Preterm birth drug given to millions of women may increase cancer risk in offspring

The offspring of mothers who received 17-hydroxyprogesterone caproate during pregnancy may face nearly double the risk for cancer compared with those who were not exposed, according to a recent study.

The findings were published in the American Journal of Obstetrics and Gynecology.

The FDA initially approved 17-hydroxyprogesterone caproate (17-OHPC), marketed under the brand name Delalutin (Bristol-Myers Squibb), in 1956 for several gynecological and obstetrical conditions, including habitual and threatened abortion, according to Barbara A. Cohn, PhD, the director of the Child Health and Development Studies at the Public Health Institute in California, and colleagues. A high dose (250 mg/mL intramuscular injection) was administered to millions of pregnant women in the 1950s and 1960s, the researchers added.

In 1973, the FDA noted there was a lack of evidence supporting the use of 17-OHPC to prevent habitual and threatened abortion and raised concerns about a possible association between its use and an increased risk for congenital heart defects in offspring, according to the researchers. The agency later removed all pregnancy-related indications and eventually withdrew its approval of the drug in September 2000 “at the request of the manufacturer and because it was no longer being marketed,” Cohn and colleagues wrote.

In 2011, the FDA again approved 17-OHPC (Makena, Covis Pharmaceuticals) — this time as a treatment to reduce the risk for preterm births. However, subsequent confirmatory trials revealed that the drug did not significantly reduce the incidence of preterm birth, and other large trials showed an excess risk for serious adverse fetal or neonatal events associated with 17-OHPC.

“Despite repeated concerns of safety and short-term efficacy, little is known about the long-term effects of 17-OHPC on health of offspring,” Cohn and colleagues wrote.

The researchers examined the association between in utero exposure to 17-OHPC and cancer risk in a population-based cohort study of 18,751 children born to 14,507 mothers who received prenatal care between 1959 and 1966. Cohn and colleagues used medical records to determine the number and timing of 17-OHPC injections and the California Cancer Registry to identify incident cancer diagnoses among offspring through 2019.

The data revealed that 1,008 offspring were diagnosed with cancer over 730,817 person-years of follow up. Overall, about 1% of offspring had in utero exposure to the drug.

Exposure to 17-OHPC in the first trimester was associated with an increased risk for any cancer (adjusted HR = 2.57; 95% CI, 1.59-4.15), according to Cohn and colleagues. Moreover, the risk increased with the number of injections administered (one to two injections: aHR = 1.8, 95% CI, 1.12-2.9; 3 injections: aHR = 3.07; 95% CI 1.34-7.05). In the 1950s and 1960s, women usually received one or two injections, according to the researchers. Today, they may receive as many as 20 injections throughout their pregnancy.

Male, but not female, offspring conferred an additional risk for cancer if they were exposed during the second or third trimester (aHR = 2.59, 95% CI, 1.07-6.28). The risk for colorectal cancer (aHR = 5.51, 95% CI 1.73-17.59), prostate cancer (aHR = 5.1, 95% CI 1.24-21), and pediatric brain cancer (aHR = 34.72, 95% CI 7.29-164.33) was higher in offspring exposed to 17-OHPC in the first trimester compared with those who were not exposed, according to the researchers.

“Pregnancy is a very important window of susceptibility, both for the mother, the infant and, perhaps, the grandchild,” Cohn told Healio Primary Care. “It is important for physicians to know that there is missing information about long-term consequences for some of the treatments done in pregnancy.”

In 2019, an FDA advisory committee voted in favor of withdrawing the agency's approval of 17-OHPC over concerns about its efficacy. Last August, FDA agreed to hold a public hearing about possibly moving forward with the withdrawal, Cohn said. An FDA representative at the Center for Drug Evaluation and Research (CDER) said that the hearing has not been scheduled yet. However, CDER determined that “the benefit-risk profile of Makena is unfavorable because its effectiveness has not been shown.”

“CDER’s proposal to withdraw Makena’s approval reflects these considerations,” the representative said. “CDER proposed that Makena’s marketing approval be withdrawn because the required confirmatory trial failed to show that Makena is effective for improving the health of babies born to women with a history of preterm birth.”

Meanwhile, a Covis spokesperson said that “as the only FDA-approved therapy to reduce the risk of preterm birth in women with a singleton pregnancy who have a history of singleton spontaneous preterm birth, Makena’s maternal and fetal safety profile is well-established.”

“This study blurs the lines between an FDA-approved treatment option used today and an earlier version of the drug introduced in the 1950s to treat a different patient population for a different purpose,” the spokesperson said. “With the exception of the formulation, the study offers no comparison to Makena in any way, nor does it differentiate between two products with different indications and demographics for use.”

However, Cohn said that “doctors may wish to weigh this evidence in making a decision about whether to prescribe 17-OHPC to prevent prematurity."

*Editor’s note: The story was updated to include comments from the FDA.

References:

Cohn BA, et al. AJOG. 2021;doi:10.1016/j.ajog.2021.10.035.

Drug for pregnant women linked to increased cancer risk in offspring. https://www.phi.org/press/drug-for-pregnant-women-linked-to-increased-cancer-risk-in-offspring/. Published Nov. 9, 2021. Accessed Nov. 9, 2021.