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Handyside A.H.,Gynaecology and Genetics Center | Handyside A.H.,University of Leeds | Montag M.,University of Heidelberg | Magli M.C.,S.I.S.Me.R | And 7 more authors.
European Journal of Human Genetics | Year: 2012

Chromosome aneuploidy is a major cause of pregnancy loss, abnormal pregnancy and live births following both natural conception and in vitro fertilisation (IVF) and increases exponentially with maternal age in the decade preceding the menopause. Molecular genetic analysis following natural conception and spontaneous miscarriage demonstrates that trisomies arise mainly in female meiosis and particularly in the first meiotic division. Here, we studied copy number gains and losses for all chromosomes in the two by-products of female meiosis, the first and second polar bodies, and the corresponding zygotes in women of advanced maternal age undergoing IVF, using microarray comparative genomic hybridisation (array CGH). Analysis of the segregation patterns underlying the copy number changes reveals that premature predivision of chromatids rather than non-disjunction of whole chromosomes causes almost all errors in the first meiotic division and unlike natural conception, over half of aneuploidies result from errors in the second meiotic division. Furthermore, most abnormal zygotes had multiple aneuploidies. These differences in the aetiology of aneuploidy in IVF compared with natural conception may indicate a role for ovarian stimulation in perturbing meiosis in ageing oocytes. © 2012 Macmillan Publishers Limited All rights reserved.

Harton G.L.,Reprogenetics LLC | Harper J.C.,University College London | Harper J.C.,Center for Reproductive and Genetic Health | Coonen E.,Maastricht University | And 3 more authors.
Human Reproduction | Year: 2011

In 2005, the European Society for Human Reproduction and Embryology (ESHRE) PGD Consortium published a set of Guidelines for Best Practice PGD to give information, support and guidance to potential, existing and fledgling PGD programmes. The subsequent years have seen the introduction of new technologies as well as evolution of current techniques. Additionally, in light of recent advice from ESHRE on how practice guidelines should be written and formulated, the Consortium believed it was timely to revise and update the PGD guidelines. Rather than one document that covers all of PGD, the new guidelines are separated into four new documents that apply to different aspects of a PGD programme, i.e. organization of a PGD centre, fluorescence in situ hybridization (FISH)-based testing, amplification-based testing and polar body and embryo biopsy for PGD/preimplantation genetic screening (PGS). Here, we have updated the sections that pertain to FISH-based PGD. PGS has become a highly controversial technique. Opinions of laboratory specialists and clinicians interested in PGD and PGS have been taken into account here. Whereas some believe that PGS does not have a place in clinical medicine, others disagree; therefore, PGS has been included. This document should assist everyone interested in PGD/PGS in developing the best laboratory and clinical practice possible. Topics covered in this guideline include inclusion/exclusion criteria for FISH-based PGD testing, referrals and genetic counselling, preclinical validation of tests, FISH-based testing methods, spreading of cells for analysis, set-up of local IVF centre and transport PGD centres, quality control/ quality assurance and diagnostic confirmation of untransferred embryos. © 2010 The Author.

Brown R.,University College London | Harper J.,University College London | Harper J.,Center for Reproductive and Genetic Health
Reproductive BioMedicine Online | Year: 2012

