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
Current Data Concerning Other Possible
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.
The National Cancer Institute (NCI) identifies a number of medical
management steps for women exposed to DES in utero (DES Daughters)
- 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.
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.
Prevalence of Reproductive Tract Structural Differences
tract structural differences are common in women exposed to DES
in utero (DES Daughters). Approximately 1/3 of DES Daughters have
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
DES while pregnant appear to be at a modestly increased risk of
breast cancer, with most studies demonstrating a relative risk of
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
Cervical Intraepithelial Neoplasia
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.
Autoimmune Disease, Psychosexual Function,
and Other Illnesses and Conditions
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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