More than 30 years of research have confirmed that health risks are associated with DES exposure. DES Daughters are at an increased risk for:

• Clear cell adenocarcinoma (CCA), a rare kind of vaginal and cervical cancer
  
  Increased risk for clear cell cancer appears to be highest for DES Daughters in their teens and early 20s. However, cases have been reported for DES Daughters in their 30s and 40s (Hatch, 1998).
• Reproductive tract structural differences (for example, T-shaped uterus)
• Pregnancy complications, such as ectopic (tubal) pregnancy and pre-term delivery
• Infertility

Clear cell adenocarcinoma (CCA) of the vagina and cervix (Figure 2), is a very rare cancer that occurs more frequently in women exposed to DES in utero (DES Daughters) than in unexposed women. It may present as a visually abnormal lesion of the vagina and/or cervix, or be identified through vaginal and/or cervical cytological screening. The relative risk of CCA in DES Daughters is 40.7 compared to the general population (179). About 1 to 1.5 in 1,000 DES Daughters will develop clear cell adenocarcinoma of the vagina and/or cervix (154,155). The peak incidence of CCA in DES Daughters occurs in the late teens and early 20s. However, cases associated with in utero exposure to DES have been reported in women in their 30s and 40s (179). In the absence of DES exposure, CCA occurs in the postmenopausal years (154). Most women enrolled in studies of DES Daughters are only now entering menopause. Therefore, it is possible that there could be a higher risk of CCA among elderly DES Daughters.

On-going cohort studies have investigated associations between in-utero DES exposure and a range of other cancers. Because the average age of women in reported studies is less than 40 years, questions remain about the possibility of increased risk for age-related cancers that may become apparent as the cohort of women exposed to DES in utero ages.

The relationship between in-utero DES exposure and increased risk for cervical intraepithelial neoplasia (CIN) is uncertain. Some studies have suggested an increased relative risk of about 2.0 (178). Other studies have not found an association.

Concerns about an increased risk of breast cancer have also been raised for DES Daughters. Until recently the majority of DES Daughters were too young to determine whether DES exposure increased their risk of breast cancer. However, a recent study provides initial results linking exposure to DES before birth with increased rates of breast cancer. The study found that among study participants, DES Daughters were more likely to experience breast cancer than were unexposed women. Overall, DES Daughters had a relative risk of 1.4 (184). However, the findings were not statistically significant. In participants over 40, DES Daughters were 2.5 times more likely than unexposed women to be diagnosed with breast cancer (184). Findings for DES Daughters were statistically significant. DES Daughters under 40 years of age did not experience an increased risk of breast cancer. The findings from this study are considered preliminary until confirmed and refined by other research.

		Medical Management Steps The National Cancer Institute (NCI) identifies a number of medical management steps for women exposed to DES in utero (DES Daughters) (289): annual examination including breast examination inspection of the vulva, vagina, and cervix vaginal and cervical cytology digital, vaginal, and cervical palpation bimanual examination, including rectal examination DES Daughters should be encouraged to receive clinical breast examinations and mammograms as recommended for all women by the National Cancer Institute (www.cancer.gov) or by the American Cancer Society (www.cancer.org). It should be noted that no one has ever reported changes in the vulva associated with DES exposure. The part of the examination most important for detection of clear cell adenocarcinoma (CCA) of the vagina and cervix, the cancer clearly associated with in utero exposure to DES, is the examination of the vagina and cervix. Careful visual examination and palpation of the vagina and cervix is essential. Cytological smears of the vagina and cervix should be taken; although cases of CCA have been diagnosed in the presence of negative cytological smears. Any grossly visible or palpable abnormal vaginal or cervical lesion should be biopsied, regardless of cytology results. Evaluation and Indications for Referral of Patients with Possible DES-Related Neoplastic Changes of the Vagina and Cervix The evaluation and management of cervical intraepithelial neoplasia (CIN) in women exposed to DES in utero (DES Daughters) should follow standard recommendations for unexposed women. All grossly abnormal visible and/or palpable lesions of the vagina and cervix should be biopsied. Although the presence of vaginal adenosis (Figure 8), suggests DES exposure, no specific treatment is necessary (46,58,62). Colposcopy and/or iodine staining of the vagina with Lugol's solution (Figure 9) may be used to further characterize abnormalities detected by cytology, visualization, and/or palpation, but are not routinely recommended as screening methods (289). Lugol's solution should be used at half strength (2.5% iodine with 5% iodide in water). When abnormalities are found, the patients should be examined by a gynecologist experienced in evaluating DES Daughters (289). Women diagnosed with CCA should be refereed to a gynecological oncologist for evaluation and treatment.

