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By Prof. Alan H Handyside, MA PhD, Scientific Advisor, Feb 18, 2020

Vitrolife Genomics: A busy year and exciting developments in PGT-A

The beginning of a year is always a time for reflection on the achievements of the past year and an opportunity to look forward to what the coming year may bring. And for the newly formed Genomics Division here at Vitrolife, 2019 was certainly a busy time that has flown by. The team was well represented at all of the main reproductive genetics and IVF annual meetings including Preimplantation Genetic Diagnosis International Society (PGDIS) meeting in Geneva and Controversies in Preconception, Preimplantation and Prenatal Genetics (CoGen) in Paris. At ESHRE in Vienna, Genomics was represented on the Vitrolife stand, which was a great opportunity to meet customers face-to-face, but equally important for us, to get to know all of our colleagues in other areas! There was a well-attended lunch time symposium at which I represented genomics and, in the evening, I had a lot of fun giving the after-dinner talk reminiscing on 30 plus years of my involvement in the field, since we published the first clinical pregnancies following preimplantation genetic diagnosis or PGD, as it was known then, for a range of X-linked inherited diseases, including Duchenne muscular dystrophy.

Progress in 2019

Vitrolife’s involvement in genomics centres around preimplantation genetic testing for monogenic inherited diseases (PGT-M) using bead array technology and preimplantation genetic diagnosis for aneuploidy (PGT-A) using a next generation sequencing based method for testing chromosome copy number. As chromosome aneuploidy (abnormal number of chromosomes) is a major cause of IVF failure and pregnancy loss, there is clear synergy with Vitrolife’s time-lapse incubator technology and plans to introduce an embryo score with artificial intelligence.

In 2019, PGT-A remained a ‘hot topic’, with many published studies, and almost exactly a year ago, I personally had an exciting beginning to the year with the publication of the clinical outcome of our IVF programme dedicated to single blastocyst transfers, cryopreserved by vitrification, with optional trophectoderm biopsy and NGS-based preimplantation genetic testing for aneuploidy (PGT-A)1. In a prospective cohort study, we used a combination of PGT-A to identify euploid blastocysts (with a normal number of chromosomes) and prioritised them for transfer based on time-lapse observations of the pattern of the first two or three cleavage divisions. This combined selection strategy yielded exceptionally high implantation rates per transfer, averaging 80%, and ranging between >90% (<35 years) and 60% (≥43 years), depending on maternal age. Clinical pregnancy/delivery rates were similarly high per transfer and estimated cumulative rates per cycle were well above the average in the UK, up to the age of about 40 years when the proportion of aneuploid embryos is high. Later in the year, Robert Anderson and colleagues published a retrospective study looking back over a period of 6 years, including a much larger data set of 7583 biopsies and 1531 transfers2. Similar to us, they observed high implantation (average 75%) and live birth rates (average 68%) when a single vitrified-warmed euploid embryo was transferred.

In September, the much anticipated outcome of one of the largest multicentre randomised clinical trials (RCTs) of PGT-A, the ‘STAR’ trial (Single Embryo Transfer of Euploid Embryo), was published online in Fertility and Sterility3. The RCT was focussed on patients between the ages of 25 and 40 years with at least two blastocysts of sufficient quality for trophectoderm biopsy and randomisation was therefore on day 6 post insemination. Given this scenario, the question addressed was simply ‘does the use of PGT-A to select euploid embryos versus embryo morphology alone improve clinical outcomes at 20 weeks gestation following single vitrified-warmed blastocyst transfer?’  The overall results in women of this age range (average age 34 years) demonstrated no significant improvement in clinical outcomes, but were equally not harmed, in these relatively good prognosis patients. In women aged 35-40 years, however, there was a significant improvement from 37 to 51% per embryo transfer (p=0.035), a relative increase of 38%. On the basis of this evidence, therefore, we recommended that patients fitting these criteria (35-40 of age with 2 or more blastocysts) and considering single embryo transfer, should be offered PGT-A to improve their chances of a clinical pregnancy and healthy singleton live birth.

At the ASRM annual meeting in Philadelphia in October, there were several highlights related to PGT-A. Tiegs and colleagues presented the preliminary results of an elegant study showing that sustained implantation rates (SIRs) following transfer of biopsied, but initially untested, and non-biopsied single vitrified-warmed blastocysts were almost identical (53 and 54%, respectively), providing strong evidence that the removal of 3-5 trophectoderm cells did not adversely affect clinical outcomes. More significantly, following PGT-A, they were able to compare the clinical outcomes of euploid and aneuploid blastocysts. The SIR of euploid blastocysts was high at 68% per transfer. In contrast, although about half of aneuploid embryos implanted none of them resulted in ongoing clinical pregnancies or live births. We all look forward to the final data being published in 2020 when the study is completed.

