Diethylstilbestrol Exposure
`
`SARINA SCHRAGER, M.D., and BETH E. POTTER, M.D.,
`University of Wisconsin Medical School, Madison, Wisconsin
`
`Diethylstilbestrol is a synthetic nonsteroidal estrogen that was used to prevent miscarriage
`and other pregnancy complications between 1938 and 1971 in the United States. In 1971, the
`U.S. Food and Drug Administration issued a warning about the use of diethylstilbestrol dur-
`ing pregnancy after a relationship between exposure to this synthetic estrogen and the devel-
`opment of clear cell adenocarcinoma of the vagina and cervix was found in young women
`whose mothers had taken diethylstilbestrol while they were pregnant. Although diethyl-
`stilbestrol has not been given to pregnant women in the United States for more than 30 years,
`its effects continue to be seen. Women who took diethylstilbestrol during pregnancy have a
`slightly higher risk of breast cancer than the general population and therefore should be
`encouraged to have regular mammography. Women who were exposed to diethylstilbestrol
`in utero may have structural reproductive tract anomalies, an increased infertility rate, and
`poor pregnancy outcomes. However, the majority of these women have been able to deliver
`successfully. Recommendations for gynecologic examinations include vaginal and cervical dig-
`ital palpation, which may provide the only evidence of clear cell adenocarcinoma. Initial col-
`poscopic examination should be considered; if the findings are abnormal, colposcopy should
`be repeated annually. If the initial colposcopic examination is normal, annual cervical and
`vaginal cytology is recommended. Because of the higher risk of spontaneous abortion, ectopic
`pregnancy, and preterm delivery, obstetric consultation may be required for pregnant women
`who had in utero diethylstilbestrol exposure. The male offspring of women who took diethyl-
`stilbestrol during pregnancy have an increased incidence of genital abnormalities and a pos-
`sibly increased risk of prostate and testicular cancer. Routine prostate cancer screening and
`testicular self-examination should be encouraged. (Am Fam Physician 2004:69:2395-400,2401-2.
`Copyright© 2004 American Academy of Family Physicians.)
`
`O A patient infor-
`mation handout on
`diethylstilbestrol,
`written by the
`authors of this arti-
`cle, is provided on
`page 2401.
`
`See page 2291 for defi-
`nitions of strength-of-
`recommendation labels.
`
`Between 1938 and 1971, as many
`
`as 4 million women in the United
`States
`took diethylstilbestrol
`(DES), an oral synthetic non-
`steroidal estrogen, for the pur-
`pose of improving pregnancy outcomes.1,2 In
`1953, it was demonstrated that DES did not
`prevent miscarriage and other pregnancy
`complications. However, physicians contin-
`ued to prescribe DES to pregnant women
`until at least 1971, when a connection was
`established between in utero DES exposure
`and the development of clear cell adenocarci-
`noma of the vagina and cervix in the daugh-
`
`In 1971, the U.S. Food and Drug Administration warned
`against the use of diethylstilbestrol in pregnant women
`because of an increased risk of clear cell adenocarcinoma in
`female offspring.
`
`ters of women who had taken DES during
`pregnancy.3 In 1971, the U.S. Food and Drug
`Administration issued a warning against the
`use of DES in pregnant women.4 DES contin-
`ued to be used in various European countries
`until the early 1980s.
`The association between in utero DES
`exposure and vaginal clear cell adenocarci-
`noma has been well documented. Other
`adverse associations have been identified in
`DES-exposed women and their offspring, and
`animal studies have shown effects in the next
`generation (grandchildren).5,6 The Centers for
`Disease Control and Prevention has instituted
`a campaign to educate health care profession-
`als and patients about the risks associated with
`exposure to this synthetic estrogen.
`It is difficult to determine the number of per-
`sons with DES exposure. However, physicians
`should be alert for patients who may have been
`exposed to this agent and should be aware of
`the possible consequences of such exposure.
`
`Downloaded from the American Family Physician Web site at www.aafp.org/afp. Copyright© 2004 American Academy of Family Physicians. For the private, noncommercial
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`Dosages of DES varied greatly, as did the time
`during pregnancy that DES was taken. These
`factors may contribute to the wide range of
`adverse effects in the offspring of women who
`took DES while they were pregnant.
