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

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2 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) (Merck) and receipt of honoraria or consultation fees from Merck, MSD, EXCEMED, Ferring, Cook, Origio. Partnership/Board membership of Genera Health Care Srl, Genera Brand Srl, Genera Veneto Srl, Genera Umbria Srl, Flam Srl.

3 Improving Success in ART: How to define it and key strategies to get the best outcomes Kiev, Ukraine, 21 September 2018 What is success in ART? (Lab and clinical outcomes for defining success in ART) Filippo Maria Ubaldi M.D., Ph.D. GENERA, Centers for Reproductive Medicine, Italy

4 Objectives Discuss the clinical outcomes to measure success in IVF Explain the idea of cumulative live birth rate (CLBR) and time to pregnancy (TTP) as a measure of success Discuss the safety outcomes: multiple pregnancy and severe ovarian hyperstimulation syndrome (OHSS) Discuss the laboratory outcomes to measure success in IVF

5 Introduction IVF is a financially and emotionally burdensome treatment which, for the majority of patients, will end in failure Most subfertile patients seek information about their condition online (Haagen, 2003; Rawal and Haddad, 2006; Talarczyk, 2012) Direct to consumer advertising of ART is ubiquitous (Huang, 2005; Abusief, 2007; Wilkinson, 2017) Clinics compete for patients reporting success rates in a manner that presents their performance as superior

6 What should be the indicators of success in IVF? The situation is particularly troubling, as the multistage nature of IVF introduces an extensive menu of: numerators: - live birth - clinical pregnancy? - biochemical pregnancy denominators: - started cycle - transfer procedure - individual embryo transferred (Heijnen, et al., 2004; Wilkinson, et al., 2016, 2017)

7 Aim of IVF Only one numerator can be considered: Live birth (of an healthy child)

8 but what denominator to use? SART (US ART Registry) now present the outcome as cumulative live birth per intended egg retrieval at the top of the performance report for each of their member clinics on their Find a Clinic facility (Society for Assisted Reproductive Technology, 2016)

9 Cumulative delivery rate per oocyte retrieval The emphasis on this cumulative numerator reduces the incentive to transfer multiple embryos in the initial fresh transfer, because it ensures that this practice is not rewarded over the safer, and poten-tially more successful (Roberts, et al., 2011), option of transferring one embryo at a time in a series of transfer procedures It is mandatory: Try to maximize the number of oocyte retrieved (the best COH strategy, the best drug) Very good embryo colture system (possibly to blastocyst) Try to select the embryo with the highest implantation potential Very good cryopreservation program (possibly vitrification)

10 What denominator to use? HFEA (UK ART Registry) present the outcome as live birth event per embryo transferred This counts birth events arising from each transfer procedure in the numerator, but increases the denominator by one for each individual embryo transferred to a patient (Abdalla, et al., 2010) Consequently, there is a penalty for multiple embryo transfer. If twins result from a double embryo transfer, live birth event per embryo transferred is 1 2 = 0.5. Patients who do not undergo a transfer procedure are excluded from the calculation A major motivation is to protect patients from unsafe treatments

11 Clear information about safe procedures These measures encourage safe practices and provide clear, relevant information to couples so that a prospective patient can decide whether and where to undergo treatment prior to the start of ovarian stimulation The availability of independently validated clinic-level success rates is a potentially powerful resource for patients, who must rely upon clinics own advertising, which may be prone to reporting biases (Wilkinson, et al., 2017)

12 Key confounders and impact on the correct information Success rates should be presented statistically adjusted for key confounders, or presenting headline results stratified according to relevant prognostic variables. With small sample sizes within strata, results should be presented over longer periods of time to reduce the impact of random noise (Chetkowski, 2014) The information is then correct, relevant and easy to understand and prospective patients will make a truly informed choice

13 Multiple pregnancy rate as an indicator of success One motivation behind live birth per embryo transferred and cumulative live birth per egg collection is to promote patient safety by disincentivising multiple embryo transfer Multiple pregnancy: one of the most important complication USA EU ITALY GENERA IVF children 75,0 % single 23,5 % twin 1,5 % triple 80,2 % single 19,2 % twin 0,6 % triple 79,3 % single 19,5 % twin 1,2 % triple 98,8% single 1,2% twin Transferred SET 20 % SET 27,5 % SET 25,8 % SET 96,8 % embryos DET 58,6 % DET 56,7 % DET 46,6 % DET 3,2 % 3 21,4 % 3 15,8 % 3 27,6 % > 3 0% CDC 2013 ESHRE 2011 ISS 2014 GENERA 2016

