This study measured an increase in the incidence of CCA among young women in their late teens and 20s who were born in the United States during the period when DES was prescribed to pregnant women, consistent with the lag period following in utero exposure that had been described in previous reports [1
]. Although we did not observe elevated risks for women in their 30s, a second peak in risk was observed among women after age 40. Our results are consistent with the experience of the DES exposed cohort in the Netherlands which also demonstrated an elevated risk of CCA after age 40 [5
]. In the follow-up of the NCI combined cohort of DES exposed women through 2001, the oldest case occurred at age 39 [4
]. A bimodal age distribution in CCA had been observed among women in the Netherlands who had not been exposed in utero to DES, leading the authors to suggest that menarche and menopause might promote the development of CCA [2
It has been estimated that between 1 and 2 million mothers the United States used DES while pregnant between 1947 and 1971, representing an exposure prevalence of about 1–2% [6
]. If the observed increase in risk for CCA was due primarily to DES exposure, then the magnitude of the risk among DES exposed women was substantially underestimated due to the dilution effect of combining exposed and unexposed women in one group. Studies of cohorts with documented exposure to DES have reported SIRs for CCA of 24 [5
] and close to 40 [4
]. In addition, we were unable to adjust for temporal variation in prenatal use of DES over time. Although prenatal use of DES occurred primarily between 1947 and 1971, some use occurred starting as early as 1940 and a small number of the women who were born in the early 1940s and assumed to be “unexposed” (Table ) might have been exposed. The resulting bias could have led to an underestimate of the risk among women in their 30s. The probability that a woman was exposed prenatally to DES was greatest for women born in the early 1950s when the prevalence of use peaked [6
]. However, the lack of SEER cancer incidence data before 1972 and the lack of NPCR/SEER data before 1998 limited the range of birth years that could be examined (Table ). This could have attenuated the measure of risk, especially at the youngest ages. Some analyses used data from SEER registries in nine geographic areas: Atlanta, Connecticut, Detroit, Hawaii, Iowa, New Mexico, San Francisco-Oakland, Seattle-Puget Sound, and Utah. Differences in risk estimates based on SEER data compared to the combined NPCR/SEER data, which includes many more areas, could be influenced by geographic differences in the prevalence of DES use.
Other than older age, DES is the most studied risk factor for CCA. Even among women with known in utero exposure to DES, however, the incidence rate of CCA is very low. The availability of high quality cancer incidence data with large nationwide coverage in the NPCR/SEER database enabled the examination of the occurrence of a very rare cancer using indirect standardization of rates. When age-specific risk estimates could be obtained using both SEER data and the combined NPCR/SEER data, the larger numbers available from the combined data set resulted in more stable estimates. The methods employed for this analysis could be repeated at periodic intervals in the future to examine CCA risk as women age. These methods also may have application for the examination of temporal trends or birth cohort patterns for other rare cancers.
These data suggest that the cohort of US women born during the period of DES use by pregnant women experienced an increased risk for CCA that continued for decades, longer than had been projected previously [16
]. If the marked elevated risk of CCA among this birth cohort was due primarily to in utero DES exposure, our findings suggest that the large number of women exposed in utero to DES in the United States may still be at special risk for CCA as they grow older. The American Congress of Obstetricians and Gynecologists advises that women exposed to DES in utero may need more frequent cervical cytology screening than that recommended for other women [17
]. The National Cancer Institute advises that such exposed women also be given a “four-quadrant” Pap test, in which cell samples are taken from all sides of the upper vagina [18
]. The American Cancer Society also specifies some differences in cervical screening recommendations for women with in utero exposure to DES [19
]. Women exposed to DES in utero also have been shown to be at elevated risk of breast cancer [20
]. To adequately assess a woman’s risks for developing cancer and to inform screening decisions for breast and cervical cancer, information on possible prenatal exposure to DES, if available, may be a relevant factor to consider for women born when DES was prescribed to pregnant women.