Workshop outcomes outcomes. Spotlight on Implantation: through medical education

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1 spring summer 2014 Annual Conference Workshop outcomes outcomes Early evaluation of fetal 02 Spotlight on Implantation: 07 echocardiography 11 Opening the black box Your EXCEMED EXCEMED: improving reproductive medicine through medical education Upcoming in EXCEMED reproductive medicine Educational activities on the horizon HIGHLIGHTS on EXCEMED activities in reproductive medicine Future focus Fertility preservation following cancer: an emerging challenge Improving the patient s life through medical education Spotlight on Implantation: Opening the black box Excellent presentations on human embryo implantation Almost 400 clinicians, biologists and researchers working in fertility medicine and ART attended the 2014 CME-accredited Annual Meeting in Reproductive Medicine. Organised by EXCEMED, the meeting took place on May, in Budapest, Hungary May Budapest, Hungary This international conference is held annually and has become a key event for professionals working in ART, from all over the world. Presentations focused on the following important subjects relating to human embryo implantation: Key biological aspects of human embryo implantation State-of-the-art techniques to maximise implantation Evidence-based recommendations to achieve the best outcomes from ART Presentations provided excellent opportunities for the participants to expand their knowledge of many aspects of ART. This publication highlights key presentations at the meeting, and provides an update on recent and forthcoming activities in reproductive medicine that are being developed by EXCEMED Annual Meeting on reproductive medicine focused on implantation, especially RIF EXCEMED Continuing medical education is our sole focus and our passion. We pour our energy and expertise into delivering the best for healthcare professionals, with patients as the ultimate beneficiaries. This is CME excellence. Our educational programmes in reproductive medicine are designed to suit the needs of physicians, scientists and biologists from all over the world who want to be at the cutting edge of research and patient care. Follow us

2 23-24 May Budapest, Hungary Improving implantation in ART by endometrial injury/scratching There is no evidence regarding effect of endometrial injury on adverse events, such as pain and bleeding Clinical evidence is emerging including data from RCTs and Cochrane reviews indicating that endometrial injury/scratching has a place in IVF. However, more research and better-quality evidence is required before endometrial injury can be considered as a standard practice. Certainly, endometrial injury (scratching) results in a cascade of events that may improve implantation rates, but physical and clinical evidence remains mixed. There is biological plausibility in the theory of endometrial scratching. Dr Aplin showed how local injury to the endometrium causes a range of events (Figure 1), together with changes in gene-expression patterns. Figure 1: injuries to epithelial tissue surfaces, such as the endometrium, are generally associated with the features listed Platelet deposition; clot formation Tissue-specific inflammatory infiltrate Epithelial repair (epiboly) Influx of myofibroblasts Matrix deposition Wound closure Local remodelling Minimal fibrosis; no scarring in mucosal tissues Immune- or stem-cell populations may be activated at the time of injury and this may support improved receptivity in the next cycle. However, there is also biological implausibility. For example, the injury is superficial (affecting only the functionalis layer), therefore tissue at the site of damage is expected to be lost at menstruation, explained Dr Aplin. It may be that endometrial injury promotes a beneficial inflammatory process where cellular memory and signalling improve over long distances, within tissues. In a debate at the meeting, Dr Raine- Fenning argued in favour of scratching and Dr Khalaf presented the case for caution. At the end of the debate, a large majority of participants voted in favour of scratching From left Dr Nick Raine-Fenning (University of Nottingham, UK) described endometrial injury as a well-tolerated, affordable procedure Dr John Aplin (University of Manchester, UK) outlined the physiological cascade of events that occur after endometrial injury Dr Yacoub Khalaf (King s College London, UK) called for further research in endometrial injury Endometrial injury appears to promote a beneficial inflammatory environment for implantation 2 extracts reproductive medicine Spring-Summer 2014 Abbreviations are defined in the Glossary, page 6