14 Multiple pregnancy: main cause of adverse perinatal outcome - 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 - Increased costs for the families and for the NHS 3 1. ASRM Practice Committee, Fertil Steril, Pinborg A, et al., Acta Obstet Gynecol Scand, 2005, Van Heesch M, et al., Hum Reprod, 2015.

15 Multiple pregnancy: significantly higher costs in the first 5 years Also, not only costs but also health outcomes of IVF/ICSI multiples and singletons should be considered in decisions regarding ET strategies as costs alone cannot be the sole reason for reducing the number of multiple births by single-embryo transfer. Multiples compared with singletons: risk of hospitalization (OR 4.9, 95% CI ) outpatient visits (OR 2.6, 95% CI ) medical procedures (OR 1.7, 95% CI ) hospital costs from birth to age 5 were 3.3-fold higher for multiples vs singletons (P= 0.001). Resource use and costs outside the hospital were not included

16 Single embryo transfer policy at GENERA: same CLBR, reduced multiple pregnancy rate 20,8% 29,4% 21,0% Change ET policy From 2013, elective SET was offered in the AMA population (>37 y) according to the following inclusion criteria: - <2 previous implantation failures - Presence of good quality blastocysts or tested euploid blastocysts CLBR per OPU miscarriage rate per clinical pregnancy multiple pregnancy rate per delivery 22,5% 20,5% 18,9%* 20,4% 6,8%* 1,9%* * P<0,01 pre-2013 (9% PGT-A) 2013 (32% PGT-A) 2014 (48% PGT-A)

17 PGT-A to reduce multiple pregnancy rate 80% 60% 40% Delivery Rate Per Patient Single euploid blastocyst transfer (N=89) Untested 2-blastocyst transfer (N=86) 61% 65% Multiple Pregnancy Rate Per Patient 100% Singletons Multiples P< % 48% 20% 0% Forman EJ et al. Fertil Steril % Single euploid blastocyst transfer Untested 2-blastocyst transfer

18 Birthweight (Grams) Better obstetrical outcomes are obtained after PGT-A/eSET than untested conventional 2 ET Mean birthweight: 3408 ± 562g Single euploid 2745 ± 743g 2-Blastocyst (P<0.001) Birthweight (<2,500g): 4.4% (2/45) Single Euploid 31.9% (22/69) 2-Blastocyst (P<0.001) Single euploid blastocyst transfer Grams Untested 2- blastocyst transfer Grams Very low birthweight (<1,500g): 0% (0/45) Single Euploid 7.2% (5/69) 2-Blastocyst (P=0.06) Forman EJ et al. Fertil Steril 2013

19 Elective single ET improves perinatal outcome

20 Cumulative live birth rate one of the most appropriate measure of success in ART Support the concept of the elective single ET Support to maximize the # of oocyte to retrieve

21 The more oocyte retrieved, the higher is the CLBR Retrospective population-based registry study including women undergoing fresh IVF cycles ( ) and FRET ( ) Increasing the number of the oocytes it increases live birth rate with frozen cycles Increasing the number of the oocytes it increases the risk of OHSS

22 Optimize the number of oocyte to retrieve to maximize the cumulative live birth rate but how to reduce the risk of OHSS in hyper responder patients? normal Modified from La Marca and Sunkara, Hum Reprod Update 2014 Main Objective: safety of the patient GnRH-antagonist protocol Low starting dose r-fsh GnRH-agonist trigger

23 GnRH antagonist for ART: OHSS risk (Al-Inani, Cochrane 2016) GnRH antagonist protocol: strategy to almost delete OHSS risk with GnRH agonist trigger

24 GnRH antagonist cycle and GnRH agonist trigger to almost eliminate the risk of OHSS

25 GnRH agonist vs HCG for oocyte maturation triggering: OHSS incidence GnRH agonist was associated with lower risk of OHSS than was seen with HCG (OR 0.15, 95% CI 0.05 to 0.47; eight RCTs, 989 women, I² = 42%) Youssef et al., Cochrane 2014

