should every embryo be screened or frozen? should we cryo...fresh set results in lower delivery...
TRANSCRIPT
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Should Every Embryo be Screened or Frozen?
What does the evidence say?
Richard T. Scott, Jr, MD, HCLDClinical and Scientific Director,
Reproductive Medicine Associates of New JerseyProfessor and Director, Reproductive Endocrinology
Robert Wood Johnson Medical School, Rutgers University
aCGH (Lab 1)
SNP array (Lab 3)
qPCR (Lab 2)
46,XY
45,XY,-8
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Contemporary Understanding of Maternal Age and Human Embryonic Aneuploidy
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Per
cen
t o
f Em
bry
os
Wh
ich
are
An
eup
loid
Age (yrs)
Franasiak et al – Fertil Steril 2014
N=15,169
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Is transferring an aneuploid embryo clinically useful?
Gain of 21
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 1718 19
2021
22
X
Chromosome #
Co
py
Nu
mb
er
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What are the “Burdens” of CCS
Thus the real questions are:
1. Safely attaining embryonic DNA
2. Predictive values of the techniques
3. Proportion of euploid embryos that will fail
4. Cost effectiveness
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Some Disagree with PGS
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Some Disagree with PGS
• All embryo selection techniques are detrimental
• Inappropriate to use “Implantation Rates” as an endpoint
• “it can be questioned whether all patients will ever be able to understand all of the complexities concerning PGS”
• “cost-effectiveness is being forgotten”
• “evidence is now accumulating that all embryos in an IVF cycle can be cryopreserved and transferred in subsequent cycles without impairing, and maybe even improving, the cumulative pregnancy rate of that IVF cycle”
• Embryo selection should therefore not be used to select out embryos, but only to determine the order in which the embryos will be transferred, as the time to pregnancy can be improved by embryo selection, if embryos with the highest implantation potential are transferred first.
• Culturing to the blastocyst may be harmful
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Does Embryo Biopsy Impact the Developmental Potential of the Oocyte
Routine IVF Care through Retrieval
Identify mature oocytes ICSI, culture, and select 2 best embryos for transfer
One embryo randomized to undergo biopsy
Transfer the embryos
Implantation, Maternal serum sampling for free fetal DNA and Fingerprinting
Cell submitted for eventual aneuploidy screening and fingerprinting
N=113 pairs; 226 embryos
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Overall implantation rates
39% reduction insignificant
27% (mean maternal age 32) reported by Gutierrez-Mateo, C., et al. Fertility and sterility 92, 1544-1556 (2009)
In our opinion, day 3 biopsy will soon be of historic interest only
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Normal Result
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CIN III or Malignancy
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Abnormal Result
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CIN III or Malignancy
Is knowing the predictive value of a normal result sufficient?
Sherman et al 95:429-36 J Natl Cancer Inst (2003)
If they were the same it would likely be a rare coincidence…
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< 32 33-35 36-38 39-40 41-42
%
Age (yrs)
With greater experience, actual negative
predictive value is ~98.8%
Scott et al Fertil Steril 2012; 97:870-5
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To have the opportunity for meaningful improvement, when you select for one criteria you most commonly deselect for another….
Transfer Based on Embryo Morphology
Abnl Abnl Nl Abnl Nl Nl
Transfer Based on Aneuploidy Screening and
Embryo Morphology
CCS changes the embryo selected 40% of the timeForman et al ASRM 2012
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aCGH enhances delivery rates – an RCT
• RCT
• Age– All < 35– Mean age of 31
• Sample Size– 55 aCGH– 48 control
• Significant improvement in outcomes
• Answers one of the four critical validation questionsMonosomy:Trisomy Ratio of 2
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Scott et al Fertility and Sterility 2013; 100:697-703
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No
-Eu
plo
id B
last
s R
ate
(%
)
Age (yrs)
The No Transfer Rate with CCS
Franasiak et al – Fertil Steril 2014
N=15,169
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ases
wit
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s av
aila
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fo
r B
iop
sy (
%)
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or
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psy
(%
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Number of Blastocyts
52% of cases had 3 or fewer evaluable embryos
How Many Embryos Do Patient Undergoing CCS Have?
