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Bourdon, M.1, Santulli, P. 1, Maignein, C.1 , Gayet, V.1, Marcellin, L.1, Blanchet, V.1, Gonnot, J.1, Chapron, C. 1
1 Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Assistance Publique – Hôpitaux de Paris (AP-‐ HP), Groupe Hospitalier Universitaire (GHU) Ouest, Centre Hospitalier Universitaire (CHU) Cochin, Department of Gynecology Obstetrics
II and ReproducMve Medicine, 75679 Paris, France
ART outcomes for fresh versus deferred frozen-‐thawed day-‐2 embryo transfer:
a matched cohort study
Mathilde Bourdon
Weinerman. R and Mainigi. M, FS., 2014
Gene expression profiles of simulated and nonsLmulated human endometrium during the window of embryo implantaLon
Adverse impact of COS on endometrial recepLvity ?
Bourgain C.and Devroey P., HR, 2003
“freeze-‐all” strategy
-‐> The hypothesis is that introducMon of a frozen-‐thawed-‐embryo into a potenMally more favorable intrauterine environment could avoid possible adverse
impact of COS on endometrial recepMvity.
cryopreservaMon of all viable embryos aXer COS, with transfer of a frozen-‐thawed embryo in a subsequent cycle
Vitrified-warmed blastocyst transfer cycles yieldhigher pregnancy and implantation rates comparedwith fresh blastocyst transfer cycles—time for a newembryo transfer strategy?
Dandan Zhu, M.D.,a Juanjuan Zhang, M.D.,a Shanren Cao, M.Sc.,a Junqiang Zhang, M.Sc.,a
Boon Chin Heng, Ph.D.,b Meiling Huang, B.Sc.,a Xiufeng Ling, M.D., Ph.D.,a Tao Duan, M.D., Ph.D.,c
and Guo Qing Tong, M.D., Ph.D.a,c
a IVF Program, Nanjing Maternity and Child Health Hospital, Nanjing Medical University, Jiangsu, People’s Republic of China;b Nanyang Technological University, Singapore; and c IVF Program, Shanghai 1st Maternity and Infant Hospital, TongjiUniversity, Shanghai, People’s Republic of China
Objective: To compare the clinical outcome of fresh versus vitrified-warmed blastocyst transfer (BT) cycles.Design: Retrospective study.Setting: Medical university affiliated hospital.Patient(s): Women aged less than 40 years undergoing BT cycles.Intervention(s): Vitrification and warming of blastocyst with the Cryotop system.Main Outcome Measure(s): Clinical pregnancy rate (CPR), implantation rate (IR), and multiple pregnancy rate(MPR).Result(s): In 110 fresh BT cycles versus 136 vitrified-warmed BT cycles performed from January 2007 to March2010, the IR and CPR of vitrified-warmed BT cycles were 37.0% and 55.1%, respectively, which were statisticallysignificantly higher than the corresponding values of 25.2% and 36.4% obtained for fresh BT cycles. Additionally,the MPR was not statistically significantly different between vitrified-warmed and fresh BT cycles when a similarnumber of blastocysts was transferred to patients.Conclusion(s): Vitrified-warmed BT cycles resulted in statistically significantly higher CPR and IR compared withfresh BT cycles. A new embryo transfer strategy is therefore proposed whereby fresh BTwould be avoided in theinitial ovarian stimulation cycle. Instead, all the patient’s available blastocysts would be vitrified-warmed andtransferred in subsequent cycles. (Fertil Steril! 2011;95:1691–5. "2011 by American Society for ReproductiveMedicine.)
Key Words: Blastocyst transfer, clinical pregnancy, implantation, vitrification
Blastocyst transfer (BT) is effective for enhancing implantation andclinical pregnancy rates, resulting in better clinical outcomes (1, 2).However, it is not always possible to perform fresh BT cycles forevery patient with in vitro fertilization/intracytoplasmic sperminjection (IVF-ICSI) embryos that have successfully been culturedup to the blastocyst stage. Occasionally, fresh BT cycles must becanceled for patients who have exhibited poor endometrialreceptivity or ovarian hyperstimulation syndrome. Under suchcircumstances, all available fresh blastocysts would be cryopreservedfor transfer in a subsequent cycle. Additionally, if there is failure inachieving pregnancy after initial transfer of fresh blastocysts, surpluscryopreserved blastocysts would be transferred in a subsequent cycle.
