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Poulton A, Menezes M, Hardy T, Lewis S, Hui L. Clinical outcomes following preimplantation genetic testing for monogenic conditions: a systematic review of observational studies. Am J Obstet Gynecol 2025; 232:150-163. [PMID: 39362513 DOI: 10.1016/j.ajog.2024.09.114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2024] [Revised: 09/13/2024] [Accepted: 09/27/2024] [Indexed: 10/05/2024]
Abstract
OBJECTIVE We aimed to report a summary of clinical outcomes following preimplantation genetic testing for monogenic conditions, by performing a systematic review of published literature on clinical pregnancy and live birth rates following preimplantation genetic testing due to a monogenic indication. Additionally, we aimed to undertake a subgroup analysis of clinical outcomes of concurrent monogenic and aneuploidy screening. DATA SOURCES Three electronic databases (MEDLINE, EMBASE, and PubMed) were searched from inception to May 2024. STUDY ELIGIBILITY CRITERIA Quantitative data audits, observational studies, and case series reporting clinical outcomes for individuals undergoing preimplantation genetic testing for a monogenic indication were included. Only studies using blastocyst biopsies with polymerase chain reaction-based or genome-wide haplotyping methods for molecular analysis were eligible to reflect current laboratory practice. METHODS Quality assessment was performed following data extraction using an adaptation of the Joanna Briggs critical appraisal tool for case series. Results were extracted, and pooled mean clinical pregnancy rates and birth rates were calculated with 95% confidence intervals (95% CI). We compared outcomes between those with and without concurrent preimplantation genetic testing for aneuploidy. RESULTS Our search identified 1372 publications; 51 were eligible for inclusion. Pooled data on 5305 cycles and 5229 embryo transfers yielded 1806 clinical pregnancies and 1577 births. This translated to clinical pregnancy and birth rates of 34.0% [95% CI: 32.8%-35.3%] and 29.7% [95% CI: 28.5%-31.0%] per cycle and 24.8% [95% CI: 23.6%-26.0%] and 21.7% [95% CI: 20.8%-23.1%] per embryo transfer. In studies with concurrent aneuploidy screening, clinical pregnancy and birth rates were 43.3% [95% CI: 40.2%-46.5%] and 37.6% [95% CI: 34.6%-40.8%] per cycle and 37.0% [95% CI: 33.9%-40.3%] and 31.8% [95% CI: 28.8%-35.0%] per embryo transfer. Studies without aneuploidy screening reported clinical pregnancy and birth rates of 32.5% [95% CI: 31.0%-34.1%] and 28.1% [95% CI: 26.6%-29.7%] per cycle and 21.2% [95% CI: 19.8%-22.6%] and 18.6% [95% CI: 17.3%-20.0%] per embryo transfer. CONCLUSION This systematic review reveals promising clinical outcome figures for this indication group. Additionally, synthesizing the published scientific literature on clinical outcomes from preimplantation genetic testing for monogenic conditions provides a rigorous, noncommercial evidence base for counseling.
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Affiliation(s)
- Alice Poulton
- Genetics, Monash IVF Group Ltd, Clayton, VIC, Australia; Department of Obstetrics, Gynaecology and Newborn health, University of Melbourne, Parkville, VIC, Australia; Reproductive Epidemiology, Murdoch Children's Research Institute, Parkville, VIC, Australia.
| | - Melody Menezes
- Genetics, Monash IVF Group Ltd, Clayton, VIC, Australia; Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia; Victorian Clinical Genetics Service, Parkville, VIC, Australia
| | - Tristan Hardy
- Genetics, Monash IVF Group Ltd, Clayton, VIC, Australia; Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia
| | - Sharon Lewis
- Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia; Reproductive Epidemiology, Murdoch Children's Research Institute, Parkville, VIC, Australia
| | - Lisa Hui
- Department of Obstetrics, Gynaecology and Newborn health, University of Melbourne, Parkville, VIC, Australia; Reproductive Epidemiology, Murdoch Children's Research Institute, Parkville, VIC, Australia; Mercy Perinatal, Mercy Hospital for Women, Heidelberg, VIC, Australia; The Northern Hospital, Epping, VIC, Australia
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Bacus J, Lammers J, Loubersac S, Lefebvre T, Leperlier F, Barriere P, Fréour T, Reignier A. [Pre-implantation genetic testing: Comparison between cleavage stage and blastocyst biopsy]. ACTA ACUST UNITED AC 2020; 49:266-274. [PMID: 33232814 DOI: 10.1016/j.gofs.2020.11.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Indexed: 11/19/2022]
Abstract
OBJECTIVES Preimplantation genetic testing (PGT) refers to the set of techniques for testing whether embryos obtained through in vitro fertilization have genetic defect. There is a lack of global standardization regarding practices between countries or even from one center to another. In ours, biopsies are preferably performed on day 3 embryos, but also at the blastocyst stage on day 5. The blastocyst biopsy often requires systematic freezing of the embryos before obtaining the genetic results, whereas day 3 biopsy allows fresh embryo transfer of the healthy or balanced embryo after getting the genetic results. We wanted to compare the chances of success for couples performing PGT in our center according to the day of the biopsy. METHODS For this, we carried out a retrospective monocentric study including all PGT cycles performed between 2016 and 2019 divided into two groups: day 3 or day 5 biopsy. RESULTS There was no significant difference in terms of live birth rate (P=0.7375) after fresh embryo transfers, as well for pregnancy rates, clinical pregnancy rates, implantation rates and miscarriage rates. On the other hand, we observed higher live birth rates after frozen-thawed embryo transfer when the biopsy was performed on day 5 rather on day 3 (P=0.0001). We also wanted to assess what was the most efficient biopsy strategy in our laboratory. Our rates of useful embryos were similar regardless of the day of the biopsy (34% in D3 and 37.7% in D5, P=0.244). No statistical difference was found in the number of unnecessarily biopsied embryos in the two groups. But still, the percentage of embryos biopsied on D5 and immediately frozen was 42.8% (118 blastocysts), while no embryo biopsied on D3 led to this case. CONCLUSION Therefore, our results are in favor of generalization of the D5 biopsy as the international standard. However, the organizational, financial and logistical implications that this technic would impose make it unsystematic in our center.
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Affiliation(s)
- J Bacus
- Service de médecine et biologie du développement et de la reproduction, CHU de Nantes, 38, boulevard Jean-Monnet, 44093 Nantes cedex 1, France
| | - J Lammers
- Service de médecine et biologie du développement et de la reproduction, CHU de Nantes, 38, boulevard Jean-Monnet, 44093 Nantes cedex 1, France; Inserm, unité mixte de recherche 1064, institut de transplantatino urologie néphrologie, centre de recherche en transplantation et immunologie, Nantes Université, 44000 Nantes, France
| | - S Loubersac
- Service de médecine et biologie du développement et de la reproduction, CHU de Nantes, 38, boulevard Jean-Monnet, 44093 Nantes cedex 1, France; Inserm, unité mixte de recherche 1064, institut de transplantatino urologie néphrologie, centre de recherche en transplantation et immunologie, Nantes Université, 44000 Nantes, France
| | - T Lefebvre
- Service de médecine et biologie du développement et de la reproduction, CHU de Nantes, 38, boulevard Jean-Monnet, 44093 Nantes cedex 1, France
| | - F Leperlier
- Service de médecine et biologie du développement et de la reproduction, CHU de Nantes, 38, boulevard Jean-Monnet, 44093 Nantes cedex 1, France
| | - P Barriere
- Service de médecine et biologie du développement et de la reproduction, CHU de Nantes, 38, boulevard Jean-Monnet, 44093 Nantes cedex 1, France; Inserm, unité mixte de recherche 1064, institut de transplantatino urologie néphrologie, centre de recherche en transplantation et immunologie, Nantes Université, 44000 Nantes, France
| | - T Fréour
- Service de médecine et biologie du développement et de la reproduction, CHU de Nantes, 38, boulevard Jean-Monnet, 44093 Nantes cedex 1, France; Inserm, unité mixte de recherche 1064, institut de transplantatino urologie néphrologie, centre de recherche en transplantation et immunologie, Nantes Université, 44000 Nantes, France
| | - A Reignier
- Service de médecine et biologie du développement et de la reproduction, CHU de Nantes, 38, boulevard Jean-Monnet, 44093 Nantes cedex 1, France; Inserm, unité mixte de recherche 1064, institut de transplantatino urologie néphrologie, centre de recherche en transplantation et immunologie, Nantes Université, 44000 Nantes, France.
