of preterm birth in the absence of cervical shortening. SMFM supports its use with shared decision-making.

Cervical length screening is recommended typically between 16-24 weeks to evaluate the risk of preterm birth in the current pregnancy. Vaginal progesterone therapy initiated by 24 weeks gestation continues to demonstrate efficacy in reducing the risk of preterm birth among pregnant people with a short cervix <25 mm.

Further review of the current literature reveals that there is no appreciable increase in the predictive value of transvaginal cervical length when performed serially. In addition, other findings such as funneling of the internal os and change with fundal pressure do not add to the predictive value of the exam. The presence of intraamniotic “sludge” or “debris” does appear to be associated with a higher risk of spontaneous preterm birth.

There continues to be evidence of benefit of cerclage placed in the setting of a history of preterm birth prior to 32 weeks gestation and a short cervix. This evidence is greatest when the cervical length measures <15 mm prior to 24 weeks gestation. Therefore, there may be some high-risk patients for whom NWP will continue to recommend serial cervical length measurements.


After review of the available evidence, FDA actions, and national recommendations, NWP is adjusting its traditional approach to management of preterm birth prevention strategies.


1. People with a history of preterm birth

Discussion of the use of vaginal progesterone for primary prevention of recurrent PTB without input of cervical length or in those with a cervical length of 25 mm or greater should include a shared decision-making process. Factors that should be discussed as part of shared decision-making include:

  • Gestational age of prior preterm birth
  • Use of progesterone in a prior pregnancy
  • Number of prior spontaneous PTBs
  • Outcome of most recent pregnancy (i.e., preterm vs term)

2. When to order TVUS CL

Offer a single transvaginal ultrasound cervical length measurement to people with a history of spontaneous preterm birth prior to 37 weeks gestation, ideally at the time of anatomic survey. For people with a history of preterm birth <32 weeks gestation or a history of cerclage, consider NWP consultation to make additional recommendations for cervical length screening.

3. People with a short cervix

Vaginal progesterone is recommended for a pregnancy complicated by short cervix <25 mm through 24 weeks gestation. Prometrium 200mg per vagina is the recommended formulation.

Please find a revised algorithm here. Our team is continuing to monitor the data and published guidelines—and we are available to discuss the risks, benefits and alternatives with you and/or your patients at any time.