In-utero exposure to diethylstilbestrol was associated with a high lifetime risk of a broad spectrum of adverse outcomes in a follow-up study of patients now in their 40s, 50s, and 60s, according to a report in the Oct. 6 issue of the New England Journal of Medicine.
Most of these risks were increased by a factor of more than two, compared with the risks in women of the same age who were not exposed to diethylstilbestrol (DES), said Dr. Robert N. Hoover of the National Cancer Institute, Bethesda, Md., and his associates.
"Although DES has not been prescribed for pregnant women in the United States for 40 years, adverse outcomes continue to occur in women exposed in utero, and continued monitoring ... for established and unexpected adverse outcomes seems prudent," they noted.
In the early 1990s, Dr. Hoover and his colleagues combined three cohort studies of DES-exposed women that had begun in the mid-1970s, so that the pooled subjects could be followed periodically with self-report questionnaires. Their Combined Cohort Study of DES Exposure involved 4,001 DES-exposed women and 1,683 nonexposed control subjects from the original cohorts, who were born between the late 1940s and the early 1960s and whose average age at last follow-up was 48 years.
All cancer diagnoses and biopsy results from cervical or vaginal specimens were verified through review of pathological reports.
Twelve adverse health outcomes that were significantly associated with DES in previous studies were assessed in the combined cohort, and all 12 were found to be significantly associated with DES in this combined analysis.
The hazard ratios (HRs) associated with DES exposure, compared with nonexposure, ranged from a low of 1.42 for preeclampsia to a high of 8.12 for neonatal death (usually related to preterm delivery).
In ascending order, the HRs were 1.64 for spontaneous abortion; 1.82 for breast cancer diagnosed at age 40 or older; 2.28 for cervical intraepithelial neoplasia of grade 2 or higher; 2.35 for early menopause; 2.37 for infertility; 2.45 for stillbirth; 3.72 for ectopic pregnancy; 3.77 for loss of second-trimester pregnancy; and 4.68 for preterm delivery, the investigators wrote (N. Engl. J. Med. 2011;365:1304-14).
In addition, three cases of clear-cell adenocarcinoma of the vagina and one case of clear-cell adenocarcinoma of the cervix were diagnosed in exposed women, compared with no cases in the unexposed women. "The number of clear-cell adenocarcinoma of the vagina or cervix expected on the basis of age-specific rates in the U.S. population was 0.102, for an observed-to-expected ratio of 39," Dr. Hoover and his associates said.
DES-exposed women who had clinical evidence of vaginal epithelial changes at a young age – a marker of high DES dose and exposure early in gestation – were found to have significantly higher risks for adverse outcomes than did exposed women who showed no vaginal epithelial changes. This finding provides additional support for the argument that DES exposure caused, and was not just linked to, the adverse outcomes, they said.
The researchers also calculated the excess risk of adverse outcomes that could be attributed directly to DES exposure. This excess risk was 1.7% for breast cancer, 3.4% for early menopause, 3.5% for CIN, 6.3% for stillbirth, 7.2% for neonatal death, 11.7% for both spontaneous abortion and ectopic pregnancy, 12.7% for preeclampsia, 14.7% for loss of second-trimester pregnancy, 17.8% for infertility, and 35.4% for preterm delivery.
The Combined Cohort Study of DES Exposure was supported by the National Cancer Institute. Dr. Robboy reports receiving consulting fees from UCB, Belgium. Dr. Karlan reports holding stock in and receiving board membership fees from IRIS International. Dr. Hatch receives royalties as a reviewer of the DES card on the UpToDate medical information site.