Reproductive tract structural differences are common in women exposed to DES in utero (DES Daughters). Approximately 1/3 of DES Daughters have vaginal adenosis (Figure 8). Abnormalities of the cervix - collars (Figure 6), hoods, septae, and cockscombs (Figure 5), — are found in up to 33% of DES Daughters (39,42,46,47,49,50,52,77,80,87,98,105,106,183). One study of DES Daughters experiencing infertility found abnormal hysterosalpingogram findings in 69% of the women (52). Of these, the T-shaped uterus (Figure 7), is most associated with prenatal exposure to DES (51,93).

Most women exposed to DES in utero (DES Daughters) who become pregnant carry a normal pregnancy to term. However, a higher than average risk of abnormal pregnancy has been consistently documented. Rates of miscarriage, ectopic pregnancy, and premature birth are higher than for the general population. In women with documented reproductive tract structural differences, these rates are higher still. The relative risk of miscarriage is 1.31 for the first trimester and 2.93 for the second trimester (92). The relative risk of ectopic pregnancy is 3.7 to 6 times higher for women with documented reproductive tract abnormalities (92). The relative risk of premature birth is 2.6 to 4.7 times higher for women with documented reproductive tract structural differences (92).

DES Daughters should be referred to an obstetrician gynecologist for preconception counseling and pregnancy management. Care by a maternal-fetal medicine specialist should be considered, particularly for women with documented reproductive tract abnormalities and/or prior complications of pregnancy. Preconception counseling should include a discussion of increased risks of infertility, ectopic pregnancy, miscarriage, premature labor and premature birth. Pelvic examination should be performed to assess for cervical abnormalities.

DES Daughters who present for infertility evaluation should undergo a hysterosalpingogram to assess for upper genital tract abnormalities. Early diagnosis of pregnancy is particularly important, because of the heightened risk of ectopic pregnancy. If patients develop bleeding and/or abdominal pain, they should be emergently evaluated for ectopic pregnancy with a human chronic gonadotropin level (HCG) and pelvic ultrasound. In the past, because of the increased risk of miscarriage in this population, prophylactic cervical cerclage was advocated for pregnant women who had been exposed to DES in utero. However, conservative programs including frequent cervical examinations, bedrest, and cervical cerclage when indicated by signs and symptoms have been shown to be equally effective. Risks of cervical cerclage in DES Daughters include an increased risk of scarring, as the procedure is often technically difficult because of anatomical abnormalities of the cervix (104).

Recent studies have demonstrated an overall increase in infertility in women exposed to DES in utero (DES Daughters) (101,108). Up to one quarter of women exposed to DES in utero may be infertile (101,108). DES exposure was most strongly associated with infertility due to uterine problems, tubal problems, and multiple problems (108). All women who may have been exposed to DES in utero who undergo infertility evaluation should have a hysterosalpingogram performed to assess for upper tract abnormalities (96).

Although much is known about health risks among DES Daughters, many questions remain about health problems that might emerge as the cohort ages. The relative youth of the study cohort has limited firm conclusions. The median age of women in reported DES cohort studies is less than 50. Thus, it is possible that health effects may be found that affect elderly DES Daughters that are not currently recognized. In addition, significant bias is introduced into non-randomized studies because women with infertility, genital abnormalities, and other conditions possibly related to DES exposure are more likely to investigate whether they were exposed to DES, and thus be identified as DES Daughters. Data from a cohort of offspring of women randomized to DES or placebo during pregnancy exist, but sample sizes are relatively small.

Women prescribed DES while pregnant appear to be at a modestly increased risk of breast cancer, with most studies demonstrating a relative risk of 1.3 (33).

Studies to date have not found a statistically significant increased risk of breast cancer among DES Daughters of all ages. However, a recent study did find significantly increased risk among DES Daughters over age 40 (RR 2.5) (184). Since this was the first study to identify a link, further research is needed to confirm a link and to determine if DES Daughters of other ages also have a greater risk of breast cancer.

The most recent follow-up studies found that DES Daughters were approximately twice as likely as unexposed women to experience cervical intraepithelial neoplasia (CIN) (178). However, this finding may be the result of increased surveillance in DES Daughters.

Animal studies of mice exposed to DES in utero suggest an increased risk of autoimmune disease in female mice. Studies in humans have yielded conflicting results. One study indicated that the incidence of autoimmune diseases was higher in women who had been exposed to DES in utero (DES Daughters) (246). However, no single autoimmune disease was found to have a statistically significant association with DES exposure in utero. Studies of this issue are ongoing.

Some animal studies have suggested links between prenatal exposure to androgens or estrogens and cognitive abilities differentiated by sex. No human studies have documented consistent findings linking DES exposure in utero to any psychological or psychiatric condition, or to sexual dysfunction.

For a complete list of the numbered citations on this page see DES References.

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