Summary of the ISPD Preconference Day, June 3, 2012, Miami Beach

Abstract

Preceding the 16th International International Society for Prenatal Diagnosis (ISPD) Conference in Miami Beach, a day of educational courses was organized on Sunday, 3 June 2012. There were eight courses, each lasting half a day. Some of the courses, but not all, were organized by the Special Interest Groups (SIGs) of the ISPD. For more information about these SIGs and their activities, please go to the ISPD website (www.ispdhome.org). Most of the courses were basic courses, designed to give the participant of the main conference background information on topics outside their specific field of expertise. The goal was to enable them to more effectively appreciate the sessions outside their own main field of interest. All courses were well attended: the total number of participants for the main conference was ~550, and for all the eight preconference courses, in total ~420 attendees registered, ranging from 19 to 115 per course. Many course attendees completed an evaluation form. These evaluations were very positive and the organizing committee will take advantage of the comments to further improve the courses in future. Summarizing, the preconference day was a great success and similar days will be organized in future. Below are the highlights of each course. The detection of chromosomal imbalances by microarray (MA) analysis is becoming common practice in prenatal diagnosis. During this course (organized by Dr. V. Cirigliano (Barcelona, Spain) and Dr. B. Faas (Nijmegen, The Netherlands)) Dr. L. Shaffer (Signature Genomics Laboratories, USA), Professor I. van den Veyver (Houston, USA), Dr. B. Faas (Nijmegen, The Netherlands), and Professor J. Vermeesch (Leuven, Belgium) covered all basic aspects of the MA technique, with Professor J. Vermeesch (Leuven, Belgium) also discussing the need for quality control. All the available techniques for the detection of chromosome abnormalities were reviewed, and advantages and disadvantages of cytogenetics, FISH, aCGH, and SNP array, and differences between available array platforms were explained. For the interpretation of MA, available tools for annotations and their use were presented, together with the reporting criteria for detected segmental imbalance. Detailed examples of abnormal results were given, with particular emphasis on copy number gains/losses of uncertain clinical significance and their classification, stressing the fact that there is a difference between continuing and temporary unclear significance. In a large dataset, Dr. Shaffer presented their experience of clinical application of MA in prenatal diagnosis. She showed that in high risk pregnancies, MA can detect up to 6.5% more chromosome abnormalities than conventional cytogenetics can, with overall 4.2% results of unclear significance. Further evidence for an additional value was presented by Dr. Faas, when reviewing the Nijmegen experience with high resolution Affymetrix 250 k and Cytoscan HD array on over 200 pregnancies with structural abnormal ultrasound and normal QF-PCR result: a total of 6.5% clinically relevant segmental imbalances were detected, about 1/3 of these being submicroscopic. Professor van den Veyver presented an overview of MA analysis in products of conceptions and stillbirth and reported data from the Stillbirth Collaborative Research Network. MA can detect chromosome abnormalities without the restrictions of sample quality, relevant for cytogenetic analysis, and MA can provide new insights into the genetic causes of early pregnancy loss. After an introductory overview on Quality Assurance in MA, Professor J. Vermeesch reported on the External Quality Assessment (EQA) scheme carried out jointly by EMQN and CEQA. Of the participating laboratories, 20% and 7% (first year and second year, respectively) reported an incorrect result. The overall quality of the reports improved during the second year, confirming the educational effectiveness of EQA schemes. In the closing lecture, Professor Vermeesch reported on improvements in single cell SNP array analysis. Although for the detection of aneuploidies and partial imbalances BAC arrays are well established in PGD laboratories, SNP genotyping and haplotyping might in the near future provide a powerful and generic method for both chromosome abnormalities and single gene disorders. The theme of course 2 was ‘Ultrasound of genetic syndromes’, with a focus on non-aneuploidy syndromes (course organizers: A Odibo, (St. Louis, USA) and A Borrell (Barcelona, Spain)). Dr. S. Cicero (London, UK) spoke on fetal limb anomalies and the association with genetic syndromes. Her talk included a summary of the 15-year experience of University College Hospital, London. The second speaker was Professor M Evans (New York, USA) who gave an overview of fetal overgrowth syndromes, describing the clinical correlations and a discussion on the role of epigenetics in these anomalies. Dr. D. Chitayat (Toronto, Canada) gave a thought-provoking talk on the diagnostic approach to prenatally detected genital