Franasiak et al – Fertil Steril 2014
N=15,169
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Trisomy:Monosomy Ratio by Age
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<35 35-37 38-40 41-42 43+
Tris
om
y:M
on
oso
my
Rat
io
Age Group (yrs)
Franasiak et al – Fertil Steril 2014Key Indicator for QA of your assay
N=15,169 Ratios consistent across nine programs
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Clinical ExperienceMisdiagnoses
• 4974 embryos
• 2976 gestations (62.1%)
• 10 errors– 1 tetraploid
– 2 monosomies
– 7 trisomies
• 3168 transfers
• 2354 ongoing / delivered (72.1%)
• Mean age 38.4 years
• 10 errors– 7 found in losses
– 3 found in ongoing preg.
Mosaicism evaluated in 4 samples – 100% mosaic
Clinical Error RatePer embryo 0.2%Per transfer 0.3%Per ongoing pregnancy 0.1%
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Consolidated Pregnancy OutcomesProportion of All Pregnancies
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< 35 35 - 38 - 41 - 43+
Clin
ical
Lo
ss R
ate
(%)
Maternal Age (yrs)
CCS - Delivery
No Screening - Delivery
CCS - Clinical Loss
No Screening - Clinical Loss
CCS - Chemical Los
No Screening - Chemical Loss
N=4,754 pregnancies
Scott KL et al – RMA
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PGS Improves but Does Not Normalize Implantation and Delivery Rates in Older Women
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<25 26-29 30-34 35-37 38-40 41-42 43+
Sust
ain
ed
Imp
lan
tati
on
Rat
e (
%)
Maternal Age (yrs)
N=28,567
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Kulkarni D et al, New Engl J Med, 2014. PMID: 24304051
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Kulkarni D et al, New Engl J Med, 2014. PMID: 24304051
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Singleton Term Delivery: The Ideal IVF Outcome
• IVF twin pregnancies are at an increased risk of:
–Preeclampsia (2-fold risk increase)1
– Extreme prematurity (7.4-fold increase delivery <32 wks) 2
–NICU admission (3.8-fold increased risk)2
–Perinatal Death (2-fold increase)2
• Two IVF singleton deliveries have better obstetrical outcomes than one IVF twin delivery3
1. ASRM Practice Committee, Fertil Steril, 2012. PMID: 221923522. Pinborg A, et al., Acta Obstet Gynecol Scand, 2004. PMID: 154881253. Sazonova A ,et al., Fertil Steril, 2013. PMID: 23219009
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Provided by a patient…
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With >2 blastocysts, even patients at high aneuploidy risk are very likely to have a euploid blastocyst
0%
10%
20%
30%
40%
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80%
90%
100%
10% 15% 20% 25% 30% 35% 40% 45% 50% 55% 60% 65% 70% 75% 80%
Pro
bab
ility
of
at le
ast
1 E
up
loid
Bla
sto
cyst
Aneuploidy Rate
2 Blastocyst
3 Blastocyst
4 Blastocyst
21%34%
55%64%
<35 35-37 38-40 41-42
Blastocyst Aneuploidy Rate by Age Group
Forman EJ et al., O-161
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FRESH SET RESULTS IN LOWER DELIVERY RATES THAN DOUBLE EMBRYO TRANSFER (DET)
• Cochrane Review of 6 randomized trials from
1999-2006 (N = 1,257)
• Young, good prognosis patients with “top quality” embryos available
• Slightly more singletons after DET
Pandian Z et al., Cochrane Database Syst Rev, 2009. PMID: 19370588
26%30%
13.2%
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
SET DET
Livebirth Rate - SET vs. DET
Twins
Singletons
0.5%
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The Dropout Rate from IVF is Significant
0%
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Dropout/cycle
Cumm Actual PR
Cycle Number
Pe
rce
nt
Dro
po
ut
Source: Schroder AK: Cumulative pregnancy rates and drop out rates of a German IVF programme: 4, 102 cycles in 2,130 patients. RBM Online (2004) 8:600-606
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Can1 ≥ 2?
