DES: Long Term Health Implications

Kelly Kruse Nelles MS, RN-C, NP

Clinical Associate Professor

UW School of Nursing

UW Women’s Health Center

Acknowledgments

Thanks to the Wisconsin Well Woman Project for sponsoring this presentation.

Diethylstilbestrol (DES)

• A synthetic nonsteroidal estrogen used for over 3 decades under the mistaken assumption that it would– Prevent miscarriages

– Lead to a healthy pregnancy

• Clearly documented as a cause of Clear cell adneocarcinoma (CCA) of the vagina and cervix

Background and Epidemiology

• In the U.S., DES was prescribed to pregnant women primarily to prevent risk of SAB

• Used from 1938, when first synthesized, to 1971, when taken off the market

• Prescribed liberally to women who had a history of miscarriage or diabetes or “simply to make a healthy pregnancy healthier”

• Peak use occurred between the late 1940’s and the early 1950’s.

A Different Time

• The years between 1938 and 1971, were a different time– Medical advice was rarely questioned– Patient belief that “physicians new best”– Concept of informed consent was unknown at

the time– Many women were unaware that they were

taking DES as the drug was marketed in combination with vitamins

Marketing of DES

• DES and DES-type drugs were marketed under dozens of brand names and manufactured by over 200 U.S. drug companies at different times.

• Randomized trials of the drug were not conducted until the early 1950s and the results failed to show a clear benefit for pregnancy outcome from the use of DES

Despite Evidence, Little Change in Practice

• Research did not stop DES use however there was a gradual decline

• In 1971 the FDA contraindicated the use of DES in pregnant women

• Prenatal exposure to DES had been undeniably linked to CCA of the vagina and cervix in very young women (late teens and early 20s)

Life-long Effects

• Research on potential health outcomes of exposure of women who took the drug while pregnant as well as their children has shown possible lifelong effects

• Current studies continue to look at third-generation effects

• Remains a concern as women and men who may have been exposed to DES in utero are young as their late 30s today

National DES Education Initiatives

• DES is still a current health concern• Centers for Disease Control (CDC) and National

Cancer Institute (NCI) have initiated a nationwide education program to increase health care providers awareness and educate those who may have been exposed

• Providers are in key positions to assess history of exposure and provide care that is sensitive to individual risks

Review of DES Exposure and Current Health Risks

• Target populations– Women who were given DES during pregnancy– Their daughters (DES daughters) exposed in

utero– Their sons (DES sons) exposed in utero

Exposure During Pregnancy

• Women who took DES while pregnant are at a modestly increased risk for developing breast cancer (RR=1.3)– No evidence of increased risk for other

hormone-related cancers– Risk of breast cancer in these women does not

appear to be compounded by the use of HRT

DES Daughters

• Women exposed in utero have the most documented negative health effects– Increased risk for

• Structural anomalies of the reproductive tract

• Pregnancy complications

• CCA of the vagina and cervix

CCA Risk

• Small, yet significant (1:1000)– In DES daughters whose mothers either took

DES before the 9th week of pregnancy or had at least one SAB, this risk may be doubled

– Neither the use of oral contraceptives (OCs) nor pregnancy is associated with an increased risk of CCA in either non-exposed or DES-exposed women

• Peak age-incidence for CCA in DES daughters is 17-23 years, but there is no upper age limit for its development

• A second age incidence of CCA is a concern as DES daughters enter menopause

Other Health Concerns for DES Daughters

• DES daughters often have higher incidences of:– infertility and pregnancy complications (ectopic,

miscarriage, preterm labor and preterm births)

– Structural and histological anomalies of the reproductive tract (T-shaped uterus, cervical malformations, vaginal adenosis, cervical intraepithelial neoplasia, leukoplakia, and mosaicism)

DES Granddaughters

• Few studies but of those done findings show:

• Female offspring of DES daughters have not experienced the same type of genital abnormalities associated with in utero DES-exposure

• The age of menarche is unaffected by the mother’s DES exposure

DES Sons

• Have a tree-fold increase in reproductive abnormalities (epididymal cysts, undescended testicles, hypoplastic testes, varicoceles)– No decrease in fertility or sexual function found– Questionable testicular cancer risk

