L2. Optimising IVF outcomes through increased number of oocytes... 03

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1 SCIENTIFIC HIGHLIGHTS EXCEMED Blended Education Ovarian stimulation strategies: maximizing efficiency in ART Rio de Janeiro, Brazil 6-7 April 2018

2 Preface Success rates following IVF treatment have increased significantly since the technique was originally developed, largely as a result of the introduction and use of ovarian stimulation. Controlled ovarian stimulation (COS) now plays a major role in optimising IVF outcomes by facilitating control of different events and increasing the number of oocytes available. COS aims to achieve maximal success with minimal side effects. Progress in and understanding of ovarian physiology, as well as new advances in ovarian stimulation strategies have made it possible for healthcare professionals to achieve the optimal outcomes for patients. The EXCEMED blended education approach employs a multi-format, multi-discipline and multi-profession approach to progressive learning and access to a network of experts, aiming to enhance clinical practice by exploring the ideal outcomes following ART desired by patients, embryologists, and clinicians. The programme is aimed to enable participants to: Understand how success in ART is defined by laboratory and clinical outcomes Describe the different COS strategies available to optimise oocytes Tailor the best protocol for patients undergoing ART by selecting the most appropriate treatment for individual patients

3 Contents L1. How should we measure success in ART? L2. Optimising IVF outcomes through increased number of oocytes L3. Choosing the most appropriate gonadotropin for your patients: Exploring the pros and cons of recombinant vs urinary FSH, and the role of LH.. 04 L4. Ovarian response groups: Suboptimal response and the POSEIDON concept L5. Is there a place for mild stimulation and modified natural cycle in icos? L6. New challenges in COS: What are the best options for luteal phase support in fresh cycles? L7. Frozen embryo strategies: Are we ready for a freeze all approach? L8. Choices in endometrial preparation for frozen embryo transfer cycles: Natural cycle or hormone replacement therapy? C1. Interactive case study session C2. Interactive case studies session EXCEMED SCIENTIFIC HIGHLIGHTS: OVARIAN STIMULATION STRATEGIES: MAXIMIZING EFFICIENCY IN ART 1

4 L1. How should we measure success in ART? Sandro C. Esteves ANDROFERT - Andrology & Human Reproduction Clinic and University of Campinas (UNICAMP) Campinas, Brazil In the opening presentation of this meeting, Sandro C. Esteves looked at how we define measures of success in IVF today. As well as preclinical measures, Dr Esteves reviewed clinical outcomes, and introduced the POSEIDON marker of success in ART as an outcome. Poor quality of service, physical burden, and lack of psychological support account for the almost 60% dropout rate among patients who discontinue after one failed ART treatment. 1 Even in countries where the programme of treatment is fully reimbursed, many couples do not complete all their treatment cycles. Dr Esteves suggested that success in ART goes far beyond a single parameter such as pregnancy rate, and told the delegates that measures of effectiveness, safety, and patientcenteredness are key elements in a quality-driven infertility care programme. Reducing the burden of treatment and maximising the outcome of the first complete ART cycle are important goals. Patient age is an important factor in measures such as the predicted Cumulative Live Birth Rate (CLBR), an estimation of the chance of delivery in relation to the number of oocytes/embryos obtained and prognostic factors such as female age, 2 and the Time-to-Pregnancy (TTP), defined as the time taken to establish a pregnancy, measured in months or in numbers of menstrual cycles. 3 Dr Esteves also explored new data on the relationship between age and euploidy, showing how the decrease in probability of a blastocyst being euploid increases progressively with every year of female age [Figure 1]. 4 Within the POSEIDON concept, 5 Dr Esteves reviewed new developments which have led to the introduction of an intermediate marker of success in ART: the ability to retrieve a certain number of oocytes needed to obtain at least one euploid blastocyst for transfer in each patient. He showed how the transfer of euploid embryos maximises IVF efficiency by offsetting the negative effect of age on implantation and pregnancy. He urged clinicians to adopt the new Poseidon criteria because they propose a unique and more detailed stratification of low responders to ovarian stimulation, a significant proportion of patients seen in daily practice. 1. Gameiro et al. Hum Reprod Update 2012;18: McLernon et al. BMJ 2016;355:i Smith et al. JAMA. 2015;314: Humaidan et al. ESHRE 2018; submitted. 5. Alviggi et al. Fertil Steril. 2016;105: Figure 1: DECREASES IN EUPLOIDY INCREASE WITH PATIENT AGE 4 2 SCIENTIFIC HIGHLIGHTS: OVARIAN STIMULATION STRATEGIES: MAXIMIZING EFFICIENCY IN ART EXCEMED