`
`Illustrative Case
`A 37-year-old woman who had been trying
`to conceive for two years came to her physi-
`cian’s office to discuss fertility issues. Her basal
`body temperature charts illustrated presumed
`ovulatory cycles, and her husband had a nor-
`mal semen analysis. She had an abnormal
`Papanicolaou (Pap) smear 15 years previously,
`but all subsequent Pap smears had been nor-
`mal. However, her previous physician had
`noted that her cervix “looked funny.” The
`
`TABLE 1
`Identifying DES-Exposed Patients
`
`Patient
`
`Woman who may
`have taken DES
`during pregnancy*
`
`Daughter or son
`who may have
`been exposed to
`DES in utero†
`
`Approach to identifying DES
`exposure, and subsequent actions
`
`Questions: Have you ever had a miscarriage? More
`than one miscarriage? Did you take any prescription
`medicines while you were pregnant? If so, what
`medicine and for what reason?
`Actions: If the patient is not sure about the medications
`that she took, try to obtain her obstetric records.
`If DES exposure is documented or surmised from the
`history, counsel all of the patient’s offspring.
`
`Questions: Did your mother have one or more
`miscarriages? Did your mother take any prescription
`medicines while she was pregnant with you?
`Actions: If the patient has reproductive tract anomalies
`consistent with those seen in DES-exposed offspring,
`attempt to obtain the mother’s obstetric records. If the
`records cannot be obtained, consider the patient to
`have been exposed to DES.
`
`DES = diethylstilbestrol.
`*—Although DES was not used in pregnant women in the United States after
`1971, it continued to be used in other countries until the early 1980s.
`†—Born in the United States from 1938 through 1971, or born outside the
`United States from 1938 through the early 1980s.
`Information from Centers for Disease Control and Prevention. DES update.
`Accessed online February 19, 2004, at: http://www.cdc.gov/DES.
`
`patient was the oldest of four siblings; her
`mother had two miscarriages before the
`patient was born.
`The patient’s general physical examination
`was normal. On pelvic examination, her
`vagina was normal, but her cervix had a
`pseudopolyp. Because of the patient’s history
`of infertility and the consideration that she
`might have been exposed to DES in utero, hys-
`terosalpingography was ordered, and the
`patient was asked to discuss the possibility of
`DES exposure with her mother.
`The patient’s mother accompanied her to
`the follow-up visit. The hysterosalpingogram
`showed that the patient had a T-shaped uterus.
`Her mother vaguely remembered taking med-
`ication to prevent another miscarriage when
`she was pregnant with her daughter.
`Subsequent to a follow-up visit, the pa-
`tient’s mother contacted her physician for a
`copy of her obstetric records. The patient was
`referred to a reproductive endocrinologist for
`evaluation of infertility.
`
`Identifying DES Exposure
`It is important to include questions about
`DES in the routine medical history of women
`who gave birth between 1938 and 1971, and of
`patients who were born during those years3,7
`(Table 1).2 In persons born outside the United
`States, there is a chance of DES exposure if
`they gave birth or were born as late as the
`1980s. Many women may not be aware that
`they received DES during pregnancy, in part
`because the synthetic estrogen was marketed
`under many different names.2,8
`One recent study9 found that an office sys-
`tem intervention was successful in increasing
`awareness of DES exposure among clinical
`staff. The intervention entailed the addition of
`questions about DES exposure to the routine
`health history form.
`
`Women Who Took DES
`During Pregnancy
`Women who took DES while they were
`pregnant have a slightly higher incidence of
`
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`DES
`
`TABLE 2
`Structural Abnormalities in Women
`with in Utero DES Exposure
`
`Women who took diethylstilbestrol during pregnancy have a
`slightly increased risk of breast cancer.
`
`Cervix
`Hypoplastic cervix
`Cockscomb cervix
`Cervical collar
`Pseudopolyp
`
`Vagina
`Clear cell adenocarcinoma
`Adenosis
`Uterus
`T-shaped uterus
`
`DES = diethylstilbestrol
`
`breast cancer compared with the general pop-
`ulation. The relative risk ranges from 1.27 to
`1.35 in several studies.10 In comparison, the
`relative risk of breast cancer is 1.3 in women
`who have taken hormone therapy for more
`than five years,11 and 2.1 in women with a
`family history of breast cancer.12 Women who
`were prescribed DES during pregnancy
`should have annual mammography and clini-
`cal breast examinations after the age of 50.12
`[Strength of recommendation (SOR) A, evi-
`dence-based guideline]
`No increased risk of other hormone-depen-
`dent cancers has been found in women with
`DES exposure during pregnancy. Therefore,
`other preventive and screening measures
`should be based on standard guidelines.
