The modern approach in ART today and tomorrow

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  • NuvaRing Vaginal Contraceptive Ring
  • Percentage of implanting embryos with cell division parameters below or above the median values. The two panels show classification for: (i) duration of second cell cycle, cc2; (ii) synchrony of divisions from 2-cell to 4-cell stage, s2. As the limits are defined as median values for all 247 investigated embryos with known implantation outcome, each column represents the same number of transferred embryos and the frequency of implantation was significantly higher for embryos with parameter values below the median.
  • With increasing maternal age infertility rates increases reaching 25% at the age of 35-39y and 29% at the age of 40-44y
  • With increasing maternal age infertility rates increases reaching 25% at the age of 35-39y and 29% at the age of 40-44y
  • The ovarian factor has been attributed to: Decline of....
    I will discuss each of these topics and later try to elucidate several treatment strategies for clinical application at present and future time
  • The modern approach in ART today and tomorrow

    1. 1. The modern approach in ARTThe modern approach in ART today and tomorrowtoday and tomorrow Daniel S. Seidman, MDDaniel S. Seidman, MD Department of Ob/GynDepartment of Ob/Gyn Sheba Medical CenterSheba Medical Center Sackler School of MedicineSackler School of Medicine Tel-Aviv UniversityTel-Aviv University
    2. 2. A long way to achieve a live birth
    3. 3. How can we improve ourHow can we improve our pregnancy rates?pregnancy rates?
    4. 4. What is the best IVF Strategy?
    5. 5. The most common IVFThe most common IVF StrategyStrategy •Historically, to compensate for low rates of implantation for individual embryos and achieve ‘‘acceptable’’ pregnancy rates, multiple embryos have been transferred to the majority of IVF patients. Fert Steril 2012;97:835–42
    6. 6. Higher Pregnancy Rates More Multifetal Gestations
    7. 7. Commonest IVF StrategyCommonest IVF Strategy DET = Transfer two embryos 21.9-42.7% 49.1-76.7%
    8. 8. Elective single-ET vs. double-ET in IVF • Patients were randomized to eSET or DET. • The ongoing pregnancy rates • eSET 28% • DET 43% (RR 0.64; P<.001) N Engl J Med 2004;351:2392–402 Twins 1% Twins 30%
    9. 9. TWINS: Blessing or a curse?TWINS: Blessing or a curse?
    10. 10. Why should we avoid Twins? • 8% Delivery <32 wk • 10.5% Neonates <1,500 g • Risk of at least one handicapped child is: ~1 in 13 pairs of twins
    11. 11. New IVF StrategyNew IVF Strategy •Advocated as the only effective means to avoid multiple pregnancy in IVF cycles
    12. 12. Elective SET is defined in the SART reporting guidelines as: • ‘‘an embryo transfer in which more than one high-quality embryo exists but it was decided to transfer only one embryo.’’
    13. 13. The negative correlation between eSET rate and multiple births
    14. 14. eSET strategy ineffective? •By reducing pregnancy chances and eliminating second twins, a rigorous eSET program eliminates approximately one- third of potential newborns.
    15. 15. Incorrect statistics • Based on incorrect statistical methodology, twins after IVF have come under attack as “adverse” outcomes. • The correct study should compare one twin pregnancy to two consecutive singleton pregnancies.
    16. 16. Elective Single Embryo Transfer (eSET( • USA ~10% • Europe 20% • Slovenia 30% • Denmark 33% • Japan 46% • Belgium 48% • Finland 50% • Australia and New Zealand 57% • Sweden 69%
    17. 17. Embryo Transfer Trends :US v. Australia/NZ Single Embryo Transfers
    18. 18. ART outcomes (%) in Sweden and U.S., 2006
    19. 19. What determines eSET rates? • Cost - Is IVF coverage mandated • Patient populations • Legislation • Guideline recommendations • Culture
    20. 20. In 2010, eSET comprised 5.6% of all fresh transfers, representing an eightfold increase since publication of first guidelines in 2004 recommending eSET.
    21. 21. eSET Strategy • Rarely used in the USA • Rarely used in Israel?
    22. 22. Proportions of transfers of one, two, three, or four or more embryos among all IVF cycles performed in the USA, 1999– 2008. Practice Committee. eSET. Fertil Steril 2012 Major Strategy: DET
    23. 23. Proportions of all liveborn children resulting from ART in the USA that were members of multiple births Practice Committee. eSET. Fertil Steril 2012 Major Strategy: DET Many Twins -> Fewer Triplets
    24. 24. Cost of eSET per deliveryCost of eSET per delivery ImmediateImmediate CostCost •Higher Long-termLong-term CostCost •Lower ? Hum Reprod 2006;21:2090–7
    25. 25. Cost of multiple birthsCost of multiple births ImmediateImmediate CostCost •Maternal hospitalization •Neonatal intensive care Long-termLong-term CostCost •Chronic illness •Rehabilitation •Special education
    26. 26. LIMITING RESOURCES TO ART PHYSICIANS PATIENTS Higher competition Increased pressure among ART clinics for immediate success Demand for higher pregnancy rates Higher number of embryos transferred More multifetal pregnancies
    27. 27. MORE RESOURCES TO ART PHYSICIANS PATIENTS Less competition Less pressure for immediate success More cauation More eSET Fewer multifetal pregnancies
    28. 28. eSET + FET Strategy
    29. 29. Elective single-ET + FET vs. double-ET in IVF • Patients were randomized to eSET+FET or DET. • The ongoing pregnancy rates • DET 43% Twins 30% • eSET 28% Twins 1% (RR 0.64; P<.001) • eSET+FET 39% (RR 0.90; P=.30) N Engl J Med 2004;351:2392–402
    30. 30. Potential disadvantages of eSET + FET •Need for good cryopreservation program •Not all thawed embryos survive •Demands two ET procedures •Additional costs
    31. 31. New Strategy: Single Blastocyst transfer • Patients were randomized to eSET or DET. • The ongoing pregnancy rates (RR 0.80; P=NS): • eSET 61% • DET 76% Fertil Steril 2004;81:551–5 Twins 0% Twins 47%
    32. 32. Potential disadvantages of Blastocyst transfer •Monozygotic twin rate 2–5-fold higher •Increased risks of epigenetic mutations in offspring •Increased risk for adverse neonatal outcomes compared with children conceived naturally (OR 1.53, 95% CI 1.23–1.90) •Higher lab costs Fertil Steril 2010;94:1680–3
    33. 33. Time for a new embryo transfer strategy? Fertil Steril 2011; 95:1691-5
    34. 34. Blastocyst-stage embryos on day 5 Before vitrification 0 hours after warming 16 hours after warming, fully hatched
    35. 35. Results • 85.7% of vitrified-warmed blastocysts survived 110 fresh 136 vitrified-warmed BLT cycles BLT cycles IR 25.2% 37.0% * CPR 36.4% 55.1%* * statistically significantly
    36. 36. Conclusion(s( • Vitrified-warmed BT cycles resulted in statistically significantly higher CPR and IR compared with fresh BT cycles. • A new embryo transfer strategy is therefore proposed whereby fresh BT would be avoided in the initial ovarian stimulation cycle. • Instead, all the patient’s available blastocysts would be vitrified-warmed and transferred in subsequent cycles.
    37. 37. NEW METHODS FOR EMBRYONEW METHODS FOR EMBRYO SELECTIONSELECTION • Traditionally, human eggs fertilized in vitro are selected for implantation based on visual assessments of embryonic fitness made at any of three developmental checkpoints: days 1, 2 or 3, and 5
    38. 38. Morphologic embryo selection <30% >5% Implantation
    39. 39. Fertil Steril 2013;99:1283– 9
    40. 40. Examples of blastocyst grading
    41. 41. How do we improve embryo selection?