5 L2. Optimising IVF outcomes through increased number of oocytes Fernando Neuspiller General IVI Buenos Aires IVI Buenos Aires Buenos Aires, Argentina The relationship between the number of oocytes collected and outcomes in IVF was explored in this presentation by Dr. Fernando Neuspiller. He reminded the audience that clinicians had to strike a balance between efficacy and safety with, on one hand, a low number of oocytes leading to low birth rate, and on the other a high number of oocytes and the corresponding risk of ovarian hyperstimulation syndrome (OHSS). 1 He explained the concept of oocyte productivity using the oocyte to baby rate, where live babies born (LBB) are considered in the context of the number of oocytes retrieved and used. In 572 cycles analysed, the utilisation rate (the total number of transferred and frozen embryos as a proportion of the total number of oocytes collected) was only 31%, and only 7% leading to a live birth. 2 An increased number of oocytes retrieved correlated with the live birth rate (LBR) in an analysis of data from UK IVF cycles, 3 suggesting that number of eggs retrieved is a surrogate outcome for clinical success. There was a non-linear relationship between the number of eggs and LBR following IVF treatment [Figure 2], with 15 eggs needed for maximal LBR. New methods of oocyte viability assessment may be needed, and several groups have been looking at preclinical outcomes, namely the relationship between number of oocytes and fertilisation rates, as well as clinical outcomes evidenced by the relationship between number of oocytes and functional competence. 3 In particular, Dr. Neuspiller reviewed recent work showing that higher ovarian response rates are related to a higher number of euploid embryos [Figure 3] 4 and, further, that oocytes from women with polycystic ovary syndrome contain molecular abnormalities. 5 Dr. Neuspiller went on to look at the POSEIDON 6 criteria and how they could be interpreted to improve oocyte numbers. He reviewed data from studies in hypo-responders and low responder POSEIDON groups which aimed to maximise egg numbers, concluding that while conventional stimulation is safe and effective, the production of higher number of oocytes can increase perinatal risk in fresh embryo transfer cycles. 1. Magnusson et al. Hum Reprod. 2018;33: Patrizio P, Sakkas D. Fertil Steril. 2009;91: Sunkara SK, et al. Hum Reprod. 2011;26: Labarta E, et al. Biomed Res Int. 2017;2017: Wood JR, et al. J Clin Endocrinol Metab. 2007;92: Alviggi et al. Fertil Steril. 2016;105: Figure 3: RATES OF ANEUPLOIDY INCREASE WITH INCREASED NUMBER OF OOCYTES 4 Number of euploid embryos oocytes oocytes oocytes > 23 oocytes Ovarian response Figure 2: LIVE BIRTH RATES INCREASE WITH LARGER NUMBER OF OOCYTES RETRIEVED 3 EXCEMED SCIENTIFIC HIGHLIGHTS: OVARIAN STIMULATION STRATEGIES: MAXIMIZING EFFICIENCY IN ART 3

