Silver Spring, MD—In October, the FDA’s Center for Drug Evaluation and Research (CDER) proposed that hydroxyprogesterone caproate injection, marketed as Makena, be withdrawn from sales because a required postmarket study did not verify clinical benefit.

The FDA concluded that the available evidence does not show that Makena is effective for its approved use. Now, a new study questions whether the issues go further than that, finding an association between use of hydroxyprogesterone caproate to reduce the risk of preterm birth (i.e., delivery before 37 weeks) in women who previously had a spontaneous preterm birth and an increased risk of cancer in offspring.

As part of the drug’s accelerated approval in 2011, the manufacturer was required to conduct a clinical trial to demonstrate the clinical benefit to newborns. “A drug that prevents preterm birth is helpful if it ultimately improves the babies’ health,” the FDA pointed out. “The required confirmatory trial failed to show that Makena is effective for improving the health of babies born to women with a history of unexplained preterm birth. We also determined that the available evidence does not show that Makena reduces the risk of preterm birth.”

Researchers from The University of Texas Health Science Center at Houston took a close look at 17-hydroxyprogesterone caproate (17-OHPC), a synthetic progestogen that was frequently used by women in the 1950s and 1960s and is still prescribed to women to help prevent preterm birth. The study, published in the American Journal of Obstetrics and Gynecology, advises that progesterone aids womb growth during pregnancy and prevents a woman from having early contractions that might lead to miscarriage.

“Children who were born to women who received the drug during pregnancy have double the rate of cancer across their lifetime compared to children born to women who did not take this drug,” explained Caitlin C. Murphy, PhD, MPH, lead author of the study and associate professor in the Department of Health Promotion and Behavioral Sciences at UTHealth School of Public Health in Houston. “We have seen cancers like colorectal cancer, pancreatic cancer, thyroid cancer, and many others increasing in people born in and after the 1960s, and no one really knows why.”

To reach that conclusion, the researchers reviewed data from the Kaiser Foundation Health Plan on women who received prenatal care between June 1959 and June 1967, and the California Cancer Registry, which tracked cancer in offspring through 2019.

With more than 18,751 live births, the study pinpointed 1,008 cancer diagnoses in offspring ages 0 to 58 years. Of those, 234 offspring were exposed to 17-OHPC during pregnancy, according to the authors, who recounted, “Offspring exposed in the womb had cancer detected in adulthood more than twice as often as offspring not exposed to the drug—65% of cancers occurred in adults younger than 50.”

“Our findings suggest taking this drug during pregnancy can disrupt early development, which may increase risk of cancer decades later," Dr. Murphy added. “With this drug, we are seeing the effects of a synthetic hormone. Things that happened to us in the womb, or exposures in utero, are important risk factors for developing cancer many decades after we’re born.”

Researchers reported that exposure in the first trimester was associated with increased risk of any cancer (adjusted hazard ratio [aHR] 2.57, 95% CI 1.59, 4.15), and risk increased with the number of injections (1-2 injections: aHR 1.80, 95% CI 1.12,2.90; ≥3 injections: aHR 3.07, 95% CI 1.34, 7.05). “Exposure in the second or third trimester conferred an additional risk for male (aHR 2.59, 95% CI 1.07, 6.28) but not female (aHR 0.30, 0.04, 1.11) offspring,” they noted.

The following cancers were higher in offspring first exposed to 17-OHPC in the first trimester compared with offspring who were not exposed:

• Colorectal cancer (aHR 5.51, 95% CI 1.73, 17.59)
• Prostate cancer (aHR 5.10, 95% CI 1.24, 21.00)
• Pediatric brain cancer (aHR 34.72, 95% CI 7.29, 164.33)

“Caution using 17-OHPC in early pregnancy is warranted, given the possible link with cancer in offspring,” the authors recommended.

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