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Making relevant academic content accessible to genetics professionals Key sources of academic content for many physicians in field of genetics are academic journals which specialize in the field of fertility and genetics such as Fertility and Sterility and Human Reproduction. Finding relevant content in boarder academic publications is difficult and requires time and effort. Journals such as the NEJM, Science, Nature, Lancet, Plus One, and others, publish high quality papers in the field of infertility however in many cases this content is overlooked by genetics professionals. We aim to change that by creating the genetics Reproductive Medical Text Aggregator which will provide professionals with easy access to important academic material in the field.

COGEN Statement on the use of Preimplantation Genetic Screening (PGS) of chromosomes for IVF patients

A Statement on the use of Preimplantation Genetic Screening (PGS) of chromosomes for IVF patients

On September 26th and 27th 2015, under the auspices of The Virtual Academy of Genetics, COGEN held its 1st meeting on Controversies in Preconception, Preimplantation and Prenatal Genetic Diagnosis.

This meeting gathered together Key Opinion Leaders from around the world to inform, discuss and consider many of the questions of our time in relation to genetics and the place of the new technologies in driving the future of medical practice in the field of human reproduction.

The Undersigned have issued the Statement below and welcome debate and comment in this forum.

CONSENSUS STATEMENT ON PGS

For all practitioners of IVF there is the clinical imperative to achieve the highest chance of a live birth per single attempt, reducing the time to delivery for each patient; to reduce the incidence of miscarriage; reduce the number of multiple pregnancies; decrease the number of non-viable embryo transfers ('unnecessary IVF transfer cycles'); eliminate the freezing of embryos that are chromosomally abnormal; to diagnose patients with no chance to deliver with IVF; and, given the high incidence of embryo aneuploidy in all IVF cycles, to minimise the chance of transferring an aneuploid embryo. The alternative to using PGS is to transfer embryos one by one, and studies have shown this can result in up to 50% patient drop out following a miscarriage.

To this aim, scientific endeavour in many laboratories and clinics worldwide has focused upon the development of methods to detect and screen out chromosome anomalies from human embryos using technologies to identify whole chromosome copy number. All IVF cycles have a significant risk of aneuploid embryos, from an average of around 30% in young female patients and also egg donors, up to 90% in women in their early 40s. Methods such as array CGH, qPCR and Next Generation Sequencing (NGS) are delivering high-fidelity information allowing for accurate assessment of chromosome copy number of embryos.

A wide-ranging expert critical evaluation of the new pre-implantation genetic screening (PGS) technologies, taking into consideration clinical data from the application of full chromosome copy number assessment including recent randomised controlled trials, concluded that there is strong evidence that PGS offers certain benefits to patients undergoing IVF. Evidence was provided indicating a significant increase in the chance of implantation per embryo transferred, as well as a reduction in the risk of miscarriage and an improved likelihood of live birth. By using PGS to screen the chromosome status of the embryo the chance of unnecessarily cryopreserving aneuploid embryos, and transferring aneuploid embryos that will lead to IVF failure or the risk of an abnormal birth is minimised. Additionally, by using such technologies, a high chance of live birth can be achieved by transferring only a single euploid embryo, and studies show singleton births results in an improved obstetric and neonatal outcome.

Whilst we recognize that as yet much of the published data do not meet the very highest level of medical analysis, there is now a significant, and increasing body of scientific literature supporting the recommendation of PGS to patients undergoing IVF, for the reasons stated above. Based on available data PGS should no longer be considered as an experimental procedure. We therefore believe that PGS should be part of the discussion with all patients considering/undergoing IVF treatment.

This Statement is a position on the current medical science, however we understand and appreciate that in several societies the offering of PGS is not permitted or available.

The scientific and clinical community remain committed to the further improvement of PGS for the benefit of patients; areas of enquiry include considering the origin of chromosome error (meiotic vs. mitotic), evaluating the level of mitochondrial activity, consideration of gene expression patterns and also of epigenetic processes. Finally, in addition to the focus on embryo genetics and other aspects of its viability, it is recognised that research into uterine receptivity and several other female factors are also of considerable importance to ensure the best and most efficient possible outcome for patients.

