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

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. 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. TRADITIONAL PGS INDICATIONS

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. EFFICIENCY

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. 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. 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 (2013) Fertil Steril, and unpublished data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. 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 (2013) Fertil Steril, and unpublished data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. 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
EFFICIENCY
Should all patients be offered aneuploidy assessment?
Harton et al. (2013) Fertil Steril, and unpublished data
Ongoing Pregnancy rate per Transfer

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 (2013) Fertil Steril, and unpublished data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. 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. 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. EFFICIENCY
Embryo euploidy rate
Munné et al. RBMO 2012.
Wells et al. 2015 unpublished

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. EFFICIENCY
Management of expectations in bad prognosis cases
• Compliance based on facts
• Offer predictive algorithms
• Offer options and alternatives
• Common decision making

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. 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. SAFETY

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. SAFETY
Myths around multiple pregnancies
Multiple pregnancies are responsible
for up to 27 % of all preterm births

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. SAFETY
Consequences of multiple pregnancies
• Economic impact
• Psycologic impact
• Higher maternal and
fetal/neonatal Morbidity
and Mortality !!!

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. 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. 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. 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. COSTS
Courtesy of Kaylen Silverberg, M.D. Texas Fertility Center, San Antonio, TX.

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. COSTS
Model Costs for 1000 patients
Courtesy of Kaylen Silverberg, M.D. Texas Fertility Center, San Antonio, TX.

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. 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. 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. 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. Special thanks to Tecnalia and Illumina
www.ivf-spain.com www.ivfdonostia.com