Disclosures Declared receipt of grants and contracts from Merck. Receipt of honoraria or consultation fees from Merck, Merck Serono, MSD

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2 Filippo Maria Ubaldi Reproductive Medicine GENERA Rome, Italy Disclosures Declared receipt of grants and contracts from Merck. Receipt of honoraria or consultation fees from Merck, Merck Serono, MSD

3 Objectives Clinical importance of embryo cryopreservation in Europe and in Italy Clinical arguments in favor and con of frozen-thawed embryo transfer Clinical results and cost-effectiveness of freeze all policy vs fresh ET Scientific evidence to support freeze all policy Conclusions

4 Cryopreservation in Europe Cryopreservation of gametes and embryos is essential in ART increasing safety and efficacy of IVF The proportion of cryopreserved embryo transfer cycles compared with fresh cycles is growing in Europe Overall it has been estimated that cryopreserved cycles contributed to 32% of the transfers in 2011 compared to 28% in 2010 Switzerland, Finland, Sweden and Iceland the proportion of cryopreserved ET is higher than 50% Kupka et al., Hum Reprod 2016

5 Pregnancy rates Cryopreservation in Italy Pregnancy rates Fresh ET cycles (55.705) 83.3% Frozen ET cycles (9.501) (14.2%) Frozen oocyte ET cycles (1.639) (2.5%) Cumulative pregnancy rates Pregnancy rates after fresh ET Thawed oocytes Thawed embryos Fresh ETs

6 Cryopreservation overall, GENERA (Centre of Rome ) Embryo transfer cycles GENERA (Centre of Rome) Fresh ET (1472) 33,6% Frozen ET (2896) 66,4% OPU Fresh ET Frozen ET

7 Fresh and segmented cycles GENERA (Centre of Rome ) Segmented cycles % 72.2% 77.4% Other reasons OHSS PGT-A/M OPU

8 Reliability of cryopreservation techniques CPR/ cycle CPR/ ET

Importance of a good crypreservation program Enables egg banking for donation and/or for oocyte accumulation Permits fertility preservation for medical and non-medical indications Enhances cumulative

9 Importance of a good crypreservation program Enables egg banking for donation and/or for oocyte accumulation Permits fertility preservation for medical and non-medical indications Enhances cumulative live birth rate per oocyte retrieval cycles Efficient cryopreservation programme for oocytes and embryos Extends time for embryo evaluation Allows systematic application of elective single embryo transfer policy Provides the opportunity to perform cycle segmentation

10 Importance of a good crypreservation program Rienzi et al., Hum Reprod Update 2017

11 Reliability of cryopreservation tecniques Despite this the prevailing view is that being able to freeze embryos is merely a welcome bonus or add-on to the assisted reproduction process rather than being the first choice option resulting in better maternal and fetal outcomes.

12 Clinical arguments that challange this view Aim of IVF Measure of success in IVF Live birth of single healthy baby Live birth rate per started cycle

13 Clinical arguments that challange this view Prevention of OHSS risk IVF cycle segmentation: GnRH antagonist protocol - agonist trigger - freeze all

14 Clinical arguments that challange this view Obstetric and perinatal outcomes Birth defects: 3-fold in fresh ET (OR 3.65; 95% CI ) but not in FETs (OR 1.60; 95% CI ) when both were compared with spontaneously conceived babies (Halliday et al., 2010) Metaanalysis: singleton pregnancies following FETs vs fresh ETs were significantly less likely to be complicated by perinatal mortality (RR 0.68; 95% CI ), small for gestational age (RR 0.45; 95% CI ), preterm birth (RR % CI ), low birthweight (RR 0.69; 95% CI ) and antepartum haemorrhage (RR 0.67; 95% CI ) (Maheshwari et al 2012) Compared with singletons born after fresh ET, singletons born after FET had a higher risk of being large for gestational age (OR 1.45; 95% CI ) and having macrosomia (OR1.58; 95% CI ), (Wennerholm et al., 2013) which is in line with findings from other large population-based studies. (Pelkonen et al., 2010; Pinborg et al., 2010; Sazonova et al., 2012)

15 Clinical arguments that challange this view Obstetric and perinatal outcomes Overall, birth outcomes after FET are better compared with fresh ET. It should also be emphasized that these studies were all observational in nature, and that the frozen/thawed embryos available for transfer were therefore inevitably second choice as the best embryos would have been transferred in the previous fresh ET. Many of these adverse perinatal outcomes may originate in impaired early placentation during stimulated IVF cycles. This may result from the associated supraphysiological estradiol levels reported in studies showing significantly lower PAPP-A levels during first-trimester (Amor et al., 2009; Giorgetti et al., 2013) Elevated serum estradiol levels are associated with an increased risk of being small for gestational age (Griesinger et al., 2007) and the development of pre-eclampsia (Imudia et al., 2012)

