cleavage vs blastocyst transfer in the time lapse era
TRANSCRIPT
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Cleavage vs Blastgthe Time L
Barry Behr, y ,Prof
Director, IVFDirector, IVFCo-Director IVF
Stanford UniversiStanford Universi
tocyst Transfer in yLapse Era.
Ph.D., HCLD,fessorF LaboratoryF LaboratoryF/ART Programity Medical Centerity Medical Center
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Disclo
I am a founder of AuxI am a founder of IviGI am a founder of IviG
osure
xogynGen/BlastogenGen/Blastogen
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Out
Lets make this interac
tline
ctive
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Human Embryoo Development
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Why go to B
Embryo Selection
HAVING to go to blastbenefit of the TLM techbenefit of the TLM tech
Blastocyst?
t removes some of the hnologyhnology
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What does a cembryo ne
Be euploidCleaveCleaveCompactF i bl bl tForm a viable blastocy
cleavage stage g geed to do?
tyst
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What does a Blado
Be euploidDifferentiate into ICMDifferentiate into ICM HatchAApposeAttachInvade
astocyst need to yo?
ad TEad TE
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$$64,000 q
Are you doing fresh vsAre you doing PGD/S?Are you doing PGD/S?When is the endometr
questions
s frozen ET???rium most receptive?
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Cleavage vs B
Simpler to measure eaFaster ( ie can ET earFaster ( ie can ET earMay be safer
Blastocyst TLM
arly eventslier)lier)
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What are we meaWhat are we mea
May determine which – Genetic (ie when is besGenetic (ie when is bes– Metabolic– (both?)(both?)
asuring with TLC?asuring with TLC?
day we ETst to do a bx)st to do a bx)
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Parameters mestagestage
easure cleavage eventsevents
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Human Embryo TiPaper Published Samples
Payne et al. Hum Reproduction 1997 50
2PN • ObsHum Reproduction 2PN
Lemmen et al.RBM Online 2008 102
2PN oocytes
• Rep• Cor
preg
Mio et al. Am J Obstet Gyn 2008 286
oocytes • Obs• Rep
Wong et al 242
• Idenby DWong et al.
Nature Biotechnology 2010 2422PN
y• Dem
exp• Dev
Pribenszky et al. RBM Online 2010 5
2PN • RepRBM Online 2010 2PN p
Meseguer et al. Hum Reprod 2011 247
2PN • Eva
Hashimoto et al. 2012 80 EHashimoto et al.Fert Steril 2012 80
2PN • Eva
Swann et. al.Fertil steril 2012 10 oocytes
or zygotes • Cor
ime-lapse StudiesConclusions
served details of the fertilization process to 20 hrs
ported PN appearance & disappearancerelated synchrony in nuclei appearance after 1st cleavage with gnancy success
served details of the fertilization processported two ICMs - monozygotic twins
ntified cell cycle parameters that predict blastocyst formationDay 2ymonstrated that parameters correlate to embryo gene pression dataveloped cell tracking software
ported a live birthp
aluated cell cycle parameters to implantation
l t d ll l t f bl t t litaluated cell cycle parameters for blastocyst quality
related cytoplasmic movements with Ca2+ oscillations.