Summary:

  • Chromosome errors (aneuploidy) in human embryos are a major cause of IVF failure, miscarriage, obstetric complications, stillbirth, infertility, and can lead to the birth of affected children.
  • Accurate technology for detecting chromosomally-normal (euploid) embryos is now available.
  • Only technologies such as array CGH, qPCR, NGS that detect ALL chromosomes with high accuracy should be applied for use in PGS.
  • Such technologies should not be considered "experimental" and, where possible, should be made available for routine practice.
  • PGS can reduce the time to a live birth by selecting only euploid embryos.
  • PGS can reduce the incidence of miscarriage.
  • Transfer of single euploid embryos gives the maximum chance of a live birth whilst minimising the risk of a multiple pregnancy.
  • We believe it is good medical practice to avoid the transfer of aneuploid embryos.
  • Some patients may have no euploid embryos and therefore no transfers – but many patients prefer to know this at that stage and prepare for a further cycle, or move on rather than wait for failure or possible miscarriage, or the birth of an affected child

 

List of signatories:

Dr Francesco Fiorentino, President Genoma Group - Italy
Prof Simon Fishel, Founder and President, CARE Fertility, UK
Dr Jason Franasiak, Reproductive Medicine Associates of New Jersey; Rutgers, Robert Wood Johnson Medical School, USA
Prof Luca Gianaroli, Scientific Director of SISMER, Italy
Dr Tony Gordon, Managing Director, Genesis Genetics, USA - UK
Prof Darren Griffin, University of Kent, UK
Prof Jamie Grifo, Program Director NYU Fertility Center, USA
Prof Samir Hamamah, Medical school and University-hospital of Montpellier , France
Prof Alan Handyside, Bridge Centre, University of Kent, and Illumina, Cambridge, UK
Prof Ariel Horowitz, IVF unit, Sheba Medical Centre, Israel
Prof Mark Hughes, Founder & CEO, Genesis Genetics, USA
Dr Milton Leong, Medical Director, The IVF Clinic, Hong Kong
Dr Santiago Munne, President, Reprogenetics, USA
Dr László Nánássy, Laboratory Director, Versys Clinics Human Reproduction Institute Hungary
PD Dr. Andreas Schmutzler, IVF Center, Kiel University, and gyn-medicum IVF Center, Goettingen, Germany
Dr Richard Scott, Founder, Reproductive Medicine Associates of New Jersey and Robert Wood Johnson Medical School, USA
Prof Zeev Shoham, Director, Reproductive medicine and IVF Unit, Kaplan Medical Center, Israel
Prof Lee Shulman, Chief of Clinical Genetics, Northwestern University, USA
Dr Attila Vereczkey, ‎CEO and Medical Director, Versys Clinics Human Reproduction Institute, Hungary
Prof Ariel Weissman, IVF Unit, Edith Wolfson Medical Center, Holon, Sackler Faculty of Medicine, Tel Aviv University, Israel
Dr Dagan Wells. Nuffield Department of Obstetrics and Gynaecology, University of Oxford; Laboratory Director, Reprogenetics, UK
Prof Yuval Yaron, Director, Preimplantation Genetic Diagnosis Laboratory Sourasky Medical Center, Israel

 

 

COGEN Position Statement on Chromosomal Mosaicism Detected in Preimplantation Blastocyst Biopsies

COGEN Position Statement on Chromosomal Mosaicism Detected in Preimplantation Blastocyst Biopsies

 

BACKGROUND

The occurrence of aneuploidy (an incomplete or abnormal chromosome copy number) in human embryos is a natural phenomenon in embryos conceived either in vivo or following the use of in vitro fertilization (IVF) technology; this has been understood since the early 1980s1,2. Alterations from the euploid (complete) chromosome copy number can occur at any age, but the incidence of aneuploidy increases with maternal age (>90% risk in women over 40 years old and approximately 50% risk in women age <35). Aneuploidy is the largest single cause of miscarriage3, and thus the ability to evaluate chromosome copy number prior to embryo transfer has been a clinical imperative of the IVF community for many years. In recent years, screening methods known as preimplantation genetic diagnosis for aneuploidy (PGD-A) or preimplantation genetic screening (PGS) have been developed to accurately assess the copy number of all 24 chromosomes from a single or multiple cell(s) biopsied from human preimplantation embryos.

