G Kakourou1, S Kahraman2, G C Ekmekci2, H A Tac2, G Kourlaba3, E Kourkouni3, A Cervero Sanz4, J Martin4, H Malmgren5, C Giménez6, V Gold7, F Carvalho8,9, C Billi10, J F C Chow11, X Vendrell12, G Kokkali13, J Liss14, J Steffann15, J Traeger-Synodinos1. 1. Department of Medical Genetics, Choremio Research Laboratory, National and Kapodistrian University of Athens, Thivon & Livadias, Athens 11527, Greece. 2. Istanbul Memorial Hospital, ART and Reproductive Genetics Unit, Piyale Pasa Bulvari, 34385 Okmeydani sisli-Instanbul, Turkey. 3. Center for Clinical Epidemiology and Outcomes Research (CLEO), 5 Chatzigianni Mexi 11528, Athens, Greece. 4. Igenomix, Parc Científic Universitat de Valéncia, Calle Catedrático Agustín Escardino 9, 46980 Paterna (València), Spain. 5. Stockholm PGD Center, Karolinska University Hospital, Karolinska Universitetssjukhuset, Karolinska vägen, 171 76 Solna, Sweden. 6. Reprogenetics Spain, Carrer de Tuset, 23, 08006 Barcelona, Spain. 7. PGD Lab, Lis Fertility Institute, Lis Maternity and Women's Hospital, Tel Aviv Sourasky Medical Center, 6 Weizmann Street, Tel Aviv 6423906, Israel. 8. Department of Pathology, Faculty of Medicine, University of Porto, Al. Prof. Hernâni Monteiro, 4200-319 Porto, Portugal. 9. Instituto de Investigação e Inovação em Saúde, Universidade do Porto, R. Alfredo Allen, 4200-135 Porto, Portugal. 10. Preimplantation Diagnosis Department, Alfalab Private Diagnostic Laboratory Medical S.A., Anastasiou Georgiou 11, 115 24 Athens, Greece. 11. Department of Obstetrics and Gynaecology, The University of Hong Kong, Tsan Yuk Hospital Preimplantation Genetic Diagnosis Laboratory, Tsan Yuk Hospital, 30 Hospital Road, Sai Ying Pun, Hong Kong. 12. Reproductive Genetics Unit, Sistemas Genómicos Ltd, Ronda G.Marconi 6, 46980 Paterna (València), Spain. 13. Genesis Athens Clinic, Reproductive Medicine Unit, 14 Papanikoli Str, Chalandri 15232, Athens, Greece. 14. Invicta Fertility and Reproductive Center, 10 Rajska St., 80-850 Gdansk, Poland. 15. Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, INSERM UMR1163, Laboratoire de Génétique, APHP Hopital Necker-Enfants Malades, 149 rue de Sévres, 75743 PARIS CEDEX 15, Paris, France.
Abstract
STUDY QUESTION: Has PGD-HLA been successful relative to diagnostic and clinical efficacy? SUMMARY ANSWER: The diagnostic efficacy of PGD-HLA protocols was found lower in this study in comparison to published PGD-HLA protocols and to that reported for general PGD by ESHRE (78.5 vs 94.1% and vs 92.6%, respectively), while the clinical efficacy has proven very difficult to assess due to inadequate follow-up of both the ART/PGD and HSCT procedure outcomes. WHAT IS KNOWN ALREADY: The first clinical cases for PGD-HLA were reported in 2001. It is now a well-established procedure, with an increasing number of cycles performed every year. However, PGD-HLA is still offered by relatively few PGD centres, the currently available data is fragmented and most reports on PGD-HLA applications are limited in number and scope. Published systematic details on methodology, diagnostic results, overall ART success and haematopoietic stem cell transplantation (HSCT) outcomes are limited, precluding an evaluation of the true clinical utility of PGD-HLA cycles. STUDY DESIGN, SIZE, DURATION: This retrospective multi-centre cohort study aimed to investigate the diagnostic and clinical efficacy of the PGD-HLA procedure and the aspects of PGD-HLA cycles influencing positive outcomes: birth of genetically suitable donor-baby (or babies) and HSCT. In April 2014, 32 PGD centres (Consortium members and non-members) with published/known PGD-HLA activity were invited to