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Jans V, Dondorp W, Mastenbroek S, Mertes H, Pennings G, Smeets H, de Wert G. Between innovation and precaution: how did offspring safety considerations play a role in strategies of introducing new reproductive techniques? Hum Reprod Open 2020; 2020:hoaa003. [PMID: 32201741 PMCID: PMC7077615 DOI: 10.1093/hropen/hoaa003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Revised: 12/23/2019] [Indexed: 12/12/2022] Open
Abstract
The field of reproductive medicine has been criticized for introducing ARTs without systematic research on possible safety risks and for failing to meet the standards of evidence-based innovation held elsewhere in medicine. In this paper, firstly, we ask whether ‘responsible innovation’ has been a concern for the field, and if so, how it has understood the practical implications of this idea for the development and introduction of potentially risky new ARTs. Secondly, we consider whether the field has indeed fallen short of its responsibilities in this respect, and if so, how things can be improved. To answer these questions, we present three case studies involving the introduction of a new reproductive technology: ICSI, preimplantation genetic testing and mitochondrial replacement therapy. As a framework for analyzing these cases, we used Per Sandin’s account of the four dimensions of dealing with risks (threat, uncertainty, action, command) that are central to debates about the possible role of the so-called precautionary principle. We conclude that, although offspring safety concerns have been on the agenda of the debate about bringing the relevant technologies to the clinic, systematic safety and effectiveness studies were not always conducted. As professionals in assisted reproduction have a responsibility to take account of the welfare of the children they are creating, we suggest a policy of proceeding with systematic caution. Legal measures may be needed to ensure that professional guidance is followed in practice. Finally, an open question concerns the threshold for acceptable risk in the context of introducing new ARTs. Multiple stakeholders, including professional societies and patient organizations, should have a role in the urgent debate about this.
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Affiliation(s)
- Verna Jans
- Department of Health, Ethics and Society and Research School GROW for Oncology & Developmental Biology, Maastricht University, Maastricht, The Netherlands
| | - Wybo Dondorp
- Department of Health, Ethics and Society and Research School GROW for Oncology & Developmental Biology, Maastricht University, Maastricht, The Netherlands
| | - Sebastiaan Mastenbroek
- Amsterdam University Medical Center, University of Amsterdam, Center for Reproductive Medicine, Amsterdam Reproduction & Development Research Institute, Amsterdam, Netherlands
| | - Heidi Mertes
- Bioethics Institute Ghent (BIG), Department of Philosophy and Moral Sciences, Ghent University, Ghent, Belgium
| | - Guido Pennings
- Bioethics Institute Ghent (BIG), Department of Philosophy and Moral Sciences, Ghent University, Ghent, Belgium
| | - Hubert Smeets
- Department of Clinical Genomics, Research School GROW for Oncology & Developmental Biology, Maastricht University, Maastricht, The Netherlands
| | - Guido de Wert
- Department of Health, Ethics and Society and Research School GROW for Oncology & Developmental Biology, Maastricht University, Maastricht, The Netherlands
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Outcomes of preimplantation genetic diagnosis in neurofibromatosis type 1. Fertil Steril 2015; 103:761-8.e1. [DOI: 10.1016/j.fertnstert.2014.11.021] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2014] [Revised: 10/30/2014] [Accepted: 11/17/2014] [Indexed: 11/19/2022]
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Couture V, Drouin R, Tan SL, Moutquin JM, Bouffard C. Cross-border reprogenetic services. Clin Genet 2014; 87:1-10. [PMID: 24798608 DOI: 10.1111/cge.12418] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2014] [Revised: 04/27/2014] [Accepted: 04/29/2014] [Indexed: 12/19/2022]
Abstract
The purpose of this review is to synthesize the current knowledge on the international movement of patients and biopsied embryo cells for pre-implantation genetic diagnosis and its different applications. Thus far, few attempts have been made to identify the specific nature of this phenomenon called 'cross-border reprogenetic services'. There is scattered evidence, both empirical and speculative, suggesting that these services raise major issues in terms of service provision, risks for patients and the children-to-come, the legal liabilities of physicians, as well as social justice. To compile this evidence, this review uses the narrative overview protocol combined with thematic analysis. Five major themes have emerged from the literature at the conjunction of cross-border treatments and reprogenetics: 'scope', 'scale', 'motivations', 'concerns', and 'governance'. Similar themes have already been observed in the case of other medical tourism activities, but this review highlights their singularity with reprogenetic services. It emphasizes the diagnostic and autologous feature of reprogenetics, the constant risk of misdiagnosis, the restriction on certain tests for medically controversial conditions, and the uncertain accessibility of genetic counseling in cross-border settings.
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Affiliation(s)
- V Couture
- Laboratory of Transdisciplinary Research in Genetics, Medicines and Social Sciences, Division of Genetics, Department of Pediatrics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada
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Thorn P, Wischmann T. German guidelines for psychosocial counselling in the area of “cross border reproductive services”. Arch Gynecol Obstet 2012; 287:599-606. [DOI: 10.1007/s00404-012-2599-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2012] [Accepted: 10/09/2012] [Indexed: 11/28/2022]
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Ressler IB, Jaeger AS, Lindheim SR. Evolving ethical issues in third party reproduction: Local and global considerations. World J Med Genet 2012; 2:1-8. [DOI: 10.5496/wjmg.v2.i1.1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
There continues to be an increase in utilization of assisted reproductive technology (ART), including the use of third party gametes. Specifically, the use of third party oocytes, most recently reported in 2010 by the United States (US) Center for Disease Control and Society of Reproductive Medicine, accounted for 15 504 cycles and 7334 live births. This translates into approximately 11% of all the in vitro fertilization cases performed in the US. As utilization increases and the technological tools advance, they have created underappreciated and unforeseen ethical quandaries. As such, many practitioners think they “have heard it all”. However, each ART scenario is novel with the potential to pose complex unforeseen issues, potentially creating global challenges that could impact broad social and legal questions and test the moral consciousness’ of practitioners, policymakers and patients. While there are published US national guidelines to assist practitioners, we have identified new complex issues in assisted reproduction that present unique challenges, and we give a perspective from our eyes in the Western Hemisphere looking out to a global level. Specifically, this review focuses on some of the more recent and evolving issues that currently are and will be confronting us in the upcoming years. Particular attention focuses on discrepancies between third party legal contracts and ART consents regarding level of information sharing, and oocyte and embryo directives and management; dilemmas and obligations surrounding disclosure of medical outcomes especially in the context of growing access to Direct to Consumer genetic testing and Reproductive Tourism-Exile. Given the complexity of these and other ethical questions, finding answers may be achieved by ending the isolation of reproductive professionals and instead promoting increased and consistent communication among physicians, embryologists, therapists and reproductive attorneys to confront these evolving ethical quandaries.
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Abstract
More than two decades after the first clinical application, preimplantation genetic diagnosis (PGD) is an established medical procedure and an accepted alternative to conventional prenatal diagnosis for patients at high risk of transmitting a genetic disorder to their offspring. The great advantage of PGD is that the diagnostic procedure is made already at the embryo stage, before transfer to the patient, and the need for pregnancy termination is thereby avoided. However, PGD can only be performed in connection with in-vitro fertilisation followed by embryo biopsy and genetic analysis of single cells, a complex and cumbersome procedure for both the couple as well as the professionals involved in the treatment. However, for couples at high risk of having an affected child, PGD may be the most attractive alternative to conceive unaffected children.