Vitrification is the preferred method of cryopreservation as op-posed to slow-freezing protocols, due to lack of ice crystallizationand convenience of the procedure itself (3, 4). Generally, it is
widely believed that fresh embryo transfer cycles yield betterclinical results than either frozen-thawed or vitrified-warmed em-bryo transfer cycles. The pertinent question that remains unan-swered is whether blastocyst vitrification compromises embryonicdevelopmental potential. We compared the implantation and clinicalpregnancy rates of fresh versus vitrified-warmed BT cycles.
MATERIALS AND METHODSPatientsFrom January 2007 to March 2010, we performed 136 vitrified-warmed BTcycles, in 48 patients undergoing ICSI treatment. During the same period, weperformed 110 fresh BT cycles, in 32 patients undergoing ICSI treatment.The two data sets were comparable as there were no statistically significantdifferences between the two groups in patient parameters such as age, dura-tion of infertility, etiology of infertility, or proportion of ICSI cycles (P>.05,Table 1). All patients in the control group had surplus vitrified blastocysts forfuture transfer. Hence, the data were not in any way skewed by the inherentlyhigher success rate of patients with excess embryos to cryopreserve ascompared with patients who had only fresh embryos for transfer.
Ovarian StimulationThe standard long protocol for ovarian stimulation was used for patients inthis study (5). Briefly, 0.1 mg SC of the gonadotropin-releasing hormone(GnRH) agonist triptorelin (Decapeptyl; Ipsen-Biotech Inc., Paris, France)was administered in the midluteal phase of the previous cycle, followed by
Received October 12, 2010; revised December 8, 2010; accepted January6, 2011; published online February 11, 2011.
D.Z. has nothing to disclose. J.Z. has nothing to disclose. S.C. has nothingto disclose. J.Z. has nothing to disclose. B.C.H. has nothing to disclose.M.H. has nothing to disclose. X.L. has nothing to disclose. T.D. hasnothing to disclose. G.Q.T. has nothing to disclose.
Reprint requests: Guo Qing Tong, M.D., Ph.D., Director, Department ofAssisted Reproductive Technology, Shanghai 1st Maternity and InfantHospital of Tongji University, Changle Road 536, Shanghai, People’sRepublic of China 200040 (E-mail: [email protected]).
0015-0282/$36.00 Fertility and Sterility# Vol. 95, No. 5, April 2011 1691doi:10.1016/j.fertnstert.2011.01.022 Copyright ª2011 American Society for Reproductive Medicine, Published by Elsevier Inc.
ARTICLE
Freeze-all can be a superior therapy toanother fresh cycle in patients with priorfresh blastocyst implantation failure
Bruce S. Shapiro a,b,*, Said T. Daneshmand a,b, Forest C. Garner a,b,Martha Aguirre a, Cynthia Hudson a
a Fertility Center of Las Vegas, Las Vegas, NV, USA; b Department of Obstetrics and Gynecology, School of Medicine,University of Nevada, Las Vegas, NV, USA* Corresponding author. E-mail address: [email protected] (BS Shapiro).
Dr Shapiro earned his MD from the University of Nevada, Reno, and his PhD from the University of Amsterdam.He completed his residency in obstetrics and gynaecology and his fellowship in reproduction endocrinology atYale-New Haven Hospital. He is chief of the Division of Reproductive Endocrinology and Infertility in the Uni-versity of Nevada School of Medicine’s Department of Obstetrics and Gynecology. He is also a high-complexitylaboratory director. He is the founder and medical director of the Fertility Center of Las Vegas. His recent re-search has included endometrial receptivity, embryo cryopreservation and alternative ovulatory triggeringtechniques.
Abstract Implantation failure has various causes, including impaired uterine receptivity following ovarian stimulation. This retro-spective cohort study compared outcomes in patients with prior implantation failure who elected to undergo another fresh cycleversus those who opted for embryo cohort cryopreservation (freeze-all) and subsequent thaw. There were 269 patients with implan-tation failure following fresh autologous blastocyst transfer opting to undergo a subsequent cycle, with 163 choosing another freshcycle and 106 electing freeze-all and subsequent thaw. Multiple logistic regression analysis indicated that cohort cryopreservationwas associated with greater chance of live birth when compared with another fresh cycle (P < 0.0001). The odds ratio for live birthwith freeze-all relative to a fresh cycle was 3.8 (95% CI 2.1–7.2). A second analysis was then performed using cumulative live birthrate as the outcome measure. Multiple logistic regression indicated freeze-all was associated with greater cumulative live birth ratethan was a fresh cycle (OR 1.9, 95% CI 1.1–3.3, P = 0.0287). These findings suggest that, following implantation failure with freshblastocysts, patients have a significantly greater chance of live birth with freeze-all and subsequent thaw than with another freshcycle.© 2014 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.
