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I Jornada Actualización en Genética Reproductiva y Fertilidad

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IVF SPAIN: Hacia el Screening de Aneuploidías en FIV, como “Standard of Care”; Resultados Clínicos, Yosu Franco

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I Jornada Actualización en Genética Reproductiva y Fertilidad

  1. 1. Hacia el Screening de Aneuploidías en FIV como “Standard of Care”: Resultados clínicos Dr. Jon Aizpurua Dr. Yosu Franco I Jornada Actualización en Genética Reproductiva y Fertilidad
  2. 2. DISCLAIMER: NO CONFLICTS OF INTEREST – NO SPONSORING Review of more than 1200 cases from 2012 to 2016 in a collaboration between the world leader in PGD/PGS and IVF-Spain Always Vitrification
  3. 3. TRADITIONAL PGS INDICATIONS
  4. 4. PGS HYPOTHESIS Beyond proven indications for PGD/PGS … Despite large studies indicating massive advantages of PGS, the notion of its universal benefit is still not shared uniformly… but we keep on working. PGS may also improve ART outcome regardless of maternal age (Munné et al. 1993)
  5. 5. EFFICIENCY
  6. 6. EFFICIENCY • Multiple studies • Different clinics • Various patient populations/indications • Alternative genetic methods (aCGH, SNP array, qPCR) • Fresh transfer and cryopreservation strategies … … and yet … … all reach the same conclusión: PGS increases efficiency of ART Yang et al., 2012; Schoolcraft et al., 2012*; Scott et al., 2013; Forman et al., 2013; Rubio et al., 2014* *Abstracts at ASRM
  7. 7. EFFICIENCY Genetic abnormalities are common and explain most implantation failures and miscarriages Aneuploidy is almost always lethal (failed implantation/miscarriage) While aneuploidy increases with age, implantation rate decreases Data from > 50.000 blastocysts analyzed by Reprogenetics
  8. 8. EFFICIENCY Aneuploidy screening eliminates the effect of maternal age on miscarriage * SART; ** Harton et al. (2013) Fertil Steril, and unpublished data Miscarriage rates with / without PGS
  9. 9. EFFICIENCY Aneuploidy screening eliminates the effect of maternal age on implantation * SART; ** Harton et al. (2013) Fertil Steril, and unpublished data Implantation rates with / without PGS
  10. 10. EFFICIENCY Impact of PGS in ongoing PR per Transfer Courtesy, Genesis Genetics – embryos tested by aCGH IVF vs PGS Clinical Pregnancy Rate / ET
  11. 11. 11 EFFICIENCY Should all patients be offered aneuploidy assessment? Harton et al. (2013) Fertil Steril, and unpublished data Ongoing Pregnancy rate per Transfer
  12. 12. EFFICIENCY Should all patients be offered aneuploidy assessment? Harton et al. (2013) Fertil Steril, and unpublished data Ongoing Pregnancy rate per Transfer Ongoing Pregnancy rate per Cycle
  13. 13. EFFICIENCY Dilemma of PGS “If I open my eyes … may be I will see what I don’t want to see” Compliance should be based on … Honesty and facts!
  14. 14. EFFICIENCY In which patients is the DGP-A indicated ? EUPLOIDY RATE N= 42,217 embryos and 7,725 cycles. All patients undergoing assisted reproduction treatments could benefit from the PGS embryo selection method. It is thus of great importance to properly inform patients on this matter so they can assess all possible options Munné et al. ASRM 2016.
  15. 15. EFFICIENCY Embryo euploidy rate Munné et al. RBMO 2012. Wells et al. 2015 unpublished
  16. 16. EFFICIENCY IVF-Spain experience - Embryobanking Strategy Age range 38 – 42 y/o NS NS NS P = 0,034 NS B. Ramos et al., ESHRE 2015 Normo Responder Low Responder M II mean 12.2 +/- 2.1 7.1 +/- 2.7 Cycles average 1 2.8 +/- 2.3 Nº Biopsed Embryos 6.1 +/- 1.2 3.9 +/- 2.1 Euploidy Rate 36.4 35.9 Transfer Cancellation (%) 28.2 31.6 Preganancy Rate (%) 66.7 69.2
  17. 17. EFFICIENCY Management of expectations in bad prognosis cases • Compliance based on facts • Offer predictive algorithms • Offer options and alternatives • Common decision making
  18. 18. EFFICIENCY Randomized Trial: SET with vs without PGS aCGH + fresh single embryo transfer, < 35 years old P < 0,05 P < 0,05 Yang et al. (2012)
  19. 19. EFFICIENCY eSET with PGS equally efficient but safer as DET without PGS Prospective randomized Clinical Trial qPCR + eSET en fresco vs morfología + 2 blastocistos fresco Forman et al. Fertil. Ster. 2013 NS NS NS P < 0,001
  20. 20. SAFETY
  21. 21. SAFETY Safety of PGS eSET fullfiling BEST criteria Birth Emphasizing Health Singleton at Term Reliable technology Very low mosaicism misdiagnosis No deleterious effects from trophectoderm biopsy Lower abortion rates and complications Lowest multiple rates and complications
  22. 22. SAFETY Myths around multiple pregnancies Multiple pregnancies are responsible for up to 27 % of all preterm births
  23. 23. SAFETY CAUSES OF HIGH INCIDENCE OF MULTIPLE PREGNANCIES IN ART ESHRE Campus Course, Antwerp, Belgium, 2007 Patients • Pacient´s emotions and expectations • Economic considerations • Deficient information about multiple pregnancy risks Physicians • Success measured in terms of pregnancy rates instead of healthy newborns per cycle • Low efficiency and predictability of treatments • Missing alternatives to achieve equal results • Low confidence in embryo thawing survival rates • No interdisciplinary feedback, no regulatory strategies
