Offspring who were exposed to a type of synthetic progestogen in utero -- a key ingredient now used in medication to prevent preterm birth -- had an elevated risk of cancer across the lifespan, according to a population-based study.
Children born to mothers who received injections of 17α-hydroxyprogesterone caproate (17-OHPC) to prevent miscarriage in the 1950s and 1960s had double the risk of cancer compared with those who were not exposed (adjusted hazard ratio [aHR] 1.99, 95% CI 1.31-3.02), reported Caitlin Murphy, PhD, MPH, of the UTHealth School of Public Health in Houston, and colleagues.
Risk of cancer was highest for offspring exposed to the drug in the first trimester (aHR 2.57, 95% CI 1.59-4.15), the researchers wrote in the .
They also found that exposure to 17-OHPC in utero was associated with a higher risk of specific cancer types, including colorectal (aHR 5.51, 95% CI 1.73-17.59), prostate (aHR 5.10, 95% CI 1.24-21.00), and pediatric brain cancers (aHR 34.72, 95% CI 7.29-164.33). The large effect size for pediatric brain cancer corresponds to two cases from the exposed group (n=234) compared with 15 cases among the unexposed group (n=15,517), the authors noted.
The drug was first approved by the FDA in 1956 to treat several gynecologic and obstetric conditions, including spontaneous abortion in pregnancy, and is now only approved for use in later trimesters.
Murphy and colleagues found an increased risk of cancer among both male and female offspring who were exposed in early pregnancy. But while first exposure in later pregnancy did not increase cancer risk among female offspring, it was associated with an increased risk in males (aHR 2.59, 95% CI 1.07-6.28).
The fact that male offspring appeared to remain at risk if exposed in later stages of pregnancy should inform how clinicians administer this drug, Murphy told 鶹ý.
"Even though the indication is slightly different and the timing is slightly different in these two time periods, it still gives me pause, in terms of weighing the risks and benefits of using this drug for the prevention of preterm birth," she added.
After 17-OHPC was administered at a high dose to millions of pregnant patients in the 1950s and 60s, evidence of fetal congenital heart defects led the FDA to remove all pregnancy indications from the label, the authors noted.
The drug was taken off the market, but the agency again approved 17-OHPC in 2011 (under the brand name ) to treat spontaneous preterm birth from 16 to 20 weeks of pregnancy. While a randomized trial showed a reduction in preterm births at 37 weeks, some analyses suggested a risk of fetal death or stillbirth.
Two subsequent trials observed similar adverse fetal or neonatal events. The FDA then required a confirmatory trial in 2019, which found no reductions in preterm birth at 35 weeks with the use of 17-OHPC. As a result, the Center for Drug Evaluation and Research recommended that the FDA withdraw approval.
In a statement to 鶹ý, a spokesperson for Covis Pharma, the manufacturer of the branded version of 17-OHPC, said that "this study blurs the line 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."
"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," the spokesperson added, noting that the approval and confirmatory trials affirmed the drug's safety.
Despite this long-standing controversy, there have been few studies on the long-term effects of 17-OHPC on those exposed in utero.
Murphy and colleagues used data from the Child Health and Development Studies, a population-based cohort of mother-child pairs who received prenatal care in the Kaiser Foundation Health Plan in Oakland from 1959 to 1966. They analyzed maternal health records to determine the number and timing of 17-OHPC injections in pregnancy, and measured the incidence of cancer by linking data to the California Cancer Registry.
They adjusted for confounders including year of birth, sex, maternal age at pregnancy, race and ethnicity, maternal education, parity at pregnancy, total family income, gestational age, maternal body mass index, and birth weight.
Of the nearly 19,000 offspring included in the study, 1,008 were diagnosed with cancer in follow-up. Around 1% of the study cohort was exposed to 17-OHPC in utero, which was most commonly indicated for threatened abortion. The first injection occurred at a mean of 12 weeks' gestation, and mothers received an average of 2.4 shots. Approximately 70% of offspring were first exposed to 17-OHPC in the first trimester.
Murphy and colleagues recognized that they were unable to measure the effect of first 17-OHPC exposure from 16 to 20 weeks of pregnancy -- as currently administered in clinical practice -- because most offspring had an earlier exposure. Additionally, the number of cancers diagnosed in this population was small, which may have limited their findings.
Disclosures
This research was supported by the National Cancer Institute and the National Institute of Child Health and Development.
Murphy disclosed a potential conflict of interest with Freenome.
Primary Source
American Journal of Obstetrics & Gynecology
Murphy CC, et al "In utero exposure to 17α-hydroxyprogesterone caproate and risk of cancer in offspring" Am J Obstet Gynecol 2021; DOI: 10.1016/j.ajog.2021.10.035.