6 L3. Choosing the most appropriate gonadotropin for your patients: Exploring the pros and cons of recombinant vs urinary FSH, and the role of LH Carlo Alviggi Federico II University of Naples Naples, Italy Recombinant gonadotropin preparations are more potent and result in an increased oocyte yield was the message from this presentation by Dr Carlo Alviggi. However, the lack of adequately sized studies in women with relative Figure 4: THE EVOLUTION OF GONADOTROPIN PREPARATIONS AND IMPROVEMENTS IN EFFICACY Figure 5: EFFICACY OF R-HFSH + R-HLH VERSUS RFSH ALONE IN THE PERSONALIZED MEDICINE ERA: A META-ANALYSIS 6 LH deficiency and the use of probably inadequate endpoints, render the use of LH controversial. Reviewing strategies aimed at optimizing ovarian response while reducing the risk of OHSS, Dr Alviggi first looked at the improvements in preparations of gonadotropins used in fertility treatment since the early part of the last century [Figure 4], with increases in purity and specific activity reflecting better safety, quality, consistency and patient convenience. Recent studies and meta-analysis comparing oocyte yield with different gonadotropins have demonstrated that the number of oocytes retrieved is increased in protocols using recombinant follicle stimulating hormone (rfsh) compared with either human menopausal gonadotropin (hmg), highly purified human menopausal gonadotropin (HP-hMG), or urinary FSH (ufsh). Studies have compared the different gonadotropins available. In the MEGASET trial, 1 pregnancy rates following COS with HP-hMG in a GnRH antagonist cycle were at least similar to that achieved with rfsh. Although rfsh yielded more oocytes than HP-hMG, there were more interventions in the rfsh group due to excessive responses. GnRH antagonists were found to be safer than agonists in a metaanalysis comparing the two classes of agents. 2 While there were no differences in LBR or ongoing pregnancy rate, there was a significantly lower incidence of OHSS in the GnRH antagonist group. Luteinising hormone (LH) has an important role in both follicular recruitment (oocyte quantity) and in oocyte quality. 3 Studies suggest that COS induces a status of relative LH deficiency, leaving it unclear whether residual LH levels are enough to support progesterone levels during IVF treatment. 4 Indeed, a recent study has found evidence that the addition of LH to the FSH protocol may be associated with a lower rate of total pregnancy outcome failure. 5 Other factors involved in this interplay of hormones include the presence of a common polymorphism of the LHbeta subunit, which is associated with hypo-sensitivity to FSH, and the age of the follicles, which affects their response to LH. Dr Alviggi ended this presentation by showing data from a recent meta-analysis [Figure 5] 6 which suggested that differences in outcomes in ART may be a result of the type of gonadotropin combination used for COS. Difficulties in interpreting these data make drawing conclusions difficult, and these topics are explored further in the next lecture. 1. Nyboe-Andersen A, et al. ESHRE, Hum Reprod 2011;suppl Al-Inany, HG, et al. Hum Reprod Update. 2011;17: Jeppesen JV, et al. J Clin Endocrinol Metab 2012;97:E Hugues JN, et al. Fertil Steril 2011;96: Humaidan P, et al. Hum Reprod 2017;25: Santi D, et al. Front Endocrinol. 2017;8: SCIENTIFIC HIGHLIGHTS: OVARIAN STIMULATION STRATEGIES: MAXIMIZING EFFICIENCY IN ART EXCEMED

7 L4. Ovarian response groups: Suboptimal response and the POSEIDON concept In his second presentation, Dr Alviggi took the delegates through the POSEIDON groups, and explained how better stratification of low prognosis women using these criteria may help to identify subgroups of patients who will benefit from specific treatments. Until recently, patients with poor ovarian response (POR) to stimulation were managed according to the Bologna criteria, 1 but this did not take into account different sensitivity to FSH and LH, or age-related decline in aneuploides. POSEIDON offers a more detailed stratification of POR patients [Figure 6]. 2 Poor response due to genetic polymorphisms in the FSH receptor and the LH-beta subunit may be overcome by using higher doses of FSH, and supplementation with LH in these patients. Dr Alviggi explained how the POSEIDON grouping could help identify patients who would benefit from these interventions. Presenting the latest data from the icos-lh initiative, 3 he concluded that in Group 1-2 women with a normal ovarian reserve, who displayed initial low FORT during COS or required Carlo Alviggi Federico II University of Naples Naples, Italy elevated dosage of r-hfsh (>2,500 IU) to achieve an adequate number of oocytes, LH supplementation increased both implantation rate and FORT. However, in older women the benefits on implantation disappear. He compared these findings with those for patients in POSEIDON Groups 3 and 4, where oocyte/blastocyst accumulation is an option. Results from an important study investigating the use of a double-stimulation approach within a single menstrual cycle (DuoStim) in these patients, showed that stimulation in the luteal phase (LP) made a significant contribution to pregnancy rates [Table 1], confirming it as a valid option for women with low ovarian reserve Ferraretti AP, et al. Hum Reprod. 2011;26: Alviggi C, et al. Fertil Steril. 2016;105: Alviggi C, et al. Fertil Steril. 2018;109: Ubaldi et al. Fertil Steril. 2016;105: Table 1: LP STIMULATION HAS A SIGNIFICANT IMPACT ON THE PREGNANCY RATE ON A PER MENSTRUAL CYCLE BASIS 4 Outcome Stimulation phase Follicular Luteal Total No. of single embryo transfers No. of clinical pregnancies (80.0) No. of miscarriages (16.7) No. of ongoing pregnancies (66.7) Figure 6: THE POSEIDON CLASSIFICATION FOR LOW PROGNOSIS WOMEN 2 GROUP 1 Young patients <35 years with adequate ovarian reserve parameters (AFC 5; AMH 1.2 ng/ml) and with an unexpected poor or suboptimal ovarian response Subgroup 1a: <4 oocytes* Subgroup 1b: 4-9 oocytes retrieved* *after standard ovarian stimulation GROUP 2 Older patients 35 years with adequate ovarian reserve parameters (AFC 5; AMH 1.2 ng/ml) and with an unexpected poor or suboptimal ovarian response Subgroup 2a: <4 oocytes* Subgroup 2b: 4-9 oocytes retrieved* *after standard ovarian stimulation GROUP 3 Young patients (<35 years) with poor ovarian reserve pre-stimulation parameters (AFC <5; AMH <1.2 ng/ml) GROUP 4 Older patients ( 35 years) with poor ovarian reserve pre-stimulation parameters (AFC <5; AMH <1.2 ng/ml) EXCEMED SCIENTIFIC HIGHLIGHTS: OVARIAN STIMULATION STRATEGIES: MAXIMIZING EFFICIENCY IN ART 5