Another highlight was the presentation from Manuel Viotti (Zouves Fertility Center, Foster City, California) on the Vitrolife stand presenting their data on clinical outcomes following transfer of embryos identified as chromosomal mosaics following PGT-A4. Chromosomal mosaicism, detected as intermediate copy number changes in a small proportion of samples, is thought to represent aneuploidies in some but not all of the trophectoderm cells sampled. The clinical significance of these mosaic aneuploidies is unknown so several groups are collecting data on clinical outcomes following appropriate genetic counselling. To date, this has confirmed that some blastocysts identified as mosaic are viable and result in apparently healthy live births but at significantly lower rates5.

Prospects for 2020 at the beginning of a new decade

About 5-6 years ago, it was discovered that cell-free DNA could be detected in ‘spent’ culture medium at the blastocyst stage and aspirated blastocoel fluid, which had the potential for PGT-A and possibly even for PGT-M. Since then an increasing number of studies have been published confirming that this DNA can be amplified and used for PGT-A, but when compared to results from trophectoderm biopsies concordance has been variable. Rubio and colleagues demonstrated that as long as the medium was changed on day 4 and the embryos were cultured to day 6 or 7 before the medium was harvested a concordance rate of over 80% is possible6. Again at the ASRM meeting last year, another talk by Clifford Librach (CreateIVF, Toronto, Canada) on the Vitrolife stand presented promising data from their lab combining spent media and blastocoel fluid7. If possible and accurate, non-invasive testing would make routine PGT-A much more feasible in already busy embryology labs. Excitingly, the answer to this question for Monash IVF, Adelaide, Australia, using their own in house validation was resoundingly positive with 95% concordance with biopsy samples for whole chromosome aneuploidy. So, in May last year they became the first group of clinics world-wide to offer niPGT-A as a clinical service. We look forward to future publications on clinical outcomes using their methodology.

My second prediction for 2020?

It is going to be another busy year ahead for the Genomics Division, but I am confident an exciting one!

Watch presentations from ASRM 2019

If you would like to watch the filmed presentations in the Vitrolife stand at ASRM 2019 by Dr. Viotti and Dr. Librach click the button below.

Watch presentations

 

References

  1. Gorodeckaja J, Neumann S, McCollin A, Ottolini CS, Wang J, Ahuja K, Handyside A and Summers M (2019) High implantation and clinical pregnancy rates with single vitrified-warmed blastocyst transfer and optional aneuploidy testing for all patients. Human Fertility (Cambridge, England) 1–12.
  2. Anderson RE, Whitney JB and Schiewe MC (2019) Clinical benefits of preimplantation genetic testing for aneuploidy (PGT-A) for all in vitro fertilization treatment cycles. European Journal of Medical Genetics 103731.
  3. Munné S, Kaplan B, Frattarelli JL, Child T, Nakhuda G, Shamma FN, Silverberg K, Kalista T, Handyside AH, Katz-Jaffe M et al. (2019a) Preimplantation genetic testing for aneuploidy versus morphology as selection criteria for single frozen-thawed embryo transfer in good-prognosis patients: a multicenter randomized clinical trial. Fertility and Sterility.
  4. Victor AR, Tyndall JC, Brake AJ, Lepkowsky LT, Murphy AE, Griffin DK, McCoy RC, Barnes FL, Zouves CG and Viotti M (2019) One hundred mosaic embryos transferred prospectively in a single clinic: exploring when and why they result in healthy pregnancies. Fertility and Sterility 111 280–293.
  5. Munné S, Spinella F, Grifo J, Zhang J, Beltran MP, Fragouli E and Fiorentino F (2019b) Clinical outcomes after the transfer of blastocysts characterized as mosaic by high resolution Next Generation Sequencing- further insights. European Journal of Medical Genetics.
  6. Rubio C, Rienzi L, Navarro-Sánchez L, Cimadomo D, García-Pascual CM, Albricci L, Soscia D, Valbuena D, Capalbo A, Ubaldi F et al. (2019) Embryonic cell-free DNA versus trophectoderm biopsy for aneuploidy testing: concordance rate and clinical implications. Fertility and Sterility.
  7. Kuznyetsov V, Madjunkova S, Antes R, Abramov R, Motamedi G, Ibarrientos Z and Librach C (2018) Evaluation of a novel non-invasive preimplantation genetic screening approach. PloS One 13 e0197262.

Topics: genetic testing

Written by Prof. Alan H Handyside, MA PhD, Scientific Advisor

Prof. Handyside did his first degree and PhD studies at the University of Cambridge and has joined Vitrolife as Scientific Advisor. Prof. Handyside developed the first transgenic mouse knockout of the HPRT gene using embryonic stem cells as a model of the human X-linked inherited disease, Lesch-Nyhan Syndrome. Afterwards he joined Prof. Lord Robert Winston at Hammersmith Hospital, London and in 1990 achieved the first pregnancies worldwide following IVF and preimplantation genetic testing (PGT) of inherited disease. Previously Prof. Handyside has been director and consultant in preimplantation genetics at the Bridge Clinc, London for twenty years and Principal Scientist at Illumina.

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