ivf preceptorship istanbul - excemed · 2015-10-26 · german ivf centres. in july 1998 the...

IVF Preceptorship Istanbul12-13 September 2013 - Istanbul, Turkey

FINAL PROGRAMME AND ABSTRACT BOOK

General information

VenueThis live educational course takes place at the:

AMERICAN HOSPITAL Güzelbahçe sok. No:20

LanguageThe official language of this live educational course is English.

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

Associate Project Manager: Simona PantaleoniSpecialist Medical Advisor: Irene ZerbettoTel.: +39 (0)6 420 413 569Fax: +39 (0)6 420 413 677E-mail: [email protected]

Serono Symposia International Foundation is a Swiss Foundation with headquarters in 14, rue du Rhône, 1204 Geneva, Switzerland

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: [email protected]

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Ni anta ı i liIstanbul, Turkey

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IVF Preceptorship Istanbul

Serono Symposia International Foundation live educational course on:

IVF Preceptorship Istanbul12-13 September 2013 - Istanbul, Turkey

Aim of the coursePoor Ovarian Response (POR) is one of the most important cause of women infertility. It usually indicates a reduction in follicularresponse, resulting in a reduced number of retrieved oocytes. POR to ovarian stimulation usually indicates a reduction in follicularresponse, resulting in a reduced number of retrieved oocytes. It has been recognized that, in order to define the poor response inIVF, the Bologna criteria define POR patients with at least two of the following three features: 1. advanced maternal age or any other risk factor for POR; 2. a previous POR; 3. an abnormal Ovarian Reserve Test (ORT). By definition, the term POR refers to the ovarian response, and therefore, one stimulated cycle is considered essential for thediagnosis of POR. Polycystic Ovary Syndrome (PCOS) is one of the most common female endocrine disoders. It is a complex,heterogeneous desease of multifactorial etiology that produces symptoms in approximately 5-10% of women during theirreproductive age (12-45 years) and is one of the leading causes of female infertility.The live educational course offers an overview on ovarian stimulation and on new laboratory technologies for in vitro fertilizationcycles. This meeting is dedicated to providing new insights on these topics, with an interactive program where each lecture isfollowed by specific cases studies or working groups in order to provide participants with both up-to-date knowledge and thepossibility to share their experiences each other’s and with the speakers.

Learning objectivesBy attending this live educational course the learners will be able to:• Optimize outcomes in poor responders patients and PCOS patient• Apply new strategies to avoid implantation failure• Identify the best technologies to individualize gametes and embryo viability• Identify markers, protocols and clinical issue

Target audienceThis live educational course is designed for restricted groups of experts physicians working in assisted reproductive medicine, whoare currently involved in infertility treatments.

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

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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 program is made possible thanks to an educational grant received from Merck Serono Middle East.

Scientific organiserRobert FischerSerono Symposia International FoundationScientific Committee MemberFertility Center HamburgHamburg, Germany

Local scientific organiserBülent UrmanAmerican Hospital IstanbulKoc UniversityIstanbul, Turkey

Serono Symposia International Foundation designed thisprogramme in collaboration with the American HospitalIstanbul.

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List of faculty membersBaşak BalabanAmerican Hospital IstanbulIstanbul, Turkey

Carlo BullettiCattolica's Cervesi General Hospital University of Bologna in RiminiRimini, Italy

Robert FischerFertility Center HamburgHamburg, Germany

Antonio La MarcaMother-Infant DepartmentUniversity of Modena and Reggio EmiliaModena, Italy

Carmen RubioValencian Infertility Institute (IVI)IVIOMICSValencia, Spain

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

Bülent UrmanAmerican Hospital IstanbulKoc UniversityIstanbul, Turkey

Scientific programme12-13 September 2013

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Chairs: R. Fischer (Germany) - B.Urman (Turkey)

09.10 L1: Etiology and pathophysiology of poorresponders S.K. Sunkara (UK)

09.35 L2: Etiology and pathophysiology of PCOS patientsS.K. Sunkara (UK)

10.00 Coffee break

10.30 L3: Individualized Controlled Ovarian Stimulation(iCOS): biomarkers and tools for matchingpatients and protocolsA. La Marca (Italy)

