The Ideal Time for Embryo Transfer. Ramazan Mercan, MD Koç University School of Medicine

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1 The Ideal Time for Embryo Transfer Ramazan Mercan, MD Koç University School of Medicine

2 Aydıner et al., Cur.Mol.Med. 2010

3 Sperm IN VITRO CULTURE OOCYTE BLASTOCYST Early Cleavage Isiklar&Balaban J Rep.Med 2002 PN Morphology Day 2 embryo Day 3 embryo Quality Balaban FS 2000, Gardner FS 2000 Balaban HR 2001 Rjinders HR 1998, Shapiro FS 2000,Ragione R.B.Endocrinol 2007 Multinucleation Yakin&Balaban FS

4 Embryo Selection Pyruvate- lactate, glucose, aminoacids, shla- G, lepdn in culture media O 2 consumpdon Omics (Metabolomics, Genomic- PGS, proteomics, transcriptomics) Polarized microscopy Time- lapse monitorizadon

5 Blastocyst stage embryo transfer-pros BeLer correladon between embryo morphology and chromosomal structure BeLer embryo/endometrium synchrony Improved the odds of transferring a viable embryo Decreased uterine contracdons Decreased muldple pregnancy rate

6 Blastocyst transfer-cons Higher cancelladon rate The risk of losing and viable embryo due to extended culture Decreased rate of freezing Increased cost of laboratory Risk of monozygous twin Altered sex rado EpigeneDc changes Increased neonatal/perinatal morbidiy

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8 Comparative Studies

9 D2/3 vs D5/6 ProspecDve- randomize follikül Max no. of embryos transferred: 2 D2/3: 80, D5/6: 64 ImplantaDon rates: %21.1 (D5/6) vs %20.9 CPR: %36.7 vs %32.5 At least 1 good quality embryo %60 vs %37.5 (higher in blastocyst group) Hreinsson J. Eur J Obstet Gynecol Reprod Biol 2004

10 Single cleavage vs single blastocyst ProspecDve randomized 351 women <36 years 176 cleavage stage and 175 blastocyst transfer LBR: %32 vs %21.6 MonozygoDc twinning 2 in the cleavage group Papanikolaou EG. N Eng J Med 2006

11 Single ET& BT: A prospective randomised trial Patients 36, 1st./2nd. Attempt, 5 2PN PR: 42.2% when 4G1, with 95.5% suitable for SBT, PR: 27.8%when 3G1, with 88.5% suitable for SBT Zech et al.,f&s 2007

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13 FETs: Higher (not.sig.) cryosurvival with cleavage embryos than with blastocysts higher no.of deliviries(not. sig..) with set compared with the SBT ProspecGve Guerif et al., HR 2009

14 Single blastocyst vs two cleavage RetrospecDve LBR %27.2 vs D2: %24.8 (NS) MulDple pregnancy rate Significantly lower in blastocyst group Zander- Fox Dl. Aust NZ J Obstet Gynaecol 2011;Oct:406-10

15 Cycles without top quality embryos 450 women, <36 years ProspecDve Single blastocyst vs two cleavage stage Embryo transfer rate %88 vs %100 LBR: % 26.7 similar in both groups MulDple pregnancy: %3.3 vs %23.3 Guerif F, Hum Reprod 2011 Apr

16 The Cochrane Library 2013, Issue 6 *Unselected * *POR * *Unselected Moderate * A clinic with 31% LBR with ET, may have a LBR of 32-42% with BT

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18 All studies used slow- freezing for blastocyst cryopreservagon!! BeYer survival, transfer and IR are expected in terms of competence and benchmarks. Alpha consensus meegng on cryo KPIs and benchmarks. RBM Online 2012

19 Cochrane-2012 LBR (D2/3 vs D5/6) %31 vs %32-42, OR: 1.40 (4RCT) CPR %38.6 vs %41.6, OR: 1.14 (NS) (23 RCT) Miscarriage rate OR: 1.13 (NS) (13 RCT) CumulaDve pregnancy rate %56.8 vs %46.3, OR: 1.58 (4RCT)