    42. 42. Metabolomics •Typical Nuclear Magnetic Resonance spectrum of embryo culture media, showing differing concentrations of key metabolites
    43. 43. •Proton NMR spectroscopy identified implantation/pregnancy with a sensitivity of 88.2% and a specificity of 88.2%
    44. 44. • Raman spectral analysis of culture media segregates embryos that implanted and led to delivery (red) and those that did not implant (blue). Metabolomic analysis of embryo culture media
    45. 45. Time Lapse Imaging
    46. 46. Period of imaging in Cambell et al., 2013 (1 frame every 1 min)
    47. 47. Analysis of fertilization-triggered cytoplasmic movements in mouse zygotes
    48. 48. Timing Cytoplasmic Flow Nat Commin 2012,3:673
    49. 49. Timing Cleavage Stages Nat Biotechnol 2010, 28:1115-
    50. 50. Eeva (Early Embryo Viability Assessment)
    51. 51. Eeva (Early Embryo Viability Assessment), in combination with D3 morphology significantly improved their ability to identify embryos that would reach the usable blastocyst stage
    52. 52. Embryoscope
    53. 53. Embryoscope • Time-lapse enabled assessment - Dynamic observation for better decision • Constant surveillance of all embryos - Undisturbed culture in stable environment • Flexible evaluation - Do it when you want, never miss anything • Complete 4D documentation - Knowledge building through retrospective analysis
    54. 54. Embyoscope
    55. 55. Better Embryo Selection •Select 3 embryos for direct side by side comparison
    56. 56. Percentage of implanting embryos with cell division parameters below or above the median values. Meseguer M et al. Hum. Reprod. 2011;26:2658-2671 © The Author 2011. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com
    57. 57. Time-lapse imaging and morphokinetic analysis
    58. 58. The three classes of aneuploidy risk (low, medium and high) based on time from insemination to a full blastocoele blastocyst has not yet started expansion (tB) hpi = hours post insemination time from insemination to start of blastulation (tSB).
    59. 59. Array comparative genomic hybridisation (CGH(.
    60. 60. A deletion in chromosome 6, detected by an array CGH test • Each black dot represents an oligo probe; there are 10 probes in the deleted region.
    61. 61. Withdrawals, deferrals and drop-outs total number of blastocysts Schematic for patients randomized either to embryo assessment by standard morphology plus aCGH (A) or morphology alone (B).
    62. 62. Representative aCGH data obtained from human blastocysts via trophectoderm biopsy performed on post-fertilization day 5 normal chromosomal status (46,XX) abnormal chromosomal status (45,XY,-12)
    63. 63. Detail of aCGH results derived from aneuploid blastocysts (n = 191) in Group A
    64. 64. Comparison of laboratory findings and clinical outcome among IVF patients undergoing SET with embryo assessment by aCGH + morphology (Group A) and blastocyst morphology alone (Group B(
    65. 65. Conclusion • The observed discordance between ploidy status and morphology means embryo selection without the benefit of information gained from aCGH would allow the transfer of a reproductively incompetent—albeit morphologically normal—embryo.
    66. 66. OBJECTIVE •To determine whether blastocyst biopsy and rapid quantitative real-time polymerase chain reaction (qPCR)-based comprehensive chromosome screening (CCS) improves in vitro fertilization (IVF) implantation and delivery rates.
    67. 67. Outcome per treatment cycle P=.03
    68. 68. • Objective: To determine whether performing comprehensive chromosome screening (CCS) and transferring a single euploid blastocyst can result in an ongoing pregnancy rate that is equivalent to transferring two untested blastocysts while reducing the risk of multiple gestation.
    69. 69. • IVF patients should be counseled that the benefits of aCGH screening will likely come at the cost of sharply limiting the number of surplus embryos available for cryopreservation.
    70. 70. NIPGD = Non-Invasive PGD?! Cell Free DNA NIPT = Non-Invasive Prenatal Testing
    71. 71. The first report of the presence of amplifiable DNA in blastocoele fluid.
    72. 72. Blastocoele fluid aspiration
    73. 73. "The work of Palini and co-workers is provocative and fascinating for it raises the possibility of a new era in diagnosis of genetic abnormalities in preimplantation embryos." Jacques Cohen Gedis Grudzinskas Martin H. Johnson
    74. 74. IVF Strategies •DET •eSET •eSET + FET •eSBltT •eSBlt- FET •CGH eSET
    75. 75. Period of imaging in Cambell et a., 2013 (1 frame every 1 min) Optimal IVF Strategy?
    76. 76. Better embryo selection strategies? • Screening for chromosomal abnormalities (nuclear component ) • Pronuclear morphology • PGD / PGS • NIPGD (?) • Analyzing the quality of embryo metabolism, the cytoskeleton or Ca2+ homeostasis (cytoplasmic component) • Analysis of metabolites • Secreted proteins • Cytoplasmic flows
    77. 77. Better embryo selection strategies? • Following the timing of embryonic cell divisions, duration and synchrony affected by • Improper chromosome segregation • Cytoskeletal properties • Energy levels • Quick diagnosis, Combination of • Genetic testing of the polar body • Examination of the cytoplasmic flows
    78. 78. Thank You!
    79. 79. Non-invasive method devised to sequence DNA of human eggs
    80. 80. Non-invasive method devised to sequence DNA of human eggs• For the first time determined the genome sequence of human egg cells without destroying them. • Amplified the DNA they contained using a technique called multiple annealing and looping-based amplification cycles (MALBAC). • The polar bodies and pronucleus together contain four copies of each of a woman’s genes — two from each of her father and her mother. • The team showed that it could use the genetic sequence of the polar bodies to accurately predict the genetic sequence of the pronucleus, by counting which three versions of a gene were contained among the polar bodies and thus deducing which version of the gene must be represented in the pronucleus.
    81. 81. Non-invasive method devised to sequence DNA of human eggs• The genome of the oocyte pronucleus, including information regarding aneuploidy and SNPs in disease-associated alleles, can be accurately deduced from the genomes of PB1 and PB2. • The MALBAC-based preimplantation genomic screening in in vitro fertilization (IVF) enables accurate and cost-effective selection of normal fertilized eggs for embryo transfer.
    82. 82. • Single-cell genome analyses of human oocytes are important for meiosis research and preimplantation genomic screening. • However, the nonuniformity of single-cell whole-genome amplification hindered its use. • Hou e al. demonstrated genome analyses of single human oocytes using multiple annealing and looping-based amplification cycle (MALBAC)-based sequencing technology. • By sequencing the triads of the first and second polar bodies (PB1 and PB2) and the oocyte pronuclei from same female egg donors, we phase the genomes of these donors with detected SNPs and determine the crossover maps of their oocytes.
    83. 83. CONCLUSION(S): •Blastocyst biopsy with rapid qPCR-based comprehensive chromosomal screening results in statistically significantly improved IVF outcomes, as evidenced by meaningful increases in sustained implantation and delivery rates.
    84. 84. Incidence (%) of major maternal complications in multiple pregnancies
    85. 85. Major perinatal morbidity and mortality outcomes in multiple pregnancies
    86. 86. Couples should be educatedCouples should be educated according to HFEA that:according to HFEA that: The chance of loosing each baby is: •1 in 113 in singleton pregnancies •1 in 21 in twin pregnancies •1 in 12 for triplet pregnancies The risk of at least one handicapped child is: • ~1 in 13 pairs of twins • 1 in 4.5 sets of triplets
    87. 87. Embryo Transfer Trends :US v. Australia/NZ Single Embryo Transfers Two Embryo Transfers Three+ Embryo Transfers
    88. 88. Multiple pregnancies should not be considered IVF success?! • Maternal bonding impaired • “Domestic overload” • Social isolation • Continual physical exhaustion • Marital disharmony • Psychological problems, depression • Emotional stress
    89. 89. SELECTIVE FETAL REDUCTION • Emotional, Ethical, Legal, and Religious Objections • Risk of loosing all fetuses after this procedure ~10%, with associated adverse psychological consequences for the couples.
    90. 90.  Conclusions:  Need How to improve our pregnancy rates  Most common strategy -> transfer more embryos  Adverse outcome: Multiple births  New Strategy -> eSET  DET better results  Need to improve embryo selection
    91. 91. Conclusions II: Embryo selection  BLT  Embryoscope  GCS Who will pay we are paid not for pregnancy but for treatment cycle
    92. 92. RESULT(S(: •We transferred 134 blastocysts to 72 patients in the study (CCS) group and 163 blastocysts to 83 patients in the routine care (control) group. •Sustained implantation rates (probability that an embryo will implant and progress to delivery) were statistically significantly higher in the CCS group (89 of 134; 66.4%) compared with those from the control group (78 of 163; 47.9%).
    93. 93. RESULT(S(: •61 of 72 treatment cycles using CCS led to delivery (84.7%) •56 of 83 (67.5%) control cycles ultimately delivered.
    94. 94. Clinical implantation rates are statistically significantly higher in embryos that have undergone CCS (P=.01).
    95. 95. Embryos selected after CCS are also statistically significantly more likely to progress to delivery than unscreened embryos from the control group (P=.01).
    96. 96. • The desire to achieve a higher per transfer pregnancy rate. • The education of both clinicians and patients on the health and wider societal benefits of eSET. • The availability of health insurance coverage for IVF sufficient to permit repeated attempts at fresh and frozen ET. • The economic pressure on patients restricting the number of ART cycles that they can attempt. • The availability of effective cryopreservation protocols. • Potential commercial competition among IVF programs to achieve the highest fresh embryo transfer delivery rates. • Other socioeconomic, cultural, and religious factors.