Since the first birth by IVF was achieved in 1978, the techniques involved in assisted reproductive technology have grown at an enormous rate. However, new technology has rarely been robustly validated before clinical use and developing scientific understanding of the available techniques has done little to alter their use. Furthermore, there are inconsistencies in the available clinical studies and endpoints. The benefits of some technologies already established for routine use are currently dubious and there are clear ethical concerns with providing them to patients when their scientific basis is not clear. As the uptake of assisted reproductive technology increases and newer technologies continue to push the boundaries of science, it is important to consider the clinical benefits and safety of all assisted reproductive technologies. This review will discuss aspects of some of the more recent techniques, including sperm DNA-damage tests, intracytoplasmic morphologically selected sperm injection, amino acid and metabolomics profiling, preimplantation genetic screening and time-lapse imaging, and those that may have substantial impacts on the field of reproductive medicine in the future including artificial gametes, ovarian transplantation and gene therapy. In 1978, the first child conceived by IVF was born. In the following 33 years, numerous technologies and techniques have been developed to further aid the ability to achieve pregnancies in couples for whom natural conception has failed. However, these techniques have rarely been robustly tested and approved before they are routinely offered to infertile couples. In other cases, a development in our scientific understanding of a technique has failed to be quickly incorporated into clinical changes. This raises the concern that some of the techniques offered to some patients offer little or no benefit, and in the worse cases is not confirmed to be safe. This is a particular concern as many of the techniques discussed here are often reserved for already vulnerable patients, such as those with recurrent IVF failure, This review begins by discussing some of the techniques already available to patients and questioning to what end they increase the likelihood of a live birth. The review then goes on to discuss the scientific developments that, although not currently in the clinic, could have substantial implications in the future. Since these newly developing techniques could be considered more controversial, discussion about their benefit and safety is urgently needed. © 2012, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

Harper J.C.,University College London | Harper J.C.,Center for Reproductive and Genetic Health | Sengupta S.B.,University College London
Human Genetics | Year: 2012

For the last 20 years, preimplantation genetic diagnosis (PGD) has been mostly performed on cleavage stage embryos after the biopsy of 1-2 cells and PCR and FISH have been used for the diagnosis. The main indications have been single gene disorders and inherited chromosome abnormalities. Preimplantation genetic screening (PGS) for aneuploidy is a technique that has used PGD technology to examine chromosomes in embryos from couples undergoing IVF with the aim of helping select the chromosomally 'best' embryo for transfer. It has been applied to patients of advanced maternal age, repeated implantation failure, repeated miscarriages and severe male factor infertility. Recent randomised controlled trials (RCTs) have shown that PGS performed on cleavage stage embryos for a variety of indications does not improve delivery rates. At the cleavage stage, the cells biopsied from the embryo are often not representative of the rest of the embryo due to chromosomal mosaicism. There has therefore been a move towards blastocyst and polar body biopsy, depending on the indication and regulations in specific countries (in some countries, biopsy of embryos is not allowed). Blastocyst biopsy has an added advantage as vitrification of blastocysts, even post biopsy, has been shown to be a very successful method of cryopreserving embryos. However, mosaicism is also observed in blastocysts. There have been dramatic changes in the method of diagnosing small numbers of cells for PGD. Both array-comparative genomic hybridisation and single nucleotide polymorphism arrays have been introduced clinically for PGD and PGS. For PGD, the use of SNP arrays brings with it ethical concerns as a large amount of genetic information will be available from each embryo. For PGS, RCTs need to be conducted using both array-CGH and SNP arrays to determine if either will result in an increase in delivery rates. © 2011 Springer-Verlag.

Mamas T.,University College London | Gordon A.,BlueGnome Ltd | Brown A.,BlueGnome Ltd | Harper J.,University College London | And 2 more authors.
Fertility and Sterility | Year: 2012

Objective: To examine the effect of mosaicism in the array comparative genomic hybridization result during preimplantation genetic screening after blastocyst biopsy. Design: Experimental study. Setting: University laboratory. Material(s): Epithelial cell lines. Intervention(s): Mixing of euploid and aneuploid cells to create mosaic trophectoderm and blastocyst models. Main Outcome Measure(s): The level of aneuploidy in samples with different ratios of aneuploid cells was measured after array comparative genomic hybridization. Result(s): A shift from normality was present when the level of aneuploid cells in the sample was >25%. Aneuploidy could be confidently called when the level of aneuploid cells was >50%. Conclusion(s): This study determined that aneuploidy in mosaic samples can be detected by array comparative genomic hybridization and that the result may also indicate the proportion of the aneuploid cells present in the sample. © 2012 by American Society for Reproductive Medicine.

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