Cancer Risk

• Recent study showed the incidence of testicular cancer to be slightly higher for DES sons as compared to non-exposed men, however the increase was not statistically significant– Whether DES exposure is associated with

testicular cancer risk is still unclear

• DES sons are just now approaching the age when the incidence of many cancers increase

• Well established that cancer is more likely to develop in hypoplastic or undescended testicles, whether or not exposed – putting DES sons secondarily at higher risk for testicular cancer

• Animal studies and biologic plausibility raise concerns of the possible risk of two kinds of rare cancer found in middle-aged and older men – cancers of the rete testes and the prostatic utricle

DES Grandsons

• Little is known about third generation males (sons of DES daughters)– One study found an increased incidence of

hypospadias among third generation males– Third generation effects just beginning to be

studied

Clinical Implications

• Provider goals– Help DES-exposed patients identify their risk

for related health problems– Provide client education based on current

research– Tailor education and interventions - no single

set of guidelines is appropriate for everyone exposed to DES

Determine DES Exposure

• Identifying Possible Exposure– OB and pharmaceutical records are the best evidence

but as time passes they frequently cannot be obtained– Suggestive medical history (prior miscarriage in

women who were prescribed DES during pregnancy)– Clinical signs (reproductive tract anomalies, ectopic

pregnancy, repeated miscarriage in DES daughters)– Assessment of known DES exposure, either by

ingestion or in utero, should be routine in health history • Especially important in women who were pregnant between

1940 and 1971, and in women and men born that time

Consider Possible DES Exposure in These Situations

• Others who should be assessed for risk– Women who develop breast cancer without

family history or other risk factors should be assessed for exposure

– Women with pregnancy related complications and/or reproductive tract cellular and structural changes

– Men with reproductive abnormalities

Importance of Knowing DES Exposure

• Knowledge of DES exposure will not change the treatment or outcome of many related health problems but it may:– Provide an explanation that may help the

individual deal with the health problem– Reach other exposed family members to initiate

routine health screening

Exposed While Pregnant

• Women who were pregnant between 1940 and 1971 with a history of SAB and preterm labor should be assessed for possible exposure– Asking about the use of DES or other

medications during pregnancy is important due to the marketing of DES under many names

– She may not know she was exposed

Potential Increased Risk of Breast Cancer

• Importance of yearly clinical breast exam should be emphasized– Mammography screening recommended

according to current guidelines and based risk factors

– Thorough breast self-exam compliments professional screenings

Risk of Other Hormone Related Cancers

• Women prescribed DES may be reassured that there is no evidence of increased risk of other hormone related cancers

• When counseling regarding the use of menopausal hormones, Providers can reassure women that the risk of breast cancer in DES-exposed women is not compounded with the use

DES Daughters

• Some women may already be aware of in utero exposure– If status is unknown, specifically ask if the

patient’s mother had a history of miscarriage, preterm labor or was prescribed a drug during pregnancy

– Obtaining the mother’s health records during pregnancy is the best way to confirm exposure

Ruling Out CCA

• In women with known or suspected DES exposure, rule out symptoms of CCA– History of abnormal vaginal bleeding or

discharge may be symptomatic of CCA– Lifelong yearly breast and pelvic exams are

recommended

• Pelvic exam should include– Vuvlar inspection – Visual inspection of the vagina and cervix for

mosaicism, vaginal adenosis, leukoplakia, cervical anomalies

– Palpation of the vaginal walls is important as CCA has been known to present as a subepithelial lump

Consider Other Characteristics of DES Exposure

• Women with vaginal inelasticity often report dyspareunia and diffulty using tampons, which may also be characteristic of exposure– Uterine abnormalities should be considered in

women with these vaginal findings – specifically a T-shaped uterus

Lifelong Follow up for DES Daughters

• Obvious or suspected findings on bimanual exam may be followed with ultrasound or biopsy