8 L5. Is there a place for mild stimulation and modified natural cycle in icos? Matheus Roque ORIGEN Center for Reproductive Medicine Rio de Janeiro, Brazil In this lecture, Dr Roque asked what is mild stimulation, when should we use it, and is there a place for it in today s ART clinic? Mild approaches in assisted reproduction may have potential advantages over standard protocols: 1 Concerns about physical, and emotional burden of conventional stimulation Risks associated with OHSS and multiple pregnancies Concerns about chromosome abnormalities in oocytes and embryos with conventional stimulation Concerns about the effect of conventional stimulation on endometrial function Moves towards Elective Single Embryo Transfer (eset) Clinical availability of antagonists Advances in endocrinology Advanced in ultrasound technology Greater efficiency in embryological techniques and training The need to protect women s health and safety during ART Concern over the cost and complexity of conventional stimulation IVF for patients The need to make ART affordable and accessible to all Reviewing the relationship between ovarian stimulation and embryo quality, he first reminded participants about the terminology used by the International Society for Mild Approaches in Assisted Reproduction (ISMAAR) [Table 2]. 2 Although mild stimulation protocols result in fewer injections, fewer days of stimulation and less FSH administered compared with standard protocols, many more cycles of mild stimulation are initiated a 35% increase over standard treatment protocols. 3 Dr Roque noted that 25 54% of couples drop out of their ART programme before completing 3 cycles, with a high proportion reporting the high physical and emotional burden of treatment, and there is some evidence that mild stimulation protocols reduce patient discomfort, risks and costs, but not pregnancies. However, he cautioned against adopting mild-stimulation protocols because the number of oocytes retrieved affects LBR in fresh cycles. Further, the higher the oocyte yield the higher the probability of achieving a live birth after taking all cryopreserved embryos into account. 4 The One-and-Done approach 5 advocates that a single, complete IVF cycle with a high oocyte yield could satisfy the average couple's overall reproductive goal of two live births [Figure 7]. This has been achieved in around one-quarter of patients, although these are from the better-responding group. The use of a single stimulation cycle to produce a maximum number of frozen embryos is an important topic, and addressed in more detail later in the programme. 1. Nargund G. Facts Views Vis Obgyn. 2011;3: Nargund G, et al. Hum Reprod 2007;22: Heijnen E, et al. Lancet 2007;369: Drakopoulos et al. Hum Reprod 2016;31: Vaughan D, et al. Fertil Steril 2017;107: Figure 7: INCREASE IN BOTH THE INDEX AND CUMULATIVE LIVEBIRTH RATE WITH INCREASING NUMBER OF OOCYTES RETRIEVED 5 Live Birth Rate * * * * * * * * * * * * * * * * * * * * * * ** * * * * * Number of oocytes retrieved in index cycle The relationship of live-birth rate in the index cycle ( ) and the cumulative live-birth rate ( ) across all (fresh and frozen) cycles per oocyte retrieved. The superimposed smoothed lines * show the live-birth rate in the index cycle (solid line) and live-birth rate across all cycles (broken line) in relation to the number of oocytes retrieved. Table 2: ISMAAR NOMENCLATURE FOR THE DIFFERENT APPROACHES TO OVARIAN STIMULATION FOR IVF 2 Terminology Aim Methodology Natural cycle IVF Single oocyte No medication Modified natural cycle IVF Single oocyte hcg only GnRH antagonist and FSH/HMG addback Mild IVF 2 7 oocytes Low dose FSH/HMG, oral compounds and GnRH antagonist Conventional IVF 8 oocytes GnRH agonist or antagonist conventional FSH/HMG dose 6 SCIENTIFIC HIGHLIGHTS: OVARIAN STIMULATION STRATEGIES: MAXIMIZING EFFICIENCY IN ART EXCEMED

