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KED - Society of Clinical Embryologists 1 st Symposium, Istanbul

KED - Society of Clinical Embryologists 1 st Symposium, Istanbul. Assessment of Gamete/Embryo Viability by the Utilization of new PGS ( Preimplantation Genetic Screening ) Techniques or PGS: an Embryologist’s Perspective OR I am doing PGS anyway Can you give me any tips?.

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KED - Society of Clinical Embryologists 1 st Symposium, Istanbul

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  1. KED - Society of Clinical Embryologists1st Symposium, Istanbul Assessment of Gamete/Embryo Viability by the Utilization of new PGS (Preimplantation Genetic Screening) Techniques or PGS: an Embryologist’s Perspective OR I am doing PGS anyway Can you give me any tips? Alan Thornhill The Bridge Centre, London , UK December 5th 2012

  2. Evidence: Clinical Value of ACGH? Implantation rate Aneuploidy rate No transfer Wells and Fragouli, unpublished

  3. Bridge Success Rates *Equivalent UK national rates for this age group are 10-13%

  4. New Technologies – The Rise of array CGH

  5. Evidence At Last? • First randomised trial* of blastocyst PGS with aCGH • Women under 35 years (good prognosis) • eSET • Day-5 (blastocyst) biopsy • All cycles had embryo transfer (day 6) • No PGS: embryo transfer on morphology (n=48) Pregnancy rate**: 41.7% • PGS (aCGH): chromosomally normal embryos transferred (n=55) Pregnancy rate**: 69.1% *Yang et al (2012) **On-going pregnancy rate ≥20 weeks/cycle started

  6. Why PGS? Do Nothing Option • Retain all embryos • No harm to embryo • No upfront cost to patient • Transfer all embryos sequentially Why Not? • Risk of abnormality NOT accepted • Miscarriage NOTTrivial • Repeated failure NOT Accepted • Multiple cycles (inc. FET) costs Time and Money

  7. Biopsy sample • 1st polar body - Single cell (small) • No role in further development • Fragmented • 2ndpolar body - Single cell (small) • Haploid, Incomplete extrusion • No role in further development • Nucleated blastomere– single cell (large) • Representative of embryo? mosaicism • critical role in further development • Trophectoderm – 6-10 cells • Representative of FUTURE BABY? • Mosaicism

  8. Biopsy Procedure • Laser or mechanical • Timing • ICSI required • Laser or mechanical • Timing (Sequential or simultaneous) • Chemical, Laser or mechanical • Safety? Reduced implantation potential • Laser or mechanical • Need to see AND AVOID ICM • Laser effects on sample? • Need for vitrification post-biopsy

  9. Biopsy – Practical Issues • Entire MII cohort analyzed • High Biopsy & diagnostic workload/costs • Proportion will not fertilize • Entire 2pn cohort analyzed • High Biopsy & diagnostic workload/costs • Proportion will not develop well • Good quality ‘day 3’ embryos only • Chance of no biopsy • Medium Biopsy & diagnostic workload/costs • Good quality blastocysts d5/6 only • Moderate chance of no biopsy • Lower Biopsy & diagnostic workload/costs

  10. Biopsy – Diagnostic Issues • High result rate (>90%) • No paternal/meiosis II/post-zygotic information • High result rate (>90%) • No paternal/post-zygotic information • High result rate (>90%) • Chromosomal mosaicism common • Extremely high result rate (>>95%) • SIGNIFICANCE OF MOSAICISM?