participate. Between February and September 2015, 14 centres submitted their data, through a custom-designed secure database, with unique login access for each centre. Data parameters covered all aspects of PGD-HLA cycles (ART, embryology and genetic diagnosis), donor-babies born and HSCT. PARTICIPANTS/MATERIALS, SETTING, METHODS: From 716 cycles submitted by 14 centres (performed between August 2001 and September 2015), the quality evaluation excluded 12 cycles, leaving 704, from 364 couples. The online database, based on REDCap, a free, secure, web-based data-capture application, was customized by Centre for Clinical Epidemiology and Outcomes Research (CLEO), Athens. Continuous variables are presented using mean, standard deviation, median and interquartile range, and categorical variables are presented as absolute and relative frequencies. MAIN RESULTS AND THE ROLE OF CHANCE: The data included 704 HLA-PGD cycles. Mean maternal age was 33.5 years. Most couples (81.3%) requested HLA-typing with concurrent exclusion of a single monogenic disease (58.6% for beta-thalassaemia). In 92.5% couples, both partners were fertile, with an average 1.93 HLA-PGD cycles/couple. Overall, 9751 oocytes were retrieved (13.9/cycle) and 5532 embryos were analysed (7.9/cycle). Most cycles involved fresh oocytes (94.9%) and Day 3 embryo biopsy (85.3%). In 97.5% of cycles, the genotyping method involved PCR only. Of 4343 embryos diagnosed (78.5% of analysed embryos), 677 were genetically suitable (15.4% of those analysed for HLA alone, 11.6% of those analysed for HLA with exclusion of monogenic disease). Of the 364 couples, 56.6% achieved an embryo transfer (ET) and 598 embryos were transferred in 382 cycles, leading to 164 HCG-positive pregnancies (pregnancy rate/ET 41.3%, pregnancy rate/initiated cycle 23.3%) and 136 babies born (live birth rate/ET 34.3%, live birth rate/initiated cycle 19.3%) to 113 couples. Data analysis identified the following limitations to the overall success of the HLA-PGD procedure: the age of the mother undergoing the treatment cycle, the number of oocytes collected per cycle and genetic chance. HSCT was reported for 57 cases, of which 64.9% involved combined umbilical cord-blood and bone marrow transplantation from the HLA-identical sibling donor; 77.3% of transplants reported no complications. LIMITATIONS REASONS FOR CAUTION: The findings of the study may be limited as not all PGD centres with PGD-HLA experience participated. Reporting bias on completion of the online database may be another potential limitation. Furthermore, the study is based on retrospective data collection from centres with variable practices and strategies for ART, embryology and genetic diagnosis. WIDER IMPLICATIONS OF THE FINDINGS: This is the first multi-centre study evaluating the clinical utility of PGD-HLA, indicating variations in practice and outcomes throughout 15 years and between centres. The study highlights parameters important for positive outcomes and provides important information for both scientists and couples interested in initiating a cycle. Above all, the study underlines the need for better collaboration between all specialists involved in the ART-PGD/HLA procedure, as well as the need for comprehensive and prospective long-term data collection, and encourages all specialists to aim to properly evaluate and follow-up all procedures, with the ultimate aim to promote best practice and encourage patient informed decision making. STUDY FUNDING/COMPETING INTEREST(S): The study wishes to acknowledge ESHRE for funding the customization of the REDCap database. There are no competing interests. TRIAL REGISTRATION NUMBER: N/A.