    97. 97. For which patients is the eSET strategy best? • Most beneficial when selectively applied according to patient characteristics and embryo quality. • Most appropriate for those with a good prognosis: • age <35 years • >1 top-quality embryo available for transfer • first or second treatment cycle • previous successful IVF • recipient of embryos from donated eggs.
    98. 98. How can we offer eSET for poor prognosis patients? • Better embryo selection • Blastocyst • Embryoscope • CGH
    99. 99. • Arch Gynecol Obstet. 2012 Sep;286(3):755-61. doi: 10.1007/s00404- 012-2396-1. Epub 2012 Jun 8. • Comprehensive genetic assessment of the human embryo: can empiric application of microarray comparative genomic hybridization reduce multiple gestation rate by single fresh blastocyst transfer? • Sills ES, Yang Z, Walsh DJ, Salem SA. • Source • Reproductive Research Division, Pacific Reproductive Center, Orange County, 10 Post, Irvine, CA 92618, USA. dr.sills@prc-ivf.com • Abstract • PURPOSE: • The unacceptable multiple gestation rate currently associated with in vitro fertilization (IVF) would be substantially alleviated if the routine practice of transferring more than one embryo were reconsidered.
    100. 100. New IVF StrategyNew IVF Strategy • As implantation rates have improved, the practice of transferring multiple embryos must be reassessed. • How to maximize the efficacy of eSET and improve its acceptability and utilization among clinicians and patients remains a challenge! Fert Steril 2012;97:835–42
    101. 101. •Owing to the high risk of multiple gestation with SO in ovulatory •women, moving directly from CC-IUI to IVF should •be considered
    102. 102. Patient(s(: •A total of 886,686 fresh, nondonor cycles reported to the National Assisted Reproductive Technology Surveillance System during 1999–2010, of which 17,166 met criteria for elective single ET.
    103. 103. Trends in the proportion of elective single ET (eSET) among all fresh, nondonor transfers, overall and stratified by age— United States, 1999–2010. For all trends, P<.001
    104. 104. ARTART Birth Order TrendsBirth Order Trends • Singleton: ↑24% • Twin: Unchanged • Higher-order: ↓77% Higher-Order Twin Singleton E. Adashi, June, 2013
    105. 105. Embryo Transfer Trends Embryo Transfer Fractions •SETs: 5→18% •DETs: 12 →55% •3+ETs: 83 →27% SETs DETs 3+ ETs E. Adashi, June, 2013
    106. 106. Result(s(: •Compared with other ETs, elective single ETs were nearly twice as likely to result in a good perinatal outcome • 37.1% vs. 18.9%, respectively •Among women using elective single ET, those aged <35 and 35–37 years had a good perinatal outcome • 40.2% and 32.5%, respectively
    107. 107. The negative correlation between eSET rate and multiple births
    108. 108. Simple equation ?Simple equation ? =+
    109. 109. IVF StrategyIVF Strategy •Success •Safety •Cost
    110. 110. Percentage of Patients Attending Fertility Clinics at Three Time Points
    111. 111. IVF StrategyIVF Strategy SuccessSuccess CostCost
    112. 112. ‫כולל‬ ,‫כחודשיים‬ ‫במשך‬ ‫פג‬ ‫גידול‬ ‫"עלות‬ ,‫הסיעודי‬ ‫והצוות‬ ‫הרופאים‬ ‫עבודת‬ ‫עלות‬ ‫מגיע‬ ‫מזה‬ ‫חלק‬ .‫דולר‬ ‫מיליון‬ ‫לחצי‬ ‫מתקרבת‬ ‫שנולד‬ ‫תינוק‬ ‫כל‬ ‫שמסבסדת‬ ,‫מהמדינה‬ -‫מ‬ ‫פחות‬ ‫של‬ ‫במשקל‬1.750-‫בכ‬ ,‫ק"ג‬130 ".₪ ‫אלף‬ ‫מחלקת‬ ‫מנהל‬ ,‫סוחוב‬ ‫פולו‬ ‫ד"ר‬ ,‫ופגים‬ ‫ילודים‬ ‫נמרץ‬ ‫טיפול‬ .‫ברמב"ם‬ ‫לילדים‬ ‫ביה"ח‬ – ‫במאייר‬ Long-term CostLong-term Cost
    113. 113. IVFIVF
    114. 114. background •A selective switch to elective single embryo transfer (eSET) in IVF has been suggested to prevent complications of fertility treatment for both mother and infants. •We compared seven IVF strategies concerning their cost-effectiveness using a Markov model.
    115. 115. methods •The model was based on a three IVF- attempts time horizon and a societal perspective using real world strategies and data, comparing seven IVF strategies, concerning costs, live births and incremental cost-effectiveness ratios (ICERs).
    116. 116. results • In order to increase pregnancy probability, one cycle of eSET one cycle of standard treatment policy [STP, i.e. eSET in patients ,38 years of age with at least one good quality embryo and double embryo transfer (DET) in the remainder of patients] one • cycle of DET have an ICER of E16 593 compared with three cycles of eSET. Furthermore, three STP cycles have an ICER of E17 636 compared • with one cycle of eSET one cycle of STP one cycle of DET, and three DET cycles have an ICER of E26 729 compared with three cycles STP.
    117. 117. Possible advantages of double intrauterine insemination • Larger fertilization period in a non-synchronized cycle • Longer exposure time for cycles deprived of additional intercourse • Increased total sperm quantity introduced to the ovulating eggs • Compensation for inferior survival rates of semen in hostile environment
    118. 118. Possible disadvantage of double intrauterine insemination • Larger fertilization period in a non-synchronized cycle • Longer exposure time for cycles deprived of additional intercourse • Increased total sperm quantity introduced to the ovulating eggs • Compensation for inferior survival rates of semen in hostile environment
    119. 119. How to improve our pregnancy rates Cheapest transfer more embryos Short term, but long term Multiple births cost – prematurity one embryo law turkey Selection of embryos – Double transfer BLT selection, embryoscope, GCS More treatments Who will pay we are paid not for pregnancy but for treatment cycle Less pressure? New registry? Budget IVF
    120. 120. Embryo selection <30% >5% Implantation
    121. 121. Representative aCGH data obtained from human blastocysts via trophectoderm biopsy performed on post-fertilization day 5.
    122. 122. Problems of multiple pregnancies • pregnancy related diseases • prematurity • increase of neonatal morbidity and mortality • costs
    123. 123. ‫והצלחה‬ ‫בטיחות‬ ‫איכות‬ ‫שיפור‬ ‫אפשרות‬ ‫של‬ ‫שלבים‬ Embryo for transfer ≈ 30% of cohort (65% of cycles) Fertilized Oocyte ≈ 80% of cohort Oocyte retrival ≈ 95% are OK Success ≈ 25% of all cycles Baby < 5% of oocytes ICSI Transfer Failure ≈ 75% of all cycles FSH hormone Stimulation Less Handling Better embryo selection 1‫המטופלת‬ ‫בחירת‬ - ‫ההורמונלי‬ ‫הגירוי‬ ‫והתאמת‬ 2‫במעבדה‬ ‫ההתנהלות‬ - ‫העוברים‬ ‫עם‬ "‫"התעסקות‬ ‫פחות‬ 3‫העובר‬ ‫של‬ ‫החזרה‬ - ‫ביותר‬ ‫האיכותי‬
    124. 124. should be transferredshould be transferred to avoid multipleto avoid multiple pregnancy?pregnancy?
    125. 125. Who should control the desire of infertile couples for a multiple pregnancy ? LEGAL REGULATION PATIENT SOCIETAL AUTONOMY INTERESTS THE PHYSICIAN
    126. 126. How many embryos should beHow many embryos should be transferred to avoid multiple pregnancy?transferred to avoid multiple pregnancy? • The Law • The Guidelines • The Experts
    127. 127. HIGH COSTS RELATED TO MULTIFETAL PREGNANCIES LIMITING RESOURCES TO A.R.T.
    128. 128. Total direct medical cost of selected chronic by sex, Maccabi Healthcare Services 2006 (in internal cost units)
    129. 129. Age-specific estimated direct medical costs (internal cost units) in women, Maccabi Healthcare Services, 2006.
    130. 130. Conclusion • The direct cost of female infertility treatments is very high, raising the need to reexamine the current policy in Israel.
    131. 131. What happens after 7 years to young couples who try to conceive through IVF?
    132. 132. SERVICES OFFERED • Genetic diagnosis • Sexing • Amniocentesis • CVS • Rapid FISH diagnosis • Preimplantation diagnosis
    133. 133. Prenatal Genetic Diagnosis (PGD)
    134. 134. SERVICES OFFERED • Prenatal Genetic Diagnosis (PGD) • Determining the sex of the baby • Choosing the characteristics of baby ?! • ”Designer Babies”
    135. 135. •Who will pay for the new technologies if the savings are only long term?
