ehlers-danlos syndrome fertility issues

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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 IssuesBrad Hurst, M.D.Professor Reproductive Endocrinology Carolinas Medical Center - Charlotte, North CarolinaBaltimore Inner HarborIndependence Day

  • ObjectivesDetermine if EDS causes infertilityDescribe infertility evaluationDiscuss cost-effective infertility treatment Consider role of IVFLearn new approaches to preimplantation genetic diagnosis that may apply to EDS

  • Ehlers-Danlos National Foundation 199468 women, most type I, III, IV43 women, 138 pregnanciesReproductive problems: Spontaneous abortion 29% (40/138)25% all pregnancies in populationSexual dysfunction (61%)43% prevalence womenIrregular menses (28%)11% college-age populationEndometriosis (16%)5-10% populationSorokin Y. et al, J Reprod Medi 39:281-4, 1994

  • Endometriosis/dyspareunia199541 women in Ehlers-Danlos clinicEndometriosis 27%5-10% populationPainful intercourse 57%45% populationGynecologic disorders in women with Ehlers-Danlos syndrome. McIntosh LJ et al, J Soc Gynecol Invest 2:559-64, 1995

  • Ehlers-Danlos Fertility Publications Since 1995In vitro fertilization (IVF) - noneOvulation - none Pelvic pain - noneEndometriosis - noneDyspareunia - noneAmenorrhea - noneOligomenorrhea - noneEctopic pregnancy - nonePreimplantation genetic diagnosis - none Insemination - noneSperm/spermatozoa - noneOocyte - noneClomiphene - noneFallopian tube - noneMedline search June 2011

  • Ehlers-Danlos and FertilityAssumptionsWomen with Ehlers-Danlos experience infertilityInfertility prevalence 1 in 8 couples in populationMore ovulation disorders, endometriosis, painful intercourse, miscarriage with EDSSome women with Ehlers-Danlos may be advised to avoid pregnancyVascular, 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 intercourseEarlier evaluation for Infrequent mensesKnown tubal disease or endometriosisKnown 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 weekRegular cycles 28 days with premenstrual breast sorenessHealthy, rest of history normal

  • Infertility: 5 Key TestsConfirm ovulation History most importantAssess uterus and fallopian tubesHysterosalpingogramAssess male fertilitySemen analysisAssess uterus and ovariesUltrasoundAssess ovarian agingDay 3 FSH and Estradiol (blood test)AMH level (blood test)

  • Ultrasound Examhttp://www.advancedfertility.com/pics/antralnormal2.jpgAntral 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 ConsensusIrregular, infrequent cyclesExcessive male hormoneHirsutismLaboratory testsUltrasound appearance12 follicles

  • 33 y.o. Evaluation Negative What Would You Recommend?Just give her more time shes only 33Clomiphene fertility medClomiphene plus inseminationIVFA Procreation Vacation

  • Answer: Evaluation Negative What Would You Recommend?Just give her more time shes only 33ClomipheneClomiphene plus inseminationIVFA Procreation Vacation

  • Unexplained Infertility Treatment OutcomesCycle 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 startAge < 35 SART.ORG

  • Clomiphene with InseminationUnexplained InfertilityClomiphene 50 mg days 5-9Ultrasound day 11-13HCG when follicle matureOvulation occurs ~ 36 hours after HCGIntercourse day of HCGInsemination 24-36 hours after HCG

    Carolinas Medical Center Protocol

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

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

  • In Vitro Fertilization and Embryo Transfer (IVF-ET)Steps:Ovarian StimulationOocyte retrievalInsemination/ICSILab fertilization and embryo cultureEmbryo transfer

  • IVF LaboratoryInsemination day of retrievalDay 1: 70% mature oocytes fertilize (2 pronuclei seen) Day 2: 4 cellDay 3: 8 cellDay 4: morulaDay 5: blastocyst

  • IVF and Age: Birth RatesSART 2009 National Data AgeBirth Rate
  • Embryo Freezing with IVFFreeze excess healthy embryosAvoids discarding healthy embryosLower cost, simpler than IVFBirth rate 35% per embryo transferSART 2009 data

