Clinical Implications of the PROLONG Study

For clinicians who provide prenatal care, the subject of progesterone injection for prevention of preterm birth has been controversial in recent months, and for their patients, it has been confusing. The reason is a series of events that began unfolding in late 2019:

• Results from the PROLONG (Progestins Role in Optimizing Neonatal Gestation) trial were published, which contradicted previous evidence of the safety and efficacy of progesterone supplementation for selected patients.
• Based on those negative findings, an advisory panel to the US Food and Drug Administration (FDA) recommended withdrawing Makena (17-OHPC) — the drug approved in the United States for preventing preterm birth — from the market.
• Guidelines from the American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine (SMFM) supporting 17-OHPC injections for pregnant women with a history of spontaneous preterm birth were reaffirmed.

How to counsel patients with questions

“Initially, we heard from providers who wanted to know how to respond to concerns from patients about 17-OHPC,” says Edward Chien, MD, MBA, Chair of the Department of Obstetrics and Gynecology. “We developed talking points to help them answer questions that women typically have about the PROLONG study.”

Counseling at Cleveland Clinic focuses on the safety and efficacy of 17-OHPC (17-alpha-hydroxyprogesterone caproate) injections for selected patients, the significant limitations of the PROLONG trial, and the fact that Makena remains on the market. The physicians in Dr. Chien’s department continue to follow the clinical guidance from ACOG and from SMFM.

Says Dr. Chien, “We explain to our patients that although PROLONG didn’t show a benefit for 17-OHPC, the population studied was very different than the women in the report by Meis and colleagues. The rate of preterm birth at less than 35 weeks also was significantly lower in the control group in PROLONG — 11.5% versus 54.9% in the earlier study.”

Comparing results from published trials

The Meis study, published in 2003, was conducted at 19 university-based medical centers in the United States and supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units (MFMU) Network. The authors found that weekly intramuscular injections of 250 mg 17-OHPC reduced risk of preterm birth by approximately 34% in women with a history of spontaneous preterm birth. Evidence of the drug’s efficacy was considered so robust that the trial was stopped early, after enrolling 463 women.

In 2011, based on results from that research and three smaller studies, the FDA granted accelerated approval for 17-OHPC and an Orphan Drug Designation. A year later, ACOG issued a practice bulletin supporting use of progesterone supplementation in women with a prior spontaneous preterm birth.

Like the MFMU trial, PROLONG was a randomized, placebo-controlled trial but it was conducted at 93 facilities — 41 in the United States and 52 in other countries. It demonstrated no statistical difference in the co-primary outcome of preterm birth < 35 0/7 weeks’ gestation for the injections (17-OHPC 11.0% versus 11.5%; relative risk 0.95; 95% confidence interval 0.71-1.26; P = 0.72). Rates of preterm birth < 37 weeks and < 32 weeks also were no different between 17-OHPC and placebo.

In its statement on the trial’s results, ACOG posited that, “a possible unintentional selection bias may have occurred in women enrolled in the United States that resulted in women with a higher risk for recurrent preterm birth not being offered or agreeing to participate in the PROLONG study in order to avoid the risk of not receiving active 17-OHPC treatment.”

Says Dr. Chien, “The US patients enrolled in the PROLONG study probably didn’t have the same risk characteristics as the women in the MFMU study.” If patients ask about the FDA advisory panel, he also notes that the majority of obstetric providers on it voted in support of use of keeping 17-OHPC on the market.

“Other treatments are available for pregnant women with short cervices, but progesterone is really the only medication we can offer, at this point, to women with normal cervical length who have had a previous preterm birth,” says Dr. Chien.

Research is underway on ways to prevent prematurity. Randomized clinical trials supported by MFMU include TOPS, which is looking at pessary in singleton pregnancies in women with short cervices, and PROSPECT, which is looking at pessary and progesterone in twin gestation. Both are currently recruiting.

Cleveland Clinic provides the following talking points for counseling patients about PROLONG and progesterone supplementation.

Progesterone for Preterm Birth: PROLONG Study Response

• An FDA panel recently recommended to remove this medication from the market based on the findings of the PROLONG study.
• It’s important to clarify that this was an advisory committee vote and the FDA has not taken actual action on the status of the drug.
• We believe this treatment will remain on the market because it’s still proven to be safe for patients.
• More research is needed before any change on the status of the drug is made.
• Cleveland Clinic will continue to offer synthetic progestin injections as a treatment option to our patients.
• We are following clinical guidance from the American Congress of Obstetricians and Gynecologists (ACOG), the nation’s leading professional association for physicians providing healthcare for women.