In Utero Exposure to DES
In Utero Exposure to DES
By Kenneth L. Noller, MD
It has been more than 25 years since the first report of an association between exposure to diethylstilbestrol (DES) in utero and the later development of vaginal clear cell adenocarcinoma. In the original report, Herbst and associates identified this rare tumor in seven young women. Their case control study established, without a reasonable doubt, that women exposed to DES before birth were more likely to develop clear cell cancer than women not exposed. This fact startled both lay and medical groups, and considerable time, effort, and money have been spent determining whether other medical problems also occur in these women, their mothers, and their male siblings.
The purpose of this article is to provide an update of the information known about in utero exposure to DES.
Vaginal Clear Cell Cancer
Although the original cases of clear cell cancer, and most of those that were reported during the next few years, occurred in young women (teens-twenties), there have been cases reported in DES-exposed women well into their forties. Since the exposed group now averages between 40-50 years, there can be no reports of even older women yet. Unfortunately, many DES-exposed women have been told by their physicians that they have "nothing to worry about because you are too old." This statement is not true.
In the few reported cases of vaginal clear cell cancer that occurred in women not exposed to DES, the most usual age of diagnosis has been in the perimenopausal years. Therefore, as the DES-exposed population enters this age, physicians should be especially diligent in their examination of these women in order to detect clear cell cancer in its earliest, most treatable stage. Digital palpation of the vaginal fornices using one digit should be performed at every annual examination.
Squamous Neoplasia
Prospective studies of women exposed to DES have shown an increased risk of developing squamous neoplasia (dysplasia, CIN, VAIN) of the lower genital tract. Only very few cases of invasive cancer of the cervix have been reported in exposed women, probably due to early detection and treatment of early lesions. Because of the increased risk of neoplasia, cytology screening should be performed on all these women, at least annually. However, colposcopy should be reserved only for those women with abnormal pap smears, or those in whom vaginal adenosis persists.
Other Cancers
Although cancers from virtually all organs have been reported in the DES-exposed population, such would be expected because of the large number of exposed women (often estimated to exceed two million). However, at the present time there has been no documented, statistically significant increase of any cancer other than vaginal clear cell cancer, and preinvasive neoplasia of the lower genital tract.
Fertility
Although most DES-exposed women are now beyond the age when childbearing is most desired, many DES-exposed daughters did experience significant infertility problems. While some of these problems were due to abnormalities of the upper genital tract, many others have remained unexplained. Unfortunately, most of the published articles concerning infertility and DES-exposed women consist of nothing more than case series from infertility clinics which, of course, are highly biased.
Pregnancy
DES-exposed women have experienced numerous problems during pregnancy. There is approximately a 30% increase in spontaneous abortion, and a three-fold increase in ectopic pregnancy.
Even if the pregnancy is successfully carried beyond the first trimester, preterm labor, preterm rupture of membranes, and premature delivery without obvious cause are all reported to be increased in exposed women. Unfortunately, no single therapy prevents these outcomes. Although some authors have suggested routine cerclage, very few DES-exposed women experience the complication of incompetent cervix. Preterm labor is much more likely and may respond to tocolytic agents.
Medical Diseases
It is possible, perhaps likely, that DES-exposed women have a higher incidence of autoimmune diseases than do non-exposed women. Unfortunately, this topic is difficult to study, as many autoimmune diseases are poorly described and often misunderstood. Nonetheless, physicians should be alert to symptoms occurring in DES daughters, which may indicate the presence of one of the many autoimmune diseases.
DES-Exposed Mothers
Two reports from a very large cohort of women who took DES during their pregnancies has shown approximately a 30% increase in the occurrence of breast cancer. This increase persists after adjustment for all of the factors known to be associated with the occurrence of breast cancer, including increased surveillance.
To date, no other cancers have been shown to be increased significantly in DES mothers.
DES-Exposed Sons
Although there were several early reports suggesting that DES-exposed males may experience reproductive problems and structural abnormalities of their genital organs, other studies have failed to confirm this observation. Adverse selection may have accounted for the apparent increase. However, if there is a true elevation in these problems, it does not appear that it occurs with the same frequency as among DES-exposed females.
There has been great concern that various cancers might occur more commonly in DES-exposed males. To date, no significant increase has been reported, but a population of DES-exposed males continues to be followed prospectively.
More Information
DES Action is a national organization committed to providing support, advice, and education to DES-exposed individuals and their physicians. They have an excellent series of pamphlets, and they can direct interested persons to the best source of information concerning any of the above information. The National Office can be reached at 1-800-DES-9288.
Suggested Reading
1. Herbst AL, et al. Adenocarcinoma of the vagina: Association of maternal stilbestrol therapy with tumor appearance in young women. N Engl J Med 1971; 284:878-881.
2. Noller KL, et al. Maturation of vaginal and cervical epithelium in women exposed in utero to diethylstilbestrol (DESAD Project). Am J Obstet Gynecol 1983; 146:279-285.
3. Robboy SJ, et al. Increased incidence of cervical and vaginal dysplasia in 3980 diethylstilbestrol-exposed young women. JAMA 1984;252:2979-2983.
4. Barnes AB, et al. Fertility and outcome of pregnancy in women exposed in utero to diethylstilbestrol. N Engl J Med 1980;302:609-613.
5. Herbst AL, et al. A comparison of pregnancy experience in DES-exposed and DES-unexposed daughters. J Reprod Med 1980;24:62-69.
6. Noller KL, et al. Increased occurrence of autoimmune disease among women exposed in utero to diethylstilbestrol. Fertil Steril 1988;49:1080-1082.
7. Leary FJ, et al. Males exposed in utero to diethylstilbestrol. JAMA 1984;252:2984-2989.
8. Colton T, et al. Breast cancer in mothers prescribed diethylstilbestrol in pregnancy. JAMA 1993;269: 2096-2100.
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