Should doctors be able to prescribe and use a drug that doesn’t work, and may cause harm? That’s the question currently in front of the FDA as it decides what to do about a drug called Makena.

The FDA approved 17-hydroxyprogesterone caproate (Makena) in 2011 as a way to prevent preterm birth in women with a prior spontaneous preterm birth. The drug got the green light through the FDA’s accelerated approval pathway, which is reserved for drugs that treat a serious or life-threatening disease or condition.

That certainly applies to preterm birth — birth before 37 weeks of pregnancy — which is a major problem in the United States and around the world. In the U.S., approximately 10% of babies are born prematurely, and the rate has been rising. Babies born too early, especially before 32 weeks, are at increased risk of dying, and those who live are at increased risk of developing health issues and long-term problems.

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The cause for many cases of premature birth is unknown. Risk factors such as infections, smoking, race, and prior preterm birth can play role.

The FDA approved Makena based on a single clinical trial, the 2003 Meis study. It showed a reduction in preterm birth, but no direct clinical benefit, such as improvements in neonatal mortality and morbidity. As a condition of accelerated approval, the FDA required Makena’s maker, AMAG Pharmaceuticals, to conduct a second trial. The results of this second trial, known as PROLONG, were announced in March of this year: Makena did not work, meaning it did not prevent preterm birth.

An FDA advisory committee met on Oct. 29 to review the research. I testified at the meeting as a specialist in maternal fetal medicine who is concerned that we are exposing thousands of moms and developing babies to an ineffective drug (or “ineffective synthetic hormone injections”). I was heartened that committee recommended withdrawing the drug, though many experts, obstetricians, FDA watchers, and patients were shocked by this seemingly surprising turn of events. How could a drug that doctors have been injecting into pregnant women for 16 years not be effective?

The truth of the matter is that the drug wasn’t effective from the start.

I’ve been concerned about the use of this drug from the start. The Meis trial had numerous problems, which Public Citizen and I detailed in a citizen petition to the FDA. The two groups in the trial were not equal: Women who got the placebo tended to be a higher-risk group with more prior preterm births than those who got Makena. The trial was conducted at many sites, and the one with the most patients had the most skewed results. In essence, the effects at one study site drove the trial findings.

In the trial, the preterm birth rate in the Makena group (36%) was roughly what would be expected in women who had previously delivered a baby prematurely. The drug appeared to be effective only because the women given the placebo had an extraordinarily high rate of preterm birth (55%).

What’s more, the drug provided no direct clinical benefit, such improved outcomes for the babies whose mothers received it. As we described in the petition, these problems and others led the FDA’s lead statistician to voice her strong opposition to the drug’s approval several times — but to no avail.

Despite the obvious deficiencies of the Meis trial, Makena was not only approved but it also became the standard of care. Yet follow-up studies looking at real-world use of the drug showed it was not effective at preventing preterm birth. The much awaited PROLONG trial confirmed these findings.

Despite the amassed evidence, some experts — including the Society for Maternal-Fetal Medicine and the American College of Obstetricians and Gynecologists, organizations that represent physicians like me and of which I am a member — continue to argue that we must keep the drug on the market. They argue that the two main studies (Meis and PROLONG) were done in different groups: Meis was conducted only in the U.S. in a higher-risk population of women while PROLONG was done in a lower-risk international group.

But that argument fails when you drill into the data. Even the highest-risk patients in the PROLONG study didn’t show benefit from the drug. In fact, in many of the high-risk PROLONG subgroups, the preterm birth rate was higher in the Makena group. Those making this “different studies/different groups” argument include organizations that have received substantial funding from Makena’s maker, AMAG Pharmaceuticals.

Others argue that there do not appear to be any short-term safety issues, so the risks associated with administering the drug pale in comparison to the detrimental effects of preterm birth. This is dangerous reasoning, however. Makena is a synthetic hormone that crosses the placenta and enters into the fetus during development. It enters the fetal brain, the reproductive organs, and permeates throughout the body. We may not see short-term effects with an exposure like this, but the long-term adverse effects of a fetal exposure to synthetic hormones are not known.

We have been down this road before.

Diethylstilbestrol (DES) was used by millions of pregnant women to prevent miscarriages and premature deliveries from the late 1930s to the early 1970s. For decades, it was believed to be effective and safe for mothers and their developing babies. It wasn’t until much later that the true effects of this drug became apparent. DES resulted in potentially severe long-term health effects for many who were exposed to it. A major part of the tragedy of DES is that, despite how the drug was promoted to the public, it was not effective in preventing miscarriage and preterm birth. The lesson we supposedly learned from DES was clear: We would never again expose pregnant women and their developing babies to a synthetic hormone that did not have good evidence of proven effectiveness.

And yet, 50 years later, we have been making that same mistake.

History will judge us poorly if we do not pull Makena from the market and continue injecting this synthetic hormone into pregnant women.

Adam C. Urato, M.D., is a maternal-fetal medicine physician in Framingham, Mass., and co-petitioner with Public Citizen on the FDA petition to remove Makena from the market.