However, since 1983 and the introduction of chorionic villus sampling (CVS), a discrepancy between the chromosomal makeup of the placenta and the fetus has been documented in approximately 1-2% of ongoing pregnancies; this is known as "confined placental mosaicism" (CPM) 4. Since trophectoderm biopsy is now widely viewed as the preferred method of aneuploidy assessment, these samples also manifest mosaicism in a small but significant percent of embryos, known as "embryonic mosaicism". During the 2016 COGEN Congress (Barcelona, September 22-25, 2016) and in the following Position Statement of PGDIS5, the issue of embryonic mosaicism in human blastocysts was discussed at length. The conclusions thereof are presented in this position statement in order to develop the best approach to this phenomenon in clinical practice.

In embryonic mosaicism, two or more genetically distinct cell lineages are present, typically one with a chromosome abnormality and the other possessing a normal chromosome constitution. Embryonic mosaicism may originate in the pre- implantation embryo through mitotic errors, or by anaphase lag. Mitotic errors that occur in earlier divisions result in embryos with a great percentage of abnormal cells.

The clinical significance of mosaicism in preimplantation embryos has become highlighted since the shift of clinical PGS toward blastocyst biopsy, vitrification, and diagnosis by high-resolution next generation sequencing (NGS). Data presented at the 2016 PGDIS conference (Bologna, May 8-11, 2016; www.pgdis.org) demonstrated that 10-20% of human blastocysts present with mosaicism when analyzed on a validated NGS platform. The presence of mosaicism in human blastocysts has been extensively reported over the years, but it is unknown if it is the same phenomenon as observed in CPM detected through CVS. There is some evidence of variation in level of mosaicism among blastocyst biopsy samples obtained from different IVF clinics, suggesting a potential iatrogenic origin distinct from mosaicism of biological significance. Technical variables affecting the quality of biopsy, or of downstream NGS procedures, may impact the significance and clinical implication of mosaic results. To date the scientific community agrees that <20% or >80% abnormal cells from a trophoblast biopsy cannot differentiate between mosaicism and ‘technical noise’. In support of the PGDIS Positon Statement (http://www.pgdis.org/docs/newsletter_071816.html), we make the following recommendations.

 

GOOD PRACTICE RECOMMENDATIONS

For reliable detection of biological mosaicism, a minimum of 5 cells (but, importantly, <10) should be biopsied, with as little cell damage as possible. If the biopsy utilizes a laser, the contact points should be minimal and preferably at cell junctions. Additionally, a validated, high-resolution NGS platform should be utilized. Diagnostic and clinical dilemmas arise when mosaicism consists of one normal euploid cell line and one aneuploid line (monosomic or trisomic). We believe these complexities can be managed with good practice recommendations and appropriate genetic counseling.