3 23-24 May Budapest, Hungary The endometrium: a biosensor for implantation Knowledge of implantation physiology is relevant to assisted reproduction and natural conception Research is revealing the events that surround peri-implantation. These advances in our understanding may help to improve IVF success rates. Equally, they may give us a clearer picture of the normal physiological mechanisms that govern implantation. It is important to ensure the safety of the mother by not increasing the implantation rate when this means that potentially abnormal embryos might implant. Dr Macklon suggested that the new question to pose is not how we can improve implantation in all cases, but whether this is something we should be doing. Implantation failures are common Normal human reproduction is characterized by a high rate of embryo loss, either before or just after implantation. Chromosomal abnormalities may be evident in the majority of embryos, therefore it is unsurprising that implantation failures are common. The endometrium (decidualising endometrial stromal cells in particular) acts as a biosensor, preventing the implantation of abnormal embryos (Figure 2): High-quality embryos actively signal to induce expression of supportive endometrial factors Low-quality embryos trigger a cellular stress response, thus leading to implantation failure This mechanism safeguards the mother, preventing the uterus from prolonged investment in embryos that are likely to be abnormal. New areas of research Studying the physiological signals within the endometrium represents a new area for research and development. By understanding the events better, we may have a clearer understanding as to why live birth rates per embryo transfer after IVF remain at relatively static levels, despite improvements in other aspects of ARM. Future avenues for research should be to confirm whether reduced embryo selectivity (i.e. failure to discriminate between high- and low-quality embryos) is a key reason for recurrent miscarriage. The implications of this, and the development of interventions that normalize the decidual phenotype, should be a focus of clinical and research attention Figure 2: Natural selection of embryos. Decidualising endometrial stromal cells serve as sensors on quality of implantation. Dr Nick Macklon (University of Southampton, UK) explained how research is opening the black box of early, preclinical pregnancy losses in humans Got a comment or questions? info@excemed.org reproductive medicine Spring-Summer 2014 extracts 3

4 23-24 May Budapest, Hungary Evidence needed for adjuvant therapy use in ART There is an urgent need for clinical trials to determine definitively whether adjuvant and complementary therapies offer benefit to people undergoing ART. Until then, clinicians have a duty to be honest with patients and to not advocate therapies that have no evidence of any benefit. Clinicians should be supportive and honest with couples about likely levels of success Advocating the use of adjuvant or complementary treatments for people with RIF may have biological plausibility but does not have current evidence of efficacy. Dr Cheong asked clinicians to be honest with patients regarding the limits of reproductive science, and adopt a supportive role rather than suggest non-evidence-based interventions in more difficult cases. A supportive approach could focus on the following: Optimizing modifiable lifestyle factors (such as diet, exercise, smoking, alcohol consumption) Addressing contributory surgical factors (such as uterine, tubal, ovarian pathologies and anomalies) Assessing the difficulties in embryo transfer in previous treatment cycles Re-evaluating the patient s history and investigations Presently, explained Dr Cheong, there is no robust evidence for many of the immunological therapies that are emerging. Further trials are needed, for example, to confirm whether administering glucocorticoids during the peri-implantation phase of ART has any significant benefit on clinical outcome. The same is also true for IVIG, TNFinhibitors and intralipid therapy. Indeed, intralipid therapy is associated with a high rate of allergic reactions, thrombocytopenia and hypercoagulability, and is therefore not recommended, Dr Cheong explained Dr Ying Cheong (University of Southampton, UK) urged clinicians to recommend only evidencebased treatments for couples undergoing ART in brief Current and emerging technologies for genetic testing (Antonio Capalbo, Italy) Several methods are available for accurate 24-chromosome aneuploidy screening with different capabilities and limitations Despite providing higher-resolution results, microarray based CCS methods are labour-intensive, costly, and have a long turnaround time Quantitative polymerase chain reaction has been developed for the purpose of blastocyst PGS and provides rapid, accurate and costeffective screening All CCS methods provide accurate aneuploidy screening when used on multiple trophectoderm cell sampled at the blastocyst stage; singlecell analysis poses several issues The introduction of next-generation sequencing platforms in IVF will further reduce the costs of PGS or preimplantation genetic diagnosis and will allow new levels of genetic testing to be explored in IVF Immunological modulation; regulation of endometrial receptivity (Nathalie Lédée, France) During the implantation window, there is a necessary immune switch for fetal tolerance that has a central role for uterine natural killer cells At this phase, documenting the local immune reaction may be useful for those with repeated and unexplained implantation failures, to help identify uterine immunological mechanisms and provide personalized IVF treatment Understanding endometrial omics (Signe Altmäe, Estonia) Omics high-throughput analyses are revolutionizing our understanding of endometrial physiology and pathophysiology Although there is much information from gene expression studies, there is a lack of consensus: - knowledge of clinical application is limited: more well-designed studies are needed - Proteomics and metabolomics will likely be important in the near future 4 extracts reproductive medicine Spring-Summer 2014 Abbreviations are defined in the Glossary, page 6