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  • I read the FDA report and I am no expert, just a regular mom who struggle with PTB. I find your arguments to be a bit biased because of a few thing. For starters, you stated that there is no clinical benefit for Makena based on PROLONG but according to FDA reports, clinical benefits is unverified. Also, I noted, PTB affects 11% North America population and 8.7% Europe but I see that the research for PROLONG had population of 36% Russia 27% Ukraine and 23% US. I think that’s an issue because over 60% of the PROLONG research population is amongst those with the least risk of PTB. Found your article interesting. My issue is that it falsely appeared to relay facts but it’s just biased opinions.
    My views were based off the information I read from the FDA article you posted.

    • Thank you for your comment, Ann. I applaud you for taking the time to look at the FDA report (https://www.fda.gov/media/132003/download.) That is exactly what’s needed to understand the Makena issue – looking at the actual scientific evidence. There are a couple of areas of confusion that I would like to clear up. I do say that there is no proven clinical benefit for Makena. The FDA says this as well. Their statement (page 7, top) is “There are no controlled trials demonstrating a direct clinical benefit such as improvement in neonatal mortality and morbidity.” This exact statement is also on the official FDA drug label. The quote you use from page 11 of the FDA report, “the clinical benefit of Makena remains unverified,” means the same thing. You also point out that PROLONG had a large number of women from outside the US. But these women were not at low risk of preterm birth. All the women in the PROLONG study had a prior preterm birth. But let’s say you take the PROLONG study and just look at US women who had more than one prior preterm birth. This group has a very high risk of recurrent preterm birth. In this group, the preterm birth rate was higher in the women who received Makena – 25% vs. 17%. This information is on page 36 and Table 22.
      The scientific facts on Makena are the following: Makena has not been proven to be effective at preventing preterm birth or providing clinical benefit. Makena is a synthetic hormone that may cause short-term harmful effects (eg gestational diabetes and stillbirth) and might also cause long-term adverse effects as we saw with DES. This is why the FDA must pull Makena off the market.

  • It will not be removed from the market. The study population was vastly different from the original trial. Please stop making claims without all the facts.

    • Of course, it’s not very profitable for someone to recall Maken, this is material make money, and again, the pregnant population as test subject, so, time will tell, unfortunately that can turn out over time as Thalidomide, DES…

    • Thank you for your comment, James. I’d like to emphasize the following points: The Meis trial had very serious flaws and showed no direct clinical benefit with Makena. In PROLONG, Makena was shown to be ineffective at preventing preterm birth. If you drill into the PROLONG data, as the FDA did, you see that there is no evidence that Makena works in any of the groups–including the highest risk groups. I encourage you to read page 32-36 of the FDA document and review Table 22:
      https://www.fda.gov/media/132003/download. Some of the highest risk groups in PROLONG had HIGHER rates of preterm birth on Makena vs Placebo. For example, women with > 1 prior preterm birth (PTB) on Makena had a PTB ( 1 PTB the rates are 25% Makena vs. 17% placebo. Again, these high-risk women (with > 1 prior PTB) had HIGHER rates of PTB on Makena. In blacks the rates of PTB were also HIGHER on Makena (24% vs 20%.) In Table 22, we see that US patients with an earliest prior PTB between 20-28 weeks had a PTB rate of 26% on Makena vs 16% on placebo–once again, HIGHER rates on Makena. All of this led the FDA to conclude that there is no “convincing evidence of efficacy over placebo in any subpopulation (page 35.)” These are the facts. I consider the “different studies/different populations” explanation for the failure of Makena in PROLONG to be nothing more than “spin” to try to keep us injecting pregnant women with this synthetic hormone that has not proven effective at preventing preterm birth and may have adverse long-term effects.

    • There was a glitch on my comment with some words/statistics cut. The middle part should read: “Some of the highest risk groups in PROLONG had HIGHER rates of preterm birth on Makena vs Placebo. For example, women with > 1 prior preterm birth (PTB) on Makena had a PTB ( 1 PTB the rates are 25% Makena vs. 17% placebo. Again, these high-risk women (with > 1 prior PTB) had HIGHER rates of PTB on Makena. In blacks the rates of PTB were also HIGHER on Makena . . . “

  • For – Adam C. Urato,
    Thank you for responding, but my question was about oral pills progesterone NOT Vaginally, do you have expanded materials about this med? As well, will be so grateful about bicillin ( I got twice 2x 4 millions by 1-2 rimester) and still have to keep going with metronidazole Vaginally gel, I hope you have… I am sorry to ask those question out of topic .

    • I’m sorry that I misunderstood your prior question, Dia. Using oral progesterone to prevent recurrent preterm birth has been studied. However, the evidence is limited. In my opinion, it has not been proven to be a safe and effective approach. There is a recent review on this issue: “Oral progesterone for the prevention of recurrent preterm birth: systematic review and metaanalysis.” It can be found here: https://www.sciencedirect.com/science/article/pii/S2589933319300084. I do recommend that you follow up on these issues with your OB provider.

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