• This careful approach to the gynecologic exam should be used throughout a woman’s life– Especially since CCA is now being diagonsed

at later ages, often beginning in the 30s and 40s

Lab Cytology

• Pap smear • of the upper vagina, middle and lower third if

epithelial changes are evident

• Sampling from the endo and ecto cervix

• Thin Prep Pap test is recommended

• DES exposure should be noted for cytology

Use of Colpobiopsy

• Colposcopy with Biopsy• Any woman with abnormal cytology

• Any woman who has a nodule or lesion

Continue Annual Screening

• Continue annual screening as previously described for

• Women with adensois or cervical anomoly with no abnormal cytology, nodule or lesion

• Women with a normal pelvic exam and cytology

Use of Endometrial Biopsy

• Perform with caution in DES-exposed women due to the possible shorter distance between the cervix and fundus

• Often indicated in evaluating menstrual irregularities

Education and Counseling Specific to DES Daughters

• Discuss:• Increased risk of infertility, ectopic pregnancies,

miscarriages, preterm labor and preterm births

• Review:• Symptoms of CCA

• Reassure:• Neither oral contraceptive use nor pregnancy

increase risk for CCA

Contraceptive Considerations

Tailor contraceptive counseling– Women with a T-shaped uterus should be informed that

this is a contraindication to the IUD

– Women with cervical malformations may have problems with barrier methods

• Cervical cap or diaphragm may not fit properly thus reducing effectiveness

– Inform women with cervical malformation that these changes may contribute to a higher incidence of pregnancy related problems

Fertility Awareness Helpful

• Incorporate Fertility Awareness Education into contraceptive counseling– Specifically the sympto-thermal method

• Weschler, T. - Fertility Awareness: The Definitive Guide to Pregnancy and Contraception

– Helpful for • contraceptive back up

• pregnancy planning

Recommendations in Pregnancy for DES Daughters

• Specific considerations:– Due to increased risk of ectopic pregnancy, inform her

of the symptoms– Instruct to call for pregnancy confirmation as soon as

period is missed– Transvaginal Ultrasound at 6 weeks LMP is usually

recommended to confirm intrauterine status– Early prenatal care is important– Inform her that she can expect more frequent

monitoring throughout her pregnancy

DES Sons

• Recommendations:– Advise to follow routine periodic health

screening regardless of age– Men who present with genital anomalies should

be assessed for a history of exposure in utero– Clinical testicular exam is recommended on a

yearly and bi-yearly basis with specific assessment for testicular lump or nodule

Cancer Screening – Testicular, Prostate and Prostatic Utricle

• Important to continue testicular exams in DES-exposed men past age 50 when increased incidence of rete testis cancer is likely

• Include regular, periodic prostate exams for middle aged and older men when prostate and prostatic utricle cancer are likely to occur– Periodic prostate-specific angien (PSA) test to detect

prostate cancer– Urinalysis to check of occult blood on regular yearly or

bi-yearly examinations is best way to detect prostatic utricle cancer

• Educate:– Testicular self-exam

– Inform men with undescended and hypoplastic testicles of possible increased risk of testicular cancer regardless of known DES exposure

• Reassure:– No known decrease in fertility or sexual function

– To date, no indication that in utero exposure to DES influences the development of cancer overall

• Encourage:– Participation in regular screening for other

types of cancer as most DES-exposed men are now approaching the age at which most cancers are detected

Third Generation Effects

• Mostly animal studies• Human studies just now beginning• In the few studies that do exist findings

indicate:– that of DES granddaughters

• Age of menarche is unaffected by the mother’s prenatal exposure

• Genital abnormalities associated with in utero DES exposure have not been found

– In third generation males (sons of DES daughters)

• Increased hypospadias have been found

• Long term health implications remain uncertain

In Conclusion

• Primary care providers are in key positions to identify DES exposure in patients

• In addition to clinical assessment, health education and counseling skills can be used to help individuals understand the health implications of DES exposure

• PCPs are in prime positions to assess whether DES exposure is creating worries, help patients identify strategies for care and assess their effectiveness

• In addition to offering support, Primary Care Providers can continue to review the literature for studies that may provide answers and clinical recommendations for DES-exposed patients