Hacia el Screening de Aneuploidías en FIV como

“Standard of Care”: Resultados clínicos

Dr. Jon AizpuruaDr. Yosu Franco

I JornadaActualización en Genética Reproductiva y Fertilidad

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

AlwaysVitrification

TRADITIONAL PGS INDICATIONS

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)

EFFICIENCY

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

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

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 (2013) Fertil Steril, and unpublished data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

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 (2013) Fertil Steril, and unpublished data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

EFFICIENCY

Impact of PGS in ongoing PR per Transfer

Courtesy, Genesis Genetics – embryos tested by aCGH

IVF vs PGSClinical Pregnancy Rate / ET

11

EFFICIENCY

Should all patients be offered aneuploidy assessment?

Harton et al. (2013) Fertil Steril, and unpublished data

Ongoing Pregnancy rate per Transfer

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 (2013) Fertil Steril, and unpublished data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

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!

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.

EFFICIENCY

Embryo euploidy rate

Munné et al. RBMO 2012.Wells et al. 2015 unpublished

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

EFFICIENCY

Management of expectations in bad prognosis cases

• Compliance based on facts

• Offer predictive algorithms

• Offer options and alternatives

• Common decision making

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)

EFFICIENCY

eSET with PGS equally efficient but safer as DET without PGS

Prospective randomized Clinical TrialqPCR + eSET en fresco vs morfología + 2 blastocistos fresco

Forman et al. Fertil. Ster. 2013

NS

NS

NS

P < 0,001

SAFETY

SAFETY

Safetyof PGS

eSET fullfiling BEST criteriaBirth Emphasizing Health Singleton at Term

Reliable technologyVery low mosaicism misdiagnosis

No deleterious effects from trophectoderm biopsyLower abortion rates and complications

Lowest multiple rates and complications

SAFETY

Myths around multiple pregnancies

Multiple pregnancies are responsiblefor up to 27 % of all preterm births

SAFETY

CAUSES OF HIGH INCIDENCE OF MULTIPLE PREGNANCIES IN ART

ESHRE Campus Course, Antwerp, Belgium, 2007Patients

• Pacient´s emotions and expectations• Economic considerations• Deficient information about multiple pregnancy risksPhysicians• 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

SAFETY

Consequences of multiple pregnancies

• Economic impact• Psycologic impact• Higher maternal and

fetal/neonatal Morbidity and Mortality !!!

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

SAFETY

INCREASED FETAL MORBIDITYHigher 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 dysfunctionsBuitendijk, 1999; Hazekamp et al, 2000; Ward and Beachy, 2003

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

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?

COSTS

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

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 cycleIdentify non-tangible benefits of procedure• Faster progression to donor

oocytes• Fewer por prognosis cycles• Less frustration and stress• Less time to newbornCourtesy of Kaylen Silverberg, M.D. Texas Fertility Center, San Antonio, TX.

COSTS

Model Costs for 1000 patients

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

PGS costs/cycle + 2 % for < 35 yearsPGS 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 treatments

1 McLaurin K, et al. Pediatrics 2009;123:653-9

COSTS

Cost effectiveness

PGS costs/birth: - 32 % for < 35 yearsPGS costs/birth: - 48 % for > 35 years

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

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 CycleDET 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 CycleCum. 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€)

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?

Special thanks to Tecnalia and Illumina

www.ivf-spain.com www.ivfdonostia.com