26 Time to pregnancy (TTP) as a measure of success Time to healthy singleton delivery is an important consideration when making treatment decisions for ART and should be included as an aspect of the decision making process for women of all ages Considerations of time are of particular importance for women aged >35 years, due to the decline in fertility observed with age and for women with reduced ovarian reserve

27 Time to pregnancy as a measure of success Discontinuation of IVF is relatively common, since 25 50% of couples discontinue treatment as early as the first or second failed IVF cycle (Troude et al, 2014) ECPR = expected CPR RCPR = real CPR (Schroder et al. 2004)

28 Time to pregnancy as a measure of success This high discontinuation rate highlights the need to maximize the live birth rate for each treatment cycle and to have the baby as fast as possible (Bosch, Delphi paper, 2017 submitted) Maximize the number of oocytes and consider fresh+frozen embryo transfer (cumulative live birth rate) Optimize the lab technologies good cryopreservation programme blastocyst colture select the blastocyst with the highest implantation potential

29 Blastocyst transfer reduces time to pregnancy Blastocyst transfer enhances embryo selection RCT Pregnancy outcome per randomized patient Cochrane review of 12 RCTs D3 group (n = 84) D5 group (n = 80) Odds ratio (95% CI) P 29,4% 36,0% Pregnancy rate (positive HCG) 41.7% (35) 66.3% (53) 2.67 ( ) Clinical pregnancy rate 32.1% (27) 52.5% (42) 2.33 ( ) Implantation rate 20.6% (35/170) 37.3% (59/158) 2.29 ( ) <0.001 Ongoing pregnancy rate 27.4% (23) 51.3% (41) 2.78 ( ) Live birth rate 27.4% (23) 47.5% (38) 2.40 ( ) 0.01 Live birth rate/et Adapted from Papanicolau, et al. Hum Reprod, 2005 Adapted from Glujovsky, et al. Cochrane Review, 2012

30 Blastocyst transfer reduces time to pregnancy Blastocyst transfer enhances embryo selection and the vast majority of arrested embryos are aneuploid 97.8%

31 Blastocyst transfer reduces time to pregnancy Reduced time-to-pregnancy The number of embryo transfers necessary until the first live birth was significantly lower for blastocyst-stage embryos (P < 0.001) The cumulative live birth rates were 52.6% for cleavage-stage and 52.5% for blastocyst-stage transfers (P = 0.989) Same CLB rates, reduced TTP

32 PGT-A reduces time to pregnancy in AMA and POR ASRM October 2017

33 Laboratory Performance Indicators in IVF LPI are quality indicators necessary for monitoring the Lab Quality

34 Laboratory Performance Indicators in IVF Amongst the LPI, the Key Performance Indicators are the most important

35 What is success in IVF Which are the key points that distinguish a highly successful IVF Clinic from an average IVF Clinic? 1. Results presented as CLBR (primary outcome) 2. Very good quality lab: Key Performance Indicators within the benchmark values 3. Clinical application of scientific evidence 4. Attention to patients safety (MPR, sohss rate) 5. Attention to patients emotional status 6. Organization everything else

36 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 Fabio Perricone Clinical staff Naples Elisabetta Trabucco Anna Sansone Roberta Venturella Pietro D Alessandro Gianfranco Merlino Marostica Antonio Ciconte Laura Buffo Antonio Gugole Cinzia Gentile Umbertide Antonio Angelini Emanuela Migliorati Fabrizio Fiorini Rome Laura Rienzi Stefania Romano Roberta Maggiulli Laura Albricci Elena Ievoli Lisa Dovere Marta Stoppa Laboratory staff Giovanna Orlando Federica Sanges Daria Soscia Danilo Cimadomo Emiliano Scepi Luisa Tacconi Veronica Morgante Umbertide Nicoletta Barnocchi Letizia Papini Naples Erminia Alviggi Roberta Vallefuoco Antonietta Della Ragione Ramona Carmelo Simona Alfano Marostica Benedetta Iussig Ludovica Dusi Sara Bertelle Grazie per la vostra attenzione

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