2. Jon Havelock - IVF and PGT-A - what the community physician … · In Vitro Fertilization In...

06/21/18

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IVF AND PREIMPLANTATION GENETIC TESTING FOR IVF AND PREIMPLANTATION GENETIC TESTING FOR IVF AND PREIMPLANTATION GENETIC TESTING FOR IVF AND PREIMPLANTATION GENETIC TESTING FOR ANEUPLOIDY (PGTANEUPLOIDY (PGTANEUPLOIDY (PGTANEUPLOIDY (PGT----A) A) A) A) –––– WHAT THE COMMUNITY PHYSICIAN WHAT THE COMMUNITY PHYSICIAN WHAT THE COMMUNITY PHYSICIAN WHAT THE COMMUNITY PHYSICIAN NEEDS TO KNOWNEEDS TO KNOWNEEDS TO KNOWNEEDS TO KNOW

Jon Havelock, MD, FRCSC, FACOG

Co-Director - PCRM

DisclosureDisclosureDisclosureDisclosure

No conflict of interest in relation to this presentation

I have received honoraria in the past 2 years from:

EMD Serono

Ferring

Merck

www.pacificfertility.ca2

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ObjectivesObjectivesObjectivesObjectives

Review the limitations of IVF in age-related infertility2

Understand the biologic mechanisms for age-related infertility3

Discuss the role of PGT-A in IVF4


Describe the process of IVF and evidence for its use1

When should PGT be offered5

DefinitionsDefinitionsDefinitionsDefinitions

In Vitro Fertilization (IVF)A sequence of procedures that involves extracorporeal fertilization of gametes. It includes conventional in vitro insemination and ICSI

Intracytoplasmic Sperm Injection (ICSI)A procedure in which a single spermatozoon is injected into the oocyte cytoplasm

Preimplantation Genetic testing (PGT)A test performed to analyze the DNA from oocytes (polar bodies) or embryos (cleavage stage or blastocyst) for HLA-typing or for determining genetic abnormalities. These include:

PGT for aneuploidies (PGT-A)

PGT for monogenic/single gene defects (PGT-M)

PGT for chromosomal structural rearrangements (PGT-SR)

Has replaced preimplantation genetic screening (PGS) or preimplantation genetic diagnosis (PGD)


Zegers-Hochschild F et al. Fertil Steril 2017. 108:393-406

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July 25, 1978 – first IVF baby born

January 24, 1992 – first birth after ICSI

2010 – Robert Edwards –Nobel Prize in Physiology or Medicine


In Vitro Fertilization In Vitro Fertilization In Vitro Fertilization In Vitro Fertilization –––– A History LessonA History LessonA History LessonA History Lesson

Only 1 RCT (Canadian)

Unexplained infertility

Average duration 4.5 years

Average age 33 years

Single IVF cycle vs 90 days expectant management

NNT = 3-4


Hughes E et al. Hum Reprod 2004. 19:1105-09

IVF IVF IVF IVF –––– Do we Have Good Evidence for its UseDo we Have Good Evidence for its UseDo we Have Good Evidence for its UseDo we Have Good Evidence for its Use

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IVF Treatment IVF Treatment IVF Treatment IVF Treatment –––– Why Does it WorkWhy Does it WorkWhy Does it WorkWhy Does it Work

IVF allows for additional oocytes to be produced

Allows for quantitative increase in chance of conception over mono-follicular ovulatory cycle

Often requires multiple embryos to be transferred Multiple pregnancies



De Geyter C et al. Swiss Med Wkly 2015. 145:w14087

Adapted from Popovic-Todorovic B, et al. Hum Reprod 2003;18:2275–2282 and La Marca A, Sunkara SK. Hum Reprod Update 2014

IVF Treatment IVF Treatment IVF Treatment IVF Treatment –––– Optimizing Success and Minimizing RiskOptimizing Success and Minimizing RiskOptimizing Success and Minimizing RiskOptimizing Success and Minimizing Risk

Too-low

efficacyRisk of OHSS

Oocytes

retrieved

Target:

8–14 oocytes

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Pregnancy

• BALANCE: obtain enough oocytes to ensure a sufficient number of embryos to transfer

• Avoid too many oocytes as this increases the risks, mainly OHSS, without an improvement in pregnancy rates

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Typical IVF Treatment ProtocolTypical IVF Treatment ProtocolTypical IVF Treatment ProtocolTypical IVF Treatment Protocol

BID, twice daily; ET, embryo transfer; hCG, human chorionic gonadotropin;

OR, oocyte retrieval; TE, trophectoderm.

