Drug Used to Prolong Gestation Linked to Increased Cancer Risk in Offspring

By Linda Carroll

November 10, 2021

(Reuters Health) - Children exposed in utero to 17 alpha-hydroxyprogesterone caproate (17-OHPC) may be at increased risk for cancer, a new study suggests.

In an analysis of data from more than 18,000 mother-child pairs, researchers found that, overall, offspring of women who were injected with the synthetic progesterone during pregnancy had nearly double the risk of any cancer compared with those not exposed to the hormone.

Exposure during the first trimester carried some of the highest risks for cancers later in life, including for pediatric brain cancer (adjusted hazard ratio 34.72), prostate cancer (aHR 5.10), and colorectal cancer (aHR 5.51), according to the report published in the American Journal of Obstetrics & Gynecology.

"Exposure in the womb to a drug used to prevent miscarriage in the 1950s and 60s increases the offspring's risk of cancer many decades later, especially for prostate, colorectal, and pediatric brain cancer," said the study's first author, Caitlin Murphy, an associate professor at the School of Public Health at the University of Texas Health Sciences Center in Houston. "This drug is still available in the United States for pregnant women to prevent preterm birth," Murphy noted.

"We were surprised by the strength of our findings," Murphy said in an email. "This is newsworthy because rates of several cancers are increasing across generations, starting with persons born in the 1960s or Generation X. Increasing rates of cancer across generations implicate exposures in very early periods of life as risk factors. This is consistent with our finding that earlier and more frequent injections of 17-OHPC in pregnancy was associated with higher risk of cancer in offspring. We need to know if risk of these cancers begins before birth, so that we can better weigh the pros and cons of medications in pregnancy."

While it isn't known exactly how the drug may raise cancer risk, Murphy says it may be because the drug isn't an exact duplicate of progesterone.

"Synthetic hormones, or drugs made to act like natural hormones, disrupt the way natural hormones work, especially during the vulnerable time of fetal development," she said. "The potential for synthetic hormones to disrupt development and increase risk of cancer is well-established by studies of diethylstilbestrol, a synthetic estrogen that was commonly prescribed to pregnant women to prevent miscarriage in the 1950s and 60s. 17-OHPC is a synthetic progestogen and may similarly contribute to risk of cancer."

To look at possible impacts of the medication on fetuses, Murphy and her colleagues turned to data from Child Health and Development Studies (CHDS), a population-based cohort of more than 18,000 mother-child dyads receiving prenatal care in the Kaiser Foundation Health Plan (Oakland, CA) between 1959 and 1966, and followed for 60 years.

CHDS monitors participants by annual linkage to the California Department of Motor Vehicles, the California Department of Vital Statistics and the California Cancer Registry.

The current analysis focused on 18,751 offspring, of whom 1,008 were diagnosed with cancer over 730,817 person-years of follow-up. About 1.0% (234) of offspring were exposed in utero to the medication, which was most commonly indicated for threatened abortion (41.0%). The first injection occurred at a mean of 12 weeks gestation and women received a mean of 2.4 injections, with the majority of offspring (165 of 234) exposed during the first trimester.

Among exposed offspring, 23 were diagnosed with cancer, including two in children and 21 in adults. Cancer types included melanoma, lymphoma, leukemia, polycythemia vera, colon and rectum, prostate, brain, breast, thyroid, oral cavity, lung and pleura, cervix, uterus, kidney, and testis.

Overall, offspring exposed in utero had an increased risk of any cancer (aHR, 1.99) compared to offspring not exposed. For those exposed in the first trimester (aHR, 2.57), the risk increase was greater.

Offspring of women who received one to two injections (aHR 1.80) had lower risk than those whose mothers received three or more injections (aHR 3.07).

The new findings are "basically in line with a lot of things we know about compounds that have hormonal properties," said Dr. Emanuela Taioli, director of the Institute for Translational Epidemiology and associate director of the Cancer Center at Mount Sinai in New York City, who wasn't involved in the study.

These drugs have been associated with harm to the fetus, including the risk for chronic diseases, malformation and cancer, Dr. Taioli said. "But this has never been shown for this product," she added.

The drug is used differently now than it was when data for this study were collected, Dr. Taioli said. "Now it's used later in pregnancy when many of the processes of embryogenesis have completed," she said. "So, the effects may be different from what the paper shows."

The authors suggest that exposure to a synthetic progesterone might have a different effect because the synthetic version degrades differently from natural progesterone, Dr. Taioli said.

"It's interesting that brain tumors were shown to be increased," Dr. Taioli said. "There is not an immediate connection between increases in brain cancer and hormones. This model might help scientists study brain cancers. This is suggesting hormones as a risk factor for brain cancer."

SOURCE: https://bit.ly/307HY7C American Journal of Obstetrics & Gynecology, online November 8, 2021. (Editing by Christine Soares)

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