11.10 WG1: Case studies on L1 and L3A. La Marca (Italy) - S.K. Sunkara (UK)

12.10 Questions time

12.30 Lunch

Optimize outcomes: clinical issuesSession I

Thursday, 12 September

08.30 Registration

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

09.00 Local scientific organiser welcomeB. Urman (Turkey)

Chairs: R. Fischer (Germany) - B.Urman (Turkey)

13.30 L4: The management of poor ovarian responsepatients A. La Marca (Italy)

13.55 L5: The management of PCOS patients S.K. Sunkara (UK)

14.20 WG2: Case studies on L4 and L5A. La Marca (Italy) - S.K. Sunkara (UK)

15.20 Coffee break

15.50 L6: Treatments and perspectives: prevention andmanagement of OHSS in PCOS patientsundergoing ART treatmentsS.K. Sunkara (UK)

16.15 Case study on L6S.K. Sunkara (UK)


17.00 Visit of the clinic (1st group)

End of the first day

Stimulation protocols and management ofcomplicationsSession II

Legend

L : Lecture; WG : Working Group;

Friday, 13 September

Chairs: R. Fischer (Germany) - B. Balaban (Turkey)

09.00 L7: Biomarkers of gamete selection and embryo viabilityB. Balaban (Turkey)

09.25 L8: PGS and micro array CGH. Indications andfuture prospectives C. Rubio (Spain)

09.50 Coffee break

10.20 L9: The role of endometrium receptivity andRecurrent Implantation FailureC. Bulletti (Italy)

10.45 L10: The different possibilities of luteal phasesupportB. Urman (Turkey)

11.10 WG3: Case studies on L9 and L10C. Bulletti (Italy) - B. Urman (Turkey)


12.30 Lunch

13.30 Visit of the clinic (2nd group)

End of the live educational course

Implantation Failure and laboratory techniquesSession 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:

Başak Balaban Declared no potential conflict of interest.

Carlo Bulletti Declared no potential conflict of interest.

Robert Fischer Declared no potential conflict of interest.

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

Carmen Rubio Declared no potential conflict of interest.

Sesh Kamal Sunkara Declared no potential conflict of interest.

Bülent Urman Declared no potential conflict of interest.

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Biosketch

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Biosketch

Başak Balaban obtained her degree in 1993 from the University of Ankara,Turkey, working in the faculty of Biological Sciences.Following clinical embryology training in Ankara she qualified in laboratory based procedural applications of IVF at The SchoysmanInfertility Management Foundation (SIMAF), Brussels, Belgium. She founded and led the IVF laboratory in the German Hospital,Istanbul Assisted Reproduction Unit and then became chief embryologist in the American Hospital of Istanbul Assisted ReproductionUnit. Her major interest areas are embryo selection, in-vitro culture techniques, cryopreservation, and blastocyst culture. She haspublished extensively in these fields. She is a board member of the National Representatives Committee of ESHRE, a past chair ofthe Alpha society –Scientists in Reproductive medicine is still a board member and is congress president for the upcoming biennialin Antalya, Turkey in 2014. She is chair of the Turkish Society of Clinical Embryologists (KED).

Başak BalabanAmerican Hospital IstanbulIstanbul, Turkey

Carlo Bulletti is Director of the Unit of Physiopathology of Reproduction at The Cattolica’s General Hospital, Department of “Scienceof Quality of life”, University of Bologna, Rimini, Italy. After an MD at the University of Bologna, he trained at centres of excellenceincluding Mount Sinai Medical Center ,New York. Professor Bulletti has been instrumental in the development of two models: theextracorporeal perfusion of the human uterus (with the first embryo implantation in an isolated uterus) and the first uterine passeffect (FUPE) of hormones delivered by the vaginal route. He has published 15 medical books, more than 180 articles and more than130 chapters in medical books.. His current research focuses on the endometrium, embryo implantation and endometriosis. He isa member of, amongst others, the American Society for Reproductive Medicine, the New York Academy of Sciences and theEuropean Society of Human Reproduction & Embryology Special Interest Group for Reproductive Surgery.