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Desmyttere S, Bonduelle M, Nekkebroeck J, Roelants M, Liebaers I, De Schepper J. Growth and health outcome of 102 2-year-old children conceived after preimplantation genetic diagnosis or screening. Early Hum Dev 2009; 85:755-9. [PMID: 19896307 DOI: 10.1016/j.earlhumdev.2009.10.003] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2009] [Revised: 10/13/2009] [Accepted: 10/15/2009] [Indexed: 10/20/2022]
Abstract
OBJECTIVE The major objective of this study was to determine whether the embryo biopsy procedure might cause growth restriction or affect health outcome of children. STUDY DESIGN Auxological data and physical findings were compared at birth and age 2 for 102 children (70 singletons and 32 twins) born after PGD/PGS and 102 matched children born after intracytoplasmic sperm injection (ICSI) in a prospective study. RESULTS No statistically significant differences regarding weight, height and head circumference standard deviation scores (SDS) at birth and at age two years were observed. At two years of age the mean BMI SDS tended to be lower in PGD/PGS children (p=0.058). PGD/PGS babies had been more often breastfed (p=0.013), but mostly during a shorter time. The prevalence of major as well as minor congenital anomalies, hospital admissions and surgical interventions was similar. CONCLUSION Children born after embryo biopsy applied in PGD/PGS present similar prenatal and postnatal growth and health outcome in the first two years of life compared to ICSI children. Up till now, PGD and PGS appear not to be associated with a higher risk for health problems.
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Affiliation(s)
- Sonja Desmyttere
- Centre for Medical Genetics, UZBrussel, Vrije Universiteit Brussel, Brussels, Belgium.
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Gutiérrez-Mateo C, Sánchez-García JF, Fischer J, Tormasi S, Cohen J, Munné S, Wells D. Preimplantation genetic diagnosis of single-gene disorders: experience with more than 200 cycles conducted by a reference laboratory in the United States. Fertil Steril 2009; 92:1544-56. [DOI: 10.1016/j.fertnstert.2008.08.111] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2008] [Revised: 08/15/2008] [Accepted: 08/21/2008] [Indexed: 10/21/2022]
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Liebaers I, Desmyttere S, Verpoest W, De Rycke M, Staessen C, Sermon K, Devroey P, Haentjens P, Bonduelle M. Report on a consecutive series of 581 children born after blastomere biopsy for preimplantation genetic diagnosis. Hum Reprod 2009; 25:275-82. [PMID: 19713301 DOI: 10.1093/humrep/dep298] [Citation(s) in RCA: 102] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Preimplantation genetic diagnosis (PGD) and subsequently preimplantation genetic screening (PGS) have been introduced since 1990. The difference from the already existing in vitro fertilization (IVF) technology, using intracytoplasmic sperm injection (ICSI), was the embryo biopsy at day 3 after fertilization. Although healthy children post-PGD/PGS have been born, the question of whether embryo biopsy could have any harmful effects has to be studied on large series in a prospective manner. METHODS A prospective cohort study was undertaken from 1992 until 2005, using the same approach as for the follow-up of IVF and ICSI children conceived in the same centre. Questionnaires were sent to physicians and parents at conception and at delivery. Children were examined at 2 months of age by trained clinical geneticists whenever possible. RESULTS Data collected on 581 post-PGD/PGS children showed that term, birthweight and major malformation rates were not statistically different from that of 2889 ICSI children, with overall rates of major malformation among these post-PGD/PGS and ICSI children being 2.13 and 3.38%, respectively (odds ratio [OR]: 0.62; exact 95% confidence limits [95% CL]: 0.31-1.15). However, the overall perinatal death rate was significantly higher among post-PGD/PGS children compared with ICSI children (4.64 versus 1.87%; OR: 2.56; 95% CL: 1.54-4.18). When stratified for multiple births, perinatal death rates among PGD/PGS singleton and ICSI singleton children were similar (1.03 versus 1.30%; OR: 0.83; 95% CL: 0.28-2.44), but significantly more perinatal deaths were seen in post-PGD/PGS multiple pregnancies compared with ICSI multiple pregnancies (11.73 versus 2.54%; OR: 5.09; 95% CL: 2.80-9.90). The overall misdiagnosis rate was below 1%. CONCLUSIONS Embryo biopsy does not add risk factors to the health of singleton children born after PGD or PGS. The perinatal death rate in multiple pregnancies is such that both caution and long-term follow-up are required.
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Affiliation(s)
- I Liebaers
- Centre for Medical Genetics, Universitair Ziekenhuis Brussel, Laarbeeklaan 101 1090, Brussels, Belgium.
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Keymolen K, Staessen C, Verpoest W, Michiels A, Bonduelle M, Haentjens P, Vanderelst J, Liebaers I. A proposal for reproductive counselling in carriers of Robertsonian translocations: 10 years of experience with preimplantation genetic diagnosis. Hum Reprod 2009; 24:2365-71. [DOI: 10.1093/humrep/dep201] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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Preimplantation genetic diagnosis for myotonic dystrophy type 1: upon request to child. Eur J Hum Genet 2009; 17:1403-10. [PMID: 19367318 DOI: 10.1038/ejhg.2009.56] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Preimplantation genetic diagnosis (PGD) is an alternative to prenatal diagnosis for patients at risk of transmitting an inherited disease such as myotonic dystrophy type 1(DM1) to their offspring. In this paper, the clinical application of preimplantation diagnosis for DM1 upon request to children born is described in a large cohort of risk couples. PGD could be offered to all 78 couples opting for PGD regardless of the triplet repeat size. The incidence of major complications was minimalised following a careful assessment in affected DM1 females anticipating possible cardiological, obstetrical and anaesthetical problems. A live-birth delivery rate per cycle with oocyte retrieval of 20% was the outcome. Forty-eight of the 49 children born are in good health and have normal psychomotor development.
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McArthur SJ, Leigh D, Marshall JT, Gee AJ, De Boer KA, Jansen RPS. Blastocyst trophectoderm biopsy and preimplantation genetic diagnosis for familial monogenic disorders and chromosomal translocations. Prenat Diagn 2008; 28:434-42. [PMID: 18444225 DOI: 10.1002/pd.1924] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
OBJECTIVE Modern in vitro fertilization practices involve transfer of embryos as blastocysts, when anabolic metabolism is well established and pregnancy rates can be maintained while transferring embryos singly to avoid multiple pregnancies. Embryo biopsy for preimplantation genetic diagnosis (PGD), however, is generally performed on day 3, when the embryo comprises just 6 to 8 cells, one or two of which are removed for testing. Implantation rates and clinical pregnancy rates have remained relatively low and a harmful effect from losing one or more cells from such early embryos has not been excluded. METHODS We performed a sequential study involving 399 egg retrievals and 1879 embryo biopsies for patients undergoing PGD to avoid a serious monogenic disease or an unbalanced chromosomal translocation. We compared implantation and viable pregnancy rates after biopsies taken on day 3 (cleavage-stage biopsy) with biopsies delayed until day 5 or 6, when the embryo is a blastocyst and 5 or more cells can be sampled from the trophectoderm while the inner cell mass, from which the fetus develops, remains intact. All embryos were transferred as blastocysts. RESULTS Despite fewer blastocysts than cleavage embryos biopsied and tested (3.6 compared to 6.6), implantation rates per embryo transferred were 43.4% if biopsied at the blastocyst stage and 25.6% if biopsied at the cleavage stage (P < 0.01), with ongoing or live-birth pregnancy rates per egg retrieval of 34.2% (average transfer number 1.1) for blastocyst biopsies and 25.5% (transfer number 1.6) for cleavage stage biopsies (P < 0.05, 1-tailed). The multiple pregnancy rate for monogenic disease exclusion fell from 16.7% to 2% (P = 0.04, 1-tailed). CONCLUSIONS For exclusion of genetic disease, day 5-6 blastocyst-stage biopsies are more likely to be followed by implantation and singleton births than is the case after PGD performed on day 3.
