Boxing Day Reflections and New Year Resolutions

The tragic story of pregnant women being exposed to an ineffective and potentially unsafe drug

This year, on Boxing Day evening, I was telling our twins about the time around their birth. What was meant to be a relaxing evening together turned into me searching the internet to check if I’d made the right choice years ago not to participate in a trial. Soon, I found myself immersed in the tragic story of millions of mother-child exposures to an ineffective and potentially unsafe drug worldwide.

Here is the story...

The AMPHIA trial

Eighteen years ago, around this time, I was having a challenging pregnancy, with concerns about premature birth. During one of the biweekly visits to the hospital, my kind and experienced obstetrician asked me to participate in one of their clinical trials.

The AMPHIA trial was a double-blind study, where women, like me, with a multiple pregnancy were randomised to receive either weekly intramuscular injections of 250 mg 17-hydroxyprogesterone caproate (17‑OHPC) or placebo injections. The idea that progesterone could prevent preterm birth actually dates back decades. In a 1930 study, Allen and Corner demonstrated that corpus luteum extracts from swine, rich in progesterone, could sustain pregnancy in rabbits after early castration.

Back then, I read through the patient information leaflet of the trial and then turned to PubMed, only to find contradictory research and a lack of evidence or reassurance about the safety of progesterone during pregnancy. What worried me most was that several studies providing evidence against the use of progesterone were not cited in the patient information leaflet. I compiled a summary of these studies and sent it to my obstetrician, expressing my concerns that mothers should have access to all available information in order to make truly informed decisions.

I remember, it wasn’t a difficult decision for me. I chose not to take part in the study.

Several negative trials

The AMPHIA trial eventually recruited 671 women with multiple pregnancies between 2006 and 2009 from 55 obstetric clinics in the Netherlands. A total of 1,322 children were born as part of this study. However, the trial turned out to be negative, as 17-OHPC did not prevent neonatal morbidity or preterm birth.

The authors, who published the results in 2011, stated that only 36% of the women who were counselled agreed to participate in the trial. Remarkably, the number of women who came to these obstetric clinics and met the criteria for counselling was at least twice as high. This raises the question of what motivated the obstetricians to present the option of the trial to some women and not others.

One possible reason could be that some obstetricians were not convinced of the efficacy of progesterone, as two randomised studies published in 2007 had already shown that 17-OHPC and vaginal progesterone do not reduce the rate of preterm birth.

FDA Accelerated Approval of 17-OHPC in 2011

In 2003, the National Institute of Child Health and Human Development (NICHD) published the results of a double-blind, placebo-controlled trial involving pregnant women with a history of preterm birth across 19 clinical centres in the United States. A total of 463 women were randomised in a 2:1 ratio to receive weekly injections of 17-OHPC or caster oil as placebo. 17-OHPC resulted in a significant reduction in preterm births: 36.3% compared to 54.9% in the placebo group.

However, there were concerns about these trial results, particularly the higher preterm birth rate in the control group, which was much higher than the national average and even exceeded the authors’ own a priori estimate of 37% preterm birth rate for the control group.

Nevertheless, the American College of Obstetricians and Gynecologists recommended the use of progesterone for women with a history of preterm delivery in their guideline, while also highlighting unresolved issues, including its efficacy in multiple gestations and long-term safety.

A few years later, in 2011, the FDA granted accelerated approval for Makena (hydroxyprogesterone caproate injections) for women with a singleton pregnancy who had a history of spontaneous preterm birth.

The results of the NICHD trial were considered “sufficiently persuasive (p < 0.001) to meet the level of statistical significance generally expected to support approval based on the findings of a single trial.”

This FDA approval caused the cost of an inexpensive drug, with questionable added benefits and unknown long-term safety, to rise 100-fold, from $300 (for the compounded version) to $30,000 for the Makena brand.

Negative confirmatory trial and FDA withdrawal in 2023

The confirmatory study required by the FDA for full market approval, the PROLONG trial, was conducted between 2009 and 2018 and involved 1,130 women receiving 17-OHPC and 578 receiving placebo. The results, published in 2019, showed that 17-OHPC does not decrease preterm birth. However, the FDA took a few more years before withdrawing the accelerated approval in 2023. This delay came at a high cost, as it is reported that only between 2018 to 2021, $700 million of the US healthcare budget (Medicare and Medicaid) was wasted on Makena.

Potentially higher cancer risk and EMA withdrawal in 2024

Sadly, over the course of 12 years, Makena was marketed to a vulnerable population that invested its time, money and hope in a drug that ultimately proved ineffective and potentially harmful. A recent study on a population from Oakland, California, shows that offspring exposed in utero to 17-OHPC (n=234) between 1959 and 1966 had a higher risk of developing cancer compared to those not exposed (n=18,517).

Finally, just a few months ago, on 28 June 2024, more than a year after the FDA withdrawal, the EMA announced that 17-OHPC medicines are to be suspended from the EU market, as studies found no effect in preventing premature birth and raised safety concerns. Their review concluded that “there is a possible but unconfirmed risk of cancer in people exposed to 17-OHPC in the womb.”

Some Thoughts for Your New Year’s Resolutions

The withdrawal of 17-OHPC highlights critical lessons for regulators, medical societies and researchers, underscoring the importance of evidence-based decision-making and patient safety. Here are some thoughts for your New Year's resolutions:

• Regulators: Why not mandate more robust evidence before granting approval, especially for treatments with significant public health implications that could even affect future generations.

• Medical Societies: Same goes for you. Why not recommend therapies only when there is robust evidence to support their use? Please also, ensure that those writing the guidelines have no competing interests.

• Researchers: As Vinay Prasad often says, ask a guiding, ethical question before designing a clinical trial: "Would I recruit my mother or father for this study?" Or, in the context of 17-OHPC, "Would I have recruited my wife, sister, daughter and my unborn child?" This reflective approach ensures trials are ethically designed, scientifically sound and genuinely prioritise patient well-being.

Best wishes for 2025, and much strength and wisdom!