Carlo BullettiCattolica's Cervesi General Hospital University of Bologna in RiminiRimini, 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 FischerFertility Center HamburgHamburg, Germany

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Antonio La Marca is associate professor in Obstetrics and Gynecology at the University of Modena and Reggio Emilia. He graduatedin Medicine and Surgery at the University of Siena in 1996, specializing in Obstetrics and Gynaecology at the same institution in 2001.In 2006 he obtained his PhD, again at the University of Siena. He has been working at the Institute of Gynaecology and Obstetrics ofthe University Hospital of Modena since 2003. Since 1998 he has published over 110 papers in the main peer-reviewed specialistjournals in the field. Scientific interests include: ovarian reserve and pharmacological manipulation of ovarian activity.

Antonio La MarcaMother-Infant DepartmentUniversity of Modena and Reggio EmiliaModena, Italy

Trained in science in the University of Valencia, Spain, Dr. Carmen Rubio specialized in cytogenetic studies in human reproduction,partly in the University of Barcelona. Becoming interested in chromosomal abnormalities in human embryos, she completed herPhD in 2004 in Valencia in the field of Reproductive Genetics. Post-doctoral research includes a sabbatical at the laboratory of Drs.Patricia Hunt and Terry Hassold at the School of Molecular Biosciences (Washington State University, USA) focusing on male andfemale meiosis and the mechanism underlying human aneuploidy. At present, she is the Head of the Preimplantation GeneticDiagnosis program for chromosomal disorders at IVIOMICS (Valencia, Spain).

Carmen RubioValencian Infertility Institute (IVI)IVIOMICSValencia, Spain

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

After his residency training in Obstetrics and Gynecology in the University of Hacettepe Dr Urman completed a 3-year fellowshipprogramme in Reproductive Endocrinology and Infertility in Vancouver, Canada. He returned to Hacettepe University in 1991 andparticipated in the foundation of one of the first IVF clinics in Turkey. He worked as an Associate Professor until 1996 in the sameinstitution. Dr Urman resigned from the university in 1996 and founded the Assisted Reproduction Unit of the American Hospital ofIstanbul, one of the biggest IVF centres in the country. His major areas of interest are clinical assisted reproduction, laparoscopicand hysteroscopic surgery, endometriosis and fibroid research. He has published extensively in these fields, having over 110 articlespublished in renowned international journals. He has written several book chapters and lectured in national and internationalmeetings. He served as the president of the Turkish Society of Reproductive Medicine between 2007 and 2012. He recently wasappointed as a clinical faculty of Obstetrics and Gynecology in the Koc University School of Medicine.

Bülent UrmanAmerican Hospital IstanbulKoc UniversityIstanbul, Turkey

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Biosketch

Abstracts

Abstract not in hand at the time of printing.

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L1. Etiology and pathophysiology of poor responders

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

Polycystic ovary syndrome (PCOS) is the most common female endocrine disorder and the commonest cause of anovulation andfemale subfertility. It was first described in 1935 by American gynaecologists Frank Stein and Irvine Leventhal. The prevalence ofPCOS ranges between 6.5% - 25% of reproductive age women and is based on the diagnostic criteria used. It is a complex disorderof uncertain etiopathogenesis characterised by heterogeneity of phenotypic manifestations. It is inherited as a complex polygenictrait and several genes in the multiple biochemical pathways implicated in PCOS have been evaluated. In addition to the underlyinggenetic basis, environmental factors have been shown to play an important role in the aetiology of PCOS. Environmental influencesare thought to unmask the underlying genetic predisposition to PCOS. This presentation will discuss the various factors that havebeen implicated in the aetiology of PCOS and the interdependence between genetic and environmental factors.

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L2. Etiology and pathophysiology of PCOS patients


Markers of ovarian reserve are associated with ovarian ageing as they decline with chronological age and therefore may predictstages of reproductive ageing, including the menopause transition. Assessment of ovarian reserve includes measurement of FSH,AMH and Inhibin B. Ultrasound determination of antral follicle count (AFC), ovarian vascularity and ovarian volume can have a rolealso. AMH is set to dominate reproductive endocrinology because of its unique relationship with ovarian reserve. In infertile womenovarian reserve markers can be used to predict low and high oocyte yield and treatment failure in women undergoing IVF. As ovarianreserve markers may permit the identification of both extremes of ovarian stimulation a possible role for their measurement maybe in the individualization of treatment strategies.

The main objective of the individualization of therapy in IVF is to offer every single patient undergoing IVF the best therapy tailoredon her own characteristics, thus allowing a high chance of success and of course limiting the risks deriving from ovarian stimulation.

