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Ehlers-Danlos Syndrome Fertility Issues

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

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Ehlers-Danlos Syndrome Fertility Issues

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  1. Baltimore Inner Harbor Independence Day Ehlers-Danlos Syndrome Fertility Issues Brad Hurst, M.D. Professor Reproductive Endocrinology Carolinas Medical Center - Charlotte, North Carolina

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

  9. Infertility: 5 Key Tests • Confirm ovulation • History most important • Assess uterus and fallopian tubes • Hysterosalpingogram • Assess male fertility • Semen analysis • Assess uterus and ovaries • Ultrasound • Assess ovarian aging • Day 3 FSH and Estradiol (blood test) • AMH level (blood test)

  10. Ultrasound Exam Antral follicle count Assessment of ovarian “aging” ?Altered in EDS? Uterine fibroid (circled) and polyp (arrow) ?Frequency in EDS? http://www.advancedfertility.com/pics/antralnormal2.jpg

  11. 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

  12. 33 y.o. Evaluation Negative What Would You Recommend? • Just give her more time – she’s only 33 • Clomiphene • fertility med • Clomiphene plus insemination • IVF • A Procreation Vacation

  13. Answer: Evaluation Negative What Would You Recommend? • Just give her more time – she’s only 33 • Clomiphene • Clomiphene plus insemination • IVF • A Procreation Vacation

  14. 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

  15. 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

  16. 33 y.o. non-vascular EDS, completed clomid+IUI X 3 What is the most cost effective treatment? • Continue clomiphene + IUI for 6 cycles • Fertility injections + insemination • IVF • Surgery (laparoscopy) to assess/treat endometriosis

  17. 33 y.o. non-vascular EDS, completed clomid+IUI X 3 What is the most cost effective treatment? • Continue clomiphene + IUI for 6 cycles • Fertility injections + insemination • IVF • Surgery (laparoscopy) to assess/treat endometriosis

  18. In Vitro Fertilization and Embryo Transfer (IVF-ET) • Steps: • Ovarian Stimulation • Oocyte retrieval • Insemination/ICSI • Lab fertilization and embryo culture • Embryo transfer

  19. 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

  20. IVF and Age: Birth RatesSART 2009 National Data • AgeBirth Rate • <35 41% • 35-37 32% • 38-40 22% • 41-42 13% • 43-44 4% SART 2009 data

  21. 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

  22. How to interpret a SART Reportfor Single Embryo Transfer Carolinas Medical Center 2009 SART Report

  23. 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

  24. Preimplantation Genetic DiagnosisDay 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

  25. 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

  26. 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)

  27. Trophectoderm BiopsyCarolinas Medical Center Trophectoderm cells: develop into placenta

  28. 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

  29. Polar Body Biopsy Diagnose before fertilization without discarding embryo

  30. 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

  31. PGS Sample Outcome Missing Chromosome 5 Normal Chromosomes Normal Chromosomes Complex Abnormal

  32. 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

  33. Infertility Surgery with Ehlers-Danlos: Special Considerations • Difficult intubation/airway • Post-operative hernia • Laparoscopy when possible! Laparoscopic Myomectomy for uterine fibroids Hurst BS et al, Fertil Steril 2005

  34. 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

  35. 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; bhurst@carolinas.org

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