    136. 136. New registry •Will the IVF Units with lowest results receive more funds or will they be closed down?
    137. 137. TO THE PATIENT:TO THE PATIENT: • Failure is defined as a negative pregnancy test • Surveys show patients overwhelmingly desire multiple gestations ! Hojgaard et al., 2007
    138. 138. TO THE PHYSICIAN:TO THE PHYSICIAN: • Live birth rate remains the overriding index of clinical excellence !? • More aware of increased perinatal morbidity and mortality associated with multiple births.
    139. 139. TO THE PATIENT:TO THE PATIENT: • Failure is defined as a negative pregnancy test • Surveys show patients overwhelmingly desire multiple gestations
    140. 140. 16% 52% 1or 2 embryos transferred? 1995to 2005!
    141. 141. 36% 76% 1or 2 embryos transferred? 1995to 2005!
    142. 142. h
    143. 143. After 7 years……… trying to conceive through IVF: • How many ? • Fulfill their dream • Spontaneously conceive • Forgive parenthood • Choose to adopt • Divorce
    144. 144. A long way to achieve a live birth
    145. 145. A long way to achieve a live birth
    146. 146. ‫יתרונות‬ - ‫מפתח‬ ‫נקודות‬ ‫אמת‬ ‫בזמן‬ ‫מתמשכת‬ ‫דינאמית‬ ‫הערכה‬ ‫הביציות‬ ‫של‬ ‫ומניפולציות‬ ‫הפרעה‬ ‫ללא‬ ,‫יום‬ ‫מידי‬ ‫הביציות‬ ‫של‬ ‫הוצאה‬ ‫ללא‬ ‫התרבית‬ ‫במדיום‬ ‫שינוי‬ ‫ללא‬ ‫ביציות‬ ‫אבדן‬ ‫או‬ ‫לנזק‬ ‫סיכון‬ ‫פחות‬ ‫סיכונים‬ ‫ניהול‬ ‫מבחינת‬ ‫מוגברת‬ ‫בטיחות‬
    147. 147. Instrument features • Tri-gas Incubator with advanced temperature control • Build-in microscope for acquisition of time-lapse images • 6 patient slides with 12 embryos each = 72 embryos • Automatic startup and un-attended operation • External workstation for monitoring, evaluation and image analysis • Place embryos in instrument and observe until transfer time ‫המכשיר‬ ‫מאפייני‬ ‫אספקת‬3‫מדוייק‬ ‫בתמהיל‬ ‫הגאזים‬ ‫הטמפרטורה‬ ‫על‬ ‫שליטה‬ - ‫אנושית‬ ‫אינטרקציה‬ ‫מינימום‬ ‫עם‬ ‫אוטומטי‬ ‫תפעול‬ - ‫המופרות‬ ‫הביציות‬ ‫להערכת‬ ‫חיצונית‬ ‫עבודה‬ ‫תחנת‬ - ‫המופרות‬ ‫הביציות‬ ‫עם‬ ‫מגע‬ ‫ללא‬ - ‫לרחם‬ ‫ההחזרה‬ ‫שלב‬ ‫עד‬ ‫ההפריה‬ ‫משלב‬3-5‫ימים‬
    148. 148. •Continuous Temperature Control and Monitoring •Temperature control by direct heat transfer to wells •Built-in dual chamber Tri-gas mixer (5% CO2, reduced O2( •>1L CO2/hr •Complete regeneration of gases every 20 minutes •HEPA and active carbon filters eliminate toxic compounds •Continuous ozone-free UV disinfection •Dry atmosphere ‫המכשיר‬ ‫יתרונות‬ ‫וטמפרטורה‬ ‫גאזים‬ ‫של‬ ‫מתמשכת‬ ‫בקרה‬ (‫העוברים‬ ‫איכות‬ ‫על‬ ‫(השפעה‬ ‫נמוך‬ ‫חמצן‬ ‫ריכוז‬ ‫לזיהום‬ ‫הסיכון‬ ‫הקטנת‬ ‫יבשה‬ ‫סביבה‬
    149. 149. EmbryoScope™ Time-lapse System ‫כיום‬ ‫המצב‬ ‫נעשית‬ ‫העוברים‬ ‫להחזרת‬ ‫ההפריה‬ ‫בין‬ ‫המופרות‬ ‫הביציות‬ ‫בדיקת‬ - .‫ביממה‬ ‫פעם‬ ‫כלל‬ ‫בדרך‬ ,‫נתונות‬ ‫זמן‬ ‫בנקודות‬ ‫פעמים‬ ‫מספר‬ ‫סיכון‬ ‫הגדלת‬ ,‫להחזרה‬ ‫ההפריה‬ ‫בין‬ ‫פעמים‬ ‫מספר‬ ‫הצלוחית‬ ‫עם‬ ‫אנושי‬ ‫מגע‬ - ‫אפילו‬ ,‫לשינויים‬ ‫גורמת‬ ‫והכנסתן‬ ‫הביציות‬ ‫בדיקת‬ ,‫הוצאה‬ ‫לצורך‬ ‫אינקובטור‬ ‫של‬ ‫פתיחה‬ ‫כל‬ - (‫גאזים‬ , ‫לחות‬ ,‫(טמפרטורה‬ ‫הגדילה‬ ‫בתנאי‬ ‫מינימליים‬ ‫אין‬ -‫מתמשך‬ ‫מידע‬‫עוברים‬ ‫שני‬ ,‫הבדיקות‬ ‫של‬ ‫הזמן‬ ‫נקודות‬ ‫בין‬ ‫העוברים‬ ‫התפתחות‬ ‫אופי‬ ‫על‬ ‫שונים‬ ‫השרשה‬ ‫וסיכויי‬ ‫באיכות‬ ‫להיות‬ ‫עלולים‬ ,‫ההחזרה‬ ‫ביום‬ ‫תאים‬ ‫מספר‬ ‫אותו‬ ‫עם‬ ‫שנראים‬ (‫וכו‬ ‫סימטריה‬ ,‫חלוקה‬ ‫(קצב‬ ‫המופרית‬ ‫הביצית‬ ‫התפתחות‬ ‫בדרך‬ ‫התלויים‬ - ‫בעל‬ ‫העובר‬ ‫של‬ ‫לבחירה‬ ‫להביא‬ ‫עשוי‬ ‫העוברים‬ ‫איכות‬ ‫על‬ ‫נקודתי‬ ‫ולא‬ ‫מתמשך‬ ‫מידע‬ ‫הגבוה‬ ‫הסיכוי‬ ,‫הריון‬ ‫להשגת‬ ‫יותר‬
    150. 150. Select √ to transfer, * to freezer and X to discard, changes by way of colour coding are reflected on the EmbryoScope screen for the embryologist. ‫ביותר‬ ‫הטובים‬ ‫העוברים‬ ‫בחירת‬ ‫זמנית‬ ‫בו‬ ‫עוברים‬ ‫מספר‬ ‫בין‬ ‫השוואה‬ ‫העוברים‬ ‫דרוג‬ ‫להחזרה‬ - ‫הקפאה‬ - ‫השמדה‬ -
    151. 151. •‫להכיל‬ ‫יכול‬ ‫אינקובטור‬ ‫כל‬6‫מהם‬ ‫אחד‬ ‫ובכל‬ ‫סליידים‬12‫איכסון‬ ‫תאי‬ •‫סה"כ‬6‫עד‬ ‫של‬ ‫אפשרות‬ ‫עם‬ ‫מטופלות‬72.‫ביציות‬ •‫אחת‬ ‫מטופלת‬ ‫של‬ ‫רק‬ ‫ביציות‬ ‫תהיינה‬ ‫סלייד‬ ‫בכל‬ ‫סיכונים‬ ‫ניהול‬ ‫מבחינת‬ ‫הזאת‬ ‫במערכת‬ ‫לגדל‬ ‫ניתן‬ ‫שבוע‬ ‫במהלך‬ -10.‫בממוצע‬ ‫מטופלים‬ •‫החדשים‬ ‫לאינקובטורים‬ ‫הפעילות‬ ‫כל‬ ‫את‬ ‫להכניס‬ ‫ניתן‬ ‫לא‬ ‫מקרה‬ ‫ובכל‬ ‫,מאחר‬ ‫המטופלות‬ ‫לבחירת‬ ‫רפואיים‬ ‫פרמטרים‬ ‫לקבוע‬ ‫צורך‬ ‫יש‬ (‫וכו‬ ‫בודד‬ ‫עובר‬ ‫להחזרת‬ ‫,רצון‬ ‫חוזרים,גיל‬ ‫רפואית,כישלונות‬ ‫אינדיקציה‬ ,‫עוברים‬ ‫)'מספר‬
    152. 152. ‫לסיכום‬ •‫חובה‬ ‫תשתית‬ ‫להיות‬ ‫תהפוך‬ ‫החדשה‬ ‫הטכנולוגיה‬ ‫דבר‬ ‫של‬ ‫בסופו‬ .‫בעולם‬ ‫היחידות‬ ‫בכל‬ •‫פחות‬ ‫בשל‬ ‫ההריונות‬ ‫באחוזי‬ ‫שיפור‬ ‫יש‬ ‫הראשונים‬ ‫הדיווחים‬ ‫לפי‬ ‫גבוהה‬ ‫איכות‬ ‫בעלי‬ ‫עוברים‬ ‫ובחירת‬ ‫המופרות‬ ‫הביציות‬ ‫עם‬ ‫מגע‬ ‫להחזרה‬ ‫יותר‬ •‫או‬ ‫לנזק‬ ‫סיכון‬ ‫פחות‬ ,‫סיכונים‬ ‫וניהול‬ ‫בטיחות‬ ‫בנושא‬ ‫חשיבות‬ .‫עוברים‬ ‫אבדן‬
    153. 153. ‫לפני‬ ‫ההטמעה‬ ‫בשלב‬ ‫הרפואיים‬ ‫הקריטריונים‬ :‫האינקובטורים‬ ‫כל‬ ‫והחלפת‬ ‫גורף‬ ‫שימוש‬ ‫לפחות‬ ‫להם‬ ‫שיש‬ ‫למטופלים‬ ‫יוצע‬ ‫השרות‬ .‫א‬6-8‫ביציות‬ .‫בשאיבה‬ ‫עובר‬ ‫ורק‬ ‫אך‬ ‫להחזיר‬ (‫חייבים‬ ‫או‬ ( ‫שמעוניינים‬ ‫מטופלים‬ .‫ב‬ ‫אחד‬ ‫עם‬ ‫מטופלים‬ .‫ג‬2‫שנכשלו‬ ‫קודמים‬ ‫טיפולים‬ ‫יותר‬ ‫או‬ ‫בלסטוציסט‬ ‫בשלב‬ ‫עוברים‬ ‫בהחזרת‬ ‫המעוניינים‬ ‫מטופלים‬ .‫ד‬ •???? ‫אמבריולוג‬ ‫ייעוץ‬ ‫עבור‬ ‫תשלום‬ •‫להסתפק‬ ‫או‬ ?? ‫האישה‬ ‫גיל‬ ‫את‬ ‫נגביל‬ ‫האם‬ .‫ה‬ .‫הרפואיים‬ ‫בקריטריונים‬
    154. 154. Karlström u. Bergh, HumRep 22: 2007 Birth rate and MBR in relation to the percentage of SET and triple embryo transfer (TET) in Sweden 1991–2004
    155. 155. Karlström u. Bergh, HumRep 22: 2007 Birth per embryo transfer(%( and MBR in Sweden and USA