Personalization of therapies in IVF should be based on the prediction of ovarian response for every patient. The starting point is tofigure out if patient will be a normal, poor or high responder. The aim is then to choose the correct treatment according to thisprediction. When a poor or high response is predicted, this kind of approach can also allow clinicians to give patients more accurateinformation, if one of these conditions then occurs.

Since personalization of controlled ovarian stimulation is based on the prediction of ovarian response, in order to increase theefficiency of this strategy, the prediction of ovarian response itself has to be based not only on age, but mostly on ultrasonographicand hormonal markers of ovarian reserve.

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L3. Individualized Controlled Ovarian Stimulation (iCOS):biomarkers and tools for matching patients andprotocols

Antonio La MarcaMother-Infant Department, University of Modena and Reggio Emilia, Modena, Italy

Poor response in IVF is generally defined as the retrieval of an inadequate number of oocytes after controlled ovarian stimulation. Ithas a prevalence between 10-20%, which increases with increasing female age. This is the consequence of the age-related depletionof the ovarian reserve, and thus of the reduction of recruitable follicles, which occurs in every woman with advancing age. But alsoin young women, genetic defects, ovarian surgery, and chemotherapy could be responsible for ovarian damage, leading to the sameresult.

Because of the need for an internationally accepted definition of poor response, ESHRE recently made the first attempt tostandardize that definition in a simple and reproducible manner. A consensus was reached on at least two of the following threefeatures being present:

• advanced maternal age (≥40years) or other risk factors for poor response• a previous poor response, with ≤3 oocytes retrieved after a conventional stimulation protocol• an abnormal ovarian reserve test (i.e. AFC <5-7follicles or AMH < 0.5-1.1ng/ml)

By definition, one stimulated cycle is essential for the diagnosis of poor response. However, patients with >40 years of age with anabnormal ovarian reserve test could be classified as “expected” poor responders.

Once a patient has been defined as a poor responder, the selection of the stimulation protocol requires attention to assure thispatient of an acceptable reproductive outcome.

A variety of different stimulation protocols have been suggested but the lack of any large-scale, prospective, randomized, controlledtrial of the different management strategies does not allow any definitive conclusion. Some studies report a slightly increasednumber of retrieved oocytes with the short protocol with GnRH antagonist compared to the long standard protocol, but the pregnancyrate does not always differ to a significant degree. Increasing the daily FSH dose over 225IU, which is considered the maximalstimulation dose, is not useful to gain a multifollicular growth.

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L4. The management of poor ovarian response patients

Antonio La MarcaMother-Infant Department, University of Modena and Reggio Emilia, Modena, Italy


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L5. The management of PCOS patients



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L6. Treatments and perspectives: prevention andmanagement of OHSS in PCOS patients undergoingART treatments


There are two important key points on the IVF laboratory side which are critical for clinical success: one is the culture of viablegametes and embryos which can mimic in-vivo conditions, and second is the selection of the gametes and embryos which are likelyto be transferred to the patient and result with 100% implantation.

The selection of gametes and embryos based on morphology had been used to correlate with the implantation potential and viabilityof the embryos transferred since the 1980s, and even after three decades grading schemes based on morphology are uniqueselection systems used globally in embryology laboratories for routine practice.

Even though the morphological grading criteria are widely applied in various laboratories worldwide, there was no consensus on astandardized grading scheme until very recently. Alpha, International Society for Scientists in Reproductive Medicine and ESHRESIGE (Special Interest Group Embryology) recommended a common language that could be used worldwide. While morphologicalgrading systems have been beneficial in improving implantation and pregnancy rates and reducing multiple gestations, theirpredictive value still remains limited.

The limitations and high subjectivity of evaluations based on morphological characteristics have led to the investigation of newobjective, non-invasive biomarkers for the selection of the viable gametes and embryos that would result with 100% implantationand healthy offspring.