5 23-24 May Budapest, Hungary New classification proposed for RIF A new classification has been proposed that aims to provide clear guidance on how to confirm RIF. Dr Nick Raine-Fenning (University of Nottingham, UK) suggested a new classification of RIF that clarifies the timepoints for confirming RIF The proposed classification describes RIF as the absence of implantation, defined by a negative serum hcg 14 days after oocyte collection, after two consecutive IVF cycles, ICSI or frozen embryo replacement, where the cumulative number of transferred embryos was no less than four for cleavage-stage embryos and no less than two for blastocyst, with all embryos being of good quality and appropriate developmental stage. Dr N Raine-Fenning advocated the widespread adoption of this new classification. He outlined the five stages of the implantation process (namely, rolling, apposition, adhesion, invasion, and vascularization), adding that implantation should only be considered when invasion of the embryo is complete and it is formally embedded within the endometrium. The timepoints when implantation can be confirmed, and when implantation failure can be diagnosed, have not been clear in previous classifications Timepoints for confirming implantation or its failure have been unclear in the past A new classification should provide clear guidance on confirming RIF in brief AH in the era of blastocyst culture/ vitrification (Basak Balaban, Turkey) AH for fresh cleavage-stage ET does not improve live-birth rates Cumulative pregnancy rate just reaches significance in favour of AH for all patient groups; significance more evident for women with RIF There are insufficient data to show the superiority of blastocyst transfers over cleavage-stage ET supported with AH Total zona removal for blastocyst transfers performed in certain patient groups may be a better than partial AH (depending on physiology) More RCTs are needed before making any recommendations for standard practice Management of RIF: what can the clinician and embryologist do? (Ying Cheong, UK; Denny Sakkas, USA) Lifestyle modifications, surgical interventions dictated by clinical history and findings and modification of ART procedures are approaches that may help in the clinical management of RIF The embryologist and IVF laboratory can help in the management of RIF by: - Strict quality control - Properly caring for gametes/ embryos - Using optimum sperm-selection techniques to ensure the best sperm are used - Assessing embryos using improved and validated morphological screening or new noninvasive and invasive tools Key biological processes in implantation (John Aplin, UK) Implantations fail in the majority of karyotypically abnormal pregnancies Many normal embryos miscarry, usually due to maternal factors (e.g. poor decidualization, spiral arteries that resist remodelling, errors of meiosis, especially in women > 40 years old, failure of immune recognition and abnormalities in blood clotting system) Follow us reproductive medicine Spring-Summer 2014 extracts 5

6 Your EXCEMED EXCEMED: improving reproductive medicine through medical education EXCEMED Excellence in Medical Education is the new name of Serono Symposia International Foundation (SSIF). Our new name marks an exciting point in our evolution, but our focus on education in reproductive medicine, ART and all aspects of fertility care remains paramount. EXCEMED has an innovative educational programme in reproductive medicine The Foundation has provided world-class education to thousands of healthcare professionals over the past four decades. During this time, over 1500 international scientific congresses have been organized, with more than 500 proceedings published in leading international journals. EXCEMED has pioneered online CME courses since 2000; the organization oversees an expanding portfolio of e-learning activities including video lectures, CMEaccredited online courses and symposia. These digital ventures reach over 12,500 people per month via the website or through EXCEMED s e-newsletters. As a non-profit global organization, EXCEMED is dedicated to improving the patient s life through the provision of independent, high-impact CME to scientists, physicians, nurses, pharmacists and other healthcare professionals. Upcoming EXCEMED events of relevance to specialists in reproductive medicine are summarized on the back page of this publication Glossary AH, assisted hatching AMH, anti-müllerian hormone ART, assisted reproductive technology CCS, comprehensive chromosomal screening CME, continuing medical education COS, controlled ovarian stimulation EACCME, European Accreditation Council for CME ET, embryo transfer hcg, human chorionic gonadotrophin ICSI, intracytoplasmic sperm injection IVIG, intravenous immunoglobulin IVF, in vitro fertilisation IUGR, intrauterine growth retardation LH, luteinising hormone OHSS, ovarian hyperstimulation syndrome PCOS, polycystic ovarian syndrome PGS, preimplantation genetic screening RCT, randomized controlled trial RIF, recurrent implantation failure RM, reproductive medicine SET, single embryo transfer SGA, small for gestational age TNF, tumour necrosis factor E-learning The EXCEMED E-learning programme in RM offers a new format of online interactive courses, accredited by EACCME. The first module, on AMH is due to launch in January This module follows a case studybased learning approach, with the content led by Professor Antonio La Marca, University of Modena and Reggio Emilia, Italy The online CME activities combine timely, insightful content with the convenience of home or workplace study. Courses are available for anyone wishing to participate Participants who obtain a satisfactory score on the posttest can obtain a certificate of completion To know more: 6 extracts reproductive medicine Spring-Summer 2014