abnormalities. He discussed the factors determining fetal gender and the new recommendations on the nomenclature for intersex disorders from a recent consensus statement. The new suggestion to replace ‘intersex’ with ‘Disorders of Sex Development (DSD)’ was very well received. Professor T. H. Bui (Stockholm, Sweden) gave the fourth lecture, an overview of non-immune hydrops. He reviewed controversial areas, such as the use of laser therapy in the management of non-immune hydrops secondary to congenital pulmonary adenomatoid malformations. The final lecture of the course was by the co-chair for the course Dr. Borrell (Barcelona, Spain). He covered the association between increased nuchal translucency and genetic syndromes and included a review of the Barcelona experience as well as a thorough overview of the literature. There is intense and prolonged interest in the prediction of adverse obstetric events due to abnormal placental implantation. This field is dynamic, with possibilities for therapeutic intervention within grasp. It therefore seemed a good idea to have a preconference course with special reference to this subject and ISPD is grateful to the Chinese Fetal Medicine Foundation for financial support for this course (course organizers: H. Cuckle (New York, USA), P. Benn (Farmington USA), P. Schielen (Bilthoven, The Netherlands), and T. Y. Leung (Hong Kong, China)). Dr. H. Kliman (New Haven, USA) gave a general introduction into physiology of placenta development, as a starting point of how things can deteriorate. Placenta problems emerge much earlier than problems with the fetus, making the placenta a good monitor for the quality of the pregnancy. Dr. Kliman especially addressed the ‘diversion hypothesis’, where PP13 plays an essential role to start a mild inflammatory reaction in the decidua to divert the mother's immune system away from the spiral arterioles. PP13 has always been an interesting candidate as a screening marker for preeclampsia (PE), as the next speaker, Dr. W. Koster (Utrecht, The Netherlands) pointed out in her presentation on existing and new serum markers for the prediction of adverse pregnancy outcome. She gave an overview of a three-phase model where (1) potential biomarkers are identified using data-mining techniques, (2) targeted assays are developed using multiplexed proteomics and metabolomics assays, and (3) candidate multiplexed assays are validated in prospective studies. She presented data on one such validation study (the Markers for UncomPlicated Pregnancies In first Trimester (MUPPIT) study) and took PE one step further, namely as a stress test for life, suggesting that women suffering from PE may also be at higher risk of cardiovascular disease. Subsequently, Dr. K. Downing (Dayton, USA) suggested that screening for adverse obstetric events was a jig saw puzzle with multiple pieces, the pulsatility index of the uterine arteries (ua-PI) surely being one of them. A risk algorithm would also include such factors as maternal history, race, body mass index, and maternal arterial pressure. A bottle neck for the ua-PI measurement currently is the availability of skilled sonographers, as well as issues concerning education and quality assurance, which are all focal points of the activities of FMF-USA. Dr. R. Akolekar (London, UK) presented risk algorithms for PE. He started from the premise that every pregnant woman is at risk for PE, and only birth prevents it. He built a model in which various risk factors pushed the normal distribution to either a higher or lower risk for PE and showed that using this algorithm and including all currently known risk factors, a very high proportion of all PE cases can be detected at a 10% FPR. Finally, Dr. E. Bujold (Quebec, Canada) presented the latest update on an actual therapy to prevent PE and IntraUterine Growth Retardation (IUGR). Reports on aspirin go back to 1978, but after 50 trials, a clear effect had not been established. A dedicated meta-analysis of these studies focusing on early administration has now clearly established that 8 to 16-week administration of low dose aspirin does prevent 50% of PE cases and 55% of IUGR cases. The effect is convincing enough for the UK's National Institute for Health and Clinical Excellence to issue as guideline, and discussions are currently focused on groups of women to be treated, at what dosage and which time of administration. In the past, the ISPD has presented courses on the ethical, legal, and social implications of prenatal genetic diagnosis. Prenatal Diagnosis regularly prints original papers, review articles, and editorials addressing the psychosocial, legal, ethical, and economic aspects of prenatal diagnosis from cross-cultural and interdisciplinary perspectives. The society acknowledges that practice guidelines and best practice standards for prenatal screening and diagnostic procedures must consider historical and cultural differences and divergent perceptions related to reproductive risk and disability and bioethical and legal reasoning. This preconference course, organized by Dr. Pergament (Chicago, USA), attempted