Timing of conception: no limits?1-2 November 2013 - Bucharest, Romania

FINAL PROGRAMME AND ABSTRACT BOOK

General information

VenueThis live educational course takes place at the:

Hotel Howard Johnson - Grand Plaza Bucharest 5-7 Calea Dorobantilor, District 1010551 Bucharest, Romaniawww.hojoplaza.ro

LanguageThe official language of this live educational course is English.

Scientific secretariatSerono Symposia International FoundationSalita di San Nicola da Tolentino, 1/b00187 Rome, Italy

Junior Project Manager: Francesca CucciollaTel.: +39 (0)6 420 413 315Fax: +39 (0)6 420 413 677E-mail: info@seronosymposia.org

Specialist Medical Advisor: Irene ZerbettoSpecialist Medical Advisor: Angelo Marino

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Organising secretariatMeridiano Congress InternationalVia Sapri, 6 - 00185 Rome, ItalyCongress Coordinator: Federica RussettiT +39 (0)6 88 595 209 - F +39 (0)6 88595 234E-mail: f.russetti@meridiano.it

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Timing of conception: no limits?

Serono Symposia International Foundation live educational course on:

Timing of conception: no limits?1-2 November 2013 - Bucharest, Romania

Aim of the live educational courseAge is the most important single variable influencing outcome in assisted reproduction. The effect of advancing age on clinicalinfertility is manifested not only in the pattern of ovarian response to controlled ovarian stimulation (COS), but also in reducedimplantation efficiency and an increased spontaneous abortion rate. One of the prevailing theories to explain this phenomenon hasbeen that women are enter the workforce more frequently, and consequently they are delaying marriage and childbearing. Thefunctional capacity of the remaining follicles and germ cells has been termed the "ovarian reserve", or ovarian age. The functionalovarian age may be discordant with chronologic age, when accelerated follicular loss and/or diminished functional capacity of theremaining follicles occurs at an earlier age than expected. What can be done to increase the chances of conception in women whowant to achieve a pregnancy in advanced age? This live educational course is dedicated to providing new insight into these topics,through an interactive programme where each lecture is followed by specific cases studies and working groups in order to provideparticipants with both up-to-date knowledge.

Learning objectivesBy attending this live educational course the learners will be able to:• Identify current evidence-based recommendation to achieve the best management in advanced maternal age• Identify the best approach to recognize the ovarian reserve• Tailor the best protocol for advanced-aged patients undergoing ART

Target audienceThis live educational course is designed for clinicians and biologist working in assisted reproductive medicine, who want to acquireup-to-date information for improving their current practice.

AccreditationSerono Symposia International Foundation (www.seronosymposia.org) is accredited by the European Accreditation Council forContinuing Medical Education (EACCME®) to provide the following CME activity for medical specialists. The EACCME® is aninstitution of the European Union of Medical Specialists (UEMS), www.uems.net

The CME course on: “Timing of conception: no limits?” held on 1-2 November 2013 in Bucharest, Romania, is designated for amaximum of 8 (eight) hours of European CME credits (ECMEC). Each medical specialist should claim only those credits that he/sheactually spent in the educational activity. EACCME® credits are recognized by the American Medical Association (AMA) towards thePhysician's Recognition Award (PRA). To convert EACCME® credit to AMA PRA category 1 credit, please contact the AMA.

Serono Symposia International Foundation (SSIF) adheres to the principles of the Good CME Practice Group (gCMEp)

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Scientific organiserRobert FischerFertility Center HamburgHamburg, Germany

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All Serono Symposia International Foundation programmes are organized solely to promote the exchange and dissemination of scientific and medical information. Noforms of promotional activities are permitted. This programme is made possible thanks to an educational grant received from Merck Romania S.r.l..

List of faculty membersCarlo AlviggiFederico II UniversityNaples, Italy

Robert FischerFertility Center HamburgHamburg, Germany

Antonio La MarcaMother-Infant Department University Hospital of ModenaModena, Italy

Sesh Kamal SunkaraGuy's and St Thomas' Foundation TrustKing's College LondonLondon, UK

We value your opinion!We are continually trying to develop and improve our educational initiatives to provide you with cutting-edge learning activities.Prior and after this live educational event you will be asked to answer an online survey to help us to better tailor our futureeducational initiatives.

