Diethylstilbestrol (DES) Update: Recommendations for the Identification and Management of DES-Exposed Individuals

Barbara Hammes, CNM, MS, Cynthia J. Laitman, PhD


J Midwifery Womens Health. 2003;48(1) 

In This Article

Effects of DES in Women Exposed in Utero

Adenocarcinoma and Cervical Cancer

A 1998 study by Hatch et al.[4] examined questionnaire results and clinical chart reviews of 4,536 DES-exposed daughters (81% response rate) and 1,544 women not exposed in utero (79% response rate) to determine relative risks of all cancers. Three exposed women (under 30 years of age) with clear cell adenocarcinoma of the vagina were identified (approximately 1:1600 DES daughters), which confirms the incidence rate of adenocarcinoma associated with in utero DES exposure previously documented by the Registry on Transplacental Hormonal Carcinogenesis. The peak incidence of clear cell adenocarcinoma in DES daughters appears to occur in the late teens and early twenties.[4] However, it has been reported in women up to age 48.

Herbst found the number of cases of clear cell adenocarcinoma markedly decreased from age 30 to 39 but then showed an increase in incidence after age 40.[32] In the absence of DES exposure, vaginal clear cell adenocarcinoma is a very rare malignancy, almost always occurring in the postmenopausal years. Because women enrolled in DES studies are only now entering menopause, there is no age beyond which a provider can be certain clear cell adenocarcinoma of the vagina or cervix will not occur. Therefore, health care providers should continue to screen DES daughters for clear cell adenocarcinoma throughout their lifetimes.

Whether DES daughters are at increased risk for cervicovaginal dysplasia and squamous-cell carcinoma of the cervix and vagina is also being debated. Although earlier DES-adenosis studies did not show an increase in dysplasia,[33] a study by Robboy et al. found the risk of squamous cell dysplasia and carcinoma in situ was doubled in DES daughters compared with women not exposed to DES in utero.[34] They hypothesized that DES daughters have a wider transformation zone, which may make them more susceptible to dysplastic changes. These findings were supported by a study reported in a letter to the editor in the June 2000 New England Journal of Medicine, performed by the Netherlands Cancer Institute, which reviewed 5,461 returned questionnaires from DES daughters.[35] The women who returned this questionnaire and who had their reports confirmed via medical record review, had significantly increased prevalence rates of cervical cancer (prevalence ratio 5.4; 95% CI 2.8-9.5) They also pointed out that one might expect DES daughters to have a lower prevalence of invasive cervical cancer because they are screened more intensively for cervical cancer and because precursor lesions detected on screening are usually treated aggressively. Indeed, the 2001 Hatch et al.[12] study found a lower incidence of pathology-confirmed invasive cervical cancer in DES daughters than in unexposed women with similar demographic characteristics (RR 0.67; 95% CI 0.12-3.67), which supports the supposition that despite a two-fold increase in cervical intraepithelial neoplasia (CIN), the incidence of invasive cervical cancer is not increased. Because this positive finding may be secondary to heightened surveillance and treatment of cervical cancer precursors, DES daughters should continue to be actively monitored for cervical cancer.

Other Cancers

Hatch et al.[4] compared cancer rates in DES daughters with cancer rates from the National Institutes of Health Surveillance Epidemiology and End Results (SEER) program. The incidence rates of all cancers, excluding clear cell adenocarcinoma, were similar to both the SEER population incidence rates and the rates in the unexposed women enrolled in the study (rate ratio 0.96; CI 0.58-1.56). Although the Hatch study revealed no increased cancer risk in DES daughters, the age of women studied was young (median age at the start of the study was 25-25 years at the start of the study), and they did not have sufficient statistical power to detect significant differences in many of the cancers surveyed for except for the already known risk for clear cell adenocarcinoma. The investigators caution the need for continued surveillance as DES daughters age and enter menopause.

Anatomic Abnormalities

The following non-malignant abnormalities are found in the lower genital tract of DES daughters more frequently than these abnormalities are noted in women not exposed to DES in utero: benign glands in the vagina (adenosis) and anatomic deformities of the lower genital tract including transverse vaginal ridges, cervical collars, and hoods (Figures 2 and 3). These anatomic changes seem to relate to the time in pregnancy when DES was ingested, being most common among offspring whose mothers took DES early in pregnancy. These anomalies frequently regress over time. One third of all DES-exposed daughters have an upper genital tract anomaly, a T-shaped uterus. There is also some question that inelastic musculature may occur in some DES daughters in the vagina as well as the uterus.[36]

Figure 1.

Pharmaceutical company advertisement for DES by the Grant Chemical Company, Brooklyn, NY, printed in the American Journal of Obstetrics & Gynecology in 1957.

Figure 2.

Coxcomb cervix. Reprinted with permission from K. Noller's personal collection.

Pregnancy Outcomes

Although pregnancy outcomes in women exposed to DES in utero will, more often than not, be successful, practitioners need to be aware that this group has significantly increased pregnancy risks. Kaufman et al.[37] reviewed 3,373 questionnaires completed in 1994 from exposed daughters identified from patient records, physician referrals, the National Collaborative Diethylstilbestrol Adenosis cohort and the Chicago Lying-In Hospital cohort. These were compared with a control group of 1,036 questionnaires from non-exposed women. Preterm births were more common in DES-exposed daughters (RR 2.93; CI 2.23-3.86), as were ectopic pregnancies (RR 3.8; CI 2.26-6.54) compared with non-exposed women. More first-trimester (RR 1.31; CI 1.13-1.53) and second trimester (RR 4.25; CI 2.36-7.66) spontaneous abortions occurred in the DES group than in the control group. Regarding fertility outcomes for DES daughters, the Dieckmann cohort reported rates of primary infertility as high as 33%.[1,38,39]

The role of incompetent cervix versus premature labor in DES-exposed daughters is difficult to separate. The reproductive tract musculature (uterine, cervical, and vaginal tract) can be flawed, lacking in elasticity, not allowing it to expand and contract in a normal fashion. Although preterm delivery in DES daughters has been attributed to an "incompetent cervix" and the incidence of incompetent cervix may indeed be greater in these women, cerclage is not recommended as a routine procedure in DES daughters because as a prophylactic procedure, it has not been shown to improve pregnancy outcomes.[37,40]


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