Ehlers-Danlos Syndrome
Fertility Issues
Baltimore Inner Harbor
Independence Day
Brad Hurst, M.D.
Professor Reproductive Endocrinology
Carolinas Medical Center - Charlotte, North Carolina
Objectives
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Determine if EDS causes infertility
Describe infertility evaluation
Discuss cost-effective infertility treatment
Consider role of IVF
Learn new approaches to preimplantation
genetic diagnosis that may apply to EDS
Ehlers-Danlos National
Foundation 1994
• 68 women, most type I, III, IV
• 43 women, 138 pregnancies
• Reproductive problems:
– Spontaneous abortion 29% (40/138)
– 25% all pregnancies in population
– Sexual dysfunction (61%)
– 43% prevalence women
– Irregular menses (28%)
– 11% college-age population
– Endometriosis (16%)
– 5-10% population
Sorokin Y. et al, J Reprod Medi 39:281-4, 1994
Endometriosis/dyspareunia
1995
• 41 women in Ehlers-Danlos clinic
– Endometriosis 27%
• 5-10% population
– Painful intercourse 57%
• 45% population
Gynecologic disorders in women with Ehlers-Danlos syndrome.
McIntosh LJ et al, J Soc Gynecol Invest 2:559-64, 1995
Ehlers-Danlos Fertility
Publications Since 1995
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In vitro fertilization (IVF) - none
Ovulation - none
Pelvic pain - none
Endometriosis - none
Dyspareunia - none
Amenorrhea - none
Oligomenorrhea - none
Ectopic pregnancy - none
Preimplantation genetic diagnosis - none
Insemination - none
Sperm/spermatozoa - none
Oocyte - none
Clomiphene - none
Medline search June 2011
Fallopian tube - none
Ehlers-Danlos and Fertility
Assumptions
• Women with Ehlers-Danlos experience
infertility
• Infertility prevalence
– 1 in 8 couples in population
– More ovulation disorders, endometriosis,
painful intercourse, miscarriage with EDS
• Some women with Ehlers-Danlos may be
advised to avoid pregnancy
– Vascular, maybe kyphoscoliotic type
– But some may still want to have children!
Esaka EJ et al, Obstet Gynecol 113:515-8, 2009
Volkov N et al, Obstet Gynecol Surv 62:51-7, 2007
What is Infertility?
• “Infertility is a disease, defined by the failure to
achieve pregnancy after 12 months or more of
regular unprotected intercourse.”
• Women ≥ 35 years old: evaluation justified after
6 months of unprotected intercourse
• Earlier evaluation for
– Infrequent menses
– Known tubal disease or endometriosis
– Known male infertility
ASRM Practice Committee 2008
Example:
What is appropriate evaluation?
• 33 year-old never pregnant EDS
• (non-vascular)
• Unprotected intercourse 2 years, 2-3 X per
week
• Regular cycles 28 days with premenstrual
breast soreness
• Healthy, rest of history normal
Infertility: 5 Key Tests
1. Confirm ovulation
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History most important
2. Assess uterus and fallopian tubes
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Hysterosalpingogram
3. Assess male fertility
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Semen analysis
4. Assess uterus and ovaries
–
Ultrasound
5. Assess ovarian aging
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Day 3 FSH and Estradiol (blood test)
AMH level (blood test)
Ultrasound Exam
Uterine fibroid (circled)
and polyp (arrow)
?Frequency in EDS?
Antral follicle count
Assessment of ovarian “aging”
?Altered in EDS?
http://www.advancedfertility.com/pics/antralnormal2.jpg
Diagnosis of Polycystic Ovarian
Syndrome (2 of 3 required)
Most common cause of irregular cycles; More common with EDS?
• Irregular, infrequent
cycles
• Excessive male
hormone
– Hirsutism
– Laboratory tests
• Ultrasound
appearance
– ≥12 follicles
ESHRE/ASRM 2003 Consensus
33 y.o. Evaluation Negative
What Would You Recommend?