    156. 156. §1,Abs. 1, Nr. 5 „a person fertilizing more oocytes than he or she intends to tranfer in the course of one treatment cycle“ §1,Abs. 1, Nr. 3 „a person transfering more than 3embryos to the womb in the course of one treatment cycle“ Prison sentence up to three years or financial penalty for
    157. 157. Preimplantation genetic screening (PGS) University of Brussels Inclusion criteria: • 37 yrs and older • prospective randomized controlled study • examined chromosomes: X, Y, 13, 18, 21
    158. 158. Results PG-Screening University of Brussels Preimplantation genetic screening (PGS) control Patients 86 82 Embryo transfer 48 (55%) 70 (85%) Abnormal embryos 20 Pregnancies per embryo transfer 10 (20.9%) 18 (26.5%) No of embryos per ET 2.1 (100) 3.1 (210) Implantation rate per embryo 10% 8% Devroey, 2006
    159. 159. Conclusion of the Brussels study: A positive effect of PGS on implantation and abortion rate of this study and others is not clearly documented.
    160. 160. Methods of cryopreservation slow cooling vitrification
    161. 161. Clin. pregnancies / ET after cryo transfer (1996-2004) Cryo transfer 67,257 Clin. pregnancy / ET 15.5 % Abortion rate after cryo transfer 21.64 % German IVF Index 2004
    162. 162. after Kuwayama, RBM-online 2005, pp.300-308 a. Polypropylen strip b. Hartplastik-Griffstück dSchutz für LN2 Lagerung c. Hartplastik-Schutzhülle Cryotop for vitrification
    163. 163. ‫להרות‬ ‫מתקשים‬ ‫זוגות‬ ‫הרבה‬ ‫כך‬ ‫כל‬ ‫למה‬ ‫?אז‬
    164. 164. ‫אפידמיולוגיה‬ ‫של‬ ‫:החשיבות‬ • ‫פריון‬ ‫אי‬ ‫זה‬ ‫?מה‬ • ‫פריון‬ ‫לאי‬ ‫השכיחות‬ ‫הסיבות‬ ‫?מה‬ • ‫פריון‬ ‫בברור‬ ‫להתחיל‬ ‫יש‬ ‫?מתי‬ • "‫"הצלחה‬ ‫מגדירים‬ ‫כיצד‬ ‫פריון‬ ‫?בטיפולי‬
    165. 165. ‫פריון‬ ‫אי‬ ‫זה‬ ‫?מה‬ •‫הגדרה‬ ‫של‬ ‫עניין‬ •?‫מחלה‬ ‫זו‬ ‫האם‬ The American Society of Reproductive Medicine (ASRM) has defined infertility to be “a disease of the reproductive system.”
    166. 166. ‫פריון‬ ‫טיפולי‬ •‫מתוחכם‬ ‫פשוט.................מאד‬ ‫מאד‬ !
    167. 167. HISTORICAL PERSPECTIVES & LANDMARKS ARTIFICIAL INSEMINATION OVULATION INDUCTION LAPAROSCOPY U/S RETRIEVAL EGG DONATION GIFT GnRH AGONISTS EPIDIDYMAL SPERM RETRIEVAL GnRH ANTAGONISTS IN-VITRO CELL CULTURE IVF RABBIT HUMAN IVF EMBRYO FREEZING AHA PGD ASSITED FERTILIZATION ICSI 1900 ///…./// 1960 1983-4 1986-8 ? 1990-2000
    168. 168. Innovations 0% 5% 10% 15% 20% 25% 30% 35% 40% 1980 1985 1990 1995 2000 IVF ZIFT ICSI GIFT Donor Egg Cryopreservation Partial Zona Dissection Subzonal Insertion Clinical Pregnancy / Transfer Nuclear Transfer Cytoplasmic Transfer Co-Culture Hatching PGD
    169. 169. ‫חידושים‬ • ‫חדשות‬ ‫תרופות‬ • ‫ביולוגי‬ ‫דבק‬ • ‫אספרין‬ • ‫פיפל‬ • ‫ויאגרה‬ • ZIFT • ‫הרחם‬ ‫שריר‬ ‫דרך‬ ‫החזרה‬ • ‫בלסטוציסטים‬ • ‫בר-טוב‬ ‫שיטת‬ • AHA • PGD • ‫הנחיית‬ ‫תחת‬ ‫עוברים‬ ‫החזרת‬ ‫אולטרא-סאונד‬
    170. 170. ‫נבוכים‬ ‫מורה‬
    171. 171. :‫חדשות‬ ‫טכנולוגיות‬ ‫בטוחות‬ ‫הן‬ ‫?האם‬ •‫רבות‬ ‫טיפול‬ ‫שיטות‬ ‫כמו‬ ICSI ‫-ו‬ PGD ‫דרישה‬ ‫ללא‬ ‫הוכנסו‬ ‫טווח‬ ‫ארוך‬ ‫למעקב‬
    172. 172. ‫אפשרויות‬ ‫יוצרות‬ ‫חדשות‬ ‫טכנולוגיות‬ ‫נוצר‬ ‫כן‬ ‫ועל‬ ‫בעבר‬ ‫קיימות‬ ‫היו‬ ‫שלא‬ ‫טיפול‬ ‫אתיים‬ ‫גבולות‬ ‫להתוות‬ ‫.צורך‬ •”Designer Babies” • ‫העובר‬ ‫מין‬ ‫קביעת‬ • ‫מסוימות‬ ‫תכונות‬ ‫בחירת‬ • ‫משכל‬ ‫רמת‬ • ‫עור‬ ‫צבע‬ • ‫מינית‬ ‫נטייה‬ ‫השרשה‬ ‫טרום‬ ‫עובר‬ ‫אבחון‬
    173. 173. ‫יצליח‬ ‫שהטיפול‬ ‫הסיכוי‬ ‫?מה‬
    174. 174. ‫יצליח‬ ‫שהטיפול‬ ‫הסיכוי‬ ‫?מה‬ "There are three kindsof lies: lies, damned lies and statistics.“ - Benjamin D’Israeli (1804-1881)
    175. 175. ‫ניתן‬ ‫עובדות‬ ‫על‬ ‫המבוססת‬ ‫הרפואה‬ ‫של‬ ‫בעידן‬ ‫רק‬ ‫טיפול‬ ‫של‬ ‫ליעילות‬ ‫באשר‬ ‫מסקנות‬ ‫להסיק‬ ‫אקראיים‬ ‫השוואתיים‬ ‫מחקרים‬ ‫סמך‬ ‫על‬
    176. 176. ‫ההצלחה‬ ‫את‬ ‫קובע‬ ‫?מה‬ • ‫הזוג‬ ‫בני‬ • ‫הרופא‬ • ‫המעבדה‬
    177. 177. ‫יצליח‬ ‫שהטיפול‬ ‫הסיכוי‬ ‫?מה‬
    178. 178. “TAKE HOME BABY RATE”
    179. 179. ?‫לדעת‬ ‫באמת‬ ‫רוצה‬ ‫הזוג‬ ‫מה‬ ?‫התוצאות‬ ‫את‬ ‫מציגים‬ ‫איך‬ ‫הנתונים‬ ‫איכות‬ ‫?מה‬
    180. 180. ‫הנתונים‬ ‫באים‬ ‫?מאיפה‬ •‫מידע‬ ‫מאגרי‬ •,‫בארה"ב‬ ‫דיווח‬ ‫חובת‬ ‫בריטניה‬ ,‫גרמניה‬ • ‫ישראל‬
    181. 181. Cumulative Pregnancy Rate ( % ) in IVF 0 25 50 75 100 0 1 2 3 4 5 6 7 > 34 yrs 35-39 yrs > 40 yrs Number of Treatment Cycles Doretal.1996 248 Dor et al. 1996
    182. 182. ‫שיעורי‬ ‫על‬ ‫שמשפיעים‬ ‫הגורמים‬ ‫מה‬ ?‫ההצלחה‬
    183. 183. PREVALENCE OF INFERTILITY BY AGE 0 5 10 15 20 25 30 15-19 20-24 25-29 30-34 35-39 40-44 Age (years( Infertile (%( (Menken J, Science 1986;223:1389)
    184. 184. WHY IS AGING AND REPRODUCTION A GROWING CONCERN? • Deferment of marriage • Postponement of pregnancy in marriage • Divorce and remarriage Delayed age of childbearing
    185. 185. DONOR EGGS
    186. 186. IVF IN ISRAEL • How Much ? • How Well ? • The Effect of Age • Micromanipulation • International Comparisons
    187. 187. Why is it good to be an IVF specialist in Israel?
    188. 188. IVF/ICSI Centers per million population • Pakistan 0.01 • China 0.02 • India 0.04 • Egypt 0.45 • Germany 1.22 • USA 1.31 • France 2.39 • Israel 3.68 Collins JA, Hum Reprod Upd 8;265, 2002
    189. 189. IVF/ICSI Cycles per Million Population per Annum • Pakistan 4 • China 5 • India 11 • Egypt 13 • Germany 417 • USA 126 • France 610 • Israel 1657 Collins JA, Hum Reprod Upd 8;265, 2002
    190. 190. ‫הפריה‬ ‫טיפול‬ ‫של‬ ‫תוצאות‬ ‫יש‬ ‫האם‬ ‫?בישראל‬
    191. 191. ISRAEL NATIONAL IVF REGISTRY • ADVANTAGES • Continuous reporting since 1989 • Very high compliance • No direct cost • Data reported by age • ART data available (GIFT, ZIFT, SUZI, ICSI)
