US mothers face uncertainty as lone, unproven drug for preterm birth pulled

Makena is the only drug approved specifically to prevent premature birth, a major health issue facing children and families, in the US. In the 12 years since it was fast-tracked by the US Food and Drug Administration (FDA), hundreds of thousands of patients in America have received injections of Makena, which is about 5,200% more expensive than generic versions of the same medication.

There was just one problem: there’s no evidence Makena actually works.

After years of crossfire with the FDA, Swiss drugmaker Covis announced earlier this month that Makena would be pulled from the market, since a major study focused on the drug indicated it had no benefit.

One in 10 babies are born early in the United States, and preemies may experience lifelong health and development issues, in addition to the economic and emotional costs of premature birth. There are also dramatic disparities among those born too soon. While 9.2% of white infants are born early, 14.2% of Black infants and 11.6% of American Indian and Alaska Natives infants are born before 37 weeks of gestation in the US, according to 2021 data from the March of Dimes.

To address this pressing issue, the FDA granted accelerated approval for Makena in 2011, allowing patients to access the medication while the injection was studied for effectiveness. An estimated 350,000 people in the US with singleton pregnancies and a history of preterm birth have since received the shots.

Makena is a synthetic version of the hormone progesterone, which has been in use since the 1950s. In 2003, a small study funded by the US National Institutes of Health found that synthetic progesterone injections, which were then available as generic formulations, could help reduce the risk of preterm birth.

A pharmaceutical company then sought to brand the synthetic hormone as the drug Makena, citing the 2003 study to seek fast-tracked approval. It was granted in 2011, with the requirement that the drugmaker conduct more in-depth research into the medication’s effectiveness.

Generics existed before Makena was created, with price tags of $10 to $20 per weekly dose from compounding pharmacies, compared to Makena’s $1,500-a-dose price tag. At an average cost over the course of pregnancy of $10, 917 compared to the generic cost of $206, Makena was about 5,200% more expensive, researchers found.

Yet a larger study, published in 2019, showed no benefit. The preterm birth rate was not lower among those who received the shots, and their babies were not healthier – even as the shots put patients at risk of complications like blood clots and depression.

Independent FDA advisers recommended in 2019 that Makena should be pulled from the market. But the maker of Makena appealed the decision, kicking off a lengthy review process.

In October 2022, the drugmaker made its case to keep Makena on the market during three days of public hearings – an unusual occurrence that only happens when a company resists FDA calls to remove a drug.

But a panel of independent advisers ultimately voted once again to remove Makena from the market – four years after the study showed no effect.

When her water broke at 26 weeks and her second baby was born three weeks later, Kathleen Nitz, a mother of three in Maryland, was “in total shock”, she said. “I was terrified.”

Her second son endured long weeks in the neonatal intensive care unit, and she knew many preemies face even greater challenges. “I would never want anyone to experience what we went through with [him], let alone anything worse,” she said.

When she became pregnant again, she received Makena injections, starting in the second trimester, until she was 37 weeks along.

“I was very scared all the time,” she said. “I would wake up every day and be like, ‘This could be it, this baby could be coming today,’ even when nothing would seem to indicate that was going to happen.”

To her relief, her third baby was born full-term, just four days before his due date.

It’s not clear whether the shots helped, she said. “I don’t believe it hurt – if anything it helped.”

Patients and providers are disappointed to lose the only specific treatment for preterm birth, but other medications and procedures can also help, and the removal of Makena could also open up the market for a more effective treatment, experts said.

“It’s a little bit disheartening for patients not to have something else as an option, but at the same time, patients don’t want to be taking something that’s not got efficacy to it,” said Thomas McElrath, associate professor of obstetrics and gynecology at Harvard Medical School and of epidemiology at Harvard’s School of Public Health, and an attending in maternal-fetal medicine at Brigham and Women’s Hospital.

In 2019, after the Makena study came out, he would explain the results to patients, and most of them elected not to get the shots. When the FDA withdrew its recommendation for use of Makena, McElrath said, he stopped offering it entirely, especially since interest had waned with the lack of evidence.

While some argue that removing the drug could worsen disparities, others argue that keeping an ineffective treatment does greater harm.

“I think that when we leave something on the market that hasn’t been shown to be effective, we lose out on other investigations that might be pursued,” Dr Anjali Kaimal, an obstetrician and administrator at the University of South Florida, said during the hearings last fall.

At the meeting in October, Covis argued that its 2019 study was flawed, particularly because it had a lower proportion of Black patients, who have the highest rates of preterm birth in the US. Black patients represented 59% of patients in the 2003 study, compared to 7% in the larger international study. Further research is needed to understand whether and how the medication might be useful to racially minoritized groups at risk, Covis said.

One reason for higher rates of premature birth among patients of color isn’t biology but racism – before, during and after pregnancy.

“Black mothers are more likely to have children with adverse birth outcomes than white mothers, regardless of their social standings,” said Asha Hassan, researcher at the University of Minnesota’s Center for Antiracism Research for Health Equity.

“It’s not always just about what resources you immediately have access to, but about what your history is and about the experiences of racism that build up in the body over the course of generations,” she said. The lifetime accumulated stress of discrimination over a lifetime takes a physical toll, research shows.

Health care providers may not realize they are treating some patients differently because of implicit bias. That can take the form of doctors dismissing symptoms that later lead to serious complications.

There are also structural issues around access to health care and insurance, with 10% of Black pregnant people receiving very late or no prenatal care in 2019 – more than double the rate of their white peers.

Changes to the reproductive health landscape in the US, including the loss of access to abortion care, will likely worsen birth outcomes, including neonatal and maternal mortality – particularly among people of color. Maternal mortality rose sharply in 2021, and Black patients were 2.6 times more likely to die than white patients, according to new data from the US Centers for Disease Control and Prevention (CDC).

“A lot of people don’t understand or realize that pregnancy is a dangerous experience for many people,” Hassan said.

While Makena was the only medication specifically approved to prevent preterm birth, other medications and procedures have a long history of helping reduce risks.

One of the few interventions that has a “clear benefit” for preventing preterm birth and perinatal death was midwifery care, according to a Cochrane review from 2018 – pointing to a non-pharmaceutical path forward that could make an enormous difference.

Education campaigns among healthcare providers and the public may also reduce the risk of preterm birth.

For those with a history of preterm birth because of shortened cervixes, vaginal progesterone seems to help reduce fetal and infant death and serious complications, according to a review of studies.

And for patients at risk of developing preeclampsia, a leading cause of preterm birth, there’s a cheap and effective treatment: baby aspirin.

These different procedures and medications point to a larger truth: the causes of premature birth are different, and thus the ways to prevent it may also be different.

The story of Makena is also an example of how complicated it is to remove an unproven medication from the market, even as FDA pushes for it, if the drugmaker is opposed. The battle over Makena could mean that “the next time someone does have a possible therapeutic, the bar might be a little bit higher, with a little more skepticism”, McElrath said.

But pulling the medication could open the market up for options that are proven to work.

“Here’s a great area of unmet need,” he said. “This is an area that is ripe for innovation, and I think it’s about time.”