STUDY QUESTION: Has PGD-HLA been successful relative to diagnostic and clinical efficacy? SUMMARY ANSWER: The diagnostic efficacy of PGD-HLA protocols was found lower in this study in comparison to published PGD-HLA protocols and to that reported for general PGD by ESHRE (78.5 vs 94.1% and vs 92.6%, respectively), while the clinical efficacy has proven very difficult to assess due to inadequate follow-up of both the ART/PGD and HSCT procedure outcomes. WHAT IS KNOWN ALREADY: The first clinical cases for PGD-HLA were reported in 2001. It is now a well-established procedure, with an increasing number of cycles performed every year. However, PGD-HLA is still offered by relatively few PGD centres, the currently available data is fragmented and most reports on PGD-HLA applications are limited in number and scope. Published systematic details on methodology, diagnostic results, overall ART success and haematopoietic stem cell transplantation (HSCT) outcomes are limited, precluding an evaluation of the true clinical utility of PGD-HLA cycles. STUDY DESIGN, SIZE, DURATION: This retrospective multi-centre cohort study aimed to investigate the diagnostic and clinical efficacy of the PGD-HLA procedure and the aspects of PGD-HLA cycles influencing positive outcomes: birth of genetically suitable donor-baby (or babies) and HSCT. In April 2014, 32 PGD centres (Consortium members and non-members) with published/known PGD-HLA activity were invited to participate. Between February and September 2015, 14 centres submitted their data, through a custom-designed secure database, with unique login access for each centre. Data parameters covered all aspects of PGD-HLA cycles (ART, embryology and genetic diagnosis), donor-babies born and HSCT. PARTICIPANTS/MATERIALS, SETTING, METHODS: From 716 cycles submitted by 14 centres (performed between August 2001 and September 2015), the quality evaluation excluded 12 cycles, leaving 704, from 364 couples. The online database, based on REDCap, a free, secure, web-based data-capture application, was customized by Centre for Clinical Epidemiology and Outcomes Research (CLEO), Athens. Continuous variables are presented using mean, standard deviation, median and interquartile range, and categorical variables are presented as absolute and relative frequencies. MAIN RESULTS AND THE ROLE OF CHANCE: The data included 704 HLA-PGD cycles. Mean maternal age was 33.5 years. Most couples (81.3%) requested HLA-typing with concurrent exclusion of a single monogenic disease (58.6% for beta-thalassaemia). In 92.5% couples, both partners were fertile, with an average 1.93 HLA-PGD cycles/couple. Overall, 9751 oocytes were retrieved (13.9/cycle) and 5532 embryos were analysed (7.9/cycle). Most cycles involved fresh oocytes (94.9%) and Day 3 embryo biopsy (85.3%). In 97.5% of cycles, the genotyping method involved PCR only. Of 4343 embryos diagnosed (78.5% of analysed embryos), 677 were genetically suitable (15.4% of those analysed for HLA alone, 11.6% of those analysed for HLA with exclusion of monogenic disease). Of the 364 couples, 56.6% achieved an embryo transfer (ET) and 598 embryos were transferred in 382 cycles, leading to 164 HCG-positive pregnancies (pregnancy rate/ET 41.3%, pregnancy rate/initiated cycle 23.3%) and 136 babies born (live birth rate/ET 34.3%, live birth rate/initiated cycle 19.3%) to 113 couples. Data analysis identified the following limitations to the overall success of the HLA-PGD procedure: the age of the mother undergoing the treatment cycle, the number of oocytes collected per cycle and genetic chance. HSCT was reported for 57 cases, of which 64.9% involved combined umbilical cord-blood and bone marrow transplantation from the HLA-identical sibling donor; 77.3% of transplants reported no complications. LIMITATIONS REASONS FOR CAUTION: The findings of the study may be limited as not all PGD centres with PGD-HLA experience participated. Reporting bias on completion of the online database may be another potential limitation. Furthermore, the study is based on retrospective data collection from centres with variable practices and strategies for ART, embryology and genetic diagnosis. WIDER IMPLICATIONS OF THE FINDINGS: This is the first multi-centre study evaluating the clinical utility of PGD-HLA, indicating variations in practice and outcomes throughout 15 years and between centres. The study highlights parameters important for positive outcomes and provides important information for both scientists and couples interested in initiating a cycle. Above all, the study underlines the need for better collaboration between all specialists involved in the ART-PGD/HLA procedure, as well as the need for comprehensive and prospective long-term data collection, and encourages all specialists to aim to properly evaluate and follow-up all procedures, with the ultimate aim to promote best practice and encourage patient informed decision making. STUDY FUNDING/COMPETING INTEREST(S): The study wishes to acknowledge ESHRE for funding the customization of the REDCap database. There are no competing interests. TRIAL REGISTRATION NUMBER: N/A.
Authors: M De Rycke; A De Vos; F Belva; V Berckmoes; M Bonduelle; A Buysse; K Keymolen; I Liebaers; J Nekkebroeck; P Verdyck; W Verpoest Journal: J Hum Genet Date: 2020-02-27 Impact factor: 3.172
Authors: Kasorn Tiewsiri; Somjate Manipalviratn; Warachaya Sutheesophon; Preeda Vanichsetakul; Piyarat Thaijaroen; Pagawadee Ketcharoon; Cara K Bradley; Steven J McArthur; Weena Krutsawad; James T A Marshall; Konstantinos I Papadopoulos Journal: Biomed Res Int Date: 2020-06-26 Impact factor: 3.411