150-450 IU/d x 5 days

Gonadotropins

1

Dosage

Adjustment daily

based on ovarian

responsiveness –

10-15 oocyte

target

6

β-hCG

9-11days

after ET

Clinical

pregnancy

6-7 weeks

gestation

10-11weeks

gestation

Ongoing

pregnancy

hCG

to induce

ovulation

3 follicles ≥17 mm

GnRH agonist trigger if

>25 follicles of ≥12 mm each

Vaginal Progesterone luteal support

Oocyte/embryo/blastocyst evaluation

OR,ICSI

OR+5

TE biopsy and freeze

all embryos if PGT-A

or embryo transfer if

no PGT-A

GnRH antagonist

0.25 mgLead follicle measures ≥14 mm and/or

serum E2 levels are ≥ 3000 pM

9

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How do We Identify Embryos to Transfer?How do We Identify Embryos to Transfer?How do We Identify Embryos to Transfer?How do We Identify Embryos to Transfer?

Poor Quality

Blastocyst

Good Quality

Blastocysts

Embryo Morphology Embryo Morphology Embryo Morphology Embryo Morphology ---- Selection Tool for TransferSelection Tool for TransferSelection Tool for TransferSelection Tool for Transfer

Morphology predicts implantation

Poor morphological appearing embryos do still implant

Good morphological appearing embryos often do not implant

Embryo selection may be enhanced by better tools for predicting implantation potential

Biologic rationale for PGT-A

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Canadian Fertility DemographicsCanadian Fertility DemographicsCanadian Fertility DemographicsCanadian Fertility Demographics


Can IVF Overcome Age related Infertility?Can IVF Overcome Age related Infertility?Can IVF Overcome Age related Infertility?Can IVF Overcome Age related Infertility?


2015 Assisted Reproductive Technology National Summary Report. US Centers for Disease Control and Prevention

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Can IVF Overcome Age related Infertility?Can IVF Overcome Age related Infertility?Can IVF Overcome Age related Infertility?Can IVF Overcome Age related Infertility?


2015 Assisted Reproductive Technology National Summary Report. US Centers for Disease Control and Prevention


Franasiak et al. Fertil Steril 2014; 101:656-63

AgeAgeAgeAge----Related Infertility Related Infertility Related Infertility Related Infertility ---- Aneuploidy Aneuploidy Aneuploidy Aneuploidy

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Scott KL, et al. Fertil Steril 2013;100:608-14

Mechanism of Aneuploidy in EmbryogenesisMechanism of Aneuploidy in EmbryogenesisMechanism of Aneuploidy in EmbryogenesisMechanism of Aneuploidy in Embryogenesis

Rationale for PGTRationale for PGTRationale for PGTRationale for PGT----AAAA

Select embryos that have better implantation potential

Euploid embryos

Perfect tool would allow binary determination of implantation potential

Discard aneuploid embryos

Potential tool with better prediction for implantation than embryo morphology

Live Birth

No Live Birth

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PGTPGTPGTPGT----AAAA

Oocytes or embryos obtained through IVF are biopsied

Embryos testing negative for disease considered for transfer

Introduced in 1990 – Initially for Sex selection for X-linked recessive disease1,2

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1. Verlinsky et al Hum Reprod 1990;5(7):826-829

2. Handyside et al Nature 1990;344(6268):768-770

Transfer of genetically normal embryos

Increase pregnancy rates and decrease miscarriage rates

Lower multiple pregnancy rates by reducing number of embryos transferred

Lower need for termination of viable aneuploidies

Lower risk and more acceptable

Inadequate embryo numbers and/or quality

No normal embryos to transfer

Damage to embryos

Testing a limited amount of genetic information

Limits to accuracy (mosaicism, false normal and abnormals)

Expense


Potential Benefits and Risks of PGTPotential Benefits and Risks of PGTPotential Benefits and Risks of PGTPotential Benefits and Risks of PGT----AAAA

POTENTIAL BENEFITS POTENTIAL RISKS

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PGTPGTPGTPGT----A A A A –––– How it worksHow it worksHow it worksHow it works


Scott RT et al. Fertil Steril 2013. 100:697-703

PGTPGTPGTPGT---- A A A A –––– Does it WorkDoes it WorkDoes it WorkDoes it Work

Age < 35 aCGH +

MorphologyMorphology P Value

Number of patients receiving transfer

55 48

Oocytes Retrieved 19.5 19.3 NS

Ongoing Pregnancy 38 (69.1%) 20 (41.7%) 0.009

Day 5 Blastocysts 8.3 8.1 NS

Yang Z et al, Mol Cytogen 2012;5:24 Q-PCR + Morphology

Morphology P Value

Number of patients 72 83

Oocytes Retrieved 17.2 17.1 NS

Embryos transferred 1.9 2.0 0.0004

Embryos Progressing to Delivery

89/134 (66.4%)

