In 2011, the FDA granted preliminary approval to progesterone injections (trade name: Makena) to prevent recurrent preterm birth, and it has been widely prescribed for this purpose ever since. Was that approval warranted? What has happened since? I’ll take you through the story in this post.
To begin with progesterone injections have never unambiguously been proven to prevent recurrent preterm birth. Nevertheless, in 2011, the FDA thought the evidence sufficiently promising to grant preliminary approval for their use.6
The FDA wasn’t entirely convinced and required a follow-up trial as a pre-requisite for granting full approval. During the interim, however, the use of progesterone spread rapidly. By the time the follow-up trial was published in 2019, a course of progesterone injections was firmly established in the minds of obstetricians as effective treatment for preventing recurrent preterm birth.
Based on that follow-up trial, the FDA is in the process of deciding whether to rescind approval.5, 11
I decided to tackle this topic for a couple of compelling reasons:
First, it is claimed that progesterone injections are safe. I want to examine whether that claim is valid. A certain level of side effects and possible risk would be acceptable when weighed against the benefits of preventing preterm birth, but not if progesterone injections have little or no effect.
Second, treatment is hugely expensive. Prior to granting preliminary authorization, the progesterone compound used in the injections cost about $15 per dose, making a full course of treatment about $300 per pregnancy.1 After preliminary approval was granted, a pharmaceutical company promptly patented the medication, named it “Makena,” and upped the price to $1440 per dose or $29,000 for treating one pregnancy. This would amount to $4.0 billion per year if all 139,000 U.S. women annually who are at risk of recurrent preterm birth are treated with progesterone.
The crucial issue, then. is whether progesterone injections reduce the incidence of recurrent preterm birth, so let’s start with a look at the evidence for and against it.
Did the Initial Evidence Warrant FDA Preliminary Approval?
As it happens, I’ve been following the progesterone story since 2009. Medical treatments for pregnancy complications are off my usual beat, but in this case, a family member approached me. She had had her first baby preterm and had been told that beginning at 20 weeks, she would be given weekly progesterone injections to prevent a recurrence. Being a member of my family, she wasn’t inclined to go along with this without finding out more about it. She asked me to look into it for her. You can read the details in “Does Progesterone Treatment Prevent Preterm Birth? A Case of Skim Milk Masquerades as Cream,” but here’s the gist of what I found.
On the surface, the data looked promising. A systematic review (a study of studies) had pooled data from four randomized controlled trials in which women with one or more prior preterm births were assigned by chance—that’s the “randomized” part—to either progesterone treatment or a placebo.4 The review concluded that progesterone treatment significantly reduced the incidence of repeat preterm birth before 34 weeks and also before 37 weeks.
That promise, though, didn’t hold up under closer examination.
To begin with, two of the trials were of progesterone vaginal suppositories, not injections. The smaller of the two had found a reduction in recurrent preterm birth but had serious flaws in how the study was conducted.8 The other, a larger, well-conducted trial, reported no benefits. That takes vaginal progesterone treatment off the table.
The other two trials were of progesterone injections, the treatment in use today. One was a trial of only 43 participants published in 1975. A small trial published this long ago raises questions of its quality and applicability. Its results can safely be dismissed. The second trial, though, was a multicenter U.S. trial of 459 women published in 2003.9 Meis & colleagues reported that 36% of women having weekly progesterone injections gave birth before 37 weeks compared with 55% of women in the group given placebo injections. The FDA relied on this trial in granting preliminary approval in 2011.
These results would seem conclusive evidence of benefit, but appearances can be deceiving. Treated women had a recurrent preterm birth rate of 36%, but the pretrial rate of recurrent preterm birth had been 37% in the hospitals participating in the trial. In other words, progesterone treatment had zero effect on the incidence of preterm birth compared with the pretrial rate. The difference in the Meis trial came from having a much higher than anticipated 55% preterm birth rate in the control group. Interestingly, while the FDA made final approval dependent on the results of a follow-up trial, the huge question mark over Meis’ data was not given as a reason for the requirement.6
The Meis trial also raised another issue: treatments should be biologically plausible. The theory behind progesterone treatment is that it quiets the uterus.4 But the Meis trial didn’t find that progesterone treatment had this effect. Just as many women in the progesterone group as the group given placebo injections needed treatment for bouts of preterm contractions. This calls into question the underlying rationale for treating with progesterone in the first place.
My conclusion: The evidence didn’t merit FDA approval.
Do the Results of Subsequent Studies Support Confirming Approval?
The follow-up trial, already in progress at the time preliminary approval was granted, was supposed to be completed in 2013.12 It took, however, until 2018 to recruit enough participants to satisfy the trial’s requirements,2 one reason being that once the FDA had approved progesterone treatment for preventing recurrent preterm birth, it was hard to recruit participants to a trial that would randomly allocate them to a placebo.11
In the meantime, another study finding no benefits with progesterone treatment was published in 2017.12 I wrote about this study in “Progesterone Injections to Prevent Recurrent Preterm Birth Neither Effective nor Harmless.” In brief, investigators did a before-and-after study, matching women with prior preterm births in a time period before the introduction of progesterone treatment with 430 similar women treated with progesterone after it became available. Recurrent preterm birth rates at 35 weeks or less were nearly identical in treated and untreated women (25% versus 23%).