    192. 192. ISRAEL NATIONAL IVF REGISTRY • LIMITATIONS • No validation • Chemical Vs. Clinical pregnancies • Reporting not complete • Data NOT reported according to etiology, ovulation protocol • No perinatal outcome data • No data on multiple gestations
    193. 193. ISRAEL NATIONAL IVF REGISTRY • 23 Centers Reporting • Up to 2006 • 253,613 Treatment Cycles • 48,554 Live Deliveries
    194. 194. IVF TREATMENT CYCLES BY YEAR 0 2000 4000 6000 8000 10000 12000 14000 16000 18000 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000
    195. 195. IVF RESULTS IN ISRAELI CENTERS Deliveries per Retrieval 0 4 8 12 16
    196. 196. IVF RESULTS BY NUMBER OF CYCLES PER YEAR Deliveries per Retrieval 0 4 8 12 16 >300 300 - 500 500 - 999 >1000No. of Cycles: %
    197. 197. ENDEND TIDAL CARBON MONOXIDE MEASUREMENT INTIDAL CARBON MONOXIDE MEASUREMENT IN PREGNANT WOMEN:PREGNANT WOMEN: OBSERVATIONS AND POSSIBLE CLINICALOBSERVATIONS AND POSSIBLE CLINICAL APPLICATIONSAPPLICATIONS Israel Hendler, MDIsrael Hendler, MD Dept. of Ob/Gyn, Sheba Medical Center, Tel- Hashomer, Tel-Aviv University. www.baby4u.co.il
    198. 198. ARE IVF RESULTS IMPROVING ? 0 4 8 12 16 20 24 28 Up to 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 % Pregnancies per Transfer
    199. 199. ARE IVF RESULTS IMPROVING ? 0 4 8 12 16 Up to 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 % Deliveries per Treatment
    200. 200. HOW DO WE AVOID MULTIPLE GESTATION? • Judicious use of ovulatory agents • Limit number of embryos transferred • Improve quality selection criteria of the embryos • Better in-vitro embryo culture • Improve cryopreservation
    201. 201. DONOR AND CRYOPRESERVED OOCYTES 1990-94 NO. Deliveries per Cycles Transfer Israel USA DONOR 2515 12.4% 33.7% CRYO 2864 7.4% 15.6%
    202. 202. WHY DO ISRAELI IVF RESULTS DIFFER FROM INTERNATIONAL DATA ? • Lower Skill (?!) • Selection Bias
    203. 203. SELECTION BIAS • Different eligibility criteria • Distinct infertility subpopulations • Age limit • “End Stage” infertility • Dropout population • Physician decision • Availability • Financial constraints
    204. 204. NUMBER OF CYCLES BY WOMEN’S AGE 19945705 2280 1369 70 0 2000 4000 6000 >36 36-40 41-45 >45
    205. 205. PREGNANCY PER RETRIEVAL BY WOMEN’S AGE 199418.7 8 5.8 17.3 0 5 10 15 20 >36 36-39 40-44 >45 %
    206. 206. INTERNATIONAL COMPARISONS NATIONAL REGISTRIES Pregnancies per Retrieval 0 5 10 15 20 25 30 % ISRAEL UK FRANCE USA
    207. 207. COMPARISON BETWEEN IVF RESULTS IN USA AND ISRAEL Deliveries per Retrieval 10 12 14 16 18 20 1989 1990 1991 1992 1993 1994 Israel USA %
    208. 208. CHANGE IN NUMBER OF IVF CYCLES IN USA AND ISRAEL -5 5 15 25 1991 1992 1993 1994 Israel USA%
    209. 209. COMPARISON BETWEEN IVF RESULTS IN UK AND ISRAEL Deliveries per Treatment 8 10 12 14 1989 1990 1991 1992 1993 1994 Israel UK %
    210. 210. IS THE ISRAELI POPULATION OLDER ?15.2 4.1 15.5 8.9 0 4 8 12 16 >40 Delivery/ Retrieval ISRAEL USA% women >40
    211. 211. INTERNATIONAL COMPARISONS NATIONAL REGISTRIES CYCLES PER 1 MILLION CITIZENS1600 440 520 150 0 400 800 1200 1600 ISRAEL UK FRANCE USA
    212. 212. CURRENT NUMBER OF USA IVF CYCLES Vs. ISRAELI RATES Current Israeli Rate
    213. 213. THE FUTURE OF THE ISRAELI IVF REGISTRY • Prospective registering of results to a centralized computerized data collection facility • Individual patient cycle specific data • Complete reporting of all patient characteristics (age, etiology, induction protocol, etc.) • Complete follow-up of pregnancy outcome
    214. 214. PREGNANCY RATE BY NUMBER OF EMBRYOS TRANSFERRED 8.4 20.2 26.6 0 5 10 15 20 25 1 2 3 % HFEA 1997
    215. 215. HIGH-ORDER PREGNANCY RATE BY NUMBER OF EMBRYOS TRANSFERRED 1.1 0.2 5.8 0 1 2 3 4 5 1 2 3 % HFEA 1997
    216. 216. PERINATAL MORTALITY (per 1000) BY SINGLE AND MULTIPLE BIRTHS 8.8 46.8 82.6 0 15 30 45 60 75 Single (4782) Twins (1678) Triplet (255) % HFEA 1997
    217. 217. Determinants of Preterm rates in Canada from 1981 through 1983 and from 1992 through 1994 •“The recent increase in preterm births in Canada is largely attributable to changes in the frequency of multiple births….” Joseph et al., N Engl J Med, Nov. 1998
    218. 218. Gestational age for all live births in Canada Joseph et al., N Engl J Med, Nov. 1998 Live Births 1981-3 1992-4 Singletons 577,013 555,351 39.4 ± 1.9w 39.2 ± 1.9w Twins 10,725 11,769 36.5 ± 3.5w 35.8 ± 3.3w Triplets 240 366 32.9 ± 3.9w 32.2 ± 3.3w
    219. 219. MULTIFETAL PREGNACIES IN IVF CYCLES IN ISRAEL 1994 (n=866) Singletons 72.4% Twins 18.6% Triplets 7.2% Quadruplets 1.3% Quintuplets 0.2%
    220. 220. HAS THE RATE OF MULTIPLE GESTATIONS AFTER IVF INCREASED IN ISRAEL?18.7 18.6 4.6 7.2 0.3 1.3 0 5 10 15 20 Twins Triplets Quadruplets Israel 1982- 89 Israel 1994 %
    221. 221. HOW DOES ISRAEL COMPARE WITH THE WORLD 18.6 24.7 29.6 7.2 4.1 6.4 0 5 10 15 20 25 30 Twins Triplets Israel 1994 World Collab. 1997 ASRM 1998 %
    222. 222. HOW MANY EMBRYOS SHOULD BEHOW MANY EMBRYOS SHOULD BE TRANSFERRED TO AVOID MULTIPLETRANSFERRED TO AVOID MULTIPLE PREGANACY?PREGANACY? • The Law • The Guidelines • The Experts
    223. 223. WHAT DOES THE LAW SAY? • In the UK there is legal restriction which limits the number of embryos transferred to a maximum of three • In the USA and Israel there is no such legal limit
    224. 224. WHAT ARE THE GUIDELINES? • Israeli Ministry of Health guidelines limit the number of embryos transferred to three, or in exceptional cases, four • ESHRE (1998) recommended transfer of either two or three embryos depending on female age
