prof. antonio pellicer - comtecgroup ppt/pellicer.pdfprof. antonio pellicer instituto valenciano de...
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![Page 1: Prof. Antonio Pellicer - Comtecgroup PPT/Pellicer.pdfProf. Antonio Pellicer Instituto Valenciano de Infertilidad (IVI) University of Valencia apellicer@ivi.es ... p = 0.02 Rubio I](https://reader033.vdocument.in/reader033/viewer/2022051809/60134465f0020f262748b7c8/html5/thumbnails/1.jpg)
Prof. Antonio Pellicer Instituto Valenciano de Infertilidad (IVI)
University of Valencia [email protected]
www.ivi.es
Improving outcomes in ART : Time-lapse technology for monitoring COS
and blastocyst culture
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DISCLOSURE
- Invitation by an unrestricted Educational Grant from
COMTECMED to ASRM - IVI is a minor shareholder in Unisense Fertilitech A/S.
- IVI is a minor shareholder in Auxogyn Co. - This work has not received any financial support from any
commercial entity and the instrumentation, disposables and utensils belong to IVI.
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EMBRYONIC IMPLANTATION
MOLECULAR
DIALOGUE
-
Health embryo at blastocyst stage
Adequate Endometrial Receptivity
To select the best embryo/s
HUMAN EMBRYONIC IMPLANTATION
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Improvement of ART outcomes
Personalized Embryo Transfer (pET)
Endometrial receptivity assay (ERA)
Other non-invasive methods
Identification/Modification of receptive endometrium
Window of Implantation
Identification of the viable embryo
Invasive methods: CCS (D3 or D5)
Non-invasive methods:
Morphology
Time-lapse Proteomics
Metabolomics
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Improvement of ART outcomes
Personalized Embryo Transfer (pET)
Identification of the viable embryo
Repeated implantation failure (RIF)
Aged patients
Reduced ovarian reserve
Endometriosis
Severe male factor
Recurrent miscarriage
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Improvement of ART outcomes
Personalized Embryo Transfer (pET)
Identification of the viable embryo
Time-lapse
Invasive methods: CCS (D3 or D5)
….in ALL ART CYCLES?
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✔
✘
Time-Lapse Technology
Time-Lapse Imaging - Blastomere Activity
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PÁG.8
Time-Lapse Development cc2= t3-t2
t5
CC2
Time post insemination, hours
0 5 10 15 20 25 30
coun
t
0
500
1000
1500
2000
2500
Regular divisionsViable 8 cellViable blastocystImplanted
t5
Time post insemination, hours
30 40 50 60 70 80
coun
t
0
200
400
600
800
1000
1200Regular divisionsViable 8 cellViable blastocystImplanted
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PÁG.9
Best correlation
with implantation
success
Predictive ability of embryo implantation
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PÁG.10
715, 14%
4510, 86%
Incidence rate of direct division 1-3 in all embryos deviding to 3 cells
Direct division 1-3cells
No direct division1-3 cells
0
10
20
30
DC 1-3 Not DC1-3
2,9 %
28,7%
Impl
anta
tion
Rat
e
*P<0.0001 *
Rubio et al. Fertil Steril 2012; 98(6)
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PÁG.11
Morphology
included
ok
Grade A Grade B Grade C Grade D Grade E Discarded
non viable
excluded
yes no
yes no no yes
PÁG.A+
PÁG.11A B+ B C+ C D+ D
CC2 5- 12h CC2 5-12h CC2 5-12h CC2 5-12h
yes no yes no yes no yes no
included
Exclusion Criteria
Direct Cleavage Uneven Blastomere
T5
48-56h
T3
35-40h
T3
35-40h
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PÁG.12
Time-Lapse: Initial findings
Embryo morphology correlates with embryo classification by time-lapse
Embryo quality and implantation correlate with embryo classification by time-lapse
In a retrospective study, time-lapse (n=1372 cycles) as compared to conventional incubators (n=5872 cycles):
reduced significantly (2.8% vs 5.2%) cycle cancellation rates
Increased significantly (59.1 vs 50%) ongoing pregnancy rates
Meseguer et al. Fertil Steril 2012; 98:1481-9
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PÁG.13
Randomized Controlled Trial
Rubio I. et al. Fertil Steril 2014; 102: 1287-94
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PÁG.14
Inclusion Criteria ICSI
MII ≥6
Age 20-38
Previous Cycles ≤2
BMI 18-25
Basal FSH <12
AMH >7 pmol/L
Exclusion Uterine Pathologies
Hydrosalpinx
Recurrent Miscarriage
Endometriosis
< 1 mill progressive sperm (A+B)
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PÁG.15
Not meeting inclusion criteria (n=52) • Patient request TMS, n=30 • IVF as fertilization procedure, n=14. • Testicular sperm or cripto, n=5. • Already randomized, n=1. • Advanced maternal age, n=1. • Low respond, n=1.