7 Workshop outcomes Early evaluation of fetal echocardiography Throughout the year, EXCEMED organizes workshops in specialist areas relevant to reproductive medicine and early pregnancy. Working in small groups, attendees have the opportunity to gain clinically focused guidance from world experts in the field. Below is a report on the fetal echocardiography workshop, held in April 2014, in Siena, Italy Technological advances in ultrasonography now enable echocardiography to be performed from as early as weeks gestation. Participants learned the correct methodology to perform early fetal echocardiography, how to optimize acquisition of the correct images and how to evaluate the role of colour/ power Doppler in fetal echocardiography Fetal echocardiography now facilitates visualization of the major cardiac structures from a very early stage of pregnancy In April 2014, physicians specialising in ultrasound and obstetrics participated in a 2-day workshop on fetal echocardiography, held in in Siena, Italy. This workshop taught participants the correct methodology to perform early fetal echocardiography, how to optimize acquisition of the correct images, and how to evaluate the role of colour/power Doppler in fetal echocardiography. The prenatal diagnosis of congenital heart diseases is important for optimizing obstetrical and neonatal care. Early fetal echocardiography now facilitates visualization of the major cardiac structures from a very early stage of pregnancy. Fetal echocardiography requires the use of high-resolution ultrasound equipment, adequate transducer frequencies and specific system settings all of which must be changed in real time to reach the best resolution, for in each patient and for each condition. The normal fetal echocardiogram is targeted to visualise: Visceral situs and cardiac position Four-chamber view, with two separate atrio-ventricular valves Aortic and pulmonary outflow tracts Two great arteries of similar size Evidence of ductal and aortic arches. Doppler techniques (colour and power) are also used to optimize fetal heart images. Organised by Dr Filiberto Maria Severi (Department of Paediatrics, Obstetrics and Reproductive Medicine, Siena University, Italy), the workshop provided participants with a complete understanding of the ultrasound settings needed to perform good fetal echocardiography. The most important scanning planes of the normal fetal heart (apical four chamber view, subcostal four chamber view, long-axis aorta, long-axis pulmonary artery, short-axis ventricles, aortic arch view) were covered in detail, and discussed from both a clinical and a diagnostic perspective. The rules of fetal echocardiography, together with practical suggestions to improve the experience for clinicians and patients alike, were also presented. Follow us extracts 7

8 Upcoming in EXCEMED reproductive medicine EXCEMED is offering a wide range of excellent online and live educational events in the coming months. Please visit to see the latest news on the Reproductive Medicine educational programme. IVF Preceptorship Hamburg, Germany 4-5 July Scientific Organiser R. Fischer, Germany this is the first IVF preceptorship in Germany. Dr Fischer s Fertility Center in Hamburg was one of the first to introduce certified quality management according to ISO 9001 physiology of LH, LH in stimulation protocols, implementing quality management systems in the fertility clinic, risk management in the ART laboratory physicians with expertise in ART lectures, workshops, Q&A discussion and a visit to the clinic and laboratory premises Challenging Issues in Reproductive Medicine Moscow, Russia 8 August Scientific Organiser R. Fischer, Germany this workshop focuses predominantly on PCOS, implantation failure and endometriosis aetiology of PCOS and its management, new strategies to avoid implantation failure, new guidelines for treating endometriosis physicians working in ART lectures, case studies and much opportunity for discussion IVF Preceptorship London, UK 5-6 September Scientific Organiser S. Lavery, UK this preceptorship is dedicated to providing new insights on hot topics in RM PCOS, COS, RIF, new laboratory techniques and equipment for optimisation of IVF, protocols to improve implantation potential and endometrial receptivity physicians with expertise in ART lectures, case studies and much opportunity for discussion 8 extracts reproductive medicine Spring-Summer 2014 Abbreviations are defined in the Glossary, page 6