1. Just give her more
time – she’s only 33
2. Clomiphene
•
fertility med
3. Clomiphene plus
insemination
4. IVF
5. A Procreation
Vacation
Answer: Evaluation Negative
What Would You Recommend?
1. Just give her more
time – she’s only 33
2. Clomiphene
3. Clomiphene plus
insemination
4. IVF
5. A Procreation
Vacation
Unexplained Infertility
Treatment Outcomes
• Cycle pregnancy rate:
– Timed intercourse 3-4%
– Clomiphene + intercourse 5-8%
– Clomiphene + IUI 10-15%
– Superovulation (FSH/HMG) + IUI 15-20%
– IVF: 41% live birth rate/cycle start
• Age < 35
SART.ORG
Clomiphene with Insemination
Unexplained Infertility
• Clomiphene 50 mg days 5-9
• Ultrasound day 11-13
• HCG when follicle mature
• Ovulation occurs ~ 36 hours after HCG
• Intercourse day of HCG
• Insemination 24-36 hours after HCG
Carolinas Medical Center Protocol
33 y.o. non-vascular EDS,
completed clomid+IUI X 3
What is the most cost effective treatment?
1. Continue clomiphene + IUI for 6 cycles
2. Fertility injections + insemination
3. IVF
4. Surgery (laparoscopy) to assess/treat
endometriosis
33 y.o. non-vascular EDS,
completed clomid+IUI X 3
What is the most cost effective treatment?
1. Continue clomiphene + IUI for 6 cycles
2. Fertility injections + insemination
3. IVF
4. Surgery (laparoscopy) to assess/treat
endometriosis
In Vitro Fertilization and Embryo
Transfer (IVF-ET)
• Steps:
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Ovarian Stimulation
Oocyte retrieval
Insemination/ICSI
Lab fertilization and
embryo culture
– Embryo transfer
IVF Laboratory
• Insemination day of
retrieval
• Day 1:  70% mature
oocytes fertilize (2
pronuclei seen)
• Day 2: 4 cell
• Day 3: 8 cell
• Day 4: morula
• Day 5: blastocyst
IVF and Age: Birth Rates
SART 2009 National Data
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Age
<35
35-37
38-40
41-42
43-44
Birth Rate
41%
32%
22%
13%
4%
SART 2009 data
Embryo Freezing with IVF
• Freeze excess
healthy embryos
• Avoids discarding
healthy embryos
• Lower cost, simpler
than IVF
• Birth rate
– 35% per embryo
transfer
SART 2009 data
How to interpret a SART Report
for Single Embryo Transfer
Fresh Embryos From Non-Donor Oocytes
<35
35-37
38-40
41-42
Number of cycles
80
39
40
7
Percentage of cycles resulting in
pregnancies
51.2
46.2
62.5
0/7
Percentage of cycles resulting in live births
42.5
38.5
42.5
0/7
Percentage of retrievals resulting in live
births
42.5
39.5
42.5
0/6
Percentage of transfers resulting in live
births
42.5
39.5
43.6
0/5
0
2.6
0
1/7
Implantation rate
30.6
25.0
26.5
0 / 17
Average number of embryos transferred
2.0
2.2
3
3.4
Percentage of live births with twins
29.4
3 / 15
6 / 17
Percentage of cancellations
Carolinas Medical Center 2009 SART Report
ART High-Tech Innovation:
Application to Ehlers-Danlos
• Elective single embryo transfer
– Important to avoid twins with EDS due to risk of
preterm labor/delivery
• Preimplantation genetic screening/diagnosis
– Limit twins/multiple pregnancies
– Minimize risk with Vascular and Kyphoscoliosis EDS
• Potential transfer of non-affected embryos to carrier
– Reduce miscarriage
Preimplantation Genetic Diagnosis
Day 3 Embryo Biopsy
PCR (1st case 1990)
Single gene defects
X-linked disorders
FISH
Chromosomal abnormalities
X-linked diseases
>50% embryos have
abnormal # chromosomes
Munne S, et al. Reprod Biomed Online 20:92-7, 2010
Limitations of Day 3 Biopsy
• Never improved pregnancy rates
– Possibly due to embryo damage
• Lowered miscarriage rate by ~ 50%
– Did not test for all 46 chromosomes
– Cleaving embryos can be mosaic on day 3
• Abnormal FISH with normal embryo
• Abnormal embryo with normal FISH
• Can’t screen for chromosome # (FISH) and gene
disorder (PCR)
– Important to do both with EDS
• Day 3 biopsy role now limited!