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Keymolen K, Goossens V, De Rycke M, Sermon K, Boelaert K, Bonduelle M, Van Steirteghem A, Liebaers I. Clinical outcome of preimplantation genetic diagnosis for cystic fibrosis: the Brussels' experience. Eur J Hum Genet 2007; 15:752-8. [PMID: 17440499 DOI: 10.1038/sj.ejhg.5201834] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
Preimplantation genetic diagnosis is an alternative for prenatal diagnosis that makes it possible to perform the diagnosis of a chromosomal or monogenic disorder at the preimplantation embryo level. Cystic fibrosis is one of the monogenic diseases for which PGD can be performed. In this study, we looked at the requests and PGD cycles for this particular disorder over an 11-year period. Sixty-eight percent of the requests eventually led to at least one complete PGD cycle. In 80% of the cycles, an embryo transfer was performed and an ongoing pregnancy was obtained in 22.2% of the cycles with oocyte retrieval. After embryo transfer, a couple had 27.8% chance of giving birth to a liveborn child. No misdiagnosis was recorded. The rate of perinatal deaths/stillborn children was relatively high, but no excess of major congenital anomalies was observed in the surviving children.
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Abstract
Pre-implantation genetic diagnosis for aneuploidy screening (PGD-AS) constitutes a technique developed to improve embryo selection in patients with a poor outcome after in-vitro fertilization treatment due to an increased frequency of numerical chromosome abnormalities in the embryos. Although multiple studies have evaluated the performance of PGD-AS in different groups of patients, inconsistencies in the evidence available have not enabled definitive conclusions to be drawn. According to randomized trials, PGD-AS does not improve the outcome of women of advanced age when there is no limitation on the number of embryos to be transferred. In patients who have experienced recurrent implantation failure or recurrent miscarriage, AS only seems to provide diagnostic information, especially when aneuploid embryos alone are found. Additional evidence is needed before AS is implemented as part of routine clinical practice.
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Affiliation(s)
- Patricio Donoso
- Centre for Reproductive Medicine, University Hospital, Vrije Universiteit Brussel, Laarbeeklaan 101, B-1090 Brussels, Belgium.
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Georgiou I, Syrrou M, Pardalidis N, Karakitsios K, Mantzavinos T, Giotitsas N, Loutradis D, Dimitriadis F, Saito M, Miyagawa I, Tzoumis P, Sylakos A, Kanakas N, Moustakareas T, Baltogiannis D, Touloupides S, Giannakis D, Fatouros M, Sofikitis N. Genetic and epigenetic risks of intracytoplasmic sperm injection method. Asian J Androl 2007; 8:643-73. [PMID: 17111067 DOI: 10.1111/j.1745-7262.2006.00231.x] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Pregnancies achieved by assisted reproduction technologies, particularly by intracytoplasmic sperm injection (ICSI) procedures, are susceptible to genetic risks inherent to the male population treated with ICSI and additional risks inherent to this innovative procedure. The documented, as well as the theoretical, risks are discussed in the present review study. These risks mainly represent that consequences of the genetic abnormalities underlying male subfertility (or infertility) and might become stimulators for the development of novel approaches and applications in the treatment of infertility. In addition, risks with a polygenic background appearing at birth as congenital anomalies and other theoretical or stochastic risks are discussed. Recent data suggest that assisted reproductive technology might also affect epigenetic characteristics of the male gamete, the female gamete, or might have an impact on early embryogenesis. It might be also associated with an increased risk for genomic imprinting abnormalities.
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Affiliation(s)
- Ioannis Georgiou
- Laboratory of Molecular Urology and Genetics of Human Reproduction, Department of Urology, Ioannina University School of Medicine, Ioannina 45110, Greece
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Feyereisen E, Steffann J, Romana S, Lelorc'h M, Ray P, Kerbrat V, Tachdjian G, Frydman R, Frydman N. Five years’ experience of preimplantation genetic diagnosis in the Parisian Center: outcome of the first 441 started cycles. Fertil Steril 2007; 87:60-73. [PMID: 17074325 DOI: 10.1016/j.fertnstert.2006.05.059] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2005] [Revised: 05/27/2006] [Accepted: 05/27/2006] [Indexed: 11/23/2022]
Abstract
OBJECTIVE To investigate the evolution of techniques and strategies and to evaluate the results of preimplantation genetic diagnosis (PGD) from January 2000 to December 2004 in chromosomal, monogenic and mitochondrial DNA disorders treated at our institution. DESIGN Retrospective study. SETTING Single French Parisian PGD center. PATIENT(S) Patients at risk of transmitting a serious genetic disorder to their offspring. INTERVENTION(S) 171 couples enrolled in the program undergoing stimulated and frozen embryo replacement cycles with PGD. MAIN OUTCOME MEASURE(S) Results of the 441 first PGD cycles performed for various genetic conditions. RESULT(S) During 5 years, 416 stimulation and 25 frozen embryo replacement cycles were started, among which 52 clinical and 47 ongoing pregnancies occurred. In stimulation cycles, the overall ongoing pregnancy rate was 24% per embryo transfer, 11% per started cycle, and 27% per couple. The implantation rate was 16%. CONCLUSION(S) These encouraging results demonstrate that PGD might be considered as a valid alternative to prenatal diagnosis. Nevertheless, couples referred for PGD must be selected and counseled appropriately, considering the complexity of the treatment and the relatively low take-home baby rate.
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Affiliation(s)
- Estelle Feyereisen
- Service de Gynécologie-Obstétrique et de Médecine de la Reproduction, Hôpital Antoine Béclère, Clamart, France
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20
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Grace J, El-Toukhy T, Scriven P, Ogilvie C, Pickering S, Lashwood A, Flinter F, Khalaf Y, Braude P. Three hundred and thirty cycles of preimplantation genetic diagnosis for serious genetic disease: clinical considerations affecting outcome. BJOG 2006; 113:1393-401. [PMID: 17176278 DOI: 10.1111/j.1471-0528.2006.01143.x] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
OBJECTIVE To report on our experience with preimplantation genetic diagnosis (PGD) cycles performed for serious genetic disease in relation to the clinical factors affecting outcome. DESIGN Retrospective review of data from a single centre. SETTING Tertiary referral PGD centre in a London teaching hospital. METHODS The PGD cycles included 172 cycles for chromosome rearrangements, 96 cycles for single-gene disorders and 62 cycles for X-linked disorders. In vitro fertilisation was the preferred method in chromosome rearrangement and X-linked cases, while intra cytoplasmic sperm injection was used in all single-gene disorders. Appropriate in situ hybridisation fluorescence probes were used in chromosome rearrangement and X-linked cases and polymerase chain reaction was used in single-gene disorders. All pregnancies were followed till delivery. MAIN OUTCOME MEASURE Live birth rate per PGD cycle started. RESULTS Eighty-six percent of cycles started (283) reached oocyte retrieval and 3743 eggs were collected, of which 2086 fertilised normally (55.7%). Two hundred and fifty cycles (76%) had embryos sutiable for biopsy on day 3 of in vitro culture, 1714 embryos were biopsied, and in 205 cycles (62%), there was at least one unaffected embryo available for transfer, resulting in 90 pregnancies, 68 clinical pregnancies and 58 live birth. The live birth rate was 18% per cycle started, 21% per egg retrieval and 28% per embryo transfer which significantly affected the live birth outcome. Woman age, number of eggs collected and achieving cryopreservation of surplus embryos had no statistically significant effect on treatment outcome. CONCLUSIONS The live birth outcome of PGD cycles for serious genetic disorder is modest and is affected by the number of embryos genetically suitable for transfer.
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Affiliation(s)
- J Grace
- Centre for Preimplantation Genetic Diagnosis, Guy's and St Thomas' Foundation Trust, Guy's Hospital, London, UK.