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Scientific programme1-2 November 2013

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Chairs: C. Alviggi (Italy) - R. Fischer (Germany)

09.15 L1: Advanced maternal age and fertility:physiology, treatment and outcome of ART S.K. Sunkara (UK)

09.45 L2: Ovarian reserve and ovarian response tocontrolled ovarian stimulation (COS):biomarkers and strategy C. Alviggi (Italy)

10.15 L3: Advanced age, poor responders and the role ofLH supplementationC. Alviggi (Italy)

10.45 Coffee break

11.15 WG1: Working Group and case studies on L2 and L3 C. Alviggi (Italy), R. Fischer (Germany), S.K. Sunkara (UK)

12.15 Discussion C. Alviggi (Italy), R. Fischer (Germany), S.K. Sunkara (UK)

12.45 Lunch

Maternal age and ovarian reserveSession I

Friday, 1 November

08.30 Registration

09.00 Serono Symposia International Foundation (SSIF) openingR. Fischer (Germany)

Chairs: R. Fischer (Germany) - S.K. Sunkara (UK)

14.00 L4: Oocyte competence and embryo quality inadvanced age and poor ovarian responseA. La Marca (Italy)

14.30 WG2: Working Group on L1 and L4R. Fischer (Germany), A. La Marca (Italy),S.K. Sunkara (UK)

15.30 Coffee break

16.00 DiscussionR. Fischer (Germany), A. La Marca (Italy), S.K. Sunkara (UK)

16.30 End of the first day

Maternal age and oocytes /embryo qualitySession II

Legend

L : Lecture; WG : Working Group;

Saturday, 2 November

Chairs: R. Fischer (Germany) - A. La Marca (Italy)

09.00 L5: Luteal phase support: role of progesteroneA. La Marca (Italy)

09.30 L6: Implantation problems and miscarriages inadvanced ageS.K. Sunkara (UK)

10.00 WG3: Working Group and case studies on L5 and L6R. Fischer (Germany), A. La Marca (Italy),S.K. Sunkara (UK)

11.00 Coffee break

11.30 L7: Pregnancy after ART: management andcomplications in the first trimester S.K. Sunkara (UK)

12.00 Discussion R. Fischer (Germany), A. La Marca (Italy), S.K. Sunkara (UK)

13.00 End of the live educational course and lunch

Maternal age and pregnancy after ARTSession III

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Disclosure of faculty relationships

Serono Symposia International Foundation adheres to guidelines of the European Accreditation Council for Continuing MedicalEducation (EACCME®) and all other professional organizations, as applicable, which state that programmes awarding continuingeducation credits must be balanced, independent, objective, and scientifically rigorous. Investigative and other uses for pharmaceuticalagents, medical devices, and other products (other than those uses indicated in approved product labeling/package insert for theproduct) may be presented in the programme (which may reflect clinical experience, the professional literature or other clinical sourcesknown to the presenter). We ask all presenters to provide participants with information about relationships with pharmaceutical ormedical equipment companies that may have relevance to their lectures. This policy is not intended to exclude faculty who haverelationships with such companies; it is only intended to inform participants of any potential conflicts so that participants may form theirown judgements, based on full disclosure of the facts. Further, all opinions and recommendations presented during the programmeand all programme-related materials neither imply an endorsement nor a recommendation on the part of Serono SymposiaInternational Foundation. All presentations represent solely the independent views of the presenters/authors.

The following faculty provided information regarding significant commercial relationships and/or discussions of investigational ornon-EMEA/FDA approved (off-label) uses of drugs:

Robert Fischer Declared being member of the Scientific Committee of Serono Symposia International Foundation.

Antonio La Marca Declared honoraria or consultation fees from Roche, Beckman Coulter, MSD, Ferring, Ibsa, Merck Serono.

The following faculty have provided no information regarding significant relationship with commercial supporters and/or discussionof investigational or non-EMEA/FDA approved (off-label) uses of drugs as of 18 October 2013.