20 Embryo freezing OR: 2.28 (11RCT) CancellaDon rate %3.4 vs %8.9, OR: 0.35 (16 RCT)

21 Clinical outcome of fresh and vitrified- warmed blastocyst and cleavage- stage embryo transfers in ethnic Chinese ART pagents <35 years (D5 vs D3) CPR: 41.07% vs 47.08%, p>0.05 ImplantaDon rate: (31.8% vs 31.2%, p>0.05 CPR with VET: %56.8 ImplantaDon rate of VET : %47 CumulaDve pregnancy rate: Blastocyst: %70.1, D3: %51.8, p<0.05 CumulaDve muldple pregnancy rate: Same >35 yaş (D5 vs D3) CPR: 33.33% vs 42.31%, p>0.05 J Ovarian Res 2012

22 Pregnancy outcome per patient in VET and cumulative pregnancy rate after fresh embryo transfer and VET D3 group (n = 46) D5 group (n = 58) StaDsDcal significance PaDents with no ongoing pregnancy in fresh IVF with vitrified embryos 65.7 % (23/35) 54.4 % (18/33) p = PaDents going through VET 87 % (20/23) 88.8 % (16/18) p = No. VET transfers/padent 1.1 ± 0.6 (22/20) 1.5 ± 0.9 (24/16) p = No. Embryos transferred/cycle 1.7 ± ± 0.48 p = 0.02 Embryo survival rate 78.8 % (37/47) 82.1 % (32/39) p = 0.7 Clinical pregnancy rate/ VET cycle 50 % (11/22) 41.6 % (10/24) p = ImplantaDon rate 43.2 % (16/37) 34.4 % (11/32) p = Miscarriage rate 18.1 % (2/11) 20 % (2/10) p = MulDple pregnancy rate 45.4 % (5/11) 10 % (1/10) p = Ongoing pregnancy rate/padent in VET 45 % (9/20) 50 % (8/16) p = CumulaDve ongoing pregnancy rate/ padent (fresh + VET) 43.4 % (20/46) 56.8 % (33/58) p = Cleavage: 46 pts, blastocyst: 58 Fernandez- Shaw et al. J Assist Reprod Genet 2015

23 Patients with poor prognosis

24 Prospective quasi-randomized, mixed general IVF population, No sig.dif. clinical parameters Weissman et al., RBM Online 2008

25 Cancellation rate: 12/70: 17.1% *** Weissman et al., RBM Online 2008

26 J Assist Reprod Genet Mar;31(3): doi: /s Epub 2013 Dec 19. Comparison of the transfer of equal numbers of blastocysts versus cleavage- stage embryos a_er repeated failure of in vitro ferglizagon cycles. Karacan M1, Ulug M, Arvas A, Cebi Z, Berberoglugil M, Batukan M, Camlıbel T. METHODS: RetrospecDve analysis of 238 couples (with previous implantadon failures) had equal number (two) of cleavage- stage embryos (n = 143) or blastocysts (n = 95) transferred in the same IVF center. RESULTS: The clinical pregnancy rates and live- birth rates were similar in the cleavage- stage embryo transfer group and the blastocyst group (35.6% vs. 40% and 32.1% vs. 35.7%; p > 0.05, respecdvely). Miscarriage rates (9.8% vs. 10.5%) and muldple pregnancy rates (15.6% vs. 23.6%) did not differ. Although implantadon rate was higher with blastocyst transfer than that with day 3 transfer, it did not reach to a stadsdcal significance (24.7% and 19%, respecdvely, p > 0.05).

27 High Estradiol Levels ProspecDve- randomized 200 pts, E2>3000 pg/ml, 4 high quality embryos Clinical pregnancy rates: %41 vs %59 (D3 vs D5) Ongoing pregnancy rates: %35 vs %52 Elgindy EA, Reprod Biomed Online 2011 Dec:789-98

28 Comparative study of pregnancy outcomes between day 3 embryo transfer and day 5 blastocyst transfer in patients with progesterone elevation RetrospecDve 2868 cycles D3 embryo transfer (n = 2345) CPR: 55.4% vs 46.7% (normal progesterone vs high progesterone) Ectopic pregnancy rates: 2.8% versus 7.9% D5 embryo transfer (n = 523) Similar clinical and ectopic pregnancy rates in both groups J Int Med Rs, 2013

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31 PGS/PGD de D5 tercih edilmeli Cleavage- stage biopsy significantly impairs human embryonic implantagon potengal while blastocyst biopsy does not: a randomized and paired clinical trial D3biyopsi + D3 biyopsi - D5 biyopsi + D5 biyopsi -

