The first systematic follow-up study of a large group of women, whose mothers were given the synthetic estrogen diethylstilbestrol (DES) during pregnancy in the 1940s and 1950s, found no increase in any type of cancer except for clear cell adenocarcinoma of the vagina and cervix in women under age 30. Among the 4,500 exposed daughters in the study, who were followed from 1978 through 1992, three cases of clear cell adenocarcinoma developed. The rate for other cancers over this same period was similar for the DES-exposed women and for women not exposed to DES. The study is reported on in the Aug. 19, 1998 issue of the Journal of the American Medical Association(JAMA). *

Elizabeth Hatch, Ph.D., of the Division of Cancer Epidemiology and Genetics at the National Cancer Institute (NCI) and primary author of the findings says, "although this study is not the final word, this is good news for women exposed to DES in the womb. We would like to see continued follow-up for some time since these women are still young (the oldest being in their 40s) and more time will allow a more thorough evaluation of cancer risks." In particular, the scientists hope to continue to monitor the women for breast cancers in their later years when breast cancer is more common.

Scientists first reported 27 years ago that some of the daughters of women who were given DES during pregnancy experienced an increased risk of clear cell adenocarcinoma of the vagina and cervix as they entered their teens and 20s. What was unclear at the time, and has remained so over the last two decades until this study, is just how frequent this rare tumor was among the exposed daughters and whether DES-exposed women would experience increased risks of more common, hormonally-related malignancies, such as breast cancer, as they grew older. "It has been hypothesized that fetuses exposed to high levels of natural estrogens during pregnancy maybe at increased risk of breast cancer when they become adults," said Hatch.

DES was given to pregnant women, primarily in the 1940s and 1950s, in the hope that it would aid women who had difficulty in carrying their pregnancies to full-term. By the mid-1970s, several investigators had started following groups of daughters of exposed women to see if they were at increased risk for cancers and pre-malignant conditions of the cervix and vagina. These daughters were followed initially with yearly clinical examinations and then were mailed questionnaires periodically to ascertain their health status. A group of women who were not exposed to DES were also followed for comparison purposes.

In 1994, investigators at NCI collaborated with scientists at Baylor College of Medicine, Boston University, Dartmouth Medical School, the University of Massachusetts, and the University of Chicago, to reassemble these previously studied DES groups. DES exposed and unexposed women filled out questionnaires and cancer cases were documented by medical records. A total of 127 cancers have been reported by both groups since 1978. The rate of new cancer cases for all cancers was very similar to the number of new cases that would be expected based on rates in the U.S. population in general and to the rates in women not exposed to DES.

The women's risk for clear cell adenocarcinoma however, was 40 times greater than the general population, confirming earlier research findings. Three cases occurred among those exposed to DES, making this type of cancer fairly rare, even though the daughters are at an increased risk for developing clear cell adenocarcinoma. But because clear cell adenocarcinoma is most common in women in their 50s and 60s in the absence of DES exposure, scientists want to follow these women for another 10 or 20 years to see if there is a rise in the risk of this very rare form of cancer following menopause.

The limitations of this study are several-fold. Because the women in this study weren't identified and studied until half of them were at least 24, there was no opportunity to assess risks of childhood cancers. Additionally,due to the length of the study and the number of years between when exposure occurred and the study began, only 80 percent of the daughters who were identified initially participated in the most recent follow-up. According to Hatch, "the biggest limitation of this study is the relatively young age of the women and the short study follow up period. Observing the women in later life for a longer period of time would allow us to assess cancer risk more thoroughly."

DES was also used in women to help dry up breast milk if the mother did not want to breast feed. It has been used to alleviate some post-menopausal symptoms and in the treatment of advanced prostate and breast cancers. Use of DES to promote the growth of poultry and cattle has been banned for decades. Although many people may have been exposed to low doses of DESby other means, the daughters in this study had documented exposure, often due to large doses of DES, and were exposed in their mother's wombs.

Other aspects of DES under investigation are the effects of DES on fertility and pregnancy outcome, and the effects on mothers who received the drugs during pregnancy. Several studies have reported a small (30 percent) greater risk for breast cancer in mothers directly exposed to DES. Cancer risk in sons whose mothers were exposed is also being studied.

"The results of this study should help reassure DES daughters that clear cell adenocarcinoma is not a common cancer and that there are no major excess risks from other types of cancers," said Hatch. "The need to continue to follow these women to determine future cancer risk is clear however."

Also working with Hatch at the NCI on this study were Patricia Hartge,Sc.D. and Robert N. Hoover, M.D. Additional researchers on the paper include Julie R. Palmer, Sc.D., and Theodore Colton, Sc.D., Slone Epidemiology Unit, Boston University School of Public Health,Linda Titus-Ernstoff, Ph.D.,Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon,N.H., Kenneth L. Noller, M.D., Department of Obstetrics and Gynecology,University of Massachusetts Medical Center, Worcester, Mass., Raymond H.Kaufman, M.D., and Ervin Adam, M.D., Department of Obstetrics and Gynecology,Baylor College of Medicine, Houston, Texas, Robert Mittendorf, M.D., Dr.Ph.,and Charise M. Cowan, Department of Obstetrics and Gynecology, University of Chicago, Ill., Stanley J. Robboy, M.D., Departments of Pathology and Obstetrics and Gynecology, Duke University Medical Center, Durham, N.C.,and Marianne Hyer, M.S., Information Management Services, Rockville, Md.

*The study is titled "Cancer Risk in Women exposed to Diethylstilbestrol (DES) in Utero." The authors are E.E. Hatch, J.R. Palmer, L. Titus-Ernstoff, K. L. Noller, R. H. Kaufman,R. Mittendorf,S.J. Robboy, M. Hyer, C.M. Cowan, E. Adam, T. Colton, P. Hartge, and R.N.Hoover. JAMA, Vol. 280, No. 8, 1998.

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