    225. 225. WHAT ARE THE GUIDELINES? ASR Practice Committee Guidelines on number of embryos transferred 1998 • Above average prognosis (e.g. age <35y) transfer no more than three • Average prognosis (e.g. age 35-40y) transfer no more than four embryos • Below average prognosis (e.g. age >40y or multiple failed cycles) transfer no more than five embryos
    226. 226. WHAT DO THE EXPERTS SAY? “Transfer 1 embryo”Without selective single embryo transfer Selective single embryo transfer Pregnancy Rate 30% 26% Twins 24% 13% Triplets 4% 2% Coustier & Dhont, Hum Reprod, Oct., 1998
    227. 227. WHAT DO THE EXPERTS SAY? “Transfer 2 embryos” • “When more than four eggs were fertilized there was no increase in the birth rate for women receiving three transferred embryos compared with those receiving two, but there was a considerable increase in the rate of multiple births when three were transferred (O.R.1.6; C.I. 1.5-1.8)” Templeton & Morris, N Engl J Med, Aug 1998
    228. 228. WHAT DO THE EXPERTS SAY? “Transfer more than 2 embryos” • Most couples feel that twins would be an ideal outcome of IVF treatment (Murdoch, Hum Reprod, Feb.,1997) • Possibility of relying on the “escape route” or “safety net” of selective fetal reduction (Murdoch, Hum Reprod, Oct., 1998)
    229. 229. WHAT DO THE EXPERTS SAY? “Transfer more than 4 embryos” • Compensate for predictors of poor outcome: Women’s age Cause & duration of infertility Number of ART cycle Embryo morphology Frozen/thawed embryos
    230. 230. HOW MANY EMBRYOS SHOULD BEHOW MANY EMBRYOS SHOULD BE TRANSFERRED TO AVOID MULTIPLETRANSFERRED TO AVOID MULTIPLE PREGANACY?PREGANACY? • The Law • The Guidelines • The Experts
    231. 231. WHAT DOES THE LAW SAY? • In the UK there is legal restriction which limits the number of embryos transferred to a maximum of three • In the USA and Israel there is no such legal limit
    232. 232. WHAT ARE THE GUIDELINES? • Israeli Ministry of Health guidelines limit the number of embryos transferred to three, or in exceptional cases, four • ESHRE (1998) recommended transfer of either two or three embryos depending on female age
    233. 233. WHAT ARE THE GUIDELINES? ASR Practice Committee Guidelines on number of embryos transferred 1998 • Above average prognosis (e.g. age <35y) transfer no more than three • Average prognosis (e.g. age 35-40y) transfer no more than four embryos • Below average prognosis (e.g. age >40y or multiple failed cycles) transfer no more than five embryos
    234. 234. WHAT DO THE EXPERTS SAY? “Transfer 1 embryo”Without selective single embryo transfer Selective single embryo transfer Pregnancy Rate 30% 26% Twins 24% 13% Triplets 4% 2% Coustier & Dhont, Hum Reprod, Oct., 1998
    235. 235. WHAT DO THE EXPERTS SAY? “Transfer 2 embryos” • “When more than four eggs were fertilized there was no increase in the birth rate for women receiving three transferred embryos compared with those receiving two, but there was a considerable increase in the rate of multiple births when three were transferred (O.R.1.6; C.I. 1.5-1.8)” Templeton & Morris, N Engl J Med, Aug 1998
    236. 236. WHAT DO THE EXPERTS SAY? “Transfer more than 2 embryos” • Most couples feel that twins would be an ideal outcome of IVF treatment (Murdoch, Hum Reprod, Feb.,1997) • Possibility of relying on the “escape route” or “safety net” of selective fetal reduction (Murdoch, Hum Reprod, Oct., 1998)
    237. 237. WHAT DO THE EXPERTS SAY? “Transfer more than 4 embryos” • Compensate for predictors of poor outcome: Women’s age Cause & duration of infertility Number of ART cycle Embryo morphology Frozen/thawed embryos
    238. 238. THE NUMBER OF EMBRYOS TRANSFERRED PER IVF CYCLE NATIONAL VS. WORLD DATA 14.4 30.4 38.5 16.7 12.8 13.7 22.4 0 10 20 30 40 50 1 2 3 4+ World Israel %
    239. 239. HIGH COSTS RELATED TO MULTIFETAL PREGNANCIES LIMITING RESOURCES TO A.R.T.
    240. 240. LIMITING RESOURCES TO ARTLIMITING RESOURCES TO ART PHYSICIANS PATIENTS Higher competition Increased pressure among ART clinics for immediate success Demand for higher pregnancy rates Higher number of embryos transferred More multifetal pregnancies
    241. 241. INSURANCE MANDARES FOR IVF COVERAGE EFFECTIVELY LOWER MULTIPLE BIRTHS Embryos Transf. <35y Mandated 3.3 No Coverage 4.1 P 0.0001 35-39y 3.0 4.1 0.0002 Multiple births <35y 9.1% 13% 0.04 35-39y 4.3% 8.3% 0.08 Frankfurter al., ASRM, Oct. 1998
    242. 242. What are the limits of spontaneous pregnancy? • According to The Guinness Book ofThe Guinness Book of World RecordsWorld Records:  A woman from Portland, Oregon, delivered when she was 57 years and 120 days old
    243. 243. WHY DOES FERTILITY DECLINE WITH AGE? • Cumulative exposures to occupational and environmental hazards • Diseases: endometriosis, myomas, adenomyosis • Sexual transmitted diseases • Decreased frequency of sexual intercourse
    244. 244. CLINICALLY RECOGNIZED SPONTANEOUS ABORTIONS BY AGE 10 18 34 0 10 20 30 <30 late 30s early 40s %
    245. 245. THE RISK OF ABORTION IN WOMEN OLDER THAN AGE 40 • Clinically recognized 34% • Overall abortion rate (recognized and unrecognized) ~75%
    246. 246. Rate of spontaneous abortion in recipients by donors’ age 14 44.5 0 10 20 30 40 50 20-24 yrs >35 yrs %
    247. 247. REPRODUCTION IN THE OLDER MALE • Male fertility -- immortalimmortal?!  A decline in testosterone  Increase in gonadotropins  Associated decrease in sperm production and the number of normal sperm -- modest changes  Capacity to fertilize maintained.