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Oct 2010
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Imaging and MoleEmbryonEmbryon
ecular Analysis of nic Cellsnic Cells
Nature Biotech ePub Oct 3, 2010
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Custom MicroIndividual culture within t
o‐Well Dishesthe same media drop
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Comparison to a Morphologic
SenSpep
1. F. Guerif et al., Limited value of morphological assessment at dA prospective study based on 4042 embryos. Hum Reprod; 20
Studyof Common cal Predictors1
4 morphological criteria:
Pronuclear morphology on day 1; early cleavage, # cells, and fragmentation on day 2
sitivity ~ 0.65cificity ~ 0.65
and fragmentation on day 2
y
days 1 and 2 to predict blastocyst development potential: 007
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Imaging Does Not PParam
Alter Fundamental tmeters
Nature Biotech ePub Oct 3, 2010
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Arrested EmbryosyCytokinesis Duri
DiviNormal
Divi
Mild
Severe
phenotype
phenotype
s Exhibit Abnormal ing 1st Cleavage sionsion
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4 ESSPs of Early Ger
Wong et al, submitted
rm Cell Development
Maternal inherited (1)EGA (2)EGA (2)Blastocyst (3)Ubiquitous (4)
Nature Biotech ePub Oct 3, 2010
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Embryo Arrest and GIndividual BIndividual B
Gene Expression in BlastomeresBlastomeres
Nature Biotech ePub Oct 3, 2010
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MoleculaCorrelated gene expression profilin
1 Embryos with aberrant cytokinesis1. Embryos with aberrant cytokinesis demonstrate underlying defects in molecular programs:
ar Analysisng revealed:
2. Using our predictors, embryo transfer can2. Using our predictors, embryo transfer can be performed prior to embryonic gene activation, minimizing risk of adverse outcomes:
7
8Gene Transcription Activation
ProposedCurrent Embryo Transfer
Point
3
4
5
6p
Transfer Point
0
1
2
3
1-cell 2-cell 3-cell 4-cell 6-cell 8-cell 9-cell Morula Blastocyst
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DiscriminationBlastocyst Receiver Operating
SenSpep
23
n Potential of Predictorsg Characteristic (ROC)
sitivity = 0.94 cificity = 0.93y
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Example Tracking on Whole Dish
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Eeva AnalysFully automated, state-of-the-art computer vis
the end o
sis Software
Eeva Timing
sion software predicts blastocyst formation by of Day 2
Eeva Parameter Eeva Prediction
Timing
20 minPASS
12 hrsPASS
PASS1 hrs
20 iPASS
15 hrs
20 min
FAIL
2 hrs
PASS
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Refinement of cell cyc
Parameter Measurements Wong/Lo
Refinement of cell cyc
Duration of first cytokinesis 14.4+
Time between first and second mitosis
11.1+2
Time between second and third mitosis
1+1.6
ParameterMeasurements
Normal CGH
Duration of first cytokinesis
14.4+4.2 Min.
Time between first and second mitosis
11.8+0.71 Hourssecond mitosis
Time between second and third mitosis
0.96+0.84 Hours
cle imaging parameters
oewke et al. Present Study
cle imaging parameters
+6 Min. 14.4+4.2 Min.
2.2 Hours 11.8+1.2 Hours
6 Hours 0.85+0.79 Hours
Meiotic Error Mitotic Error
117.2+166.5 Min. 36.0+66.9Min.
4.0+5.2 Hours 6.4+6.6 Hours
2.0+4.3 Hours 2.0+3.9 Hours
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Detection of chromosomal dusimple and comp
plications/deletions and both plex mosaicism
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Calculation of Embryonic ERi k U i M h lRisk Using Morpholog
Asses
A table showing the calculation (number of euploid embryos/total number expressed as a percentage for each morphological and/or parameter assehighest percentage of embryonic euploidy over aneuploidy was obtained wand cellular fragmentation analysis.
Euploidy Versus Aneuploidyi l d/ P tgical and/or Parameter
ssment
of embryos) and the resulting probability of embryonic euploidy essment. (B) Graphic representation of the table demonstrating that the with the combination of cell cycle parameters that predict normal A-CGH
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Wong et al., 2010, Mesg , ,and Hashimoto
Table courtesy of Michael Tucker
seguer et al., 2011 g ,et al., 2012
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Putting it aall together
Nature Biotech ePub Oct 3, 2010
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Summary
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Summ
Any TLM approach is betteUterine receptivity will play– Which will influence which sy
Practical matters like best tinfluence the decision
mary
er than a static system a role in when we ETystem will dominatetime to bx or vit may also
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ThThe
y
E dEnd
Thanks for your attention
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