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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  • After losing my first baby at 17 weeks, my Ob suggested taking it with my son and my water broke at 36 weeks. He is a healthy 3 year old now. When I was pregnant this last time with my daughter, I again took Makena (with hesitation after educating myself more on it). I had many discussions with my OB and MFM at length from weeks 16 to 24 about the Makena as I was having a great deal of spotting to full on bleeding with no explanation at all. I was questioning everything because of the fear of losing this baby. I ended up hospitalized and had an emergency c-section at 24 weeks. My daughter is 6 weeks old and will likely be in the NICU for another couple months. I do wonder if Makena had a hand in this as one of the side effects listed is pre-term birth.

    • Thank you for your comment and for sharing your story, Bren. I hope that your daughter is doing OK. I would encourage you not to blame yourself. I do think you raise some important issues. Based on the best available scientific research, Makena has not been proven to be effective in preventing preterm birth. What this means is that it doesn’t appear to work — it doesn’t prevent preterm deliveries. You raise the issue of whether it might cause harm (i.e. cause preterm birth.) This causation has not been established and, again, I wouldn’t blame yourself. That being said, I am concerned by the subgroup findings in PROLONG. I recommend that readers look at Table 22 on page 52 of the FDA Briefing Document, https://www.fda.gov/media/132003/download. What you see here is that in some of the highest risk subgroups, there were HIGHER rates of preterm birth in the Makena arm compared with placebo. For example, for women with more than 1 prior preterm delivery (PTD), the rate of preterm birth in the Makena group was 25.6% versus 18.5% in the Placebo group. And that was looking at 245 women with > 1 prior PTD, which is a fairly large number. If one looks just at the 106 US women with > 1 prior PTD (the middle columns, “Trial 003 US Subset”) one sees that the preterm birth rate in the Makena group was 25.3% versus 17.1% in the Placebo group. So, there is no evidence there that Makena is more likely to work in higher-risk women, and it is possible that there could be an increased risk of preterm birth with Makena use.

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