`
`Daughters with in Utero DES Exposure
`In the daughters of women who took DES
`during pregnancy, the incidence of clear cell
`adenocarcinoma of the vagina and cervix
`ranges from 1.4 cases per 1,000 exposed per-
`sons to one case per 10,000 exposed persons.13
`Clear cell adenocarcinoma is most likely to
`develop when women with in utero DES
`exposure are between 17 and 22 years of age.
`However, cases have been diagnosed in
`women in their 30s and 40s, and there is con-
`cern about a possible second age-incidence
`peak of clear cell adenocarcinoma as women
`with in utero DES exposure grow older.14
`
`Clear cell adenocarcinoma of the vagina and
`cervix is rare in women without in utero DES
`exposure; in such cases, the cancer usually
`develops in the postmenopausal period.15
`Many women who were exposed to DES in
`utero are just beginning to reach menopause.
`Because of the concern about a second peak in
`the incidence of clear cell adenocarcinoma,
`continued surveillance for this cancer is war-
`ranted in these women.16
`Women with in utero DES exposure do not
`have a higher documented incidence of any
`other cancer. Data from several studies17,18
`suggest that these women may have a higher
`incidence of high-grade cervical intraepithe-
`lial neoplasia, but not invasive cervical carci-
`noma. However, the findings of these studies
`have been questioned, in that women with in
`utero DES exposure may receive increased
`cytologic screening. A link with breast cancer
`is under investigation.2
`Many women who were exposed to DES in
`utero have a range of structural reproductive
`tract abnormalities19,20 (Table 2). The National
`Collaborative Diethylstilbestrol Adenosis pro-
`ject19 followed approximately 4,500 DES-
`exposed women for almost 20 years and
`found an 18 percent incidence of structural
`uterine, cervical, or vaginal abnormalities. The
`incidence of these abnormalities may be as
`high as 33 percent in women with in utero
`DES exposure.2
`DES can cause changes in the vaginal
`epithelium, including adenosis (columnar
`epithelium located in the upper one third of
`the vagina). Although vaginal adenosis is
`benign, it sometimes causes abnormal bleed-
`ing. The degree of adenosis depends on the
`DES dosage and the stage during the preg-
`nancy that the agent was taken. The most
`severe changes occur in the daughters of
`
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`TABLE 3
`Clinical Recommendation for Women
`with in Utero DES Exposure
`
`Perform colposcopy as part of the first pelvic
`examination. If the colposcopic examination is
`normal, no further screening is needed. If the
`examination is abnormal, repeat colposcopy
`annually along with cervical and vaginal
`(four-quadrant) cytology.
`Perform annual cervical cytology, four-quadrant
`vaginal cytology, and careful digital palpation for
`adenosis and vaginal clear cell adenocarcinoma.
`Provide counseling about increased risk of infertility
`and poor pregnancy outcome.
`Refer pregnant patients for high-risk obstetric
`management.
`
`women who took DES during the first
`trimester.20 Although vaginal clear cell adeno-
`carcinoma generally develops in areas of
`adenosis, whether individual areas of adenosis
`progress to this cancer remains unknown.
`Performance of colposcopy (to assess for
`abnormal epithelium) frequently is recom-
`mended during the first pelvic examination
`in all women with in utero DES exposure
`(Table 3).21 If the initial colposcopic examina-
`tion is normal, annual pelvic examinations
`and annual cervical Pap smears and four-
`quadrant vaginal Pap smears are adequate,
`and colposcopy does not need to be
`
`The Authors
`SARINA SCHRAGER, M.D., is assistant professor in the Department of Family Medicine
`at the University of Wisconsin Medical School, Madison. Dr. Schrager received her
`medical degree from the University of Illinois at Chicago College of Medicine. She
`completed a family practice residency and a primary care women’s health fellowship
`at MacNeal Hospital, Berwyn, Ill.
`
`BETH E. POTTER, M.D., is a faculty member in the family practice residency program
`at the University of Wisconsin Medical School, Madison. Dr. Potter received her med-
`ical degree from Rush Medical College of Rush University, Chicago, and completed a
`family practice residency at the University of Wisconsin.