    248. 248. REPRODUCTION IN THE OLDER MALE • A paternal age >40 associated with a 20% greater chance of birth defects • Advanced paternal age NOTNOT associated with increased frequency of trisomy 21 Lian et al., Am J Hum Genet 1986
    249. 249. PREVALENCE OF INFERTILITY BY AGE 0 5 10 15 20 25 30 15-19 20-24 25-29 30-34 35-39 40-44 Age (years) Infertile (%) (Menken J, Science 1986;223:1389)
    250. 250. INFERTILITY AND WOMEN’S AGE • 1:7, age 30 - 34 yrs • 1:5, age 35 - 39 yrs • 1:4, age 40 - 44 yrs
    251. 251. PREGNANCY RATE BY AGE 0 4 8 12 16 20 24 28 32 <29 30-34 35-39 40-44 >45 Own Eggs Donted Eggs% WOMAN’S AGE ** * # # p<0.05 * p<0.001 (Templeton et al., 1996)
    252. 252. ETIOLOGY OF FERTILITY DECLINE WITH AGE • Ovarian Factor • Decline of oocyte reserve • Genetic abnormalities • Poor response to ovarian stimulation • Early luteinization
    253. 253. EVALUATION AND TREATMENT PLAN
    254. 254. Statistics in Infertility • The effect of maternal age • Expectations from treatment • Presentation of outcome results
    255. 255. BACKGROUND • Infertility is defined as one year of unprotected coitus without conception. • It affects approx. 10-15% of couples in reproductive age group. • One in 6 women seeks professional help during their life time because of infertility.
    256. 256. CONCEPTION RATE PER CYCLE AFTER IVF 24 26 28 30 32 34 36 38 41 45 0 5 10 15 20 25 30 AGE (yrs) % (Tan et al., 1992)
    257. 257. Pregnancy loss rate after documentation of fetal cardiac activity in 1570 IVF pregnancies 4.1 9.9 10.7 23.6 0 5 10 15 20 25 <31 31-34 35-39 >39 % * *p<.001 (Spandorfer et al., 1997)
    258. 258. IVF IN WOMEN >40 yrs • Should not delayed long as the patients chances to conceive diminish quickly!
    259. 259. Intracytoplasmic Sperm Injection (ICSI) • The deposition of a single spermatozoon directly into the cytoplasm of the oocyte, thus bypassing the ZP and the oolemma. • First reported by Palermo et al in 1992.
    260. 260. HISTORICAL PERSPECTIVES & LANDMARKS ARTIFICIAL INSEMINATION OVULATION INDUCTION LAPAROSCOPY U/S RETRIEVAL EGG DONATION GIFT GnRH AGONISTS EPIDIDYMAL SPERM RETRIEVAL GnRH ANTAGONISTS IN-VITRO CELL CULTURE IVF RABBIT HUMAN IVF EMBRYO FREEZING AHA PGD ASSITED FERTILIZATION ICSI 1900 ///…./// 1960 1983-4 1986-8 ? 1990-2000
    261. 261. Innovations 0% 5% 10% 15% 20% 25% 30% 35% 40% 1980 1985 1990 1995 2000 IVF ZIFT ICSI GIFT Donor Egg Cryopreservation Partial Zona Dissection Subzonal Insertion Clinical Pregnancy / Transfer Nuclear Transfer Cytoplasmic Transfer Co-Culture Hatching PGD
    262. 262. Intracytoplasmic Sperm Injection (ICSI) • “No other technique since IVF itself has had such a positive and almost explosive impact in helping infertile patients to achieve conception.” Oehninger & Gosden, 2002
    263. 263. ICSI to overcome Male Factor -0.1 0 0.1 0.2 0.3 0.4 0.5 1988 1990 1992 1994 1996 1998 2000 % lower Fertilization % fewer Deliveries % micromanip. % ICSI % lower Fertilization % fewer Deliveries
    264. 264. The use of ICSI in 1999 • 43% of 258,460 ART cycles in 22 European countries • Hum Reprod 2002 Dec;17:3260-74 • 41% of 88,077 ART cycles in the United States • Fertil Steril 2002 Nov;78:918-31
    265. 265. Limitations of ICSI  Complex  Expensive  Safe ?
    266. 266. Concerns regarding ICSI Is ICSI really the treatment of choice for all cases of IVF? What is the risk of transmission of chromosomal or genetic disease Long-term health of children conceived after ICSI
    267. 267. INDUCTION OF OVULATION PROTOCOLS 12.2 7.6 51.5 28.7 0 10 20 30 40 50 60 HMG / FSH CC Long GnRH Short GnRH %
    268. 268. " "‫האדם‬ ‫רביית‬ ‫פלאו‬ - ‫שרינג‬ ‫צוות‬ ‫עם‬ ‫הדרכה‬ ‫מפגשי‬ ,'‫ד‬ ‫יום‬9,‫אפריל‬2008‫משעה‬09:00‫עד‬13:00 9:00 - 9:30 ‫באדם‬ ‫אי-פריון‬ ‫של‬ ‫ואפידמיולוגיה‬ ‫.מבוא‬ 9:30 - 10:00 :‫הרבייה‬ ‫מערכת‬ ‫של‬ ‫ופיסיולוגיה‬ ‫אנטומיה‬ ‫המזלג‬ ‫קצה‬ ‫על‬ . 10:00 - 10:45 ‫וטיפול‬ ‫בירור‬ ,‫סיבות‬ :‫האישה‬ ‫פריון‬ ‫.אי‬ 10:45 – 11:00‫הפסקה‬ 11:00 - 11:45 ‫וטיפול‬ ‫בירור‬ ,‫סיבות‬ :‫הגבר‬ ‫פריון‬ ‫.אי‬ 11:45 - 12:30 ‫שחלתי‬ ‫יתר‬ ‫גירוי‬ ‫ותסמונת‬ ‫ביוץ‬ ‫השראת‬ (OHSS). 12:30 – 13:00‫פריון‬ ‫.תרופות‬
    269. 269. " "‫האדם‬ ‫רביית‬ ‫פלאו‬ - ‫שרינג‬ ‫צוות‬ ‫עם‬ ‫הדרכה‬ ‫מפגשי‬ ,'‫ה‬ ‫יום‬10,‫אפריל‬2008‫משעה‬08:00‫עד‬12:00 ‫מתקדמות‬ ‫רבייה‬ ‫שיטות‬ (T.R.A): 8:00 - 8:30 ‫גופית‬ ‫חוץ‬ ‫הפריה‬ 8:30 - 9:00 ICSI, ‫מהאשך‬ ‫זרע‬ ‫שאיבת‬ ((TESA 9:30 - 10:00 ‫השרשה‬ ‫טרם‬ ‫גנטי‬ ‫אבחון‬ (PGD) 10:00 10:15 - ‫הפסקה‬ 10:15 - 11:00 ‫בעתיד‬ ‫:חידושים‬ IVM, ‫,פיפל‬ DHEA ‫ועוד‬ 11:00 - 12:00 ‫אתיים‬ ‫היבטים‬ :‫הפריון‬ ‫.גבולות‬
    270. 270. INTERNATIONAL COMPARISONS NATIONAL REGISTRIES •US and Canada: Society of Assisted Reproductive Technology (SART) •UK: Human Fertilization Embryology Authority (HFEA) •French In Vitro National (FIVNAT)
    271. 271. Cost •Patients opted for eSET over DET 50% more often when • had insurance coverage •participated in a refund guarantee program Fertil Steril 2009;92:1895–906
    272. 272. The cost of eSET • In the Netherlands, Evers calculated that every IVF offspring contributes a lifelong economic net of $310,000 to the country’s Gross National Product. • Concluded that, theoretically, up to that sum could be spent on a successful IVF cycle without society incurring a net loss.
    273. 273. Cost of multiple births ?Cost of multiple births ? IncreasedIncreased •Neonatal health care DecreasedDecreased •No need for additional infertility treatments •Lifelong economic contributions of second twins to society
    274. 274. The cost of eSET • eSET economically sound only with the presence of medical contraindications to twin pregnancies or when couples simply do not wish to conceive twins.
    275. 275. conclusions •A choice has to be made between three cycles of eSET, STP or DET. •Depends on society’s willingness to pay which strategy is to be preferred from a cost-effectiveness point of view.
    276. 276. eSET should NOT be routinely offered •The need for a second pregnancy to achieve equal outcome (2 children), resulting treatment delays, increased efforts and costs, in absence of any guarantees that a second successful singleton pregnancy/delivery will ever be accomplished, invalidates eSET as a routine procedure.

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