Not meeting inclusion criteria (n=22) • No embryoslides available, n=8 • IVF as fertilization procedure, n=5. • Testicular Sperm or Cripto, n=5. • Already randomized, n=1. • Low respond, n=3.
SI group
Allocated to intervention(n=412) Received allocated to intervention (n=412)
TMS group
Allocated to intervention(n=444) Received allocated to intervention (n=444)
Randomized (n=856)
Analyzed (n=438)
Excluded (n=6) • Cancelled donation, n=2. • Embryo vitrified, n= 4.
Analyzed (n=405)
Excluded (n=7) • Endometrial bleeding, n=1. • Cancelled donation, n=2. • Embryos vitrified, n=4.
Assessed for eligilibility (n=930)
Follow-up (n=412) Follow-up (n=444)
Rubio I. et al. Fertil Steril 2014; 102: 1287-94
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PÁG.16
TMS GROUP(n=438) CONTROL GROUP(n=404) p
Blastocyst rate (%) 27.5 24.5 NS
Embryo Fragmentation (%) 7.5 (7.2-7.9) 6.9 (6.5-7.1) 0.06
Number of Blastomeres 6.9 (6.8-6.9) 6.9 (6.8-7.0) NS
Optimal Embryos (D3) (%) 46.2 43.1 0.010
Blastocyst rate (%) 52.3 50.5 NS
Optimal Blastocyst (D5) (%) 20.9 16.6 0.001
Transferred embryos (per treatment) 1.86 (1.8-1.9) 1.86 (1.8-1.9) NS
Cryopreserved embryos (per treatment) 3.9 (3.6-4.1) 3.6 (3.4-3.9) NS
46.2 43.1 0.010
20.9 16.6 0.001
Rubio I. et al. Fertil Steril 2014; 102: 1287-94
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PÁG.17
Pregnancy (%)
Ongoing pregnancy (%)
Positive ßHCG
Intention to treat All treated cycles All transfers
57.9
49.1
20
25
30
35
40
45
50
55
60
TMS (n=466) SI (n=464)
48.2
36.4
20
25
30
35
40
45
50
TMS (n=466) SI (n=464)
61.6 56.3
202530354045505560
TMS (n=440) SI (n=405)
51.4
41.7
20
25
30
35
40
45
50
55
TMS (n=440) SI (n=405)
54.5
45.3
20
25
30
35
40
45
50
55
60
TMS (n=415) SI (n=373)
65.3 61.1
20
30
40
50
60
TMS (n=415) SI (n=373)
Fetal Heart Beat
p = 0.007
p = 0.0003
p = 0.12
p = 0.005
p = 0.22
p = 0.01
Rubio I. et al. Fertil Steril 2014; 102: 1287-94
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PÁG.18
16.6
25.8
0
5
10
15
20
25
30
TMS (n=271) SI (n=228)
All pregnancies
Early pregnancy loss: Positive ßhCG but no FHB
All transferred embryos
p = 0.01
44.9
37.1
20
25
30
35
40
45
50
TMS (n= 775) SI (n=699)
Implantation rate: # embryo sacs / # embryos transferred
Ear
ly p
regn
ancy
loss
(%)
Impl
anta
tion
rate
(%)
p = 0.02
Rubio I. et al. Fertil Steril 2014; 102: 1287-94
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PÁG.19
Model effect values OR p value
Incubation TMS versus SI 1.41 (1.06-1.871) 0.017 Day of Transfer Day 5 versus Day 3 1.76 (1.22-2.52) 0.002 Oocyte source Autologous versus
Donation 0.83 (0.60-1.14) ns
Age years per year 0.99 (0.94-1.05)
ns
TMS versus SI 1.41 (1.06-1.871) 0.017
Rubio I. et al. Fertil Steril 2014; 102: 1287-94
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PÁG.20
If all of the 6000 treatments in the conventional incubator had been carried out using Time-Lapse Incubator, we could have expected about 545 additional pregnancies.