78/163 (47.9%)

0.001

Day 5 Blastocysts 8.0 7.9 NS

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Illumina Website (unpublished) – Co-Sponsored by Reprogenetics

Single Embryo Transfer of Single Embryo Transfer of Single Embryo Transfer of Single Embryo Transfer of EuploidEuploidEuploidEuploid Embryo Trial (Embryo Trial (Embryo Trial (Embryo Trial (StARStARStARStAR) Trial) Trial) Trial) Trial

NGS Morphology P Value

Number of patients 274 314

Ongoing Pregnancy - Overall 50% 46% NS

Ongoing Pregnancy – Age < 35 49% 53% NS

Ongoing Pregnancy – Age 35-40 51% 37% 0.04

Miscarriage Rate 10% 10% NS

No Improvement in Ongoing Pregnancy Rate Per Embryo Transfer

No Improvement in Ongoing Pregnancy Rate per Embryo Transfer for Age < 35 Years

Improvement in Ongoing Pregnancy Rate per Embryo Transfer for Age 35-40

Study Remains Unpublished


Summary of PGTSummary of PGTSummary of PGTSummary of PGT----A TrialsA TrialsA TrialsA Trials

PGT-A MorphologyRelative

RiskP Value

Number of Embryos Transferred 463 525

Ongoing Implantation 57% 46% 1.24 <0.05

11% absolute difference in pregnancy rates

Need to transfer nine PGT-A embryos to result in one additional ongoing pregnancy/live birth

Does not Address Pregnancies from Subsequent Embryo Transfers from same IVF Cycle

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Scott et al Fertil Steril 2012;97:870-875

Throwing the Baby out with the BathwaterThrowing the Baby out with the BathwaterThrowing the Baby out with the BathwaterThrowing the Baby out with the Bathwater

Abnormally identified embryos

very good at excluding

possibility of normal

pregnancy

4% of abnormally identified

embryos still resulted in normal

pregnancy


Greco E et al. N Engl J Med 2015; 373:2089-2090

False Abnormal Errors False Abnormal Errors False Abnormal Errors False Abnormal Errors –––– Mosaic Embryos?Mosaic Embryos?Mosaic Embryos?Mosaic Embryos?

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Werner MD et al. Fertil Steril 2014; 102:1613-18

False Normal Error RateFalse Normal Error RateFalse Normal Error RateFalse Normal Error Rate

ACOG Practice Bulletin No. 163 (May 2016):Patients who conceive after preimplantation genetic screening for aneuploidy should be

offered aneuploidy screening and diagnosis during their pregnancy.


PGTPGTPGTPGT---- A A A A –––– Canadian TrendsCanadian TrendsCanadian TrendsCanadian Trends

Treatment Type

Treatment Year

2013 2015

All ART Treatment Cycles (#) 25767 31174

Gestational Surrogacy Cycles (#) 413 639

PGT cycles (#) 371 4475

Percentage of ART Cycles that are PGD/PGS 1.4% 14%

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PGTPGTPGTPGT----A A A A –––– The Canadian ExperienceThe Canadian ExperienceThe Canadian ExperienceThe Canadian Experience

Why Should a Patient do PGT?Why Should a Patient do PGT?Why Should a Patient do PGT?Why Should a Patient do PGT?

PGT-A - Test/tool to provide informationNeed to understand the limitations and false positives

PGT-MBoth partners carrier of AR disease or one partner has AD diseaseX-linked carrierHLA matchingChild affected by a single gene disorder

PGT-SRIdentifying a known chromosomal abnormality

Important pointsPre-conceptional genetic counseling is importantDiscuss alternatives of spontaneous conception and antenatal genetic testingNeed to offer confirmatory antenatal genetic testing

Non-medical sex determination is illegal


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ConclusionsConclusionsConclusionsConclusions

IVF is an effective fertility treatment forSevere pelvic/tubal disease

Severe male factor

Unexplained infertility in women under age 40

IVF does not reduce the impact of age-related infertility

PGT-A may modestly improve per embryo transfer pregnancy rates Will not increase likelihood of live birth per IVF cycle started

Patient best suited for PGT-A in IVF remains unclearOlder patients with good ovarian response to IVF likely best

Patients and clinicians need to be aware of false normal PGT-A resultsPrenatal genetic screening still recommended



Just Because You Can, Doesn’t Mean You Should!Just Because You Can, Doesn’t Mean You Should!Just Because You Can, Doesn’t Mean You Should!Just Because You Can, Doesn’t Mean You Should!

2. Jon Havelock - IVF and PGT-A - what the community physician … · In Vitro Fertilization In...

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