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By Dr. Tine Qvistgaard Kajhøj, Feb 29, 2016

Using PGS and time-lapse in synergy will enhance your decision making

Embryo viability after transfer depends on the embryo itself, the environment in which it has been before transfer and the uterine environment into which it is transferred to. Picking out the embryo(s) most likely to be viable is the goal of any embryo selection process. Both time-lapse and preimplantation genetic screening (PGS) are well established methods for enhancing the chance of transferring a viable embryo. In this blog post I will describe how using them together can enhance your decision making.
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Applying time-lapse and PGS in IVF gives you different types and levels of information

It is important to remember that neither method changes the potential of the embryo to give rise to a healthy live birth, but instead both methods are used to identify embryos that fulfil traits that are considered normal.

The type of answer that you get from the two methods is fundamentally different. PGS is designed to answer a question about the genetic material within a sample of the embryo; is the embryo chromosomally normal? The answer is binary: yes or no. This answer is extremely helpful in achieving the ultimate goal in all IVF cycles – a healthy live birth. However transferring a chromosomally normal embryo does not ensure a positive pregnancy outcome.

Time-lapse on the other side can be used to classify embryos according to their chance of implantation and live birth1,2,3,4,5. With time-lapse, the amount of information that can be collected about an embryo is vast. Morphokinetics, cleavage patterns and morphology observed as a dynamic trait can be used to assess the chance of implantation and livebirth.

Predictive models using time-lapse technology

Time-lapse has also been demonstrated as a method that can be used for indicating the chance of an embryo to be chromosomally normal. The CARE group in the UK has developed a model to predict the risk of embryo aneuploidy based on time-lapse information about the blastocyst formation process and correlation to PGS results6.. The model was designed to rank embryos into “high”, “low” or “medium” risk of aneuploidy when applied to embryos after time-lapse monitoring and assessment.

Similarly, the IVI group in Spain developed a time-lapse-based model to reflect the chance of an embryo to be chromosomally normal. In this case, the prediction was done on day 3 after oocyte insemination and based on PGS results of cleavage stage biopsies7.

In both examples time-lapse is used to classify likelihood of embryo ploidy status and therefore is not a method that aims to give a diagnostic yes/no answer to the question of whether the embryo is aneuploid. Time-lapse information is gained through the monitoring of embryo development during culture and as such is a non-invasive assessment method.

Time-lapse information can be used to reflect the relative embryo potential within a cohort by ranking embryos according to a defined set of criteria reflecting “highest chance of implantation” or “risk of embryo aneuploidy”. Due to the variability in factors such as culture environment and patient cohort these criteria will often be clinic specific8, 9.   

In this way, the answers and questions that can be asked and gained from these two very different approaches to embryo assessment are fundamentally different.

Better together

PGS is able to answer only one question: is the embryo chromosomally normal or not? While this is valuable information it may not alone be sufficient for selecting THE embryo for transfer with the best developmental trait. Having a normal chromosome content may not necessarily ensure successful embryonic genome activation or metabolic potential.

In some cases multiple embryos which are termed “euploid” by PGS will be available for selection. Then comes the need to decide between the euploid embryos which one(s) to transfer in a SET or DET cycle. Here, applying criteria based on time-lapse information is a consistent and non-invasive way of ranking embryos for transfer10. In such cases, developmental progress information for euploid embryos that were grown in time-lapse can be retrospectively evaluated in order to assess development after biopsy11.

PGS is an invasive and relatively costly method for embryo assessment. Time-lapse can be used as a pre-screen to prioritise which embryos should be sent for biopsy and diagnosis by classifying those embryos with the highest risk of being aneuploid. In such cases you may choose to test only those embryos that, according to time-lapse assessment, have a fair chance of being chromosomally normal. Alternatively you may biopsy all embryos but send only biopsies from embryos with a higher chance for diagnosis and keep the other biopsy material frozen.

Embryo characteristics correlated to aneuploidy

Classical embryology has identified embryo characteristics that have been correlated with embryo aneuploidy. These include the relative size of blastomeres, multinucleation of blastomeres during cleavage stage and developmental pace 12,13,14. These characteristics can also be observed through time-lapse monitoring, but with the advantage of being more precise and more consistent.

As an example, a correlation between nucleation errors and embryo ploidy status and between nucleation errors and embryo developmental potential have been reported many years ago, however, traditional embryo assessment may miss more than 70% of such errors due to suboptimal timing of assessment15. Continuous monitoring by time-lapse ensures sufficient basis for identifying such errors.   

Embryo mosaicism is prevalent and as a result PGS may give results that are not representative of the whole embryo16, 17. A number of embryos termed “aneuploid” by PGS have been shown to implant and give rise to healthy live-born babies. Speculations have been made that this may be the result of a self-correction mechanism or simply reflecting the nature of mosaicism where the inner cell mass can be normal while trophectoderm cells may be aneuploid18,19. Although PGS provides an answer to a specific and important question, it may not be comprehensive and therefore additional assessment of the embryo cohort is needed to reveal more truths about embryo developmental potential.