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CCS Results in Higher Implantation Rates
Implantation = cardiac activity at time of discharge to obstetrical care (~9 weeks)
66.3%
51.2%
0%
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50%
60%
70%
80%
Euploid SET Traditional DET
P=0.02
N=83 N=170
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Same Delivery Rate:Randomized Controlled Trial
Forman EJ et al. Fertil Steril 2013
61%65%
0%
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Delivery Rate Per Patient (n=175)
Single euploid blastocyst transfer (N=89)Untested 2-blastocyst transfer (N=86)
P=0.5
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P<0.001
Eliminates Multiples
100%
52%
0%
48%
Single euploid blastocyst transfer Untested 2-blastocyst transfer
Singletons Multiples
P<0.001
Forman EJ et al. Fertil Steril 2013
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1000
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5000
5500
Single euploidblastocyst
transfer Grams
Untested 2-blastocyst
transfer Grams
Bir
thw
eig
ht
(Gra
ms)
Better Obstetrical Outcomes are Attained CCS/eSET than Conventional Two Embryo Transfer
•Mean Birthweight:3408 ± 562g – Single euploid2745 ± 743g – 2-Blastocyst
(P<0.001)
•Low birthweight (<2,500g):4.4% (2/45) – Single Euploid31.9% (22/69) – 2-Blastocyst
(P<0.001)
•Very low birthweight (<1,500g):0% (0/45) – Single Euploid7.2% (5/69) – 2-Blastocyst (P=0.06)
Single euploid
blastocyst transfer
Untested 2-blastocyst
transfer
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Ongoing Pregnancy Rates Fresh vs. Frozen Transfers
37%
57%
43%
54%
ControlSET CCSSET
FreshET
FrozenET
66%oftransfers
50%oftransfers
P = 0.4 P = 0.7
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Obstetrical Costs for 100 PatientsCurrent Standard Of Care
Costs per Delivery*
Singleton $21,458
Twins $104,831
Triplets $407,199
Does not include:Pediatric costs after 28 days of age
Disability costs during bed rest
Loss of productivity in the work place
Lemos et al Am J Obstet Gynecol 2013; 209:586
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Overall Cost to Provide CareCCS with SET versus Conventional Treatment
$0
$10
$20
$30
$40
$50
$60
$70
$80
CCS / SET NationalAvg
RegionalAvg
Tho
usa
nd
s
Costs per Delivery*• Use actual cost data
• Inclusive of all IVF costs including
– IVF cycle costs
– CCS costs
– Medication costs
• Delivery costs and subsequent hospital stay through 28 days of life
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Do we ever recommend two embryo transfers?
Yes – but with caution…
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Follow Up on Prospective Trials
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Time Lapse Observations in the Embryology Laboratory
And others…..
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loid
Quartile
ICSI to start of 1st cytokinesis (p=0.61)
0102030405060708090
100
1st 2nd 3rd 4th
% E
up
loid
Quartile
Duration of the 2 cell stage (p=0.88)
0
10
20
30
40
50
60
70
80
90
100
1st 2nd 3rd 4th
% E
up
loid
Quartile
Duration of the 3 cell stage (p=0.12)
Time Lapse and AneuploidyTraditional Markers
Hong KH et al – in review
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0
10
20
30
40
50
60
70
80
90
100
1st 2nd 3rd 4th
Rat
e o
f eu
plo
id e
mb
ryo
s (%
)
Quartile
Time from start of 1st cytokinesis to start of cavitation (p=0.01)
0
10
20
30
40
50
60
70
80
90
100
1st 2nd 3rd 4th
Rat
e o
f eu
plo
id e
mb
ryo
s (%
)
Quartile
Time from start of 5 cell stage to start of cavitation (p=0.0076)
Hong KH et al in review
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Can Time Lapse Help Distinguish Which Euploid Blasts will Deliver from those Destined to Fail?