  • How to interpret a SART Reportfor Single Embryo TransferCarolinas Medical Center 2009 SART Report

    Fresh Embryos From Non-Donor Oocytes

  • ART High-Tech Innovation: Application to Ehlers-DanlosElective single embryo transferImportant to avoid twins with EDS due to risk of preterm labor/deliveryPreimplantation genetic screening/diagnosisLimit twins/multiple pregnanciesMinimize risk with Vascular and Kyphoscoliosis EDSPotential transfer of non-affected embryos to carrierReduce miscarriage

  • Preimplantation Genetic DiagnosisDay 3 Embryo BiopsyPCR (1st case 1990)Single gene defectsX-linked disordersFISHChromosomal abnormalitiesX-linked diseases>50% embryos have abnormal # chromosomesMunne S, et al. Reprod Biomed Online 20:92-7, 2010

  • Limitations of Day 3 BiopsyNever improved pregnancy ratesPossibly due to embryo damageLowered miscarriage rate by ~ 50%Did not test for all 46 chromosomesCleaving embryos can be mosaic on day 3Abnormal FISH with normal embryoAbnormal embryo with normal FISHCant screen for chromosome # (FISH) and gene disorder (PCR)Important to do both with EDSDay 3 biopsy role now limited!

    Mosaic Fish

  • New Preimplantation Testing Trophectoderm biopsy with CGHTrophectoderm cells that will become placental cells in a day 5 embryoCGH Microarray Comparative Genomic HybridizationDetermine if the correct # chromosomes are present in the embryoScreen for gene disorders (ex: COL3A1 gene vascular type)

  • Trophectoderm BiopsyCarolinas Medical CenterTrophectoderm cells: develop into placenta

  • Trophectoderm BiopsyMore cells for testing (4-10) Screen proven embryos only (blastocysts)Transfer embryos with 46 chromosomesPregnancy rates ~ 75%+ for single embryo transferScreen for gene abnormalities (ex: COL3A1gene)Disadvantages:Requires high technical proficiencyFreeze embryos while awaiting test resultsDelayed transfer of frozen embryos

  • Polar Body BiopsyDiagnose before fertilization without discarding embryo

  • High Tech Application for EDS: Potential Case31 year-old Vascular-type EDSAdvised to avoid pregnancyHaving children is lifelong dream/expectationConsidering IVF with gestational carrierProblems:Risk associated with ovarian stimulation with EDS vascular typeCost of gestational carrierBirth 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 offspringSolution: PGD, freeze embryos, single FET of unaffected embryo with normal number of chromosomes to carrier

  • Missing Chromosome 5Normal ChromosomesComplex AbnormalPGS Sample OutcomeNormal Chromosomes

  • CMC 2011 Applications forTrophectoderm Biopsy / PGDExpected large cohort of frozen embryosRecurrent pregnancy lossesSingle gene disordersElective single embryo transferRepeated implantation failuresPolar body or blastocyst biopsyApplication for gestational carrierFertilize, blastocyst biopsy, PGD, freezeAllows single embryo transfer to gestational carrierIf chromosome number is correct, maternal age is irrelevant

  • Infertility Surgery with Ehlers-Danlos: Special ConsiderationsDifficult intubation/airway Post-operative herniaLaparoscopy when possible!Laparoscopic Myomectomyfor uterine fibroidsHurst BS et al, Fertil Steril 2005

  • Endometriosis InfertilityLaparoscopySurgery required for large endometriosis cysts Treatment Stage I / II endometriosis: preg rate 1-2% / monthLong-term success (stage I / II)35-70%Risks: surgery delay treatment

  • ConclusionsProbable higher incidence infertility with Ehlers-DanlosBetter data needed. Please complete ANONYMOUS Survey Monkey Survey!!!Early IVF with single embryo transfer often best option for infertile women with EDSPGS/PGD improves embryo selection and efficiency of IVF, especially for single embryo transferGestational carrier for vascular and kyphoscoliosis-type EDS; PGD advisableIf surgery, laparoscopy!Contact: Brad Hurst, M.D., Carolinas Medical Center, Charlotte (704) 355-3149; bhurst@carolinas.org

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