to further these educational efforts by encouraging discussion on the legal, regulatory, policy, psychosocial, and cultural influences that affect the development and provision of prenatal clinical genetic services. Professor J. Berg (Cleveland, USA) presented an enthusiastically received talk entitled ‘Testing the Baby and the Bathwater: Prenatal Diagnosis and the Law’. A compelling overview was given of the many aspects of the legal regulations and bioethical dilemmas that surround the development of prenatal genetic technologies and their clinical use. Next, Professor D. Roberts (Chicago, USA) spoke on ‘The Social Context of Prenatal Diagnosis: Gender, Race, and Wealth’. She discussed the influence of the social constructions of gender, race, and wealth on genetics and reproductive genetics technologies and posed several thought-provoking questions about how the emphasis on the use of racial categories influences the provision of culturally sensitive and scientifically valid diagnostic services. The formal presentations concluded with a brief presentation by Dr. Pergament herself, entitled ‘Prenatal Genetic Clinical Services in the Internet Age’. She questioned whether the widespread acceptance of prenatal ultrasound images sent via the internet by clinicians and patients has unintentionally contributed to the acceptance of legally mandated ultrasounds designed to discourage women from accessing prenatal genetic and other types of reproductive health care in the USA. The course ended with a formal question period and a lively informal discussion about informed consent, reproductive rights and autonomy, and the role of race and gender in the design of social science research on noninvasive prenatal testing. This course (organized by P. Devers (North Carolina, USA) and M. Savage (San Carlos, USA)) was designed for health care professionals who counsel about MA in the prenatal setting or assisted reproductive technologies (ART) and preimplantation genetic diagnosis (PGD) or preimplantation genetic screening (PGS), in the preconception setting. The course provided background on the technologies and discussed potential counseling dilemmas that arise in these unique settings, using case examples as the main teaching point. The course began with a brief introduction to the use of MA in the prenatal setting by Professor O. Zuffardi (Pavia, USA), who introduced common terms and compared the available microarray platforms, before exploring counseling for MA in the prenatal setting. M. Savage provided a comprehensive overview of the basic components of pretest and posttest counseling for prenatal MA. Pretest counseling should be tailored on the basis of the indication for testing and the microarray platform being considered. Informed consent is essential. Elements essential to obtaining informed consent include an explanation of the technology and the types of disorders for which testing is being performed; benefits, risks, and limitation of MA; and possible results, with a highlight on results of uncertain clinical significance. All patients should be offered posttest counseling with their results, regardless of the outcome. Additional resources, such as patient-friendly websites, publications, and follow-up referrals or consultations, should be provided to those receiving abnormal or unclear results. Current guidelines regarding the use of MA in prenatal situations, including those from ACMG and ACOG are contradictory; multiple professional organizations (ISPD, NSGC) currently have guidelines in development. It is clear that there is a need for more guidance on the appropriate use of MA prenatally. Some of the more complex issues that arise were explored using a case-based approach. Detecting a variant of uncertain significance (VUS) appears to be of greatest concern to clinicians considering using MA prenatally. M. Savage and Professor Zuffardi reviewed the published literature regarding the incidence of detection of VUS, which varies depending on indication for testing and platform used. Overall, there is ~1% to 2% chance of detecting a VUS. The methods and resources utilized by laboratories in the classification of variants were described, and the differences between the USA and European laboratories were addressed. How to read MA results and a basic introduction to the use of databases for assistance with interpretation was reviewed. Subsequently, M. Savage and Professor C. van Ravenswaaij-Arts (Groningen, The Netherlands) used cases to highlight other possible outcomes, including, reduced penetrance/variable expressivity, consanguinity, nonpaternity, detection of carrier status, and detection of adult-onset conditions. It was noted that in the USA, laboratories are disclosing all results to clinicians, who then have the responsibility of discussing these results with their patient. In some European laboratories, patients are deciding prior to testing which categories of results they would want to receive and are able to opt out of receiving specific results such as variants of uncertain significance or detection of carrier