1
1.5
2
2.5
3
3.5
4
4.5
5
Failed Succesful
syn
_rm
: ti
me
fro
m s
yn
ga
my t
o 1
st
cyto
kin
es
is
Transfer Outcome
NO: None of the 5 traditional parameters or 5 additional blast
related parameters prognosticate outcome
Temporal data evaluated:
• 5 conventional endpoints through cleavage stage
• Additional temporal endpoints from extended culture:• First compaction• Morula formation• First cavitation• Blastocyst Expansion• First contraction
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Follow Up on Prospective Trials
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Next Generation SequencingAligned Results
Reference sequence from
human genome database
Mu
ltip
le R
ea
ds (
de
pth
)
![Page 43: Should Every Embryo be Screened or Frozen? Should we cryo...FRESH SET RESULTS IN LOWER DELIVERY RATES THAN DOUBLE EMBRYO TRANSFER (DET) •Cochrane Review of 6 randomized trials from](https://reader034.vdocuments.site/reader034/viewer/2022042414/5f2f0885a8eaf00d202d7eca/html5/thumbnails/43.jpg)
The Economics of NextGenA Major Factor for Accuracy
$$$$$$$
NextGen Sequencing Chip
![Page 44: Should Every Embryo be Screened or Frozen? Should we cryo...FRESH SET RESULTS IN LOWER DELIVERY RATES THAN DOUBLE EMBRYO TRANSFER (DET) •Cochrane Review of 6 randomized trials from](https://reader034.vdocuments.site/reader034/viewer/2022042414/5f2f0885a8eaf00d202d7eca/html5/thumbnails/44.jpg)
NextGen Molecular Barcoding Reduced Costs
Embryo 1 Embryo 2
Barcode 1
Barcode 2
CTAAGGTAAC
TAAGGAGAAC
combine samples for a single sequencing chip
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The Economics of NextGenA Major Factor for Accuracy
$$$$$$$/2
NextGen Sequencing Chip
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The Economics of NextGenA Major Factor for Accuracy
$$$$$$$/4
NextGen Sequencing Chip
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The Economics of NextGenA Major Factor for Accuracy
$$$$$$$/48
NextGen Sequencing Chip
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The Economics of NextGenA Major Factor for Accuracy
$$$$$$$/96
NextGen Sequencing Chip
96 or more…
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WGS(16 per chip)
chromosome
copy number
known trisomy
known monosomy
unpublished data
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WGS(48 per chip)
chromosome
copy number
unpublished data
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Targeted NGS (96 per chip)
chromosome
copy number
unpublished data
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Embryo calibration results
chromosome
copy number
unpublished data
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Chromosome specific cutoffs
1
0
2
3
4
NGS based copy number
on chr16
chr16 specific cutoffs
unpublished data
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Embryonic Endometrial Synchrony
It take two…..
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Embryonic-Endometrial Asynchrony Increases with Maternal Age
0
10
20
30
40
50
60
70
80
Elev P Day 6 Blast OverallAsynch
% o
f Tr
eat
me
nt
Cyc
les
<30 31-34 35-40
• Retrospective
• 1,341 IVF cycles
• Thresholds for Asynchrony (either)– P >1.5 mg/mL on day of hCG – No blastulation prior to day 6
• Risk for asynchrony increases with maternal age
• Live birth predicted – Day 5 blastulation (P<0.0001)– P < 1.5 ng/mL (P=0.0002)
Shapiro BS et al Fertil Steril 2013 100:S287
P<0.01
(419) (436) (486)
Is it asynchrony or an intrinsic diminution in quality?
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Late follicular rise in progesterone
• Retrospective study
• 4032 patients
• P4 ≥1.5ng/mL associated with lower ongoing pregnancy rates
Bosch E, et al. Hum Reprod. 2010 Aug;25(8):2092-100.