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21
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Mertes H, Pennings G, Van Steirteghem A. An ethical analysis of alternative methods to obtain pluripotent stem cells without destroying embryos. Hum Reprod 2006; 21:2749-55. [PMID: 16951428 DOI: 10.1093/humrep/del233] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Although few ethical concerns exist regarding the use of adult stem cells, the field of embryonic stem cell research is fraught with moral qualms. Several alternative sources of pluripotent stem cells have recently been presented that try to sidestep the destruction of human embryos. The goal of these new proposals is to avoid embryo destruction, the main objection to embryonic stem cell research and thus introduce a type of stem cell research that would gain widespread approval and support. This article suggests that most embryo-saving alternatives fail to reach this goal given the concessions they require with regard to the speed of progress, technical complexity, safety and security of applications, degree of dependence on limited resources and extent of the field of application. The second part of the article identifies and analyses the two main strategies that alternative sources of pluripotent stem cells are based on and points out their shortcomings.
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Affiliation(s)
- Heidi Mertes
- Centre for Environmental Philosophy and Bioethics, Ghent University, Belgium.
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22
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Feyereisen E, Romana S, Kerbrat V, Steffann J, Gigarel N, Lelorc'h M, Burlet P, Ray P, Hamamah S, Chevalier N, Fanchin R, Foix-L'hélias L, Tachdjian G, Munnich A, Frydman R, Vekemans M, Frydman N. Indications et résultats du diagnostic pré-implantatoire (DPI). ACTA ACUST UNITED AC 2006; 35:356-72. [PMID: 16940905 DOI: 10.1016/s0368-2315(06)76408-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
OBJECTIVE To report the results of preimplantation genetic diagnosis (PGD) cycles performed in our unit from 2000 to 2004. Materials and methods. One hundred and seventy-one couples were enrolled in the PGD program over this period. The collected oocytes were inseminated by intracytoplasmic sperm injection (ICSI). The resulting embryos were biopsied on the third day of development and the genetic analysis was performed on the same day. Embryo transfers were carried out on the fourth day. RESULTS The 416 stimulation cycles started yielded 280 oocyte pick-ups, 3506 oocytes retrieved, of which 2966 were suitable for ICSI. Among the 1982 embryos obtained, 1337 embryos were biopsied and genetic diagnosis was performed for 1083 (81%) of them. 381 embryos were transferred during the course of 189 transfer procedures. There were 51 clinical and 46 ongoing (35 single, 11 twin) pregnancies. In addition, 25 frozen embryo replacement cycles were initiated, leading to 6 embryo transfers and 1 ongoing pregnancy. A total of 58 unaffected children were born. CONCLUSION PGD has gained a place among the choices offered to couples at risk of transmission of a serious and incurable genetic disease. It might be a realistic alternative to prenatal diagnosis for patients carrier of chromosomal rearrangements, single gene defects, X-linked disesases or mitochondrial DNA disorders.
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Affiliation(s)
- E Feyereisen
- Service de Gynécologie-Obstétrique et de Médecine de la Reproduction, Hôpital Antoine-Béclère, 157, rue de la Porte-de-Trivaux, 92141 Clamart Cedex
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23
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Abstract
Understanding the molecular mechanisms defining totipotency and cell differentiation in humans is a promising strategy in order to expand knowledge about reprogramming. Totipotency and the very first steps of cell differentiation can be studied well in early human embryos. Based on analysis of marker genes such as Oct-4 and -HCG, blastomeres seem to differ in their potency and can be regarded as lineage-specific stem cells as early as the 4-cell stage. The allocation of these stem cells to specific fates might hereby follow a pattern reminiscent of animal and vegetal poles. On the opposite end of the developmental spectrum, differentiated human cells can be used as a means of studying nuclear reprogramming. Intact human 293T kidney cells and primary leukocytes were reprogrammed towards a more undifferentiated state by Xenopus laevis egg extract. Molecular screens identified the chromatin-remodelling ATPase BRG1 as a factor required for this process. Based on these results, more efficient reprogramming protocols allowing for the generation of fully differentiated or undifferentiated human cells for clinical application may be developed.
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Affiliation(s)
- Christoph Hansis
- Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Southern California Keck School of Medicine, 1240 North Mission Road, Los Angeles, CA 90033, USA.
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24
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Fiorentino F, Biricik A, Nuccitelli A, De Palma R, Kahraman S, Iacobelli M, Trengia V, Caserta D, Bonu MA, Borini A, Baldi M. Strategies and clinical outcome of 250 cycles of Preimplantation Genetic Diagnosis for single gene disorders. Hum Reprod 2005; 21:670-84. [PMID: 16311287 DOI: 10.1093/humrep/dei382] [Citation(s) in RCA: 72] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND We report on our experience with preimplantation genetic diagnosis (PGD) for single gene disorders (SGDs), from 1999 to 2004, describing strategies and overall clinical outcome of 250 cycles in 174 couples for 23 different genetic conditions. METHODS PGD cycles included 15 for autosomal dominant, 148 for autosomal recessive and 19 for X-linked SGDs. In addition, 68 cycles of PGD for SGDs were performed in combination with HLA matching. The strategy in each case used an initial multiplex PCR, followed by minisequencing to identify the mutation(s) combined with multiplex PCR for closely linked informative markers to increase accuracy. Linkage analysis, using intragenic and/or extragenic polymorphic microsatellite markers, was performed in cases where the disease-causing mutation(s) was unknown or undetectable. RESULTS In 250 PGD cycles, a total of 1961 cleavage stage embryos were biopsied. PCR was successful in 3409 out of 3149 (92.4%) biopsied blastomeres and a diagnosis was possible in 1849 (94.3%) embryos. Four hundred and twenty-seven embryos were transferred in 211 cycles, resulting in 71 pregnancies (33.6% per embryo transfer), including 15 biochemical pregnancies, six spontaneous miscarriages, two ectopic pregnancies, which were terminated, and nine pregnancies which are still ongoing. The remaining pregnancies were confirmed to be unaffected and went to term without complications, resulting in the birth of 35 healthy babies. CONCLUSIONS Minisequencing for mutation detection combined with multiplex fluorescence PCR for linkage analysis is an efficient, accurate and widely applicable strategy for PGD of SGDs. Our experience provides a further demonstration that PGD is an effective clinical tool and a useful option for many couples with a high risk of transmitting a genetic disease.
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Affiliation(s)
- F Fiorentino
- EmbryoGen-Centre for Preimplantation Genetic Diagnosis, GENOMA-Molecular Genetics Laboratory, Via Po 102, 00198 Rome, Italy.
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25
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Edwards RG, Hansis C. Initial differentiation of blastomeres in 4-cell human embryos and its significance for early embryogenesis and implantation. Reprod Biomed Online 2005; 11:206-18. [PMID: 16168219 DOI: 10.1016/s1472-6483(10)60960-1] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
This brief review is devoted to the nature of early blastomere differentiation in human 4-cell embryos and its consequences for embryonic development. Precursor cells of inner cell mass, germline, and trophectoderm may be formed at this stage, the clearest evidence being available for trophectoderm. The sites of these precursor cells in the embryo could be ascertained using markers for animal and vegetal poles, observing specific cleavage planes, and assessing gene and protein expression. This opens new opportunities for studying 4-cell embryos and removing or replacing specific cells. Knowledge of the properties of individual blastomeres should help in improving assisted human reproduction, performing preimplantation genetic diagnosis, and perhaps establishing specific stem cell lines. Special attention is paid to well-characterized trophectoderm, the trophectoderm stem cell, and possible new forms of clinical application.