In 2019, the follow-up trial was finally published.2 Trialists had used the same treatment regimen as the earlier Meis trial. Recurrent preterm birth before 35 weeks was chosen as the main outcome of interest along with a composite measure of perinatal mortality and serious morbidity. With 1708 participants, the trial was big enough to establish with near certainty whether treatment worked if injected progesterone was as effective as the Meis trial had concluded it was. But it wasn’t. Progesterone treatment had zero effect on reducing recurrent preterm births (11.0% vs. 11.5%) and zero effect on reducing severe morbidity and mortality (5.6% vs. 5.0%). And as with the Meis trial, it had zero effect on preventing episodes of preterm labor (16.5% vs. 14.5%).
The trialists came up with various reasons why their trial results shouldn’t be considered conclusive—you would expect that, seeing as the drug’s manufacturer sponsored the trial and the investigators all had financial ties to the company—but results that conclusive make it a hard sell. Furthermore, the FDA conducted analyses of the trial’s data to see whether the investigators’ theories as to why the two trials got such different results held up and found that they didn’t.7
My conclusion: Progesterone injections are ineffective at preventing recurrent preterm birth.
Where Do Matters Stand Now?
The follow-up trial would seem a black-and-white disconfirmation of progesterone treatment, but it has not been seen as such by the obstetric community. After the trial’s publication, the American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine (SMFM) both made statements endorsing progesterone treatment for prevention of recurrent preterm birth.11 The FDA itself was deeply divided. It convened an advisory committee to deliberate the trial’s findings that met in October of 2019. While the advisory committee voted for withdrawing approval, it was a close call. Seven of its sixteen members voted against withdrawal. Subsequent to publishing the advisory committee’s recommendation, the SMFM reaffirmed its endorsement of progesterone treatment (SMFM 2020).16 One year later, despite the follow-up trial’s publication and the FDA advisory committee’s recommendation, Medicaid filled 19,554 progesterone prescriptions to treat recurrent preterm birth in the third quarter of 2020 alone.15
Having recommended that approval be withdrawn, the FDA stood its ground. For example, it issued a rebuttal last March explaining why a new systematic review’s conclusion that progesterone treatment might be beneficial in some situations didn’t apply to the case.7
Makena’s maker, however, fought back. The drug company issued a response to the committee’s recommendation to withdraw approval in which it made the same arguments for continuing use as were given in the follow-up trial, and it cited ACOG’s and SMFM’s endorsements in progesterone’s favor as support.11, 13 It has also had at least one commentary written by doctors with ties to the drug company published in a major U.S. obstetric journal.11
The withdrawal process continued to drag on. It took until October of 2020 for the FDA’s Center for Drug Evaluation and Research to recommend that the FDA withdraw approval.5 The drug company countered by exercising its right to a public hearing, which brings us up to the present day.7
At last, the saga, may finally be coming to an end. On October 19, an FDA advisory committee voted 14 to 1 to withdraw approval of Makena from the market on the basis that the confirmatory trial failed to show that progesterone injections reduced newborn morbidity or mortality from complications of preterm birth.3 Presumably, the FDA will follow the committee’s recommendation and withdraw approval, although who knows when that will be.
My conclusion: The FDA will withdraw approval, and it will have very little effect. There is enough obfuscation around the facts and enough motivation—desperation to have an effective treatment, nearly two decades of believing we had one—that doctors will go right on prescribing progesterone injections. The only change will be that they will be prescribing it “off label,” meaning manufacturers cannot claim that it is intended for this use.
What about Harms?
The story wouldn’t be complete without considering potential harms. Whatever the dispute over effectiveness, all seem to agree that progesterone injections haven’t been shown to cause serious harms. I don’t think we know enough to have that confidence.
As I wrote back in 2009, progesterone is a female sex hormone. Without tracking the children of treatment recipients at least through puberty and probably beyond, we have no idea whether exposing babies in utero, especially boys, to weeks of artificially high levels of a sex hormone has no ill effect.
A troubling study recently raised the possibility of an elevated risk of cancer.10 Back in the 1950s and 1960s, large numbers of women were given injections of high doses of progesterone early in pregnancy in the belief that it would prevent miscarriage. It didn’t, and it increased heart defects, which led to the removal of pregnancy-related indications from its label.10 This study traced 18,000 mother-child pairs from that time period up to 2019 and found an increased risk of colorectal, prostate, and childhood brain cancer compared with unexposed babies. The actual difference was small, but it was statistically significant, meaning unlikely to be due to chance. Risk increased with the number of injections and specifically in males exposed in the second or third trimester compared with females. The circumstances were different from today’s use in that exposure consisted of one to three high-dose injections early in pregnancy while the regime for preventing preterm birth consists of lower-dose weekly injections from 20 to 36 weeks. Nonetheless, this is far from reassuring.