9 L6. New challenges in COS: What are the best options for luteal phase support in fresh cycles? Sandro C. Esteves ANDROFERT - Andrology & Human Reproduction Clinic and University of Campinas (UNICAMP) Campinas, Brazil In his second presentation of the meeting, Dr Sandro Esteves explained to delegates that LPS regimen should be individualised for each patient according to the trigger. Starting with the pathophysiology of luteal phase defect in stimulated cycles, Dr Esteves reviewed the role of the corpus luteum and the pulsatile secretion of progesterone during the menstrual cycle. The abnormal cycle that occurs in stimulated cycles [Figure 8] 1-4 means that luteal phase support (LPS) with progesterone, hcg or gonadotropin-releasing hormone (GnRH) agonists is needed to improve implantation and pregnancy rates. Progesterone should be used as LPS in all cycles. Progesterone and hcg LPS led to better live birth and ongoing pregnancy rates compared with placebo or no treatment, and LPS with progesterone + GnRH agonists led to improvement in pregnancy outcomes compared with the progesterone-only group. 5 Different routes of progesterone administration are equally effective, with vaginal preparations rating higher for patient satisfaction, with greater convenience and ease of use, and less pain. The main advantage of using a GnRH agonist-- trigger is the prevention of OHSS, but it is associated with LP deficiency and reduced pregnancy rates. 6 This can be overcome using an intensified luteal support. Concluding his presentation, Dr Esteves showed real-life data using best practice in his own clinic, and wrapped up with a summary of LPS protocols: hcg trigger: Progesterone alone is enough GnRh-a trigger: Progesterone plus hcg (either bolus or low-dose daily) Modified LPS in GnRHa trigger needs to be refined further hcg trigger and conventional LPS method of choice for eligible patients 1. Damewood et al. Fertil Steril; 1989;52: Gonen et al. J Endocrinol Metab 1990;71: Itskovitz et al.fertil Steril 1991;56: Bonduelle et al. Hum Reprod 1988;3: van der Linden et al., Cochrane Database Syst Rev 2015:CD Lu et al. Fertil Steril. 2016;106: Figure 8: THE ABNORMAL LUTEAL PHASE OF STIMULATED CYCLES 1 4 Progesterone concentrations Hyperstimulated cycle Normal cycle EXCEMED SCIENTIFIC HIGHLIGHTS: OVARIAN STIMULATION STRATEGIES: MAXIMIZING EFFICIENCY IN ART 7