  1. PREFERED TRANSFER OF EUPLOID NON-MOSAIC EMBRYOS
    1. Non-mosaic euploid embryos should preferentially be transferred whenever available.
    2. Fully aneuploid embryos (greater than 70% abnormal cells, for the purposes of clinical practice) should not be transferred, as they may result in adverse obstetric or pediatric outcomes.
    3. If a non-mosaic euploid embryo is not available, another IVF cycle with appropriate preimplantation testing should be offered.
  2. TRANSFERRING MOSAIC EMBRYOS IN ABSENCE OF ALTERNATIVES
    1. If non-mosaic euploid embryos are not available and there is no option for undergoing another IVF cycle, a mosaic embryo may be considered for transfer. In such circumstances, the following constitutes good practice.
      • Embryos with lower levels (20-40%) of mosaic aneuploidy are preferential to those with higher levels (40-70%).
      • For embryos with higher levels of mosaicism in the trophectoderm, there exists a higher probability that aneuploidy is present in the inner cell mass. (ICM). Such embryos will likely implant less and miscarry more.
    2. In the case of complex mosaicism (mosaicism observed across multiple chromosomes), transfer is not recommended.
  3. RECOMMENDATIONS FOR PRIORITIZING MOSAIC EMBRYOS FOR TRANSFER
    1. If a decision is made to transfer a non-complex, low-level mosaic embryo, one can prioritize selection based on the specific chromosome involved.
    2. Embryos mosaic for trisomies capable of live born viability (chromosomes 13, 18, 21, 22) are of lowest priority.
    3. Embryos mosaic for trisomies associated with uniparental disomy (chromosomes 14, 15) are low priority.
    4. Embryos mosaic for trisomies associated with intrauterine growth retardation (chromosomes 2, 7, 16) are low priority.
    5. Mosaicism involving chromosomes 1, 3, 4, 5, 6, 8, 9, 10, 11, 12, 17, 19, 20, have not been associated with the aforementioned adverse outcomes; only adverse outcomes have been observed when mosaicism is present in the fetus.
    6. Mosaic monosomies seem to implant with a similar incidence to mosaic trisomies. They may contain trisomic cell lines, and should be considered to have similar risk as their counterpart trisomies.
  • PATIENT REVIEW
    1. It is self-evident that special care is required with regard to counselling patients, and appropriate professional guidance at the highest level must be available.
    2. Equally, all parties must be reassured that the signing of informed consent for embryo transfer is undertaken after such counselling and demonstrable understanding by the patient.
  • FOLLOW UP AFTER TRANSFER OF MOSAIC EMBRYOS
    1. If ongoing pregnancy is established after transfer of a mosaic embryo, the developing fetus should be retested for aneuploidy by prenatal diagnosis. Amniocentesis is recommended over CVS as the mosaicism persists in the trophoblast.
    2. Reproductive outcomes of mosaic embryo transfers should be conveyed to the PGS laboratory performing the original diagnosis, enabling data collection to refine and improve practice recommendations.
    3. And where possible a follow-up on mosaic data should be obtained from the live birth

CONCLUSIONS

  1. Aneuploid embryos exist at a high incidence in human conception; it is therefore incumbent on IVF practitioners to try to detect and avoid the transfer and cryopreservation of such embryos using PGS technology
  2. The use of PGS technology has been shown to improve the incidence of live birth, whilst, importantly, also reducing multiple pregnancy by the transfer of fewer, but viable embryos6
  3. Mosaicism is a natural occurrence and therefore is present in trophoblast biopsy of a few but significant number of embryos
  4. It is equally important to provide patients with advanced counselling on this issue as well as essential to have access to appropriate genetic counselling should mosaicism occur following biopsy
  5. The purpose of this COGEN Consensus Statement on Mosaicism is to underscore the need for PGS in IVF practice whilst supporting, with some modification, the appropriate PGDIS Statement on the recommendations for clinical practice
  6. And finally, but most importantly, best practice in all aspects of medicine will evolve over time, and whilst we all endeavor to maximize the most efficient route to a healthy birth for our patients in a single attempt, that which we agree to be the best approach today will inevitably modify as knowledge increases.

References

  1. R.R. Angell, R.J. Aitken, P.F. van Look, M.A. Lumsden, A.A. Templeton, Chromosome abnormalities in human embryos after in vitro fertilization, Nature 303 (1983), 336–338.
  2. R.R. Angell, A.A. Templeton, R.J. Aitken, Chromosome studies in human in vitro fertilization, Hum. Genet. 72 (1986) 333–339
  3. T. Hassold, P. Hunt, To err (meiotically) is human: the genesis of human aneuploidy, Nat. Rev. Genet. 2 (2001) 280–291
  4. Kalousek D.K and Dill F.J. Chromosomal mosaicism confined to the placenta in human conceptions. Science. (1983), 12;221(4611):665-7
  5. http://www.pgdis.org/docs/newsletter_071816.html
  6. Forman EJ, Hong KH, Ferry KM, Tao X, Taylor D, Levy B, et al. In vitro fertilization with single euploid blastocyst transfer: a randomized controlled trial. Fertil Steril 2013;100:100–7

 

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