Carlo Alviggi

Sesh Kamal Sunkara

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Biosketch

Biosketch

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Carlo Alviggi works as a Specialist in Reproductive Medicine at the Fertility Unit of the University of Naples “Federico II”. Since 2006,he has been working in the same unit as Assistant Professor. Dr Alviggi’s current research interests are the role of luteinizinghormone (LH) in folliculogenesis, the use of LH-containing drugs in patients undergoing controlled ovarian stimulation for in vitrofertilization, the pathogenesis of pelvic endometriosis, and the genetics of human reproduction. Dr Alviggi has published extensivelyand has been invited to lecture at over 40 international meetings dealing with reproductive medicine and gynaecologicalendocrinology. He has also served as ad hoc reviewer for international journals of these fields and has participated in severalnational and international (phase II-III) multicentre, prospective randomized trials.

Carlo AlviggiFederico II UniversityNaples, Italy

Robert Fischer is Founder and Medical Director of the IVF unit at the Hamburg Fertility Center, one of the largest and leadingGerman IVF centres. In July 1998 the Fertility Center of Hamburg was one of the first centres in Germany and worldwide to introducecertified quality management according to the ISO 9001. In 2002 the IVF laboratory was ISO 17025 certified. Prior to this he wasMedical Director of the first outpatient IVF unit in Hamburg. Author of numerous publications in national and international scientificjournals and books, as well as lectures at conferences worldwide, Dr Fischer is an active member of the American Society ofReproductive Medicine, founding member of the European Society of Human Reproduction and member of its advisory committeeas well as founding member of the “AG Gynäkologische Endokrinologie und Fortpflanzungsmedizin” and “BerufsverbandReproduktionsmedizinischer Zentren”, both in Germany.

Robert FischerSSIF Scientific Commitee MemberFertility Center HamburgHamburg, Germany

Antonio La Marca is a professor for reproductive medicine at the Mother-Infant Department, University of Modena and Reggio Emilia,Modena, Italy. He was trained at the University of Siena, where he graduated in Medicine in 1996. He completed his residency inObstetrics and Gynecology at the same university in 2001. His PhD was on biology of germ cells. Since 2004 he is working at the unitfor Reproductive Medicine and Surgery of the University Hospital of Modena. He has published over 110 papers in the main peer-reviewed specialist journals. His research areas are the physiology of ovarian function and its pharmacological manipulation. In thelast years research has been focused particularly on the AMH, antral follicle count and ovarian reserve.

Antonio La MarcaMother-Infant Department University Hospital of ModenaModena, Italy

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Sesh Kamal Sunkara (MD, MRCOG) is an Obstetrician, Gynaecologist and a Subspecialist in Reproductive Medicine and Surgery. Herresearch interests include ovarian ageing and its impact of female fertility, ovarian stimulation regimens, implantation failure inwomen undergoing assisted reproduction treatment and evidence based medicine in the context of infertility. Her MD research istitled “interventions to improve outcome of poor responders’ undergoing IVF treatment”. She has published in this field and iscurrently undertaking translational research at King’s College London. She has lectured both nationally and internationally on herareas of interest relating to Reproductive Medicine.

Sesh Kamal SunkaraGuy's and St Thomas' Foundation TrustKing's College LondonLondon, UK

Abstracts

Although the demographics and the age of childbearing in women have been changing over the decades, the physiology of femalefertility remains rather unchanged. Human ovaries have a finite number of oocytes endowed before birth and there is a constantdepletion of the oocyte pool right from that time. This impacts female fertility due to an exponential decline in oocyte quantity and aparallel decline in oocyte quality. Epidemiological observations in natural fertility populations have shown declining fecundity withmaternal age. With women delaying childbearing there has been an increase in the burden of infertility especially in westernsocieties and fertility clinicians are faced with the challenges in managing older women seeking fertility. This lecture will discuss theimpact of advanced maternal age on fertility treatments and outcomes.

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L1. Advanced maternal age and fertility: physiology,treatment and outcome of ART

Sesh Kamal SunkaraGuy's and St Thomas' Foundation Trust, King's College London, London, UK

Variability in the subfertile patient population excludes the possibility of a single approach to controlled ovarian stimulation (COS)covering all the requirements of a patient. Modern technology has led to the development of new drugs, treatment options andquantitative methods that can identify single patient characteristics. These could potentially be used to match patients with the righttreatment options to optimize efficacy, safety and tolerability during COS. Predictive biomarkers could be used to facilitate treatmentdecisions and to tailor therapy to increase the chances of achieving pregnancy while reducing stimulation burden and cancellationrates as well as treatment-related complications such as multiple pregnancies and OHSS.

