Preterm birth continues to be a leading cause of neonatal morbidity and mortality, with little progress made in reducing its frequency. Despite research efforts, scientists have little understanding of the causes of premature labor and rupture of membranes. However, in 2003, there appeared to be a breakthrough in prevention. An article in The New England Journal of Medicine described a randomized clinical trial showing a one-third reduction in preterm birth for women with a prior preterm delivery with weekly injections of a drug called 17-hydroxy-progesterone caproate, or 17P. This drug has been around for decades, with small studies showing mixed results for its efficacy. However, the 2003 study was sponsored by the NIH and performed with scientific rigor, and appeared to establish this medication as a huge step forward in treatment for the problem. And safety data showed no adverse side effects of this drug on the mother or the baby.
Upon publication of this article, clinicians quickly rallied behind this treatment for this vexing pregnancy condition. The only issue was that it was made by any drug company and was not on the market. So, clinicians went to pharmacies that could make drugs not currently available to begin making 17P. The American College of Obstetricians and Gynecologists recommended using 17P for patients with a prior preterm birth, and the March of Dimes advocated publicly for such patients to receive it. Patients with a previous preterm birth readily accepted this medication, not wanting to repeat the difficulties they had experienced, so the drug became increasingly used in this situation. Of note, trials using 17P for other risk factors (twins, triplets, short cervical length) did not find it to be effective for preventing preterm birth in any other situation.
After many years, a drug company applied for FDA approval to market 17P. Not often granting authorization based on a single trial, the FDA eventually gave consent for its marketing on the condition that the drug company perform another trial in women with a prior preterm birth to verify its effectiveness. There was trouble recruiting patients in the United States to participate in the trial, as very few women who had experienced this complication and could get access to 17P outside the trial were willing to risk being randomized to the placebo group. So, most women recruited for the study were recruited internationally. Published in 2020, the trial was four times larger than the original trial published in 2003. The results were very disappointing—there was no benefit with regard to the frequency of preterm birth, neonatal complications, or fetal/neonatal death.
Earlier this year, after considerable debate and consultation, the FDA withdrew approval for 17P, saying that it was ineffective, and the drug company stopped making it. The American College of Obstetricians now advises against prescribing it. It is unclear how the two very well-conducted trials came to such different conclusions, but it turns out that this is not uncommon at all in medicine. When studied in multiple trials, hardly any treatment shows universal agreement—researchers now routinely use a statistical technique called meta-analysis to combine data from various trials to see where the preponderance of the evidence lies.
We are back to where we started with preterm birth—no effective preventive treatments. It is most disappointing for the patients who have watched a child struggle in the neonatal ICU. But research continues, and hopefully, another treatment will come along with the promise of reducing the morbidity and mortality of preterm birth. With all of the advances being made in medicine, there is reason to be optimistic.
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