Biomarkers of Oocytes & Embryos

1. Measurement of specific molecules that could be metabolic determinants of oocyte and embryo viabilityThese techniques are based on the hypothesis that an embryo which results in a pregnancy and implantation alters itsenvironment differently compared to a non-viable embryo. A proper metabolic turnover is essential for a pre-implantation embryoto remain viable and develop an optimal phenotype for pregnancy potential. Pyruvate and lactate as well as glucose can be non-invasively measured by microfluorometric enzymatic assays to reflect the embryo’s developmental potential and viability.Amino acid types secreted and taken up by human embryos at different stages of pre-implantation development were alsocorrelated with embryo viability and implantation potential. Oxygen consumption has been suggested to be correlated with embryo viability as the consumption of oxygen may reflect itsmetabolism. HLA-G molecule may play a role in immune tolerance in pregnancy, being expressed in the placenta. Both membrane and solubleforms are identified, possibly sHLA-G having the role of protecting the developing embryo from the maternal immune system. It’ssuggested that there’s a positive correlation between sHLA-G in the culture media which can be measured by ELISA, andincreased embryo viability and improved pregnancy rates.

2. Measurement of multiple markers that could be correlated with oocyte and embryo viabilityOmics technologies are known as novel methods that allow simultaneous profiling of multiple markers (measured from secretedand consumed components within culture medium) of embryonic phenotype. Omics technologies described in the literature are:genomics, transcriptomics, proteomics and metabolomics. Omics technologies in their present forms can be invasive, technicallychallenging, and time consuming, and require agents such as radioactive probes or fluorescent dyes, making them unsuitable forassessment of embryo viability in a clinical setting. Despite these technical obstacles, a combined omics contribution to thecharacterization of human embryonic secretome might be needed when taking into account the complexity and diversity of thehuman embryo.

3. Viability assessment of human oocytes by using polarized microscopyBirefringence imaging of meiotic spindle and inner layer of zona pellucida can be provided by using special polarized microscopytechniques.

4. Morphokinetic characters of human embryos: time-lapse imaging systemsOne of the fundamental problems of the current embryo quality assessment by morphology is the static evaluation of a highlycomplex and dynamic developing cell: the embryo. Current systems can evaluate the quality of embryos at different stages withina limited period of time so as not to expose the cells to various physical changes outside the incubator. This had been shown todecrease the viability of embryos. Some of the specific morphological characteristics which might be important clues for viabilityof the embryos could be unnoticed by this method of quality assessment with a limited number of observations. Continualmonitoring within the incubator environment might provide valuable information on embryo developmental kinetics and improvethe success rate of viable embryo selection.

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L7. Biomarkers of gamete selection and embryo viability

Başak BalabanAmerican Hospital Istanbul, Istanbul, Turkey

Biomarkers of sperm selection

Current sperm selection techniques for IVF or ICSI procedures are mainly based on morphological characteristics. World HealthOrganization criteria for concentration and motility parameters, and Kruger strict criteria for morphological parameters are widelyused worldwide. However the selection of a single spermatozoon for microinjection is mainly performed at a cursory level by theembryologist usually at >200 times or maximum >400 times magnification selection under the inverted microscope. Someconcerns over the use of poorer quality sperm for microinjection retrieved from men with severe male factor infertility have beenraised in the last two decades with the increasing utilization of ICSI as the insemination method. Therefore the utilization of objectivebiomarkers for the selection of a single spermatozoon is of major importance compared to diagnostic tests demonstrating thenormality and quality of the whole semen sample. New approaches published to date in clinical practice for the selection of anindividual viable spermatozoon are mainly correlated with the morphology and the membrane characteristics of the spermatozoa.To date there are three novel technologies that are used in clinical practice with the evidence based on prospective randomized trialsperformed in large patient populations:

• Selection of single spermatozoon based on high-magnification selection technique

• Selection of single spermatozoon by birefringence analysis of the sperm head

• Selection of single spermatozoon by sperm binding to hyaluronic acid

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Preimplantation Genetic Screening (PGS) is used to identify numerical chromosome anomalies in couples having normal karyotypesbut with fertility problems. In PGS programs, the most widely employed technique has been fluorescence in situ hybridization (FISH)for a selected panel of chromosomes. Prospective randomized controlled trials (RCT) using FISH concluded that PGS should not berecommended. Other authors argued that some important methodological pitfalls, such us patient inclusion criteria, embryo biopsyprocedure, embryo culture conditions, and type of genetic analysis performed, may have influenced RCT outcomes. Further, manyclinicians propose that greater benefit would be obtained if PGS could test the complete set of chromosomes rather than a subset.The best approximation to attain this goal seems to be array-CGH, which currently offers the most complete analysis of the embryoby providing information about all 24 chromosomes.

