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Baltimore Inner Harbor Independence Day. Ehlers-Danlos Syndrome Fertility Issues. Brad Hurst, M.D. Professor Reproductive Endocrinology Carolinas Medical Center - Charlotte, North Carolina. Objectives. Determine if EDS causes infertility Describe infertility evaluation - PowerPoint PPT Presentation
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Ehlers-Danlos Syndrome Fertility Issues
Brad Hurst, M.D.Professor Reproductive Endocrinology
Carolinas Medical Center - Charlotte, North Carolina
Baltimore Inner HarborIndependence Day
Objectives
• 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/dyspareunia1995
• 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
• 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• Fallopian tube - none
Medline search June 2011
Ehlers-Danlos and FertilityAssumptions
• 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 – History most important
2. Assess uterus and fallopian tubes– Hysterosalpingogram
3. Assess male fertility– Semen analysis
4. Assess uterus and ovaries– Ultrasound
5. Assess ovarian aging– Day 3 FSH and Estradiol (blood test)– AMH level (blood test)
Ultrasound Exam
http://www.advancedfertility.com/pics/antralnormal2.jpg
Antral follicle countAssessment of ovarian “aging”
?Altered in EDS?
Uterine fibroid (circled)and polyp (arrow)
?Frequency in EDS?
Diagnosis of Polycystic Ovarian Syndrome (2 of 3 required)
Most common cause of irregular cycles; More common with EDS?
ESHRE/ASRM 2003 Consensus
• Irregular, infrequent cycles
• Excessive male hormone– Hirsutism– Laboratory tests
• Ultrasound appearance– ≥12 follicles
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 InseminationUnexplained 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:– 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 RatesSART 2009 National Data
• Age Birth Rate• <35 41%• 35-37 32%• 38-40 22%• 41-42 13%• 43-44 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 Reportfor 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
Percentage of cancellations 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
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 DiagnosisDay 3 Embryo Biopsy
PCR (1st case 1990)Single gene defectsX-linked disorders
FISHChromosomal abnormalitiesX-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 BiopsyCarolinas 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: COL3A1gene)
• Disadvantages:– 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:
– 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
Missing Chromosome 5
Normal Chromosomes
Complex Abnormal
PGS Sample Outcome
Normal Chromosomes
CMC 2011 Applications forTrophectoderm Biopsy / PGD
• 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 Ehlers-Danlos: Special Considerations
• Difficult intubation/airway
• Post-operative hernia
• Laparoscopy when possible!
Laparoscopic Myomectomyfor uterine fibroids
Hurst BS et al, Fertil Steril 2005
Endometriosis InfertilityLaparoscopy
• 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) 355-3149; [email protected]