Two studies have reported that progesterone injections increased the probability of gestational diabetes.12, 14 This is plausible because progesterone is known to promote insulin resistance, its function being to increase circulating glucose to provide the fuel to support the growing baby. The follow-up trial reported low and similar rates in treated and untreated women,2 but I’m not sure the concern can entirely be laid to rest.
And what about not-so-serious-harms? The weekly injections are quite painful. That’s a relatively minor issue but only if the treatment is effective.
Then, too, the high cost of treatment is itself an adverse effect. How might those healthcare dollars have been better spent?
If progesterone treatment were effective, the benefits of preventing the morbidity and mortality consequent to preterm birth tip the scales in its favor, but it seems pretty clear that it isn’t.
My conclusion: The follow-up trial is the best data we have and the only data we will ever have given the cost and logistics of mounting another trial. Going by that data, we have an ineffective treatment with unknown long-term and potentially serious adverse effects being administered at huge cost to tens of thousands of women annually.
I’m with the authors of the 2021 commentary, who wrote:
- Armstrong J. Unintended consequences–the cost of preventing preterm births after FDA approval of a branded version of 17OHP. N Engl J Med 2011;364(18):1689-91.
- Blackwell SC, Gyamfi-Bannerman C, Biggio JR, Jr., et al. 17-OHPC to Prevent Recurrent Preterm Birth in Singleton Gestations (PROLONG Study): A Multicenter, International, Randomized Double-Blind Trial. Am J Perinatol 2020;37(2):127-36.
- Revoke approval of preterm birth drug, FDA advisors say. Medpage Today, Oct 19, 2022. (Accessed Oct 27, 2022, 2022, at https://www.medpagetoday.com/obgyn/pregnancy/101311#:~:text=An%20FDA%20advisory%20committee%20recommended,and%20to%20improve%20neonatal%20outcomes.)
- Dodd JM, Flenady V, Cincotta R, et al. Prenatal administration of progesterone for preventing preterm birth. Cochrane Database Syst Rev 2006(1):CD004947.
- CDER proposes withdrawal of approval for Makena. 2020. (Accessed Feb 6, 2022, at https://www.fda.gov/drugs/drug-safety-and-availability/cder-proposes-withdrawal-approval-makena.)
- FDA approves drug to reduce preterm birth risk. National Institutes of Health, Feb 16, 2011. (Accessed Apr 25, 2017, at https://www.nichd.nih.gov/newsroom/releases/021611-FDA-approves-drug)
- Makena (hydroxyprogesterone caproate injection) information. CDER Statement. 2021. (Accessed Feb 6, 2022, at https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/makena-hydroxyprogesterone-caproate-injection-information.)
- Keirse MJ. Progesterone and preterm: seventy years of “deja vu” or “still to be seen”? Birth 2004;31(3):230-5.
- Meis PJ, Klebanoff M, Thom E, et al. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. N Engl J Med 2003;348(24):2379-85.
- Murphy CC, Cirillo PM, Krigbaum NY, et al. In utero exposure to 17alpha-hydroxyprogesterone caproate and risk of cancer in offspring. Am J Obstet Gynecol 2022;226(1):132 e1- e14.
- Nelson DB, McIntire DD, Leveno KJ. A chronicle of the 17-alpha hydroxyprogesterone caproate story to prevent recurrent preterm birth. Am J Obstet Gynecol 2021;224(2):175-86.
- Nelson DB, McIntire DD, McDonald J, et al. 17-alpha Hydroxyprogesterone caproate did not reduce the rate of recurrent preterm birth in a prospective cohort study. Am J Obstet Gynecol 2017;216(6):600 e1- e9.
- FDA proposes Makena be withdrawn from the market. MPR, Oct 7, 2020. (Accessed Feb 9, 2022, at https://www.empr.com/home/news/safety-alerts-and-recalls/fda-center-drug-evaluation-research-cder-makena-hydroxyprogesterone-caproate/.)
- Rebarber A, Istwan NB, Russo-Stieglitz K, et al. Increased incidence of gestational diabetes in women receiving prophylactic 17alpha-hydroxyprogesterone caproate for prevention of recurrent preterm delivery. Diabetes Care 2007;30(9):2277-80.
- Sachs RE, Gavulic KA, Donohue JM, et al. Changes in the Use of Hydroxyprogesterone Caproate Injection After Confirmatory Trial Failure. JAMA Intern Med 2022;182(2):226-7.
- Society for Maternal-Fetal Medicine Publications Committee. Electronic address pso. SMFM Statement: Use of 17-alpha hydroxyprogesterone caproate for prevention of recurrent preterm birth. Am J Obstet Gynecol 2020;223(1):B16-B8.