9 Upcoming in EXCEMED reproductive medicine International School of Ultrasound in Obstetrics and Gynecology Paolo Mascagni Workshop on monitoring of fetal growth Siena, Italy September Scientific Organiser F.M. Severi, Italy this course aims to give a complete understanding of the role of ultrasound in deteriming fetal growth, weight and wellbeing SGA fetuses, macrosomia, IUGR, fetal weight index, use/application of ultrasound examinations physicians with expertise in ultrasound and obstetrics ultrasound examinations in pregnant women, using numerous different approaches 8 th IVF Preceptorship: current practice in the 21 st century Madrid and Valencia, Spain September Scientific Organisers J. A. García Velasco, A. Requena and E. Bosch, Spain this unique preceptorship is delivered through an innovative mix of evidence-based lectures, interactive case studies, working groups and video sessions across two leading centres in IVF care COS and the role of LH, RIF, SET, new laboratory techniques and equipment for optimization of IVF, including current evidence on hysteroscopy for women with infertility clinicians with < 5 years experience in ART lectures, interactive case studies and workshops, and Q&A discussions. IVI 1:1 Intensive shadow course Valencia, Spain, October Scientific Organiser E. Bosch, Spain this intensive one-to-one clinical course provides a unique and exclusive opportunity to work directly alongside experts in IVF, shadowing their practice consultations covering general aspects of IVF management, diagnostic and therapeutic hysteroscopies, oocyte donation clinics clinicians with < 5 years experience in ART sessions involve shadowing consultations and procedures in a working clinic, in daily practice IVF preceptorship Naples, Italy 6-7 November Scientific Organisers F. Maria Ubaldi, L. Rienzi, F. Zullo, Italy this preceptorship in IVF takes place in the clinical setting of GENERA, a pioneering new centre for ART services subjects of current and future interest in IVF clinical management physicians with expertise in ART lectures, workshop, Q&A discussion and visit to the clinic premises Follow us reproductive medicine Spring-Summer 2014 extracts 9

10 Upcoming in EXCEMED reproductive medicine Embryology course St Petersburg, Russia November Scientific Organisers R. Fischer, Germany T. Hardarson, Sweden P. Nagy, USA this course represents a partnership between EXCEMED and ALPHA (Scientists in RM), with ALPHA providing substantial input into the scientific programme new technologies in embryology, latest laboratory practice guidelines, optimizing laboratory conditions, culture environments and selection criteria for human embryos scientists, embryologists, biologists and interested clinicians with experience in this field. lectures, workshop and much opportunity for discussion International conference on fertility preservation Paris, France 3 December Scientific Organisers R. Frydman and M. Grynberg, France this course represents a partnership between EXCEMED and ALPHA (Scientists in RM) chemotherapy-induced loss of follicles, cancer and testicular function, impact of radiotherapy on gonadal function, fertility in cancer survivors, fertility preservation strategies, medical treatments for gonadal damage, ovarian stimulation in cancer patients, ovarian tissue transplantation and cryopreservation physicians and scientists working in reproductive medicine or oncology lectures and Q&A discussion sessions Cryopreservation: focus on fertility preservation Brussels, Belgium January, 2015 Scientific Organisers M.M. Dolmans and J. Donnez, Belgium innovative meeting that includes oral presentations that present the best research findings from young physicians and researchers all aspects of cryopreservation physicians and scientists working in reproductive medicine keynote lectures, workshops, Q&A discussion and oral presentations EXCEMED is a non-profit organization dedicated to providing CME to healthcare professionals. This newsletter is intended for healthcare professionals and provides a brief summary of a selection of previous educational events. EXCEMED will make reasonable efforts to include accurate and current information, wherever possible, but makes no warranties or representations as to its accuracy or completeness. This information is provided as is without warranty of any kind, either express or implied, including but not limited to implied warranty of fitness for particular purpose. EXCEMED has implemented and maintains a Quality Management System which fulfils the requirements of the ISO 9001:2008 standard for the activity of design and provision of training events in the healthcare sector. EXCEMED, All rights reserved. EXCEMED Excellence in Medical Education, Salita di S. Nicola da Tolentino, 1/b, Rome, Italy. Copyright 2014 EXCEMED. All rights reserved. Editorial development: Shalene Chugh, Linda Edmondson, Michèle Piraux, Emma Wadland Contributors: Rene Frydman, Michael Grynberg, Sesh Sunkara, Irene Zerbetto Design: 10 extracts reproductive medicine Spring-Summer 2014 Abbreviations are defined in the Glossary, page 6

