November 08, 2019
3 min read

FDA may withdraw approval of drug that manufacturer says prevents preterm birth

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Sean Blackwell
Sean C. Blackwell

An FDA advisory committee recently voted in favor of withdrawing the agency’s approval of Makena, a synthetic progestin, for the prevention of preterm birth in pregnant women who have a history of preterm birth.

According to Amag Pharmaceuticals, which manufactures Makena, the FDA committee came to its decision after a confirmatory trial concluded that the treatment did not decrease the risk for recurrent preterm birth. The findings contradict those that led the FDA to approve an injectable form of the drug in 2011.

Sean C. Blackwell, MD, of the department of obstetrics, gynecology and reproductive sciences at McGovern Medical School-UTHealth in Houston, was an investigator on the confirmatory trial. He explained to Healio Primary Care that the differences in the study cohorts likely explains the different results.

“In the first study, 60% of the women were black, more of them had a history of preterm birth and their socioeconomic status put them at high risk for preterm birth,” he said. “In the newer study, 80% of the women were white, most were from outside the United States, most had a higher socioeconomic status and about 50% fewer women had a preterm birth.”

Pregnant women in hospital 
An FDA advisory committee recently voted in favor of withdrawing the agency’s approval of Makena, a synthetic progestin, for the prevention of preterm birth in pregnant women who have a history of preterm birth.

Hyagriv Simhan, MD, of the department of obstetrics, gynecology and reproductive science at the University of Pittsburgh Medical Center, who was not affiliated with either study of the treatment, said the confirmatory trial was not enough to justify the FDA committee vote.

“The population [in the confirmatory trial] was at lower risk, demonstrating the effect of the treatment required a larger sample size,” Simhan told Healio Primary Care. “The authors themselves admit that their study was underpowered compared to previous trials.”

Blackwell noted that since the treatment has become the standard of care in the U.S. for preventing preterm birth in pregnant women with a prior history of spontaneous preterm birth, the FDA mandated that most of the confirmation trial’s participants be from outside America.

He discussed the conflicting results.

“It could be that one of the studies is wrong. It could be both studies are right,” Blackwell said. “I’m in the group that thinks the treatment still works in patients with a very high risk of preterm birth. But my ability to clearly prove that is limited.”

Societies’ stances

The Society for Maternal-Fetal Medicine (SMFM) and the American College of Obstetricians and Gynecologists (ACOG) contend that the treatment Ccan still be administered under the right circumstances.

“It is reasonable for providers to continue to use 17-OHPC in the context of a shared decision-making model that includes consideration of risk level for recurrent [preterm birth],” SMFM said in a statement. “Important factors to discuss include: uncertainty regarding the benefit, the lack of short-term safety concerns, the possibility of injection site pain, extra patient visits, and substantial costs.”

In a separate statement, ACOG said physicians “should take into account the body of evidence for progesterone supplementation, the values and preferences of the pregnant woman, the resources available and the setting in which the intervention will be implemented.”

Next steps

A date for a full FDA decision has not been set. Although the agency is not required to follow the committee’s recommendation, it has done so in the past — examples include the use of brexanolone for postpartum depression and romosozumab for osteoporosis.

Hyagriv Simhan
Hyagriv Simhan

Simhan said he hopes the FDA considers all the evidence when deciding the treatment’s future, not just selected pieces of it.

“We have one underpowered negative trial that we need to place into context,” he said. “The extant body of literature that existed even before the approval was positive.”

He said that if the FDA withdrew its approval, Amag Pharmaceuticals would likely cease production of its hydroxyprogesterone caproate injection. Should that occur, he hoped that additional generics or a compounded version of the drug, could emerge.

“The lack of FDA approvals for an obstetrical indication is not so unusual for us,” he said. “There are innumerable examples of drugs where we have excellent safety data and decades of obstetrics experience but are not under the auspices of the FDA. If obstetricians only worked with drugs that were FDA approved there would be so much regarding mom and baby that we could not do.”

Blackwell said that depending on an individual patient’s needs and previous safety data, he would also still prescribe the treatment without FDA approval. “Obstetricians are used to giving their pregnant patients off-label uses of drugs. It’s all about improving outcomes.” – by Janel Miller


Blackwell SC, et al. Am J Perinatol. 2019;doi:1055/s-0039-3400227.

FDA. Advisory committee briefing materials: Available for public release. Accessed Nov. 7, 2019.

Meis PJ, et al. N Engl J Med. 2003.June 12;348(24):2379-85.

Disclosures : Blackwell and Simhan report no relevant financial disclosures.