  24. 24. SAFETY Consequences of multiple pregnancies • Economic impact • Psycologic impact • Higher maternal and fetal/neonatal Morbidity and Mortality !!!
  25. 25. SAFETY Higher maternal morbidity and mortality in multiple pregnancies Problems in prenatal diagnostics Higher incidence of: • Hypertensive disease, Preeclampsia/Eclampsia • Thromboembolism (mortality) • UTI, Anemia, Haemorrhagies, preterm births • Fluid overload (parenteral tocolisis) Derivation in: • More sick leaves, hospitalization days and costs • Increased frequency of cesarean section or cerclage
  26. 26. SAFETY INCREASED FETAL MORBIDITY Higher incidence of - Low birth weight - Congenital malformations (RR x 1.39) - Preterm birth • Low Apgar after 5’ • Intraventricular bleeding (cerebral palsy: 5-20 fold) • Sepsis and/or Enterocolitis necroticans • RDS (respiratory distress syndrome) • Retinopathy • Ductus arteriosus persistance - Neurologic disorders from subclinic to retardation • Large term development problems • Mental and linguistic dysfunctions Buitendijk, 1999; Hazekamp et al, 2000; Ward and Beachy, 2003
  27. 27. SAFETY Increased fetal mortality Neonatal mortality • Twins: 7 fold • Triplets or more: 20 fold Mortality rate in the USA (2000) • 6,1 per 1000 newborns for singletons • 31,1 for multiple pregnancies (Increases with number of gestational sacs) Russel et al, 2003
  28. 28. SAFETY What can universal PGS potentially offer? • Achieve very high efficiency eSET • No multiples and lower morbidity and mortality • Faster time to pregnancy • Avoid unnecessary embryo transfers • Avoid cryopreservation of non-viable embryos • Reduce miscarriage rate • Reduce risk of Down syndrome Should all patients be offered aneuploidy testing? YES! But, management of patient expectations is crucial … and what about costs?
  29. 29. COSTS Courtesy of Kaylen Silverberg, M.D. Texas Fertility Center, San Antonio, TX.
  30. 30. COSTS 30 Identify costs related to outcomes Cost of baseline procedure (IVF) Cost of procedure PGS Cost of potential outcomes • Delivery • Miscarriage • No pregnancy • No transfer Potencial cost savings of PGS • Canceled embryo transfers • Fewer vitrification procedures • Fewer multiple pregnancies • Lower gonadotropin usage in subsequent canceled cycle Identify non-tangible benefits of procedure • Faster progression to donor oocytes • Fewer por prognosis cycles • Less frustration and stress • Less time to newborn Courtesy of Kaylen Silverberg, M.D. Texas Fertility Center, San Antonio, TX.
  31. 31. COSTS Model Costs for 1000 patients Courtesy of Kaylen Silverberg, M.D. Texas Fertility Center, San Antonio, TX.
  32. 32. PGS costs/cycle + 2 % for < 35 years PGS costs/cycle + 38 % for > 35 years COSTS PGS Benefits included in Model • Increase in live birth rates/ET - Biggest increase in women ≥ 35 • Fewer SAb, missed abortions • Lower SAb management costs (expectant and medical/surgical) PGS Benefits NOT included in Model • Fewer repeat IVF cycles – more pregnancies/births in initial cycles • Decrease in unnecessary embryo storage expense • Fewer unnecessary FET cycles • Anticipated reduction in prenatal genetic testing in women 35 years • Lower costs for lifetime care - Related to premature births1 - Genetically abnormal offspring • Intangible effects - Less marital stress - Less time off of work - More rapid progression to alternative treatments1 McLaurin K, et al. Pediatrics 2009;123:653-9
  33. 33. COSTS Cost effectiveness PGS costs/birth: - 32 % for < 35 years PGS costs/birth: - 48 % for > 35 years Courtesy of Kaylen Silverberg, M.D. Texas Fertility Center, San Antonio, TX.
  34. 34. COSTS Costs review tailored to IVF-Spain up to Ongoing Pregnancy Costs of Delivery (SD vs CS), Costs of Multiples, standard complications and non tangible Costs not included in the calculation 1 Cycle DET Vs eSET 6 Blastos Vs 3 Euploids 1-3 Cycles (mean 2.2) DET Vs e SET 6-8 Blastos Vs 1-3 Euploids < 35 years - PGS < 35 years + PGS > 35 years - PGS > 35 years + PGS Cost per Cycle Cum. PR / Drop Out 8.900€ 77.5% 10.400€ 82.5% 24.200€ 35% 18.800€ 5% Difference + 15% (1.500€) - 22% (6.400€) Cost per OP 11.480 € 12.600 € 37.900 € 26.500 € Difference + 9% (1.120€) - 30% (11.400€)
  35. 35. COSTS Conclusion: YES Universal PGS is worth • Increases live birth rates for all patients and the overall safety • Reduces the complications and costs of multiples and miscarriages • Is cost effective for the average IVF patient, mainly at cost per birth • Allows proper and faster clinical decision making: • Saves some patients from unnecessary egg donations and specifically indicates egg donations for other patients, particularly in the ≥ 35 age group • Avoids life compatible aneuploidies and deletion syndroms • Reduces time to PR and delivery and saves worsening of ovarian reserve • Reduces stress, time loosing, tangible and non-tangible costs • Reduces Drop Out rates in multiple cycles > 35 years • Is ethically defendable…are non-PGS cycles too?
  36. 36. Special thanks to Tecnalia and Illumina www.ivf-spain.com www.ivfdonostia.com

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