11 Future focus Fertility preservation following cancer: an emerging challenge EXCEMED, in partnership with ALPHA (Scientists in Reproductive Medicine) is organizing a pioneering conference at which oncologists and specialists in reproductive endocrinology will discuss strategies for supporting fertility in people with cancer. The meeting takes place on 3 December 2014 in Paris, France We are in an exciting and interesting time, when oncologists and reproductive endocrinologists across the globe rise to the challenge of providing fertility services for people with a history of cancer. Scientific Organisers Rene Frydman (Suresnes, France) and Michael Grynberg (Bondy, France) As more patients survive cancer, preserving their right to have children will become an expectation of treatment and a standard aspect of clinical practice Developments in oncology have improved longterm survival rates for many types of malignancy. However, to survive cancer is no longer enough. The emphasis is shifting, to enable people to live the most normal life possible after cancer; this includes giving them the best possible opportunity to have their own biological children. However, the science and clinical practice of fertility preservation in people with cancer remains at a pioneering-level. Approaches to fertility preservation vary greatly, depending on the age of the patient, the type of malignancy and the RM services that are available locally. Techniques are being developed, but their longterm success is not proven. Organize services; offer urgent care It is possible for reproductive medicine clinics to offer emergency care to people, even when the window between diagnosis and initiation of cancer treatment is narrow. But providing rapid support and intervention requires well-informed oncologists and adaptable fertility clinics. The emergency service must encompass rapid counselling and treatment; the long-term service must offer tissue/gamete storage and ART. Currently only around 30% of oncologists routinely refer patients of child-bearing potential for reproductive counselling. But the need for clinicians to provide adequate fertility preservation to people with cancer is likely to rise considerably over the coming years. Best practices in cancer treatment, emerging data on cryopreservation, tissue transplantation and gonadal stimulation strategies, will be presented at the Paris conference The Paris conference These emerging issues have prompted us to organize the inaugural international conference on fertility preservation. This one-day event is suitable for oncologists and specialists in reproductive endocrinology or fertility care. Lectures and discussions aim to stimulate future improvements in research and clinical practice. Topics to be covered include: Chemotherapy-induced loss of follicles, Cancer and testicular function Impact of radiotherapy on gonadal function Fertility in cancer survivors Fertility preservation strategies Medical treatments for gonadal damage Ovarian stimulation in cancer patients Ovarian tissue transplantation and cryopreservation Fertility preservation is not a magic situation; it is not one where oncologists or reproductive endocrinologists can over-promise success to their patients. However, it is very important that we now develop and test techniques that offer greater hope to people, so that their life after cancer treatment can routinely include the right to have a family. Please join us in Paris, this December, to take these early steps forward in fertility preservation for people with cancer. Got a comment or questions? info@excemed.org reproductive medicine Spring-Summer 2014 extracts 11

12 EXCEMED at your fingertips Improving the patient s life through medical education It s active in here > Six specialty micro sites, including reproductive medicine > Accessible and accredited e-learning packages > A world-class repository of CME knowledge and learning materials > Monthly updates about our events and resources in reproductive medicine > Register with us online and access it all free Better outcomes for patients start here. With over 40 years of experience, EXCEMED has been delivering continuing medical education (CME) longer than any other provider. 12 extracts reproductive medicine Spring-Summer 2014