16 Effect of the peri-implantation environment on mouse placentation and fetal growth P<0.05 P<0.001 (A) Fetal and placental weights of embryos resulting from the transfer of naturally conceived blastocysts to control and superovulated recipient mice. Fetal and placental weights were significantly smaller in the superovulated group. (B) Placental histology differed significantly: placentas from superovulated recipients showed limited invasion of the junctional zone by the labyrinth zone with decrease in the junctional:labyrinth zone ratio. (Weineman, 2014)

17 Clinical arguments that challange this view Serum Progesterone rise in the follicular phase

18 Clinical arguments that challange this view Reduction of the ectopic pregnancy risk SUMMARY ANSWER: The lowest risk of ectopic pregnancy was associated with the transfer of blastocyst, frozen and single embryo compared with cleavage stage, fresh and multiple embryos

19 Clinical arguments that challange this view Adenomiosis (endometriosis?)

20 Clinical arguments that challange this view Preimplantation Genetic Testing (PGT) Trophectoderm biopsy (day5/6/7) acgh SNP array qpcr NGS

21 What evidence to support freeze all

What evidence to support freeze all In an IVF cycle, ovarian multifollicular development exposes the endometrium to supraphysiological concentrations of E2 and P, which can dramatically impact the

22 What evidence to support freeze all In an IVF cycle, ovarian multifollicular development exposes the endometrium to supraphysiological concentrations of E2 and P, which can dramatically impact the timing of endometrial development and/or the achievement of receptivity (Fauser and Devroey, 2003) Early histological studies When an IVF/ICSI stimulated endometrium is advanced >3 days (as assessed by using Noyes criteria for endometrial dating) there is a complete failure to achieve pregnancy/implantation (Ubaldi, 1997; Kolibianakis and Devroey, 2002; Van Vaerenbergh, 2009)

What evidence to support freeze all Istological/immunoistochemical studies A recent more comprehensive histological/immunohistochemical study suggests that the absence of receptivity is more

23 What evidence to support freeze all Istological/immunoistochemical studies A recent more comprehensive histological/immunohistochemical study suggests that the absence of receptivity is more complicated than mere developmental advancement, and that a complex lack of synchrony of development between the different cellular and structural compartments of the endometrium results from ovarian stimulation protocols (Evans et al., 2012) Fertile women Fertile donors Agonist pregnant Agonist/antagonist no pregnant

What evidence to support freeze all Altered gene expression In an advanced endometrial maturation (>3 days) on the day of OPU it has been observed an elevation of 1337 genes and a downregulation of

24 What evidence to support freeze all Altered gene expression In an advanced endometrial maturation (>3 days) on the day of OPU it has been observed an elevation of 1337 genes and a downregulation of 1213 genes (Van Vaerenbergh et al., 2009). Transcriptomic profiling of the IVF endometrium has revealed alterations in gene expression in the endometrium taken between hcg+2 and hcg+7 compared with the natural cycle (Horcajadas et al., 2005, 2008; Liu et al., 2008; Macklon et al., 2008; Haouzi et al., 2009, 2010). Up-regulated (LH+7) Down-regulated (LH+7) Dickkopf-related protein 1 (DKK-1) Leukemia inhibitory factor (LIF) CXCL-chemokines: Glycodelin IL-1b; IL-5; IL-10; IL-12; eotaxin; Heparin-binding epidermal growth factor elevated inflammation and advancement deficicient receptivity and failure of impantation Horcajadas, 2005; Macklon, 2008; Tulac, 2006; Haouzi, 2010; Evans 2012; Boomsma, 2010; Yoshii, 2013

25 What evidence to support freeze all Immunologic changes to the endometrium NK cells, have been associated with endometrial receptivity (Flynn, 2000) and at the mid-secretory phase and early pregnancy represent 70% of uterine leukocytes (Lee, 2011) Patients with RPL or RIF have shown changes in NK cell concentration compared to fertile patients (Fatemi, 2013; Mariee, 2012) Endometrial biopsies obtained from oocyte donors during natural and stimulated cycles, endometrial NK cells were significantly reduced following superovulation compared to the natural cycles (Junovich, 2011) Changes in NK cell number and subtype may impair implantation through their roles as regulators of implantation (Chaouat 2013)

Clinical results of freeze all strategy Conclusion(s): Our results suggest that there is evidence that IVF outcomes may be improved by performing FET compared with fresh embryo

26 Clinical results of freeze all strategy Conclusion(s): Our results suggest that there is evidence that IVF outcomes may be improved by performing FET compared with fresh embryo transfer. This could be explained by a better embryo-endometrium synchrony achieved with endometrium preparation cycles. (Fertil Steril 2013;99: American Society for Reprod Medicine)