status or adult-onset conditions. In those cases, the laboratory does not disclose the opt-out results to the clinician or the patient. This session concluded with an in-depth presentation by Dr. D. Lililenthal (New York, USA) regarding counseling for ART, PGD, and PGS. An emphasis was made on the current use of 24 chromosome screening (MA for PGS). Finally, several case examples were discussed, demonstrating some of the counseling challenges that can be encountered when offering and performing PGD or PGS. Monochorionic (MC) twins remain a true challenge for clinicians. Most attention has been given to the twin-to-twin transfusion syndrome (TTTS). However, several other major clinical problems of twins diagnosis and adverse is The course was organized by Professor D. The Netherlands) and Professor R. (Leuven, The first speaker was Dr. who covered many aspects of fetal Professor R. USA) with an overview of management or in fetal including results from the by Professor laser with The results of this study will be published It was that laser may be especially to prevent due to in case of or in the the is more than in He gave insights into the of with that may depending on and of A lively discussion the to and the method for For future and to an consensus on these aspects was and was to a review and other to Dr. E. USA) gave a and talk on the management of with one abnormal on techniques for with evidence for the method This is clearly where research is and is to She also discussed of a that interest from the and Professor the use of in the in particular for as a of Professor presented a review of and discussed management using a recent clinical Finally, Professor discussed management of twins with after of one The value and of fetal ultrasound and was The session was to at but the participants seemed to be to the discussion for many more This course, organized by P. Benn USA), T. Y. Leung (Hong Kong, and P. Schielen (Bilthoven, The Netherlands), was designed for those new to prenatal The included clinicians, laboratory genetic and The included a number of the and of prenatal This course began with a talk by Professor H. Cuckle (New screening for syndrome and PE, was how a of maternal and various serum and ultrasound markers can be to Professor K. (London, UK) reviewed the specific methods used to including how the in the screening are how are used and the of risk He how were made for clinical such as maternal multiple pregnancies, and assisted For many there has been a about whether may be used as an to the model used in prenatal In an Dr. USA) the model and then compared the results that be when was to a single the basis of data from the and was that the screening was with both addressed the of quality and quality in prenatal Professor P. Benn the used laboratory methods for and He pointed out that are sensitive to Dr. the results and in and testing that is provided in the USA by the College of He also reviewed data on the of prenatal screening in the USA. External for ultrasound markers and the of review were presented by K. Professor M. Evans provided an overview of and out that there are to be from on how to quality of these presentations the need for in that testing to the use of in prenatal diagnosis is to noninvasive testing for fetal as is becoming more and more in all of a basic course on this was as a The course were Dr. B. Faas (Nijmegen, The Netherlands) and Dr. V. Cirigliano (Barcelona, Spain). The first presentation was given by Dr. M. She all the basic aspects of including both and the platforms and their and or and the analysis after the sample has been An of Dr. was that the and the sample is the of the The second speaker, Dr. H. (Nijmegen, The Netherlands), this when about of in analysis, informed Dr. focused on the difference between or targeted and discussed the differences in terms of and can be carried out by only including of interest in the with low on new and a low risk on It can, also be carried out by and only performing the analysis analysis can then be to include more as all the data are This of analysis can also genetic information on other or are not for techniques might and analysis might A discussion on the and of and counseling and the between the and or her to on the other care with these new The speaker was Professor R. (Hong Kong, who gave an overview of the use of in Prenatal to of can be in one and using and several can be in each for the is more The of in the maternal is of maternal with only to 20% being a for there will be more chromosome in the maternal as compared with normal of the low of fetal in the maternal this difference can only be made relevant of per sample can be of can be and to the reference Subsequently, these can be and in case of a fetal a difference for the number of of chromosome can be for the is only used to of and not to have about the and of has been to be a powerful and on to the subject of noninvasive of the fetal and showed that in an of study both and maternal in the fetal be and that prenatal diagnosis of be She concluded with a number of examples of prenatal of