CRC in Middle Age Linked to Morning Sickness Pill From 60s, 70s

Bendectin (originally a combination of three drugs: the antispasmodic/anticholinergic dicyclomine, the antihistamine doxylamine, and pyridoxine, a form of vitamin B6) is a pill that was commonly used to treat morning sickness during the 1960s and 1970s. It has been linked to an increased risk of colorectal cancer (CRC) among middle-aged people who had been exposed to the drug in utero.

The risk of CRC was more than three times higher among adults exposed to the medication in utero than among unexposed adults ― 30.8 vs 10.1 cases per 100,000 people ― after controlling for potential confounding factors.

The study was published March 10 in JNCI Cancer Spectrum.

Bendectin was approved in 1956 and quickly became the most prescribed treatment for nausea and vomiting during pregnancy. It was used by up to a quarter of pregnant women.

Dicyclomine was removed from the formulation in 1976 after it was found to be associated with gastrointestinal anomalies in newborns — pyloric stenosis and esophageal atresia — as well as congenital heart disease.

Production of the two-part formulation (doxylamine/pyridoxine) continued until 1983, when it was discontinued amid ongoing lawsuits suggesting it may cause birth defects.

The two-part formulation has since returned to the US market for morning sickness under new brand names. Dicyclomine is currently available for irritable bowel syndrome (IBS) as a pregnancy category B medication.

“The goal of our study was to understand why rates of colorectal cancer are increasing in young people,” lead researcher Caitlin Murphy, PhD, a public health researcher at the University of Texas Health Science Center, Houston, told Medscape Medical News. “Our findings suggest events in the earliest period of life, including in the womb, may contribute to colorectal cancer many decades later.”

Data came from a pregnancy research project — the Child Health and Development Studies program — which enrolled 14,507 pregnant women in the Oakland, California area from 1959–1966. Among many other things, women’s prescriptions during pregnancy were recorded.

The investigators crosslinked to the California Cancer Registry to correlate in utero Bendectin exposure to CRC incidence among the women’s 18,751 offspring. The researchers then compared CRC rates among the 1014 adults who had been exposed to the drug (about 5%) with those who had not been exposed. Women who had taken Bendectin did so mostly in the first trimester; most patients received one prescription.

The team found that as of December 31, 2021, 83 CRC cases had occurred. Of those cases, 12 occurred in adults who had been exposed Bendectin. The risk of CRC was more than three times higher in offspring exposed to the morning sickness drug (adjusted hazard ratio, 3.38). Overall, 0.012% of exposed adults and 0.004% of unexposed adults developed CRC.

Adults who had been exposed to Bendectin were diagnosed with CRC at a slightly younger age than those who had not been exposed (mean age, 47 vs 49 years). The risk associated with Bendectin started to separate out from unexposed adults at about age 35 and was higher at every age thereafter, Murphy said.

Although it’s unclear how exposure to the antispasmodic might increase CRC risk decades later, the researchers suspect dicyclomine may be the culprit.

“There is not yet enough information to make different recommendations for screening based on prenatal exposure to Bendectin,” Murphy said, but because in utero exposure to dicyclomine is still possible through IBS drugs, further research into its effects may be warranted.

When asked for comment, Alan Venook, MD, a CRC specialist and medical oncologist at the University of California, San Francisco, said he was not sure what to make of the findings.

“If this is real, [I’m] not sure it is actionable or helpful, since the current recommendations are for screening to begin at age 45, which would encompass every individual who would have been” exposed to Bendectin in utero through 1976, Venook said.

The study was funded in part by the National Cancer Institute. Murphy is a consultant for Freenome. Another investigator is a consultant for Exact Sciences, GRAIL, Freenome, and Universal Dx.

JNCI Cancer Spectr. Published online March 10, 2023. Abstract

M. Alexander Otto is a physician assistant with a master’s degree in medical science and a journalism degree from Newhouse. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape. Alex is also an MIT Knight Science Journalism fellow. Email: [email protected]

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