The objective of the present study was to evaluate the usefulness of comprehensive chromosome screening (CCS) using arraycomparative genomic hybridization (aCGH) for different indications. The study included 1420 CCS cycles in which clinical indicationswere: recurrent miscarriage (RM, n=204); repetitive implantation failure (RIF, n=187); severe male factor (MF, n=116); previoustrisomic pregnancy (n=33); and advanced maternal age (AMA, n=880). CCS was performed in cycles in which all oocytes and embryoscame from fresh cycles (n=774); mixed cycles with fresh plus vitrified oocytes (n=320); mixed cycles with fresh plus vitrified day-2embryos (n=235); and mixed cycles with fresh plus vitrified day-3 embryos (n=121). Single cell day-3 embryo biopsy was performedwith aCGH analysis and day-5 embryo transfer. Consistent implantation (range 40.4 - 54.2%) and pregnancy rates per transfer (range46.0 - 62.9%) were obtained for all indications and independently of the origin of oocytes or embryos. However, lower pregnancy rateper cycle was achieved in women ≥40 years (19.3), due to the higher percentage of aneuploid embryos (85.3%) and lower numberof cycles with at least one euploid embryo available per transfer (40.3%). We concluded that aneuploidy accounts as one of the majorcauses affecting embryo implantation.

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L8. PGS and micro array CGH. Indications and futureprospectives

Carmen RubioValencian Infertility Institute (IVI), IVIOMICS, Valencia, Spain

Adhesion, penetration and invasion of the maternal wall are the steps taken by embryos during an ongoing pregnancy. The receptivewindow of the endometrium is observed when biophysical (e.g. pinopodes development etc) and biochemicals (e.g. endometrialintegrins activation by the interleukin-I system (IL-I)) features are developing during the cycle. Embryo swim and travel through theendometrial fluid drawn from endometrial glands, stromal decidualized cells and microvascular cast surrounding the luminalsurface epithelium of the cavity. From the external tube to the inner part of the lumen itself occurs in approximately three days.During this time, embryos reveal their own genetic and biochemical techniques to activate their adhesion and invasion potentiality.The detrimental role of Hoxa 10 and Hoxa 11 reduction observed in women with endometriosis or uterine myomas is one fixed stepin the implantation analysis. Embryo attachment results from the expression of adhesion proteins and the invasion of the embryois controlled by the trophoblastic proteolytic enzymes which in turn may be activated by endometrial co-factors. Leucemia InhibitoryFactor (LIF) is produced from the decidual natural killer lymphocytes when counteracting the invading trophoblast and it may induceuPA (urokinase pasminogen activator) and gelatinase enzymes to play the crucial role in trophoblast invasion. Estrogens areinducing and progesterone is inhibiting the LIF. The role of endometrial contractility (UC) in displacing human embryos with ongoingpregnancy or wastage is another factor of this complex phenomenon ending in human live birth. There are other factors that mayplay a crucial role in controlling the embryonic implantation such as the ovarian steroids used in controlled ovarian stimulation (withunknown specific genomic vs non genomic effects), submucosal myomas, and other risk factors such as obesity and coagulationpathologies.

Spontaneous recurrent miscarriage still represents a poorly understood phenomenon when pregnancy occurs in vivo or in vitroThere is also a general consensus, based on historical series, that its diagnosis requires at least three consecutive miscarriages.However, the new social habit of conception at an older age require a redefinition of this pathology, because clinical investigationand possible treatments may be too late if initiated only after the third miscarriage. Furthermore, there is no convincing evidencesupporting a difference between the aetiopathogenesis of spontaneous single and recurrent abortion. Patients with one or moreepisodes of miscarriage are studied and treated differently only because conventional medical consensus avoids sophisticated, time-consuming and expensive tests for patients with spontaneous abortion, confining these investigations to patients who have had threeor more miscarriages.

Spontaneous abortion or embryo implantation failures may need endometrial histological and biochemical evaluation ofdecidualization, the exclusion of intraluminal myomas as well as an exclusion of endometriosis . Possible determination of adequateendometrial contractility in pregnancies occurred both in vivo and in vitro and the determination of embryonic aneuploidisms inpregnancies occurred in vitro may represent a further diagnostic (and strategic) option.