Mosaic Fish
New Preimplantation Testing
Trophectoderm biopsy with CGH
• Trophectoderm – cells that will become
placental cells in a day 5 embryo
• CGH
– Microarray Comparative Genomic
Hybridization
• Determine if the correct # chromosomes
are present in the embryo
• Screen for gene disorders
– (ex: COL3A1 gene – vascular type)
Trophectoderm Biopsy
Carolinas Medical Center
Trophectoderm cells: develop into placenta
Trophectoderm Biopsy
• More cells for testing (4-10)
• Screen “proven” embryos only (blastocysts)
• Transfer embryos with 46 chromosomes
– Pregnancy rates ~ 75%+ for single embryo transfer
• Screen for gene abnormalities (ex:
• Disadvantages:
COL3A1gene)
– Requires high technical proficiency
– Freeze embryos while awaiting test results
– Delayed transfer of frozen embryos
Polar Body Biopsy
Diagnose before fertilization without discarding embryo
High Tech Application for EDS:
Potential Case
• 31 year-old Vascular-type EDS
– Advised to avoid pregnancy
– Having children is lifelong dream/expectation
• Considering IVF with gestational carrier
• Problems:
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Risk associated with ovarian stimulation with EDS vascular type
Cost of gestational carrier
Birth rate ~ 40-50% at age 31 (~ 50% have 46 chromosomes)
Transfer multiple embryos? Increased risk for carrier!!!
50% risk of transmitting EDS vascular type to offspring
• Solution: PGD, freeze embryos, single FET of unaffected
embryo with normal number of chromosomes to carrier
PGS Sample Outcome
Missing
Chromosome 5
Normal
Chromosomes
Normal
Chromosomes
Complex Abnormal
CMC 2011 Applications for
Trophectoderm Biopsy / PGD
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Expected large cohort of frozen embryos
Recurrent pregnancy losses
Single gene disorders
Elective single embryo transfer
Repeated implantation failures
– Polar body or blastocyst biopsy
• Application for gestational carrier
– Fertilize, blastocyst biopsy, PGD, freeze
– Allows single embryo transfer to gestational carrier
– If chromosome number is correct, maternal age is
irrelevant
Infertility Surgery with EhlersDanlos: Special Considerations
• Difficult intubation/airway
• Post-operative hernia
• Laparoscopy when
possible!
Laparoscopic Myomectomy
for uterine fibroids
Hurst BS et al, Fertil Steril 2005
Endometriosis Infertility
Laparoscopy
• Surgery required for large
endometriosis cysts
• Treatment Stage I / II
endometriosis:
– ↑ preg rate 1-2% / month
• Long-term success (stage I / II)
– 35-70%
• Risks:
– surgery
– delay treatment
Conclusions
• Probable higher incidence infertility
with Ehlers-Danlos
– Better data needed. Please complete
ANONYMOUS Survey Monkey Survey!!!
• Early IVF with single embryo transfer
often best option for infertile women
with EDS
• PGS/PGD improves embryo selection
and efficiency of IVF, especially for
single embryo transfer
• Gestational carrier for vascular and
kyphoscoliosis-type EDS; PGD
advisable
• If surgery, laparoscopy!
• Contact: Brad Hurst, M.D., Carolinas
Medical Center, Charlotte (704) 3553149; bhurst@carolinas.org