Abstract 858: In utero exposure to anti-nauseants and risk of young-onset colorectal cancer
Authors: Murphy Caitlin C. , Cirillo Piera M. , Krigbaum Nickilou Y. , Cohn Barbara A. 
Published: July 2021

Abstract
Background: Incidence rates of colorectal cancer (CRC) have increased markedly in Generation X, implicating exposures increasingly prevalent in their early life. Bendectin was a common anti-nauseant prescribed in early pregnancy during the 1960s and parallels increasing rates of young-onset CRC. Initially approved in 1956, Bendectin contained doxylamine (antihistamine), pyridoxine (vitamin B6), and dicyclomine (antispasmodic) but was reformulated in 1976 to contain only doxylamine and pyridoxine. Bendectin was removed from the market in 1983 after a series of lawsuits. In utero exposure to Bendectin has been implicated in birth defects and childhood leukemia, but little is known about its effects on health of adult offspring.
Methods: We examined the effect of in utero exposure to Bendectin on risk of CRC in adult offspring in the Child Health and Development Studies, a population-based cohort of women receiving prenatal care between June 1959 and September 1966, with deliveries through June 1967 (n=18,751 live births excluding neonatal deaths among 14,507 mothers). Diagnosed conditions and prescribed medications were abstracted from mothers' medical records beginning 6 months prior to pregnancy through delivery. We identified mothers who received Bendectin in early pregnancy (day 1 - 140 of gestation). Incident cases of CRC in offspring were ascertained through 2018 by linkage with the California Cancer Registry. We used Cox proportional hazards models to estimate hazard ratios (HR), with follow-up accrued from birth through CRC diagnosis, death, or last contact. To address the possibility of confounding by indication, we also examined the effect of nausea and hyperemesis on risk of CRC in offspring.
Results: About 6% of mothers (n=890) received Bendectin in early pregnancy. We identified 68 cases of CRC in offspring, diagnosed at ages 23 - 56 years (median age 50 years). In utero exposure to Bendectin was associated with increased risk of CRC in offspring (HR 2.93, 95% CI 1.45, 5.92). Dicyclomine was also associated with increased risk (HR 34.88, 95% CI 4.31, 282.50) when used alone as an antispasmodic (tradename Bentyl). There was no association with risk of CRC in offspring and other anti-nauseants containing meclizine only (HR 1.05, 95% CI 0.38, 2.89) or pyridoxine only (HR 2.20, 95% CI 0.31, 15.85) or with mothers' nausea (HR 0.62, 95% CI 0.23, 1.70).
Conclusions: Our findings suggest in utero exposure to Bendectin, and specifically dicyclomine, increases risk of young-onset CRC. These results provide compelling evidence that events in utero are important risk factors of this disease. Bendectin was commonly prescribed in pregnancy during the 1960s, and there may be other medications prescribed during this time that contribute to increasing incidence rates of young-onset CRC.
Citation Format: Caitlin C. Murphy, Piera M. Cirillo, Nickilou Y. Krigbaum, Barbara A. Cohn. In utero exposure to anti-nauseants and risk of young-onset colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 858.