32 Metaanalysis Sex rado OR: 1.29 (4 studies) Chang Hj. FerDl Steril, 2009 MonozygoDc twin OR: 3.08 (9 studies) Luke et al., 2014

33 Papanikolaou et al.,f&s 2010 Total:587 Natural conception:0.42% Demographics&Etiology : no stat.dif. Except mean age(29.9bvs 30.8 E.) Treatment charecteristics: no.stat.dif. Except no.of COCs (12.3B vs. 10.4E) **Delivery of 24 healthy babies reported MZT: Hardening of ZP, disorder in the cell adhesion process secondary to the culture media, Costa HR 2001, Milki F&S 2003) ICSI causing splitting of ICM through the artifical gap (Tarlatzis F&S 2002).

34 Result(s): No differences were found between the incidence of MZT in cycles that did vs. did not use micromanipulagon techniques. In addigon, the length of embryo culgvagon or type of culgvagon media used did not affect the results. Estradiol levels and implantagon rates were significantly higher in group A. The incidence of MZT in families in group A was significantly higher than that in groups B and C. F&S 2015

35 Neonatal Outcome

36 Kallen et al., F&S 2010

37 Kallen et al., F&S 2010

38 Neonatal Outcome Cleavage stage: Blastocyst transfer: 1311 Blastocyst stage transfer Congenital anomalies Preterm delivery Clinics performing only blastocyt transfer Preterm Labor, Low birth weight, Low Apgar score, and respiratory problems Kallen B. FerDl Steril 2010

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40 <32 weeks <37 weeks

41 Metaanalysis: 4 observagonal study Blastocyt Stage Transfer Congenital abnormalides OR: 1.29 (2 studies) Preterm delivery OR: 1.32 Dar S. Hum Reprod Update 2014

42 Large for gestational age Zhu et al., 2014 Maheswari and BhaLacharya., 2013 Makinen et al., 2013

43 AJOG 2016

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48 Possible etiologic factors for differences in neonatal outcome Extended culture of embryos in blastocyst group- epigenedc effects Higher percentage of good prognosis padents in blastocyst group and impaired placentadon due to higher estradiol levels Higher preterm delivery and similar small for gestadonal age rates suggest that increased perinatal mortality is primarily due to embryonic factors in blastocyst group Maheshwari F&S 2013

49 Conclusions Blastocyst stage transfer shortens the Dme to pregnancy Decreased muldple pregnancy rate Although cumuladve pregnancy rate is higher in D2/3 transfers, there is a need for further studies Neonatal outcome seems to be beler in D2/3 transfer

50 Does vitrificadon increase the cumuladve pregnancy rate in blastocyst group? CumulaDve pregnancy rate may even be higher in high responders when D2/3 transfer performed Blastocyst transfer seems to be beler in selected group of padents: Good prognosis High estradiol levels? High progesterone levels? Male factor?

51 All-freeze protocol

52 Figure 2 SWOT analysis of a freeze- all strategy. OHSS, ovarian hypersgmulagon syndrome.

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54 Advantages of all-freeze Decreased risk of OHSS The need for PGS/PGD BeLer endometrial/embryo synchrony Increased endometrial recepdvity Decreased ectopic pregnancy rate Fang et al., 2015 BeLer obstetrical and neonatal outcomes Pelkonen et al., 2010; Sazonova et al., 2012; Wennerholm et al., 2013; Ishihara et al., 2014 The incidences of LBW and preterm birth of singleton FET pregnancies are similar to natural concepdons Pinborg et al., 2013

55 A posidve impact not only on implantadon, but also on placentadon and fetal growth Pinborg, 2012 Scheduling of oocyte retrievals becomes easier The endocrine profile and, mainly, high progesterone levels (.1.5 ng/ml) at the end of the follicular phase also become much less important Hormonal cycle monitoring becomes less crucial The avoidance of oocyte retrievals during weekend

56 The possibility to inidate ovarian sdmuladon on any given day of the menstrual cycle The freeze- all protocol could also allow for a different approach to prevent premature LH surges, namely the use of oral medroxyprogesterone acetate (MPA) instead of injectable GnRH analogs

57 Disadvantages Based on a few small and heterogeneous RCTs restricted mostly to high responders Aflatoonian et al., 2010; Shapiro et al., 2011a, 2011b OHSS is not completely avoided

58 Metaanalysis Higher implantadon, clinical and ongoing pregnancy rate by performing FET Roque et al., 2013