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Affiliation(s)
- Robert G Edwards
- Reproductive BioMedicine Online, Duck End Farm, Dry Drayton, Cambridge CB3 8DB, UK
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26
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Frydman N, Romana S, Ray P, Hamamah S, Tachdjian G, Marcadet-Fredet S, Munnich A, Vekemans M, Frydman R. [The Paris experience in preimplantation genetic diagnosis: evaluation after the first births]. ANNALES D'ENDOCRINOLOGIE 2005; 66:294-301. [PMID: 15988395 DOI: 10.1016/s0003-4266(05)81766-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Abstract
OBJECTIVE To report the birth of the first thirteen infants conceived after preimplantation genetic diagnosis (PGD) within the medical assistance federation of Paris. PATIENTS AND METHODS Fifty-nine couples were enrolled between January 2000 and July 2001. They had a total of 71 oocyte pick-up cycles. The collected oocytes were inseminated by intracytoplasmic sperm injection. The resulting embryos were biopsied on the third day of development and the genetic analysis was performed on the same day. Most of the embryo transfers were carried out on the fourth day. RESULTS The 71 oocyte pick-up cycles yielded 872 oocytes of which 731 were suitable for intracytoplasmic sperm injection. 421 embryos were biopsied and genetic diagnosis was obtained from 312 (74%) of these. 127 embryos were transferred during the course of 58 transfer procedures. There were 18 biologic and 12 clinical (7 singles, 4 twins and 1 triple) pregnancies. Thirteen infants have been born and 4 are expected. CONCLUSIONS PGD has gained a place among the choices offered to couples at risk of transmission of a serious and incurable genetic disease.
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Affiliation(s)
- N Frydman
- Service d'Histologie-Embryologie-Cytogénétique à orientation Biologique et Génétique de la Reproduction, Hôpital Antoine Béclère (AP-HP), 157, rue de la Porte de Trivaux, 92141 Clamart
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27
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Vernaeve V, Festré V, Baetens P, Devroey P, Van Steirteghem A, Tournaye H. Reproductive decisions by couples undergoing artificial insemination with donor sperm for severe male infertility: implications for medical counselling. ACTA ACUST UNITED AC 2005; 28:22-6. [PMID: 15679617 DOI: 10.1111/j.1365-2605.2004.00501.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Since 1992, ICSI has been introduced as a successful treatment for male infertility, including azoospermia. The present study is aimed at evaluating the practice of insemination with donor sperm (AID) in infertile couples who may benefit from the new developments that ICSI has brought in the last decade. AID was performed in 440 heterosexual couples. Twelve couples were lost for follow-up (3%). In 128 (29.9%) and 229 (53.5%) of the couples the husband was either oligozoospermic (OAT) or azoospermic. In 60 couples (14.0%) the man had a transmissible genetic trait. In 11 couples (2.6%) there were other indications for performing AID. In the OAT group 36 couples never had ICSI treatment (28.1%) because they had already an AID child born before the introduction of ICSI (n = 16), the burden of ICSI treatment was too high (n = 9) or they considered that ICSI success rate was too low (n = 7). Ninety-two couples tried ICSI treatment before opting for AID (71.9%), mainly because ICSI failed (n = 43). In 229 couples the husband had azoospermia (53.5%). In 112 couples (49%) no sperm or too few testicular sperm were found at testicular biopsy (TESE) and 15 couples (6.5%) had more than three failed ICSI-TESE attempts. Eighty-one azoospermic men refused TESE (35.4%) because of an anticipated low success rate (n = 28) or the burden of this approach (n = 23). Although a majority of patients could opt for ICSI, our results show that AID is still an option for many couples for whom these techniques were either not feasible or not successful. A substantial proportion of patients (33%) did not even opt for these advanced fertility treatments.
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Affiliation(s)
- V Vernaeve
- Centre For Reproductive Medicine, University Hospital, Dutch-speaking Brussels Free University (Vrije Universiteit Brussel), Laarbeeklaan 101, 1090 Brussels, Belgium.
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Abstract
In 2004, the Italian Parliament enacted a law regulating medically assisted reproduction. Although the law recognizes as legal certain assisted reproduction techniques, several other procedures are implicitly or expressly banned: oocyte and sperm donation, using embryos for the scientific research purposes and reproductive cloning. In this article, I outline the new legal framework, pointing out some of the shortcomings of its provisions, such as the failure to define what an 'embryo' is, the contradictions between this law and the law on abortion, the opportunity for Italian couples to circumvent some of the prohibitions by resorting to 'reproductive tourism', and the central role that physicians play in the new legal framework.
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Affiliation(s)
- Andrea Boggio
- Unité de recherche et d'enseignement en bioéthique, Centre Médical Universitaire, Université de Genève, Switzerland.
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29
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Rubio C, Pehlivan T, Rodrigo L, Simón C, Remohí J, Pellicer A. Embryo Aneuploidy Screening for Unexplained Recurrent Miscarriage: A Minireview. Am J Reprod Immunol 2005; 53:159-65. [PMID: 15760376 DOI: 10.1111/j.1600-0897.2005.00260.x] [Citation(s) in RCA: 56] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
PROBLEM The aim of this study was to investigate the incidence of chromosomal abnormalities in unexplained recurrent miscarriage (RM) patients and assess the role of pre-implantation genetic diagnosis (PGD) in preventing subsequent pregnancy loss and improving pregnancy outcome. METHOD OF STUDY Pre-implantation genetic diagnosis was performed in 241 RM cycles and in 35 cycles in patients undergoing PGD for sex-linked diseases (control group). Chromosomes 13, 16, 18, 21, 22, X and Y were analysed by fluorescence in situ hybridization. RESULTS The implantation and pregnancy rates in RM patients were 26.4 and 36.5% versus 20.6 and 29.0% in the control group, respectively. The percentage of abnormal embryos was significantly increased in RM patients compared with controls. CONCLUSIONS Recurrent miscarriage is associated with a higher incidence of chromosomally abnormal embryos. In vitro fertilization (IVF) plus PGD is an important step in the management of these couples.
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Affiliation(s)
- Carmen Rubio
- Instituto Valenciano de Infertilidad (IVI), University of Valencia, Spain
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30
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Abstract
Legislation of ethical issues illustrates the uneasy mix of ethics and politics. Although the majority has the political right to express its moral views in the law, a number of important ethical values like autonomy, tolerance and respect for other people's opinions urge the majority to take the minorities' position into account. Ignoring pluralism in society will inevitably lead to reproductive tourism. Although European legislation and harmonization in the domain of medically assisted reproduction is presented as a partial solution to this phenomenon, it is argued that European legislation should be avoided as much as possible. Regulation of these private ethical matters should be left to the national parliaments. A soft or compromise legislation will keep reproductive travelling to a minimum. Reproductive tourism is a safety valve that reduces moral conflict and expresses minimal recognition of the others' moral autonomy.
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Affiliation(s)
- Guido Pennings
- Centre for Environmental Philosophy and Bioethics, Ghent University, Blandijnberg 2, B-9000 Ghent, Belgium.
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31
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Abstract
Cell allocation and subsequent lineage commitment in the human embryo may be established as early as in the unfertilized oocyte. This phenomenon might be the result of subtle differences of gene expression and protein distribution. To assess whether gene expression profiling by reverse transcription-polymerase chain reaction could be a suitable tool for the detection of cell allocation and lineage commitment, the expression pattern of the putative inner cell mass marker gene Oct-4 and the trophectodermal marker genes beta-HCG and beta-LH were correlated in individual blastomeres of preimplantation human embryos. In 2- to 5-cell stage embryos, expression of beta-HCG and Oct-4 mRNA was negatively correlated in all blastomeres with statistical significance, suggesting that cell allocation can be assessed by those markers at early stages. In 7- to 10-cell stage embryos, expression of beta-LH and Oct-4 mRNA was negatively correlated in some blastomeres without statistical significance, suggesting that more experiments are necessary to decide if lineage commitment can be assessed in some cells by those markers at later stages.
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Affiliation(s)
- Christoph Hansis
- Program for In Vitro Fertilization, Reproductive Surgery and Infertility, New York University School of Medicine, 660 First Avenue, 5th Floor, New York, NY 10016, USA.