KEYWORDS: embryo cryopreservation, endometrial receptivity, implantation failure, IVF, ovarian stimulation
http://dx.doi.org/10.1016/j.rbmo.2014.04.0091472-6483/© 2014 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.
Reproductive BioMedicine Online (2014) ■■, ■■–■■
ARTICLE IN PRESS
Please cite this article in press as: Bruce S. Shapiro, Said T. Daneshmand, Forest C. Garner, Martha Aguirre, Cynthia Hudson, Freeze-all is a superior therapy toanother fresh cycle in patients with prior fresh blastocyst implantation failure, Reproductive BioMedicine Online (2014), doi: 10.1016/j.rbmo.2014.04.009
www.sciencedirect .comwww.rbmonl ine.com
DAY-‐2 ET to freeze or not to freeze?
?
fresh day-‐2 embryo transfer (ET) deferred frozen-‐thawed day-‐2 embryo transfer (def-‐ET)
ART outcomes
10/2012 12/2014
A"er the first ET: ü Clinical PR ü Ongoing PR ü ImplantaMon rate
Fresh Group Deferred Group
Matched for: ü Age ü Number of previous IVF cycle
Day-‐2 deferred group Day-‐2 fresh group
Material and methods
Controlled observaMonal cohort study
IndicaLons Deferred ET
OHSS risk
≥ 2 IVF Failures
Endometriosis
Endometrial AbnormaliLes: Premature progesterone elevaMon
Anatomical defects (polyps, fibroids, hydrosalpinx)
Thromboembolism Risk Autoimmune diseases
deferred ET
COS
GnRHa triggering or hCG
OR
Blasto.
or
P4 Menses Deferred ET 5 weeks later
P4 E2
Frozen ET CryopreservaGon of all embryos
Frozen ET
< 7 Zygotes ≥7 zygotes
All zygotes VitrificaMon and warmed Extended
culture for extra embryos
VitrificaMon at blastocyst stage
VitrificaMon at blastocyst stage
VitrificaMon algorithm
Transfer of 2 best cleavage stage embryos
Transfer of 1 blastocyst
Scheduled ART cycles from 10/2012 to 12/2014
n=3116 Cancelled cycles* n=535
Fresh embryo transfer (ET) n=1667
Oocytes retrieval n=2581
Deferred frozen-‐thawed embryo transfer (def-‐ET)
N=594
day 5-‐6 FET n=269
Matched for: ü Age
ü Number of IVF cycle
Day-‐2 def-‐ET N=325
Day-‐2 Fresh ET
N=1296
Def-‐ET group $ N=325
Fresh ET group $ N=325
No embryo obtained n= 247 Oocytes vitrificaMon n= 35 Inclusion in another ART research protocol n=38
day 5-‐6 fresh ET n=25
≥7 zygotes obtained n=346
Flow chart
<7 zygotes
Fresh (n=325)
Def-‐ET (n=325) P value
PaLent’s Age at IVF (years) 35.96 ± 4.4 35.65 ± 4.3 NS Number of previous IVF cycles
2.41 ± 1.27 2.51 ± 1.33 NS
Length of inferLlity (years) 4.98 ± 2.91 5.08 ± 2.83 NS BMI (kg/m2) 23.88 ± 4.08 23.66 ± 4.01 NS Smoking 29 (8.92) 30 (9.23) NS Cause of inferLlity: NS . Ovula2on disorder 31 (9.54) 35 (10.77)
. Male factor 125 (38.46) 104 (32.00)
. Tubal factor 37 (11.38) 35 (10.77)
. Endometriosis 49 (15.08) 76 (23.38)
. Idiopathic 57 (17.54) 52 (16.00)
. Diminished ovar ian reserve
15 (4.62) 9 (2.77)
. More than 1 e2ology 11 (3.38) 14 (4.31) PaLent’s ovarian reserve: . Day 3 FSH (UI/L) 7.35 ± 2.31 7.07 ± 2.07 NS . Day 3 LH (UI/L) 4.85 ± 2.18 4.97 ± 2.53 NS . Day 3 Estradiol (pg/mL) 46.39 ± 21.91 44.46 ± 24.84 NS . AFC 13.17 ± 6.72 14.44 ± 8.28 0.039 t . AMH (ng/mL) 2.87 ± 2.10 3.70 ± 3.50 <0.001t
PaLents basal characterisLcs
Fresh (n=325) Def-‐ET (n=325) P value
SLmulaLon protocol <0.001 k -‐ Long protocol 65 (20.00) 22 (6.77) -‐ GnRH antagonist 196 (60.31) 273 (84.00) -‐ Short protocol 64 (19.69) 30 (9.23) Total dose of injected gonadotropin (IU)
2710.39 ± 1056.30 2466.00 ± 857.02 <0.001t
DuraLon of sLmulaLon (days) 9.56 ± 1.35 10.47 ± 1.53 <0.001t