Among the hormonal biomarkers, AMH has been shown to have the highest predictive value. Recent studies also demonstrated thatAMH may play a role in predicting live birth. Although age clearly remains the primary determinant of the probability of a live birthafter assisted conception, for any given age, women with a higher circulating AMH will have higher chances than their counterpartswith a lower AMH. AMH has been al so proposed as a tool for choosing stimulation protocol. AFC is a well-known functionalbiomarker that is used to predict ovarian response to stimulation. It is also an important factor in determining the optimal startingdose of FSH for ART. However, the use of AFC could be limited by the variability in technical methods used to count and measureantral follicles.

In the last decades, it has been clearly understood that women with similar demographic, anthropometric and hormonalcharacteristics, including basal levels of gonadotrophins, may display totally different profiles of ovarian reserve. More recently, itappeared that even similar profiles of ovarian reserve can be associated with different sensitivity to exogenous FSH.

On these bases, it has been argued that, although hormonal and functional biomarkers are useful tools for predicting ovarianresponse, genetic factors also need to be taken into consideration. For example, a subgroup of patients with a hypo-response torecombinant FSH has recently been identified, comprising young, normogonadotrophic women with normal AFC and goodprognosis. Such patients have an apparent hypo-sensitivity to FSH. This results in a need for longer stimulation periods and highertotal doses of FSH, and leads to poor treatment response and low pregnancy rates. The pathogenesis of this phenomenon is stillunknown. Preliminary data have shown that woman with ovarian hypo-sensitivity to exogenous FSH may benefit from LHsupplementation. In addition, it has been found that hypo-response to FSH is associated with an increased frequency of a commonand less bioactive LH polymorphism (v-LH [Trp8Arg/Ile15/Thr]).

A polymorphic variant of the FSH receptor (FSH-R) in which Asn at position 680 is replaced by Ser has been associated with higherFSH basal levels and increased number of antral follicles during the early follicular phase. Recent studies have also proven that thiscommon polymorphism is associated with a higher consumption of exogenous FSH during ovarian stimulation for IVF/ICSI cycles.

These lines of research reinforce the hypothesis that ovarian resistance (hypo-response) to exogenous FSH can be related to specificgene polymorphisms. In addition, these data support the idea of a tailored administration of gonadotrophins based on apharmacogenomic approach. The future will, potentially, hold a combination of hormonal, functional and genetic biomarkers thatwill be utilized to define ovarian reserve, and tailored COS protocols that will provide the right treatment for the right patient with thehighest safety and efficacy outcomes.

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L2. Ovarian reserve and ovarian response to controlledovarian stimulation (COS): biomarkers and strategy

Carlo AlviggiFederico II University, Naples, Italy

Availability of recombinant products allows independent use of the two gonadotrophins, giving the opportunity for evaluating theimpact of LH and different FSH:LH ratios on ovarian response. On these bases, LH supplementation has been tested in differentsubgroups of patients. Available data indicate that recombinant LH (r-hLH) is able to improve the ovarian response and the outcomeof IVF in women identified as “hyporesponders” to r-hFSH monotherapy. In particular, the concept of “hypo-response” to COS hasbeen proposed to identify normogonadotrophic women who have normal estimated ovarian reserve but, when stimulated withstandard GnRH-a long protocol, require high amounts of FSH to obtain an adequate number of oocytes retrieved (De Placido et al.,2001, 2004, 2005; Ferraretti et al., 2004; Mochtar et al., 2007; Devroey et al., 2009). These women seem to be distinct from classicalpoor responders because they have normal ovarian reserve, but unexpectedly show sub-optimal response when stimulated withstandard regimens. Conversely, specific adjustments of classical protocols, including the use of r-hLH supplementation seem tooptimize their ovarian response. On the basis of the current literature, it is possible to argue that hypo-response is related to geneticcharacteristics. More specifically, it has been found that this condition is associated with an increased frequency of a common andless bioactive LH polymorphism (v-beta LH [Alviggi et al., 2001; 2013]).