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Progesterone and the Endometrial Transcriptome
Adapted from S. Young, MD, PhD
2.5 mg/d IM
Leuprolide acetate 1 mg/d td sc
40 mg/d IM
5 mg/d IM
Estradiol 0.2 mg/d td
10 mg/d IM
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Progesterone Pharmacokinetics
Adapted from S. Young, MD, PhD
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Progesterone and the Endometrial Transcriptome
Adapted from S. Young, MD, PhD
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Progesterone and Impaired Implantation:A Pilot Study of Euploid Embryos
0
10
20
30
40
50
60
70
< 0 0 1 2 3 4 5 6 7 8 9 10 11 12 >12
Sust
ain
ed
Imp
lan
tati
on
Rat
e (
%)
Hours Relative to “Closure” of the Window
All patients had normal P levels prior to the administration of hCG
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Beware of Interference in your P Assay
• Patients receiving DHEA have elevated DHEA-SO4 levels
• These levels may falsely elevate P levels
• Assay dependent
Forman - RMANJ
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Natural Cycle
hCG
administration
Progesterone
Rise
Ovulation
Embryonic
Window of
Implantation
Endometrial
Window of
Implantation
time
Franasiak et al ASRM 2013
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hCG
administration
timeEndometrial
Window of
Implantation
Embryonic
Window of
Implantation
embryo and endometrium synchrony -revisited
Progesterone
Rise
24h
Ovulation
Franasiak et al ASRM 2013
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Fresh day 5 embryo transfer
44%
18%
64%
56%
0%
10%
20%
30%
40%
50%
60%
70%
<35 ≥35
D5 M-B1 D5 B2-B6
p <.001p <.001
Franasiak et al ASRM 2013
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Fresh day 6 embryo transfer
p <.05
52%
32%
63%
48%
0%
10%
20%
30%
40%
50%
60%
70%
<35 ≥35
D5 M-B1 D5 B2-B6
p <.005
Franasiak et al ASRM 2013
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timeEndometrial
Window of
Implantation
Frozen synchronous cycle
Progesterone
Start
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Older patients are more likely to have “slow” embryos
31%
46%
0%
10%
20%
30%
40%
50%
60%
70%
<35 years old ≥35 years old
Proportion of "Slow" Blastocysts
P<0.0001
Forman et al ASRM 2013
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Frozen day 6 embryo transfer
p =0.5
57%
37%
60%
42%
0%
10%
20%
30%
40%
50%
60%
70%
<35 ≥35
D5 M-B1 D5 B2-B6
p =0.3
Franasiak et al ASRM 2013
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Obstetrical Outcomes Following Fresh versus Cryopreserved Embryo Transfer
• Fresh embryos at increased risk for• Preterm birth• Low birth weight• Small for gestational age
Wennerholm et al Hum Reprod 2013 28:2545-53
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The supraphysiologic milieu which accompanies superovulation impact low birth weight risk
0
5
10
15
20
25
30
35
LowBirth Wt
TermLBW
PretermLBW
Fresh ET
Cryo ET
• Retrospective review of SART data
• 2004-2006
• 56,792 neonates
• Fresh embryo transfer at increased risk for LBW
%
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The RMA New Jersey TeamScientific Director
Richard T. Scott
PhysiciansPaul Bergh
Michael BohrerMaria CostantiniMichael Drews
Eric FormanRita Gulati
Doreen HockKathleen Hong
Thomas KimMarcy Maguire
Thomas MolinaroJamie Morris
Eli RybakWendy Schillings
Shefali Shastri
FellowsMarie Werner
Jason FranasiakCaroline Juneau
The Treff LaboratoryNathan Treff
Xin TaoAgnes LonczakDavid GabrieleChelsea BohrerTori Gartmond
Margaret LebiedzinskiOksana Bendarsky
Mariya RozovAnna CzyrsznicKay Green, MDMeir Olcha, MDDavid Goodrich
BioinformaticsDeanne TaylorJessica Landis
Yuanchao Zhang
Clinical EmbryologyKathleen Upham
Xinying LiRosanna Pangasnan
Tian ZhaoMichael ChengHokyung Lee
Ayesha WinslowAngela Romaniello
Stephanie MilneSarah DunnLauren Rary
Kristen PauleyDesiree GreeneSerhan Ozensoy
Erin DubellSusan Ng
Maria MorelJessica Wall
FAEECRebekah
ZimmermanBrynn Levy
Lindsey McBainHeather Garnsey Andrew Behrens Sylvia Kloskowski
Erica Vuu
Clinical ResearchChristine RedaTalia MetzgarJennifer Tyler
SupportAndrew Ruiz
Nancy NiemaseckRMANJ Nurses