Peak estradiol levels (pg/ml) a 1627.26 ± 655.90 1881.05 ± 1052.84 <0.001t
Peak progesterone levels (ng/ml) a 0.75 ± 0.35 0.91 ± 0.84 <0.001t
Number of oocytes retrieved 6.84 ± 3.42 7.90 ± 4.52 <0.001t
Number of mature oocytes retrieved
5.43 ± 2.60 6.20 ± 3.55 <0.001t
Number of 2PN embryos 3.41 ± 1.58 3.56 ± 1.72 NS
FerLlizaLon rate 68.08±25.40 66.00±27.24 NS
ART-‐characterisLcs
Fresh (n=325) Def-‐ET (n=325) P value Survival rate NA 92.9% NA Mean number of embryos transfer 1.77 ± 0.44 1.72 ± 0.47 NS Total number of embryos transferred
574 555 NS
Quality of transferred embryos *
Grade 1
Grade 2
Grade 3
141(24.56)
135(23.52)
298(51.92)
122(21.98)
111(20.00)
322(58.02)
NS
≥ 1 embryo grade 1* transferred 114(35.08) 104(32.00) NS
Embryo characterisLcs
* embryos were morphologically assessed according to Consensus scoring system for cleavage-‐stage embryos (Alpha ScienMsts in ReproducMve Medicine and ESHRE Special Interest Group of Embryology, 2011)
Fresh (n=325) Def-‐ET (n=325) P value
ImplantaLon rate 0.20 ± 0.33 0.17 ± 0.31 NS Clinical pregnancy rate 98/325 (30.15) 85/325 (26.15) NS Miscarriage 27/98 (27.55) 25/85 (25.51) NS MulLple pregnancy 11/98 (11.22) 9/85 (10.59) NS On going pregnancy rate 71/325 (21.85) 60/325 (18.46) NS
ART-‐outcomes
30,15
21,85 26,15
18,46
0
10
20
30
40
50
Clinical PR Ongoing PR
Fresh ET Def-‐ET
%
% %
% %
NS
NS
Parameters Odds raLo 95% CI p
PaLent’s Age at IVF (years) 0.92 0.88-‐0.97 0.001
BMI (kg/m2) 0.94 0.89-‐0.99 0.030
Number of 2PN embryos 1.19 1.04-‐1.40 0.010
≥ 1 embryo grade 1* transferred
1.97 1.26-‐3.05 0.003
Independent predictors for ongoing pregnancy mulLple logisLc regression analysis
Age Number of previous IVF cycles BMI AMH levels total dose of injected gonadotropin type of protocol number of 2PN transfer of at least one embryo grade 1
PotenMal confounding factors for ongoing pregnancy found to be staMsMcally significant at the threshold of p ≤ 0.10 in univariate analysis were tested in a mulMple logisMc regression model.
• ART outcomes were not improved by a deferred day-‐2 ET as compared to
a fresh day-‐2 ET • This provided us an overall view of the impact of day-‐2 deferred ET on
ART outcomes regardless of the indicaLons for the deferred transfers.
• Further invesMgaMons may be required to determine for which specific subgroups the “freeze -‐ all strategy” may be most efficient for ensuring increased-‐pregnancy rates
• Randomized controlled studies seems necessary to confirm theses results
Conclusion
Gynecology Surgical unit: C Chapron, B Borghese, P Santulli,
H Foulot, MC Lafay-Pillet, A Bourret, G Pierre, M Even, MC Lamau, L Marcellin, P Marzouk, Medical unit: A Gompel, G Plu-Bureau, L Maitrot
Reproductive Endocrinology unit: D de Ziegler, P Santulli, V Gayet, C Maignien, FX Aubriot
Intestinal surgery B Dousset, S Gaujoux, M Leconte
Radiology AE Millischer, L Maitrot
Laboratory: Genetic D Vaiman, F Mondon, S Barbaux
Laboratory: Imunulogy
F Batteux, S Chouzenoux C Nicco, C Chéreau, B Weill
Laboratory: Reproductive biology
JP Wolf, V Lange, K Pocate, JM Kuntzman, C Chalas
Statistical unit
F Goffinet, PY Ancel, C Prunet
D. de Ziegler, Professor and Head, Reproductive Endocrinology and Infertility unit, A. Gompel, Professor and Head, Medical Gynecological unit,
C. Chapron, Professor and Chair, Gynecology Obstetrics II and Reproductive Medicine