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Outcome Measurement for Assisted Reproductive Technology DAVID L. KEEFE, M.D. Tufts New England Medical Center, Boston, Massachusetts Laboratory for Reproductive Medicine, Marine Biological Laboratory, Woods Hole, MA Brown University, and Women & Infants Hospital, Providence, RI
Overview of Presentation ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Assisted Reproductive Technologies ,[object Object],[object Object],[object Object],[object Object],[object Object]
IVF Steps ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
IVF- Clinical Processes Assess sperm quality and count Wash sample Sperm collection Egg equilibration Assessment of fertilization Incubate Wash/remove excess sperm Assess & Transfer
IVF- Laboratory Processes Eggs retrieved Eggs stripped and cleaned Assess sperm quality and count Wash sample Sperm collection Egg equilibration Fertilization- IVF or ICSI Assess fertilization Incubate Wash/remove excess sperm Assess & Transfer Embryos
Controlled Ovarian Hyperstimulation Regimens for Assisted Reproductive Technology  GnRH Antagonist Protocols GnRH  Agonist Protocols   225 IU per day (150 IU Europe) Individualized Dosing of FSH/HMG 250   g per day antagonist Individualized Dosing of FSH/HMG GnRHa 1.0 mg per day  up to 21 days 0.5 mg per day of GnRHa 225 IU per day (150 IU Europe) Day 6 of  FSH/HMG Day of  hCG Day 1  of FSH/HMG Day 6 of  FSH/HMG Day of hCG 7 – 8 days after estimated ovulation Down regulation Day 2 or 3 of menses Day 1  FSH/HMG OCP
Overview of Presentation ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Differences in Study Populations be Factored Into ART Studies ,[object Object],[object Object],[object Object],[object Object]
Overview of Presentation ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Outcome Measures for ART ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Outcome Measures for ART- Deliveries/Initiated Cycles ,[object Object],[object Object],[object Object],[object Object]
Outcome Measures for ART- Surrogate Clinical Outcomes ,[object Object],[object Object],[object Object],[object Object],[object Object]
Outcome Measures for ART- Surrogate Biologic Outcomes ,[object Object],[object Object],[object Object]
How Should Success be Defined? ,[object Object],[object Object],[object Object],[object Object]
Success Should be Defined Based on Equivalence or Non-Inferiority to Comparator ,[object Object],[object Object],[object Object],[object Object]
Example-  Antagonist improves convenience w/o improving pregnancy outcome (also, vag. prog, s.q. gts.) ,[object Object],Agonist vs. * Based on median duration of use.  North American Ganirelix study.
Safety Endpoints ,[object Object],[object Object],[object Object],[object Object]
Safety Endpoints- Ovarian Hyperstimulation syndrome ,[object Object],[object Object],[object Object]
Safety Endpoints-Miscarriage Rate ,[object Object],[object Object],[object Object]
Multiple Gestations and ART ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Overview of Presentation ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
The Future of IVF Outcome Measurement ,[object Object],[object Object],[object Object]
The Future of IVF Outcome Measurement-Improving Biological Surrogate Outcomes ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Aneuploid Embryos Can Develop Normally Until Day 5 of Life!  Development of Embryo with Trisomy 21, determined by PGD on day 3, with develoment to normal-appearing blastocyst  Day 1 Day 5 Day 4 Day 3 Day 2
Preimplantation Genetic Diagnosis (PGD) Can Improve Implantation Rate ,[object Object],[object Object],[object Object],[object Object],[object Object]
Preimplantation Genetic Diagnosis (PGD) Predicts IVF Outcome ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Preimplantation Genetic Diagnosis (PGD) in Patients with Repeated Miscarriages ,[object Object],[object Object]
Gt.s’ Play Key Role in Meiosis FSH then LH (Gonal F, Repronex, Follistim, Bravelle, then hCG) Immature Oocytes w/I  Follicles Metaphase II (MII) Metaphase I (MI)
Eggs From Older Women Have Abnormal Spindles Age (years)   % Abnormal Spindles   20-35    17   40-45    79 Battaglia et al,  Hum Reprod.  1996;11:2217 .
Spindle Function Imaged by Polscope
Eggs With Normal Spindles Develop Better
Telomere Shortening Explains Effects of Age on Aneuploidy: ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

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Infertility2

  • 1. Outcome Measurement for Assisted Reproductive Technology DAVID L. KEEFE, M.D. Tufts New England Medical Center, Boston, Massachusetts Laboratory for Reproductive Medicine, Marine Biological Laboratory, Woods Hole, MA Brown University, and Women & Infants Hospital, Providence, RI
  • 2.
  • 3.
  • 4.
  • 5. IVF- Clinical Processes Assess sperm quality and count Wash sample Sperm collection Egg equilibration Assessment of fertilization Incubate Wash/remove excess sperm Assess & Transfer
  • 6. IVF- Laboratory Processes Eggs retrieved Eggs stripped and cleaned Assess sperm quality and count Wash sample Sperm collection Egg equilibration Fertilization- IVF or ICSI Assess fertilization Incubate Wash/remove excess sperm Assess & Transfer Embryos
  • 7. Controlled Ovarian Hyperstimulation Regimens for Assisted Reproductive Technology GnRH Antagonist Protocols GnRH Agonist Protocols 225 IU per day (150 IU Europe) Individualized Dosing of FSH/HMG 250  g per day antagonist Individualized Dosing of FSH/HMG GnRHa 1.0 mg per day up to 21 days 0.5 mg per day of GnRHa 225 IU per day (150 IU Europe) Day 6 of FSH/HMG Day of hCG Day 1 of FSH/HMG Day 6 of FSH/HMG Day of hCG 7 – 8 days after estimated ovulation Down regulation Day 2 or 3 of menses Day 1 FSH/HMG OCP
  • 8.
  • 9.
  • 10.
  • 11.
  • 12.
  • 13.
  • 14.
  • 15.
  • 16.
  • 17.
  • 18.
  • 19.
  • 20.
  • 21.
  • 22.
  • 23.
  • 24.
  • 25. Aneuploid Embryos Can Develop Normally Until Day 5 of Life! Development of Embryo with Trisomy 21, determined by PGD on day 3, with develoment to normal-appearing blastocyst Day 1 Day 5 Day 4 Day 3 Day 2
  • 26.
  • 27.
  • 28.
  • 29. Gt.s’ Play Key Role in Meiosis FSH then LH (Gonal F, Repronex, Follistim, Bravelle, then hCG) Immature Oocytes w/I Follicles Metaphase II (MII) Metaphase I (MI)
  • 30. Eggs From Older Women Have Abnormal Spindles Age (years) % Abnormal Spindles 20-35 17 40-45 79 Battaglia et al, Hum Reprod. 1996;11:2217 .
  • 31. Spindle Function Imaged by Polscope
  • 32. Eggs With Normal Spindles Develop Better
  • 33.