Rubio I. et al. Fertil Steril 2014; 102: 1287-94
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PÁG.21
Time-lapse data to predict blastocyst development
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PÁG.22
Embryo temporal distribution to reach blastocyst stage.
PNF (h)
010203040506070
<22.6 22.7-24.3 24.4-26.3 >26.4
1stC (h)
010203040506070
<25.2 25.3-27.1 27.2-29.1 >29.1
2ndC(h)
01020304050607080
<37.6 37.7-40.1 40.2-43.3 >43.4
p<0.05 p<0.05
Time-lapse data to predict blastocyst development
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PÁG.23
Embryo temporal distribution to reach expanded blastocyst stage.
p<0.05 p<0.05
PNF (h)
05
101520253035
<22.6 22.7-24.3 24.4-26.3 >26.4
1stC (h)
05
10152025303540
<25.2 25.3-27.1 27.2-29.1 >29.2
2ndC (h)
05
10152025303540
<37.6 37.7-40.1 40.2-43.3 >43.4
Time-lapse data to predict blastocyst development
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PÁG.24 PÁG.24
P<0.001
N= 872
Time-lapse data to predict blastocyst development
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PÁG.25 PÁG.25
P<0.001
N= 396
Optimal blastocyst
Time-lapse data to predict blastocyst development
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PÁG.26
*
*
229 477 74 134 14
Time-lapse data to predict blastocyst development
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PÁG.27
Blastocyst prediction
Tracks cell divisions
Calculates timing intervals
Feeds timings to the classification tree
Generates an automated prediction
2. Classification Tree • HIGH probability to form a blastocyst if cell
cycle markers are within range
• LOW probability to form a blastocyst if cell cycle markers are outside of range
1. Automated Cell Tracking Software:
Time-lapse data to predict blastocyst development
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PÁG.28
Eeva. HIGHHIGH
LOWLOW
PÁG.28
MEDIUMMEDIUM
P2: 9 h 20 min ≤ P2 ≤ 11 h 28 min P3: 0 ≤ P3 ≤ 1 h 44 min
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PÁG.29
EEVA category Blastocyst Rate (%)
Optimal Blastocyst Rate
(%) HIGH
(n=103) 77.7 27.2
MEDIUM (n=467)
56.3 19.3 LOW
(n=270) 49.6 17.4
HIgh High-Med Med-High Low
yes no
yes no no yes
cc2
9.33-11.47
s2
0-1.73h
s2
EEVA category Blastocyst Rate Optimal
Algorithm Results Blastocyst prediction (n=840)
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PÁG.30
Algorithm Results KID (n=245 transferred embryos)
EEVA category Implantation (%)
HIGH (n=88)
45.5
MEDIUM (n=108)
31.7
LOW (n=49)
30.6
Eeva Morpho
HIgh High-Med Med-High Low
yes no
yes no no yes
cc2
9.33-11.47
s2
0-1.73h
s2
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PÁG.31
# p<0.0001 **p<0.001 relative to Morphology only
• Specificity – measures false positives
• Significantly improved
in 3 out of 3 embryologists
• More consistent
embryo assessment using D3 morphology + Eeva information
Conaghan et al. Fertility & Sterility (2013)
Time-lapse data to predict blastocyst development
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Time-lapse and COS
a-
GnR
H
an-G
nRH
hCG FS
H
FSH
N= 319 ICSI oocyte donation cycles N= 2132 embryos
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CONCLUSIONS
Personalized Medicine is the next step in ART
Time-lapse is a good method of embryo selection: correlation with embryo quality, implantation, ongoing pregnancy rates and miscarriage.
Time-lapse increases ongoing pregnancy rates by 10% in RCTs
Time-lapse is helpful in the prediction of blastocyst development
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Aknowledgements
Marcos Meseguer Irene Rubio
Carmen Rubio Daniela Galliano Manuel Munoz Carlos Simón