10 L7. Frozen embryo strategies: Are we ready for a freeze all approach? Matheus Roque ORIGEN Center for Reproductive Medicine Rio de Janeiro, Brazil Freeze-all strategies are an important part of ART today, but they are not for everyone, concluded Dr Matheus Roque in his second visit to the lectern at this meeting. Cryopreservation of embryos can be used in patients who are hyper-responders, those at risk of OHSS, those undergoing preimplantation genetic testing (PGT), and also potentially for those with high progesterone levels or having a history of implantation failure. Dr Roque explained how ovarian stimulation can lead to changes in the endometrium. endometrium advancement, which could result in failure of implantation. However, by freezing and delaying the transfer of an embryo to a later cycle and allowing better embryo-endometrium synchrony, better outcomes could be achieved. For those patients at risk of OHSS, he showed how a freeze-all strategy could be used as a secondary preventative measure. In a meta-analysis, frozen embryo transfer (FET) significantly increased both the ongoing pregnancy rate compared with fresh transfer (Risk Ratio [RR] 1.32) and the rate of clinical pregnancies, (RR 1.31; Figure 9). 1 However, a recent Cochrane review suggested that there was no difference between fresh and frozen cycles in cumulative and overall live birth rates. 2 Looking at the strategy from the perspective of response to COS, recent data from Dr Roque s clinic suggest that while women who are normal responders (10 15 oocytes) can benefit from a freeze-all strategy, sub-optimal responders (4 9 oocytes don t benefit from this strategy. In women with polycystic ovary syndrome (PCOS), FET led to increased rate of live birth, a lower risk of OHSS and miscarriage, but a higher risk of pre-eclampsia. 3 In cycles where elevated progesterone is an issue, FET also leads to higher implantation and ongoing pregnancy rates compared with fresh cycles. 4 Finally, a recent cumulative meta-analysis has confirmed that while FET has reduced risks for small for gestational age, low birth weight and preterm delivery, it has increased risks of large for gestational age and high birth weight, concluding that it should not be used in all cases Roque et al. Fertil Steril 2013; 99: Wong et al. Cochrane Database Syst Rev 3, CD Chen et al. NEJM 2016; 375: Wang et al. Fertil Steril 2017;108: Maheshwari et al. Hum Reprod Update 2018; 24: Figure 9: META-ANALYSIS OF STUDIES INVESTIGATING OUTCOMES WITH FET COMPARED WITH FRESH CYCLES. A: ONGOING PREGNANCY RATE; B: RATES OF CLINICAL PREGNANCIES. 1 A Frozen-Thawed Fresh Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Fixed, 95% CI M-H, Fixed, 95% CI Aflatoonian % 1.40 [1.05, 1.88] Shapiro Normal % 1.38 [0.97, 1.98] Shapiro High % 1.15 [0.86, 1.55] Total (95% CI) % 1.32 [1.10, 1.59] Total events Heterogeneity: Chi df 2 (P 0.60): I 2 0% Test for overall effect: Z = 3.00 (P = 0.003) B Favours Fresh Favours Frozen-Thaw Frozen-Thawed Fresh Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Fixed, 95% CI M-H, Fixed, 95% CI Aflatoonian % 1.34 [1.02, 1.77] Shapiro Normal % 1.39 [0.99, 1.94] Shapiro High % 1.19 [0.88, 1.59] Total (95% CI) % 1.31 [1.10, 1.56] Total events Heterogeneity: Chi df 2 (P 0.74): I 2 0% Test for overall effect: Z = 3.04 (P = 0.002) Favours Fresh Favours Frozen-Thaw 8 SCIENTIFIC HIGHLIGHTS: OVARIAN STIMULATION STRATEGIES: MAXIMIZING EFFICIENCY IN ART EXCEMED

11 L8. Choices in endometrial preparation for frozen embryo transfer cycles: Natural cycle or hormone replacement therapy? Fernando Neuspiller General IVI Buenos Aires IVI Buenos Aires Buenos Aires, Argentina The embryo and the endometrium are two pieces of the pregnancy puzzle, Dr Fernando Neuspiller explained to delegates. Preparation of the endometrium to receive the embryo is key to a successful outcome. Luteal phase support will depend on the applied endometrial preparation protocol used and Dr Neuspiller reviewed the available protocols, including Modified Natural Cycle (NC) FET, Artificial FET, Hormone Replacement Therapy (HRT) + GnRH agonist, and Ovarian Stimulation. There is no benefit in delaying transfer of frozen embryos after a failed attempt, as there is no impact on pregnancy rates. Dr Neuspiller went on to review the optimal timing for embryo transfer. Recent analysis of the literature suggests progesterone intake should be started on the theoretical day of oocyte retrieval in HRT and to perform blastocyst transfer at hcg + 7 or LH + 6 in modified or true NC, respectively [Figure 10]. 1 Optimising the procedure is an ongoing area of development; Endometrial Receptivity Array (ERA) analysis can reduce the number of failed FET cycles. By identifying the genes involved in endometrial development, and subsequently pinpointing the most receptive time for the endometrium to receive the embryo (the window of implantation (WOI)), personalised frozen embryo transfer significantly improves the pregnancy rate. Premature progesterone elevation is one of the factors involved in slow growing embryos, and when combined with an advanced endometrium the outcome may be a lower rate of live births Mackens S, et al. Hum Reprod. 2017;32: Healy MW, et al. Hum Reprod. 2017;32: Figure 10: EMBRYO TRANSFER TIMING DEPENDING ON THE CYCLE 1 Day 3 Day 4 Day 5 hcg trigger tor HRT E2 supplementation 1st day of P 2nd day of P 3st day of P 4st day of P 5st day of P 6st day of P P+0 P+1 P+2 P+3 P+4 P+5 modified NC (with hcg trigger) hcg trigger NC (with spontaneous LH surge) LH surge EXCEMED SCIENTIFIC HIGHLIGHTS: OVARIAN STIMULATION STRATEGIES: MAXIMIZING EFFICIENCY IN ART 9