Recent data clearly demonstrated that normogonadotrophic women displaying higher endogenous LH levels during classical GnRH-a long protocol benefit from r-hLH supplementation, suggesting that less-performing LH receptors may be involved (Humaidan etal., 2004). Finally, RCTs demonstrate that r-hLH improves the ovarian response and the outcome of IVF in women in advancedreproductive age (between 35 and 39 years [Bosch et al., 2011]).

Taken together, these lines of evidence support the idea that specific subgroups of IVF women benefit from LH supplementation.

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L3. Advanced age, poor responders and the role of LHsupplementation

Carlo AlviggiFederico II University, Naples, Italy

Cellular abnormalities occur as oocytes age. A sequence of molecular processes that deteriorate during ageing, negatively impactfertilization of oocytes and embryo development.

“Omics” methodologies have begun to be used to investigate systematically the mechanisms of reproductive competence that arealtered with oocyte aging. On the basis of the most relevant concept of ageing, age-associated dysfunction of female reproductionresults from physiological accumulation of irreparable damage to biomolecules. This is an unavoidable side effect of normalmetabolism. Several years have passed since the hypothesis that free radicals may be the centre of the pathogenesis ovarian ageing,and strong scientific evidence indeed suggests the involvement of oxidative injuries in ovarian follicle ageing. Approximately 30% ofoocytes in humans carry a chromosomal imbalance. This condition has severe clinical consequences as approximately one-third ofspontaneous abortions are aneuploid. The most obvious link to the increase of aneuploidy in oocytes is maternal age.

However, low oocyte quality has also been linked to low oocyte quantity independent of female age. This leads to the hypothesis thatyoung women with reduced ovarian reserve may have low quality as well. While several studies indicate that the fertility outcome foryoung women is always better than their older counterparts, recent data demonstrates that independently of age, low quantity goestogether with low quality.

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L4. Oocyte competence and embryo quality in advancedage and poor ovarian response

Antonio La MarcaMother-Infant Department, University Hospital of Modena, Modena, Italy

Progesterone prepares the endometrium for pregnancy by stimulating proliferation in response to human chorionic gonadotropin(hCG), which is produced by the corpus luteum. This occurs in the luteal phase of the menstrual cycle. In assisted reproductiontechniques the progesterone is low and the natural process is insufficient. The cause of luteal phase defect in IVF appears to berelated to the supraphysiological levels of steroids.

The luteal phase in stimulated cycles can be supported with either progesterone, hCG or gonadotropin releasing hormone (GnRH)agonists. However it is done, luteal phase support improves implantation rate and thus pregnancy rates. It is still a matter of debatewhat kind of progesterone, what route of administration and for how many weeks luteal support should be administered in womenat single level.

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L5. Luteal phase support: role of progesterone

Antonio La MarcaMother-Infant Department, University Hospital of Modena, Modena, Italy

The process of implantation is influenced by complex interactions involving maturational events in the embryo, synergism of theendometrium, maternal hormonal changes and immune responses. The advent of IVF has provided a unique opportunity to studyfactors affecting human embryo implantation. The negative impact of advanced female age on implantation has been demonstratedby IVF studies. Whilst, it was accepted that female age influences implantation it was initially debated whether this was a result ofthe embryonic or endometrial factors. Studies of oocyte donation involving young donors in older recipients confirmed that theformer was the main contributory factor to reduced implantation with advanced female age. There is surmounting evidence that theincreased risk of miscarriage in older women including women undergoing ART is a result of chromosomal aneuploidy as aconsequence of oocyte aneuploidy. This lecture will cover implantation problems and miscarriage as impediments to successful ARToutcome in older women.

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L6. Implantation problems and miscarriages in advanced age

Sesh Kamal SunkaraGuy's and St Thomas' Foundation Trust, King's College London, London, UK

Success in ART should be defined as achieving a healthy live birth at term. However the advent of ART has presented with pregnancycomplications due to a multiplicity of factors. ART is endowed with a unique risk of late onset ovarian hyperstimulation syndrome(OHSS) in early pregnancy. It has been a matter of debate whether there is an increased incidence of early pregnancy complicationssuch as early/ late miscarriages and ectopic pregnancy following ART. This lecture will explore the potential complications inpregnancies following successful ART and discuss their management.

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L7. Pregnancy after ART: management andcomplications in the first trimester

Sesh Kamal SunkaraGuy's and St Thomas' Foundation Trust, King's College London, London, UK

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