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Transcript
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 thirdgeneration 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 DESexposed 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