The therapeutic efforts aimed at improving the efficiency of human embryo preservation during the first trimester start from theimplantation process up to the conclusion of primitive placenta formation signalled by the switch from progesterone corpus lutei tothe trophoblast production around the 8th week of pregnancy. They are mainly based on surgical repair of anatomical defects ofuterine cavity (including the myomas removal) , detection and removal of endometriotic foci, and possible detection of aneuploidismsin the in vitro fertilization before embryo transfer. Progesterone adequacy in the endometrial preparation in pregnancies startingafter in vitro as well as in vivo procedures will be considered.

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L9. The role of endometrium receptivity and RecurrentImplantation Failure

Carlo BullettiCattolica's Cervesi General Hospital, University of Bologna in Rimini, Rimini, Italy

Luteal phase support is essential for the success of assisted reproduction treatment as without luteal phase support clinicalpregnancy and live birth rates are lower while miscarriage rates are higher. Defective luteal phase is generally ascribed to the effectof ovarian hyperstimulation and the use of GnRH analogues both with agonist and antagonist protocols. Luteal phase can besupported with hCG or progesterone while adjuvants such as GnRH agonists and estrogen have also been used. Although hCG andprogesterone yield similar pregnancy and live birth rates, the use of hCG has been associated with an increased incidence of ovarianhyperstimulation that has limited its use. Progesterone is the mainstay of luteal phase and can be administered by oral, vaginal, orintramuscular routes. Oral progesterone is associated with lower pregnancy rates, erratic absorption (bioavailability < 10%), lowerserum levels due to liver first pass effect, and side effects such as sedation, dizziness, somnolence, fatigue, headache, urinaryfrequency. Progestagens such as dydrogestrone and chlormadinone acetate appear to be comparable to IM progesterone in termsof efficacy and are associated with a lower side effect profile. However, data regarding the use of these progestagens are limited.Although intramuscular progesterone is associated with high pregnancy rates, it is difficult to use, patient preference is lesscompared with vaginal progesterone, and it results in painful injections and injection site complications. Rare occurrence of severeallergic reactions, ARDS and Eosinophilic pneumonitis has also been reported. Vaginal progesterone similar to intramuscularprogesterone is also associated with high pregnancy rates. Side effects of oral administration are prevented due to lack of liver firstpass effect. This is the route that is most preferred by the patients. However, vaginal progesterone may result in vaginal dischargeand vaginal irritation. Spotting before the day of the pregnancy test is common in women who did not conceive. Gel and vaginaltablets have a similar side effect profile, however, gel is more preferred by the patients due to its ease of use. Vaginal andintramuscular progesterone are similar in terms of histologic maturation of the endometrium, P4 receptor expression,ultrasonographic parameters such as endometrial thickness and uterine artery Doppler measurements. Although earlier studiesand meta-analyses showed higher pregnancy rates with the use of intramuscular versus vaginal progesterone, a more recent meta-analysis and Cochrane review concluded that both routes of administration are associated with similar pregnancy, live birth andmiscarriage rates. More recent studies also support these findings. Moreover, vaginal progesterone is associated with significantlyincreased patient satisfaction rates. When vaginal progesterone is used for luteal phase support, gels, capsules and micro insertsyield similar outcomes. More recent data suggest that increasing the dose of vaginal gel after embryo transfer is associated with abetter cycle outcome. In conclusion the vaginal route should be preferred for luteal phase support in patients undergoing assistedreproduction treatment due to similar efficacy and increased patient convenience and satisfaction. The impact of adjuvants used in the luteal phase on the success of IVF is currently limited and not supported by the current data.These include estrogens and GnRH analogues.

Luteal support in over-responding patients is different as the current practice is to use GnRH agonist trigger for final maturation ofthe oocytes. Luteal phase should be supported with additional low dose hCG or IM progesterone combined with estrogen.

The duration of luteal phase support is another controversial issue. According to recently published randomized trials luteal supportcan safely be stopped once the pregnancy test is positive. There does not appear to be any difference in ongoing pregnancy ratesaccording to published randomized trials.

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L10. The different possibilities of luteal phase support

Bülent UrmanAmerican Hospital Istanbul, Koc University, Istanbul, Turkey

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