  11. What is the aim of PGS? • ….to transfer embryos with • the correct amount of genetic material • to increase the chance of having a healthy baby & • reduce the risk • of having a pregnancy with a chromosomal abnormality • ..identify patients with high risk of aneuploid gametes/embryos to inform future treatment

  12. Life is never that simple….. And Neither Is PGS….. So What Happens In The Real World?

  13. Case studies: PB1 only • 49 year old • 2ND attempt IVF/ICSI • FAVOURABLE AMH/AFC • Results: 11 OOCYTES ALLWITH MULTIPLE ANEUPLOIDIES • Extensive PRE- AND POST-TEST counselling • Suggested egg donation • Last chance/diagnostic closure • FOLLOW-UP OF EMBRYOS CONFIRMED PB1 RESULTS

  14. New IVF test – Array CGH – produces baby Oliver, offering hope to infertile September 2nd 2009 13 previous failed IVF cycles 7/9 first polar bodies aneuploid

  15. Summary of Net Gains and Losses in The Aneuploid Zygotes ESHRE data 2010

  16. Case studies: PB1+2 • 41 year old (AMA) • 2nd attempt (1st PB1 – LB) • 11 x oocytes/7 x 2pns • Results: 6 x abnormal, 1 x normal* • *Reciprocal gain and loss (chr 9 + 13) Reported ‘normal’ (no plots/correction?) • Counsel for risk of patau’s syndrome • Need for data on outcomes of G/L • Need for truth data

  17. RECIPROCAL GAIN/LOSS – PB1+2

  18. Case studies: PB1+2 • 40 year old (AMA) • 1st attempt (top – trisomy 21) • 6 x oocytes/5 x 2pns • Results: • 1x Normal, 2 x Abnormal, 2 x Normal (but no result for PB2) – D5 rebiopsy • Partial deletion in chr 5 • Reported as abnormal • Mosaicism in TE/ICM? • Counsel for risk of cri-du-chat • Need for data on mosaicism

  19. Case studies: Trophectoderm • 38 year old • RIF (4 x IVF) • Frozen d3 (5) + D5 (1) thawed for TE BIOPSY • Results: • DELAYED DEVELOPMENT (no Fresh ET) • 2 x Euploid, 2 x Aneuploid • 1 x multipleaneuploid* (every chromosome!) • Reliability of aCGH? • *5AB – discard/re-biopsy/et? • Question diagnostic lab • Repeat test? Follow-up

  20. Single blastomere analysis: Complex pattern of gains and losses

  21. Algorithms and reporting Estimation of confidence in aneuploidy call Automated calling

  22. Karyomapping and 24sure from a single cell SurePlex amplification • Cells disaggregated from the remainder of embryo. Data supplied with courtesy of Professor Alan Handyside, London Bridge Fertility Centre. • FISH probes 13, 16, 18, 21, 22 • Trisomy 17 • Monosomy 18, 21, 22 • FISH probes X, Y, 21 • Trisomy X • Monosomy 21

  23. (NEW) Indications - 24 chromosome test • Advanced maternal age (>35 yr) Most embryos aneuploid No embryo transfer in most cycles Prognostic for chance of pregnancy with the patient’s own eggs Optimal age range for embryos selection 37 to 43 years of age • eSBT (<35 yr) good prognosis patients at high risk of twins Moderate incidence of aneuploidy All cycles with ≥1 aneuploid blastocyst All cycles with ≥1 euploid blastocyst for transfer • Severe male factor infertility • Idiopathic repeat IVF failure • Miscarriage risk/previous abnormal/TOP

  24. Summary i – What patients/providers need to know FACTS • Aneuploidy INCIDENCE c.50%affects all ages • Aneuploidy main cause of failed implantation • Aneuploidy testing CANNOT change the cumulative pregnancy rate POTENTIAL BENEFITS • Prevent transfer or storage of aneuploid/non-viable eggs/embryos • Identify AMA women with good/poor prognosis for a livebirthusing their own eggs • Increase pregnancy/live birth rate/ET (eSBT) • Reduce time to live birth or resolution

  25. Summary ii – how to provide good PGS • Genetic Counsellor provides Face to face, telephone, email support for clinicians/ embryologists/patients throughout process • Single point of contact for patients • Excellent patient information & consent forms • Secondary reports (combine embryology and diagnostic information) • Time-lapse incubation? • Treat every egg/embryo as important • Question diagnostic team

  26. Acknowledgements The Bridge Centre • Alan Handyside • Michael Summers • Karen Sage • Shaun Rogers Bluegnome • Tony Gordon Reprogeneticsuk • Dagan Wells

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