Are you considering introducing PGS in your IVF clinic? 

My colleague Dr. Marcus Montag has written a blog post about practical considerations when introducing PGS that might be helpful for you.  

Learn more about why time-lapse and PGS are better together

In this recorded version of a live webinar I will discuss how time-lapse and PGS can be used together to offer the best overall possibility for improving outcomes and clinical workflow.   

Watch webinar

 

References

  1. Rubio, I., et al., Clinical validation of embryo culture and selection by morphokinetic analysis: a randomized, controlled trial of the EmbryoScope. Fertil Steril, 2014
  2. Chamayou, S., et al., The use of morphokinetic parameters to select all embryos with full capacity to implant. J Assist Reprod Genet, 2013. 30(5): p. 703-10
  3. Kovacs, P., et al., Time-lapse embryo selection for single blastocyst transfer - results of a multicenter, prospective, randomized clinical trial. Fertility and Sterility, 2013. 100(3, Supplement): p. S90, O-295
  4. Basile, N., et al., The use of morphokinetics as a predictor of implantation: a multicentric study to define and validate an algorithm for embryo selection. Hum Reprod, 2015. 30(2):p. 276-83
  5. Siristatidis, C., et al., Morphokinetic parameters of early embryo development via time lapse monitoring and their effect on embryo selection and ICSI outcomes: a prospective cohort study. J Assist Reprod Genet, 2015. 32(4): p. 563-70
  6. Campbell, A., et al., Modelling a risk classification of aneuploidy in human embryos using non-invasive morphokinetics. Reprod Biomed Online, 2013. 26(5): p. 477-85.
  7. Basile, N., et al., Increasing the probability of selecting chromosomally normal embryos by time-lapse morphokinetics analysis. Fertil Steril, 2014. 101(3): p. 699-704.
  8. Kirkegaard, K., J.J. Hindkjaer, and H.J. Ingerslev, Effect of oxygen concentration on human embryo development evaluated by time-lapse monitoring. Fertil Steril, 2013. 99(3): p. 738-744 e4.
  9. Freour, T., et al., Comparison of embryo morphokinetics after in vitro fertilization-intracytoplasmic sperm injection in smoking and nonsmoking women. Fertil Steril, 2013. 99(7): p. 1944-50.
  10. Sundvall, L., , Ingerslev, H., Knudsen, U., Kirkegaard, K., Inter- and intra-observer variability of time-lapse annotations. Hum Reprod, 2013. 28(9): p. O-213.
  11. Kofinas, J.D., et al., Do time lapse morphokinetic (TLM) parameters distinguish between good versus poor prognosis embryos of known ploidy status? Fertil Steril, 2015. 103(2): p. e27, P-42.
  12. Magli, M.C., et al., Embryo morphology and development are dependent on the chromosomal complement. Fertil Steril, 2007. 87(3): p. 534-41.
  13. Hardarson, T., et al., Human embryos with unevenly sized blastomeres have lower pregnancy and implantation rates: indications for aneuploidy and multinucleation. Hum Reprod, 2001. 16(2): p. 313-8.
  14. Yakin, K., B. Balaban, and B. Urman, Impact of the presence of one or more multinucleated blastomeres on the developmental potential of the embryo to the blastocyst stage. Fertil Steril, 2005. 83(1): p. 243-5.
  15. Ergin, E.G., et al., Frequency of embryo multinucleation detected by time-lapse system and its impact on pregnancy outcome. Fertil Steril, 2014. 102(4): p. 1029-1033.
  16. Scott, R.T., Jr. and D. Galliano, The challenge of embryonic mosaicism in preimplantation genetic screening. Fertil Steril, 2016.
  17. Munne, S., J. Grifo, and D. Wells, Mosaicism: "survival of the fittest" versus "no embryo left behind". Fertil Steril, 2016.
  18. C. Lagalla, N.T., R. Sciajno, M. Nadalini, M. Di Santo, V. Distratis, D. Wells, A. Borini, Embryos with cell division aberrations monitored by time-lapse imaging in a PGS program: are they able to develop into euploid blastocysts? Human Reprod, 2015. 30(suppl 1): p. i1-i501.
  19. Greco, E., M.G. Minasi, and F. Fiorentino, Healthy Babies after Intrauterine Transfer of Mosaic Aneuploid Blastocysts. N Engl J Med, 2015. 373(21): p. 2089-90. 

Topics: Time-lapse, genetic testing

Written by Dr. Tine Qvistgaard Kajhøj

Tine did her PhD in the stem cell field. One of her responsibilities at Vitrolife is holding workshops where clinics both get started with and develop their skills in using time-lapse technology, in order to improve their results.

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