27 Clinical results of freeze all strategy Ongoing pregnancy rate Clinical pregnancy rate Miscarriage rate Roque, Fertil Steril 2013

28 Clinical results of freeze all strategy

29 Clinical results of freeze all strategy Increased live birth rates Segmentation freeze all embryos vs fresh ET Segmentation Fresh P value Frozen ET ET Live birth 49,3% 42% 0,004

30 Clinical results of freeze all strategy

31 Clinical results of freeze all strategy

32 Clinical results of freeze all strategy: for good responders only?

33 Clinical results of freeze all strategy It would certainly be more reassuring to find that the cumulative live birth rates from one oocyte retrieval are equivalent (Evans et al., Hum Reprod Update 2014)? The answer: prospective randomized multicenter study to assess the CLBR per intention to treat? Is the freeze all a cost-effective strategy

Clinical experience at GENERA centers with cycle segmentation, elective single

patients older than 35 years, performed between Jan 2010 and Dec 2013 and

Pre-intervention group January 2010 December 2012 1609 opu Post-intervention group

34 Clinical experience at GENERA centers with cycle segmentation, elective single blastocyst transfer, PGS in AMA patients All consecutive oocytes retrievals in patients older than 35 years, performed between Jan 2010 and Dec 2013 and subsequent cryopreservation cycles were included. Pre-intervention group January 2010 December opu Post-intervention group January December opu No specific ET policy (mean n ET = 2,1) eset offered (mean n ET = 1,1) Embryo selection procedures

35 Same efficacy and improved efficiency (AMA patients) Freeze all Ubaldi et al., Hum Reprod, 2015

36 Freeze all strategy: CLBR case-controlled study

37 Is the freeze all a cost effective strategy?

38 Is the freeze all a cost effective strategy?

39 Take-home message 1 The evidence supporting efet, is growing, not only in terms of achieving higher pregnancy rates (in good responders) but, more importantly, also in terms of lower maternal and infant morbidity and mortality. Several indications suggest freeze all policy BUT Vitrification yields excellent clinical results, is a new technology and the-re is some evidence from mice to suggest that vitrification may affect methylation of the early embryo (Wang, 2010; Zhang, 2012) Additionally, retrospective studies showing an increased rate of large for gestational age babies after frozen embryo transfer cycles require further investigation (Wikland, 2010; Dungodan, 2010)

40 Take-home message 2 Additional RCTs in less selected populations are welcome and they will have to prove higher cumulative pregnancy rates or lower costs In the absence of such RCTs, the major pressures against efet remain the required upskilling of IVF units, patient preference, restrictive health-care funding models and government regulation It is likely that the implementation of efet will be gradual Freeze all for all patients? Freeze all for for many but not yet for all patients

the fertility drugs have faded away and their menstrual cycle were back to normal.

41 it was 1976 There is an alternative I said to Jean. We could try freezing human embryos, and keep them in store until the effects of the fertility drugs have faded away and their menstrual cycle were back to normal. The womb would then be receptive, and capable of sustaining the growth of the fetus Modified from Nick Macklon

42 Thank you for your attention Rome Silvia Colamaria Maddalena Giuliani Fabio Sapienza Alberto Vaiarelli Rossella Mazzilli Susanna Ferrero Francesco Timpano Mauro Schimberni Annalise Giallonardo Giovanna Vettraino Naples Fulvio Zullo Maurizio Muzzi Clinical staff Naples Elisabetta Trabucco Anna Sansone Roberta Venturella Pietro D Alessandro Fabio Perricone Gianfranco Merlino Marostica Antonio Ciconte Laura Buffo Antonio Gugole Cinzia Gentile Umbertide Antonio Angelini Emanuela Migliorati Fabrizio Fiorini Laboratory staff Rome Laura Rienzi Stefania Romano Roberta Maggiulli Laura Albricci Elena Ievoli Lisa Dovere Marta Stoppa Giovanna Orlando Catello Scarica Daria Soscia Marostica Benedetta Iussig Ludovica Dusi Sara Bertelle Umbertide Nicoletta Barnocchi Letizia Papini Naples Erminia Alviggi Roberta Vallefuoco Federica Sanges Ramona Carmelo Simona Alfano Cytogenetic Antonio capalbo Danilo Cimadomo Emiliano Scepi Adriano Giancani Grazie per la vostra attenzione

Disclosure. Filippo Maria Ubaldi GENERA Centers For Reproductive Medicine Rome, Italy

Disclosure. Filippo Maria Ubaldi GENERA Centers For Reproductive Medicine Rome, Italy Disclosure Filippo Maria Ubaldi GENERA Centers For Reproductive Medicine Rome, Italy Declared receipt of grants from Fertility Innovation (Merck), Forward 2016 (Finox), Investigator Sponsored Trial (IST)