`
`Address correspondence to Sarina Schrager, M.D., University of Wisconsin Medical
`School, Department of Family Medicine, 777 S. Mills St., Madison, WI 53715 (e-mail:
`sbschrag@wisc.edu). Reprints are not available from the authors.
`
`repeated.21,22 [Reference 22: SOR C, consen-
`sus practice guideline based on expert opin-
`ion] If the initial colposcopic examination
`demonstrates any abnormalities, annual col-
`poscopy with cytology is indicated.
`For the four-quadrant Pap smear, cells are
`obtained from all four walls of the upper
`vagina. Cells first are obtained from the two
`lateral walls; then the speculum is rotated
`90 degrees, and specimens are obtained from
`the anterior and posterior walls. The four-
`quadrant Pap smear should be performed
`annually to screen for adenosis and clear cell
`adenocarcinoma in women with in utero DES
`exposure.
`Routine cervical cytology also should be
`performed annually in women who were
`exposed to DES in utero. In addition, the
`cervix and upper vaginal walls should be pal-
`pated carefully during the bimanual examina-
`tion to feel for thickening that might indicate
`adenosis or clear cell adenocarcinoma.22
`Women with in utero DES exposure should
`be counseled about their slightly increased
`risk of infertility and a possibly increased risk
`of adverse pregnancy outcome. Infertility is
`most common in women with underlying
`structural abnormalities and usually is caused
`by uterine or tubal factors.23 Women who
`were exposed to DES in utero should be mon-
`itored closely during pregnancy.24-26
`Although most women with in utero DES
`exposure have normal pregnancies, there is
`evidence for an increased risk of first- and sec-
`ond-trimester spontaneous abortion, ectopic
`pregnancy, and preterm delivery.26 The most
`comprehensive study26 to date found that
`64.5 percent of women with in utero DES
`exposure had full-term infants, compared
`with 84.5 percent of matched women who
`had not been exposed to DES. In addition, the
`DES-exposed women had higher rates of
`preterm delivery (19.4 percent versus 7.5 per-
`cent), ectopic pregnancy (4.2 percent versus
`0.77 percent), and second-trimester sponta-
`neous abortion (6.3 percent versus 1.6 per-
`cent). Consequently, high-risk obstetric care
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`DES
`
`The sons of women who took diethylstilbestrol during preg-
`nancy have an increased incidence of genital structural abnor-
`malities, testicular cancer, and sperm and semen abnormalities.
`
`Future Considerations
`An increased susceptibility to reproductive
`tract tumors has been demonstrated in mice
`that are descended from parents with prenatal
`DES exposure (i.e., multigenerational effect),6
`but this relationship has yet to be observed in
`humans. To date, no studies have shown an
`increased risk of cancer in the offspring of men
`and women who were exposed to DES in
`utero. Two studies34,35 of “DES granddaugh-
`ters” (third-generation females) have found no
`health effects related to DES exposure. How-
`ever, one small study36 of “DES grandsons”
`showed an increased risk of hypospadias.
`DES currently is being studied as an exper-
`imental hormonal treatment (i.e., a type of
`estrogen therapy) in men with refractory
`prostate cancer.37
`
`The authors indicate that they do not have any con-
`flicts of interest. Sources of funding: work on this
`article was supported by grants from the Centers for
`Disease Control and Prevention’s Educational Cam-
`paign on DES and the University of Wisconsin
`National Center of Excellence in Women’s Health.
`
`REFERENCES
`
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`adverse effects on the reproductive tract and
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`may be indicated for pregnant women who
`were exposed to DES in utero.
`Contraceptive management may be com-
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`
`Sons with in Utero DES Exposure
`The sons of women who took DES during
`pregnancy are three times more likely to have
`genital structural abnormalities than men
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`abnormalities are epididymal cysts, unde-
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`who were exposed to DES in utero showed a
`significantly higher incidence of squamous
`metaplasia in this müllerian-derived tissue.
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`the sons of women who took DES during
`pregnancy should be encouraged to practice
`routine testicular self-examination.
`
`MAY 15, 2004 / VOLUME 69, NUMBER 10
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`2400 AMERICAN FAMILY PHYSICIAN
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`www.aafp.org/afp
`
`VOLUME 69, NUMBER 10 / MAY 15, 2004
`
` P. 6
`
`UT Ex. 2045
`SteadyMed v. United Therapeutics
`IPR2016-00006