12 C1. Interactive case study session Carlo Alviggi Federico II University of Naples Naples, Italy In this first of three case studies, Dr Alviggi presented the case of a couple, where the 31-year-old male partner was normozoospermic, and the 32-year-old female partner had tubal factor infertility. She received standard GnRH-a long protocol with a daily administration of 0.1 mg of triptorelin from day 21 of the cycle, and r-hfsh (starting dose of 150 IU). Dr Alviggi took the meeting participants through the couple s journey, explaining the options at various points, and why the choices were made. Twelve oocytes were retrieved, 6 of which were subject to IVF, leading to four embryos, 2 Grade 1 embryos were implanted, resulting in 1 gestational sac. The second case involved a 36-year-old normozoospermic male and a 31-year-old female with tubal factor infertility. Treatment began in the same way as the first case, but at Day 5, (S 1), her E2 was 15.3 pg/ml, and LH was 1.4 miu/ml. Consequently, the daily dose of r-hfsh was increased to 225 IU for the rest of the cycle. Nine oocytes were retrieved, 6 underwent IVF, leading to 4 with 2 implanted, but no gestational sacs were obtained. In both cases, the hypo-response profile could be explained by a genetic polymorphism, leading to the need to increase FSH. Differences in slow response compared with hypo-response and how to manage them are shown in Table 3. Table 3: DIFFERENCES BETWEEN SLOW AND HYPO-RESPONSE Hypo-response Poor response Etiologic factors LH over-inhibition Decrease in ovarian reserve LHR, LH, FSHR polymorphism Ovarian reserve (AFC, AMH) Normal Decreased Relationship with age Not obviously related The incidence rate increases with the increase of age Previous history of ovarian Not obvious related High risk factors injuries Therapeutic measures Add LH activity drug Comprehensive management regimen Number of oocytes retrieved Normal 3 10 SCIENTIFIC HIGHLIGHTS: OVARIAN STIMULATION STRATEGIES: MAXIMIZING EFFICIENCY IN ART EXCEMED

13 C2. Interactive case study session Matheus Roque ORIGEN Center for Reproductive Medicine Rio de Janeiro, Brazil Fernando Neuspiller General IVI Buenos Aires IVI Buenos Aires Buenos Aires, Argentina In this session, an interactive case was jointly presented by Dr Matheus Roque (Brazil) and Dr Fernando Neuspiller (Argentina), and explored options for a couple where COS appeared to have no effect on oocyte/embryo euploidy. A 35-year-old male partner and his 33-year-old female partner had a history sub-fertility for 4 years and of miscarriage after a spontaneous pregnancy. Endoscopic examination revealed she had endometriosis and PCOS. In the first IVF cycle, a freeze-all strategy was used and 20 embryos were obtained after stimulation with an antagonist protocol + ufsh + GnRH agonist trigger. None of the subsequent FET resulted in a pregnancy. In a second cycle, the antagonist protocol + rfsh (150IU/day) + GnRH agonist trigger led to 12 follicles > 14 mm and an endometrium 8.7 mm. Hormones were measured at P4=1.6 ng/dl; E2: 1950 pg/ml on the trigger day. Although 2 embryos were retrieved and frozen, none resulted in a pregnancy. The couple underwent a third cycle of IVF at a different centre. Mild stimulation with r-fsh 100 IU/day and a freeze-all strategy led to 9 retrieved oocytes and 2 FETs, but both were negative. Finally, a fourth cycle was undertaken and the participants were asked to choose how they would manage this couple. A scenario using priming with norithesterone 10mg/day for 10 days; rfsh+rlh led to a single embryo transfer and a pregnancy. Concluding that freeze-all is not for everyone, the case illustrates that details can make all the difference and the IVF lab managing the patient is of fundamental importance. EXCEMED SCIENTIFIC HIGHLIGHTS: OVARIAN STIMULATION STRATEGIES: MAXIMIZING EFFICIENCY IN ART 11

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