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32
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Pennings G, Bonduelle M, Liebaers I. Decisional authority and moral responsibility of patients and clinicians in the context of preimplantation genetic diagnosis. Reprod Biomed Online 2003; 7:509-13. [PMID: 14686350 DOI: 10.1016/s1472-6483(10)62068-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Case reports reveal that clinicians applying preimplantation genetic diagnosis are increasingly confronted with requests by patients which they consider ethically problematic. These requests raise the question to what extent physicians share responsibility for the welfare of the future child. Two categories of situations are analysed: when patients unilaterally review the agreement made with the medical staff and when they request an application that increases rather than reduces the risk of having a termination of pregnancy. It is concluded that physicians have their own responsibility in the process, which allows them to introduce conditions before starting infertility treatment.
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Affiliation(s)
- Guido Pennings
- Department of Philosophy, Dutch-Speaking Free University Brussels, Pleinlaan 2, B-1050 Brussels, Belgium.
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33
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Rubio C, Simón C, Vidal F, Rodrigo L, Pehlivan T, Remohí J, Pellicer A. Chromosomal abnormalities and embryo development in recurrent miscarriage couples. Hum Reprod 2003; 18:182-8. [PMID: 12525464 DOI: 10.1093/humrep/deg015] [Citation(s) in RCA: 171] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND Chromosomal abnormalities are an important cause of spontaneous abortion and recurrent miscarriage (RM). Therefore, we have analysed the incidence of chromosomal abnormalities and embryo development in patients with RM. METHODS Preimplantation genetic diagnosis (PGD) was performed on 71 couples with RM and 28 couples undergoing PGD for sex-linked diseases (control group). Chromosomes 13, 16, 18, 21, 22, X and Y were analysed by fluorescence in-situ hybridization. RESULTS The implantation rate in RM patients was 28% and three patients (13%) miscarried. The percentage of abnormal embryos was significantly increased (P < 0.0001) in RM patients compared with controls (70.7 versus 45.1%). All of the embryos were abnormal in 19 cycles (22.1%) and repeated PGD cycles yielded similar rates of chromosomal abnormalities in 14 couples. Anomalies for chromosomes 16 and 22 were significantly higher (P < 0.01) in RM cases. In the RM population, euploid embryos reached the blastocyst stage more frequently than abnormal embryos (61.7 versus 24.9%; P < 0.0001). CONCLUSIONS RM is associated with a higher incidence of chromosomally abnormal embryos, of which some are able to develop to the blastocyst stage. IVF plus PGD is an important step in the management of these couples, but the technique has to move towards a full chromosome analysis.
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Affiliation(s)
- C Rubio
- Instituto Valenciano de Infertilidad (IVI), Plaza Policia Local, 3, 46015 Valencia, Spain
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Pickering S, Polidoropoulos N, Caller J, Scriven P, Ogilvie CM, Braude P. Strategies and outcomes of the first 100 cycles of preimplantation genetic diagnosis at the Guy's and St. Thomas' Center. Fertil Steril 2003; 79:81-90. [PMID: 12524068 DOI: 10.1016/s0015-0282(02)04540-5] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
OBJECTIVE To establish strategies for the implementation of a successful preimplantation genetic diagnosis (PGD) service. DESIGN Retrospective review of data from a single center. SETTING A United Kingdom National Health Service hospital. PATIENT(S) Patients (60 couples) were referred for PGD from UK genetic centers. INTERVENTION(S) We followed the protocol of ovarian stimulation, oocyte retrieval, fertilization, single cell biopsy on day 3, and embryo transfer on day 4. Pregnancies unaffected by the familial genetic condition. RESULT(S) A total of 60 couples was treated for 20 different conditions. Early cycles using nonsequential embryo culture media were less successful (13% pregnancy rate/embryo transfer) than later cycles using sequential media (33.5%). Ninety-four percent of embryos (n = 473) had a single cell removed at biopsy. The overall pregnancy rate was 24% per cycle started, 29% per egg collection, 38% per transfer, and 40% per couple treated. In one cycle, an affected pregnancy followed PGD for spinal muscular atrophy (SMA). CONCLUSION(S) The use of sequential media and single cell biopsy results in a successful PGD program with encouraging pregnancy rates.
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Affiliation(s)
- Susan Pickering
- Center for Preimplantation Genetic Diagnosis, Guy's and St. Thomas' NHS Trust, Guy's Hospital, London Bridge, London, United Kingdom.
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35
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Abstract
Preimplantation genetic diagnosis (PGD) is an evolving technique that provides a practical alternative to prenatal diagnosis and termination of pregnancy for couples who are at substantial risk of transmitting a serious genetic disorder to their offspring. Samples for genetic testing are obtained from oocytes or cleaving embryos after in vitro fertilization. Only embryos that are shown to be free of the genetic disorders are made available for replacement in the uterus, in the hope of establishing a pregnancy. PGD has provided unique insights into aspects of reproductive genetics and early human development, but has also raised important new ethical issues about assisted human reproduction.
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Affiliation(s)
- Peter Braude
- Centre for Preimplantation Genetic Diagnosis, Thomas Guy House, Guy's Hospital, London SE1 9RT, UK
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36
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Platteau P, Sermon K, Seneca S, Van Steirteghem A, Devroey P, Liebaers I. Preimplantation genetic diagnosis for fragile Xa syndrome: difficult but not impossible. Hum Reprod 2002; 17:2807-12. [PMID: 12407031 DOI: 10.1093/humrep/17.11.2807] [Citation(s) in RCA: 40] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND In this paper, we review our clinical preimplantation genetic diagnosis (PGD) programme for fragile Xa syndrome, analysing if PGD for these couples is still a valuable option, as it is particularly difficult for two reasons. First, the couples have to be informative (the number of triplet repeats on the healthy FMR-1 allele of the mother has to be different from the number of repeats on the healthy FMR-1 allele of the father) and second, women with a premutation are at increased risk of premature ovarian failure. METHODS A total of 34 couples attended our genetics department between December 1998 and July 2001, requesting information about PGD for fragile Xa syndrome. RESULTS Eight couples decided not to go further with the procedure and of the 26 remaining couples, 16 were informative (61.5%). Four couples have so far not started ovarian stimulation, one patient was totally refractive to stimulation and 11 couples have had a total of 19 oocyte retrievals. From these, there have been 13 embryo transfers with a clinical pregnancy rate per embryo transfer of 23%; the implantation rate was 13.6% and the live birth rate per couple was 27.3%. CONCLUSIONS PGD for fragile Xa is feasible for a number of couples. A pre-PGD work-up should include a determination of the premutation or mutation carrier status, the maternal or paternal origin of the premutation and an estimation of the ovarian reserve of the patient. Fragile Xa premutation carriers should be advised not to postpone reproduction for too long.
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Affiliation(s)
- Peter Platteau
- Centres for Reproductive Medicine, University Hospital and Medical school, Dutch-speaking Brussels Free University, Laarbeeklaan 101, 1090 Brussels, Belgium.
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37
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Miny P, Tercanli S, Holzgreve W. Developments in laboratory techniques for prenatal diagnosis. Curr Opin Obstet Gynecol 2002; 14:161-8. [PMID: 11914694 DOI: 10.1097/00001703-200204000-00010] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Ongoing trends in prenatal diagnosis aim at early, rapid, and ideally noninvasive diagnosis as well as at the improvement of risk-screening for aneuploidy. Interphase-fluorescence in situ hybridization and quantitative fluorescence polymerase chain reaction are efficient tools for the rapid exclusion of selected aneuploidies in addition to the established direct preparation of chromosomes from chorionic villi. Interphase fluorescence in situ hybridization has also made possible the diagnosis of selected chromosome abnormalities in single cells (e.g. in preimplantation genetic diagnosis) or noninvasive diagnosis. More complex multicolor fluorescence in situ hybridization approaches are currently being evaluated. Single cell polymerase chain reaction is the key technique for the molecular diagnosis of a growing number of monogenic conditions before implantation or, still more experimental, in fetal cells retrieved from the maternal circulation. New sources for noninvasive diagnosis came into play such as fetal DNA or cell nuclei in maternal plasma. The combination of biochemical parameters in the maternal serum, namely free beta-human chorionic gonadotropin with pregnancy associated plasma protein A and sonographic markers, has already dramatically increased the sensitivity of risk screening in the first trimester of pregnancy.
