35
Ehlers-Danlos Syndrome Fertility Issues Brad Hurst, M.D. Professor Reproductive Endocrinology Carolinas Medical Center - Charlotte, North Carolina Baltimore Inner Harbor Independence Day

Ehlers-Danlos Syndrome Fertility Issues

  • Upload
    ember

  • View
    82

  • Download
    0

Embed Size (px)

DESCRIPTION

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

Citation preview

Page 1: Ehlers-Danlos Syndrome  Fertility Issues

Ehlers-Danlos Syndrome Fertility Issues

Brad Hurst, M.D.Professor Reproductive Endocrinology

Carolinas Medical Center - Charlotte, North Carolina

Baltimore Inner HarborIndependence Day

Page 2: Ehlers-Danlos Syndrome  Fertility Issues

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

Page 3: Ehlers-Danlos Syndrome  Fertility Issues

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

Page 4: Ehlers-Danlos Syndrome  Fertility Issues

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

Page 5: Ehlers-Danlos Syndrome  Fertility Issues

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

Page 6: Ehlers-Danlos Syndrome  Fertility Issues

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

Page 7: Ehlers-Danlos Syndrome  Fertility Issues

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

Page 8: Ehlers-Danlos Syndrome  Fertility Issues

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

Page 9: Ehlers-Danlos Syndrome  Fertility Issues

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)

Page 10: Ehlers-Danlos Syndrome  Fertility Issues

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?

Page 11: Ehlers-Danlos Syndrome  Fertility Issues

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

Page 12: Ehlers-Danlos Syndrome  Fertility Issues

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

Page 13: Ehlers-Danlos Syndrome  Fertility Issues

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

Page 14: Ehlers-Danlos Syndrome  Fertility Issues

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

Page 15: Ehlers-Danlos Syndrome  Fertility Issues

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

Page 16: Ehlers-Danlos Syndrome  Fertility Issues

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

Page 17: Ehlers-Danlos Syndrome  Fertility Issues

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

Page 18: Ehlers-Danlos Syndrome  Fertility Issues

In Vitro Fertilization and Embryo Transfer (IVF-ET)

• Steps:– Ovarian Stimulation– Oocyte retrieval– Insemination/ICSI– Lab fertilization and

embryo culture– Embryo transfer

Page 19: Ehlers-Danlos Syndrome  Fertility Issues

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

Page 20: Ehlers-Danlos Syndrome  Fertility Issues

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

Page 21: Ehlers-Danlos Syndrome  Fertility Issues

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

Page 22: Ehlers-Danlos Syndrome  Fertility Issues

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

Page 23: Ehlers-Danlos Syndrome  Fertility Issues

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

Page 24: Ehlers-Danlos Syndrome  Fertility Issues

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

Page 25: Ehlers-Danlos Syndrome  Fertility Issues

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

Page 26: Ehlers-Danlos Syndrome  Fertility Issues

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)

Page 27: Ehlers-Danlos Syndrome  Fertility Issues

Trophectoderm BiopsyCarolinas Medical Center

Trophectoderm cells: develop into placenta

Page 28: Ehlers-Danlos Syndrome  Fertility Issues

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

Page 29: Ehlers-Danlos Syndrome  Fertility Issues

Polar Body Biopsy

Diagnose before fertilization without discarding embryo

Page 30: Ehlers-Danlos Syndrome  Fertility Issues

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

Page 31: Ehlers-Danlos Syndrome  Fertility Issues

Missing Chromosome 5

Normal Chromosomes

Complex Abnormal

PGS Sample Outcome

Normal Chromosomes

Page 32: Ehlers-Danlos Syndrome  Fertility Issues

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

Page 33: Ehlers-Danlos Syndrome  Fertility Issues

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

Page 34: Ehlers-Danlos Syndrome  Fertility Issues

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

Page 35: Ehlers-Danlos Syndrome  Fertility Issues

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]