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Affiliation(s)
- Peter Miny
- Division of Medical Genetics, University Children's Hospital, Basel, Switzerland
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38
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Abstract
Preimplantation genetic diagnosis (PGD) represents an alternative to prenatal diagnosis and allows selection of unaffected IVF embryos for establishing pregnancies in couples at risk for transmitting a genetic disorder.
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Affiliation(s)
- E Kanavakis
- Medical Genetics, University of Athens, Aghia Sophia Children's Hospital, Athens 11527, Greece.
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39
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Carvalho F, Sousa M, Fernandes S, Silva J, Saraiva MJ, Barros A. Preimplantation genetic diagnosis for familial amyloidotic polyneuropathy (FAP). Prenat Diagn 2001; 21:1093-9. [PMID: 11746170 DOI: 10.1002/pd.250] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
Preimplantation genetic diagnosis (PGD) was developed more than a decade ago to offer an alternative to prenatal diagnosis for couples at risk of transmitting an inherited disease to their offspring. Portuguese-type familial amyloidotic polyneuropathy (FAP type I), is an autosomal dominant disease presenting an inherited mutation in the gene encoding the plasma protein transthyretin (TTR). We here report the first protocol for single-cell detection of the Met30 mutation in FAP type I and its application to PGD. A nested PCR reaction for exon 2 of the TTR gene was developed. The PCR product was then analysed by restriction enzyme analysis and SSCP allowing the detection of the point mutation. Ten clinical cycles were performed in seven couples. From the 93 metaphase II (MII) injected oocytes, 82 were normally fertilized and 78 were biopsied. A positive signal in the nested PCR reaction was obtained in 61 blastomeres, corresponding to a DNA amplification efficiency of 78.2%. No allele dropout (ADO) or contamination were detected. A biochemical pregnancy was obtained in three cases and a clinical pregnancy in one couple is actually in normal evolution.
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Affiliation(s)
- F Carvalho
- Department of Medical Genetics, Faculty of Medicine, University of Porto, Porto, Portugal.
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40
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De Vos A, Van Steirteghem A. Aspects of biopsy procedures prior to preimplantation genetic diagnosis. Prenat Diagn 2001; 21:767-80. [PMID: 11559914 DOI: 10.1002/pd.172] [Citation(s) in RCA: 107] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Today, preimplantation genetic diagnosis (PGD) is offered in over 40 centres worldwide for an expanded range of genetic defects causing disease. This very early form of prenatal diagnosis involves the detection of affected embryos by fluorescent in situ hybridization (FISH) (sex determination or chromosomal defects) or by polymerase chain reaction (PCR) (monogenic diseases) prior to implantation. Genetic analysis of the embryos involves the removal of some cellular mass from the embryos (one or two blastomeres at cleavage-stage or some extra-embryonic trophectoderm cells at the blastocyst stage) by means of an embryo biopsy procedure. Genetic analysis can also be performed preconceptionally by removal of the first polar body. However, additional information is then often gained by removal of the second polar body and/or a blastomere from the embryo. Removal of polar bodies or cellular material from embryos requires an opening in the zona pellucida, which can be created in a mechanical way (partial zona dissection) or chemical way (acidic Tyrode's solution). However, the more recent introduction of laser technology has facilitated this step enormously. Different biopsy procedures at different preimplantation stages are reviewed here, including their pros and cons and their clinical applications. The following aspects will also be discussed: safety of zona drilling by laser, use of Ca2+/Mg2+-free medium for decompaction, and removal of one or two cells from cleavage-stage embryos.
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Affiliation(s)
- A De Vos
- Centre for Reproductive Medicine, University Hospital, Dutch-speaking Brussels Free University (Vrije Universiteit Brussel), Brussels, Belgium.
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41
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Piyamongkol W, Harper JC, Sherlock JK, Doshi A, Serhal PF, Delhanty JD, Wells D. A successful strategy for preimplantation genetic diagnosis of myotonic dystrophy using multiplex fluorescent PCR. Prenat Diagn 2001; 21:223-32. [PMID: 11260612 DOI: 10.1002/1097-0223(200103)21:3<223::aid-pd52>3.0.co;2-3] [Citation(s) in RCA: 41] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The most common form of inherited muscular dystrophy in adults is myotonic dystrophy (DM), an autosomal-dominant disease caused by the expansion of an unstable CTG repeat sequence in the 3' untranslated region of the myotonin protein kinase (DMPK) gene. Expanded (mutant) CTG repeat sequences are refractory to conventional PCR, but alleles with a number of repeats within the normal range can be readily amplified and detected. Preimplantation genetic diagnosis (PGD) of DM has been successfully applied. However, a misdiagnosis using the reported protocol was recently documented. Two new PGD protocols for DM have been developed which utilise multiplex fluorescent PCR. Ideally a linked polymorphic marker, APOC2, is amplified in addition to the normal DMPK alleles, thus providing a back-up diagnostic result. However, the two couples reported in the present study were not fully informative at the APOC2 locus and so an unlinked short tandem repeat (STR) marker, D21S1414, was substituted. The highly polymorphic nature of the D21S1414, DMPK and APOC2 loci means that a very simple genetic fingerprint can be generated by analyses of these loci. This allows most DNA contaminants to be detected. Contamination is a significant problem for PGD and is the primary reason for the inclusion of D21S1414 and APOC2 in this protocol. This paper reports the first clinical experience and pregnancies following PGD for DM using a multiplex fluorescent PCR protocol.
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Affiliation(s)
- W Piyamongkol
- UCL Centre for Preimplantation Genetic Diagnosis and the Assisted Conception Unit, Department of Obstetrics & Gynaecology, University College London, 86-96 Chenies Mews, London WC1E 6HX, UK
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Van de Velde H, De Vos A, Sermon K, Staessen C, De Rycke M, Van Assche E, Lissens W, Vandervorst M, Van Ranst H, Liebaers I, Van Steirteghem A. Embryo implantation after biopsy of one or two cells from cleavage-stage embryos with a view to preimplantation genetic diagnosis. Prenat Diagn 2000; 20:1030-7. [PMID: 11180226 DOI: 10.1002/1097-0223(200012)20:13<1030::aid-pd977>3.0.co;2-d] [Citation(s) in RCA: 92] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Preimplantation genetic diagnosis (PGD) can be offered as an alternative to prenatal diagnosis (PND) to couples at risk of having a child with a genetic disease. The affected embryos are detected before implantation by fluorescent in situ hybridisation (FISH) for sexing (X-linked diseases) and chromosomal disorders (numerical and structural) or by polymerase chain reaction (PCR) for monogenic disorders (including some X-linked diseases). The accuracy and reliability of the diagnosis is increased by analysing two blastomeres of the embryo. However, the removal of two blastomeres might have an effect on the implantation capacity of the embryo. We have evaluated the implantation of embryos after the removal of one, two or three cells in 188 PGD cycles where a transfer was done. The patients were divided into five groups: a first group which received only embryos from which one cell had been removed, a second group which received only embryos from which two cells had been removed, a third group which received a mixture of embryos from which one and two cells had been taken, a fourth group where two and three cells had been removed, and a fifth group where three cells had been removed. The overall ongoing pregnancy rate per transfer was 26.1%, the overall implantation rate per transfer was 15.2% and the overall birth rate was 14.2%. Although pregnancy rates between the groups cannot be compared because the second group (two cells removed) contains more rapidly developing and therefore 'better quality' embryos, an ongoing pregnancy rate of 29.1% and an implantation rate of 18.6% per transferred embryo in this group is acceptable, and we therefore advise analysing two cells from a > or =7-cell stage embryo in order to render the diagnosis more accurate and reliable.
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Affiliation(s)
- H Van de Velde
- Centre for Reproductive Medicine, Dutch-speaking Brussels Free University (Vrije Universiteit Brussel), Laarbeeklaan 101, 1090 Brussels, Belgium.
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