Reproductive Medicine - Not true: If you are not using time-lapse as part of your culture system, your patients are disadvantaged

Summary of the talk by Nicolas Zech at COGI 2015


 The ultimate goal in ART is to achieve a singleton pregnancy with birth of a healthy baby per transfer.

Carl Nygren stated: « You can put back as many embryos as you like, but one at a time ».

As consequence, the challenge for ART clinics is to transfer one embryo either in a fresh or cryopreservation cycle, thereby minimizing the risk of multiples without compromising success rates. In view of implementing elective single embryo transfer (eSET), it is a challenge for IVF labs to accurately produce and select the most viable embryos with the highest implantation potential.

  • First, it is essential to fulfill quality control (QC) standards in culture system (e.g. media, air quality, incubator).
  • Next, labs should be able to select the most viable embryo for transfer out of a cohort presenting various morphologies; and this, as simple and as non-invasive as possible.
  • Labs should also be able and willing to effectively freeze surplus embryos.

With such policy several issues arise:

  1. Do widely accessible non-invasive techniques exist that accurately predict developmental potential of embryos?
  2. It is known that almost 50% of day 2/3 morphologically “good looking” embryos will never reach the blastocyst stage. The possibility to identify the most implantation-competent embryos is limited using static/ sequential evaluation, especially if selection is performed before the onset of the maternal to full genome transition (i.e. PN scoring, early cleavage, number and size of the blastomeres, degree of fragmentation and multinucleation).
  3. Time-lapse recording more and more replaces static evaluation. For those who are in favor of day 2/3 ET, the introduction of the morphokinetic evaluation was considered as the method of choice to select the right embryo for transfer. However, there is still not yet a universal embryo selection algorithm reported that permits to select with high predictive value the one cleavage embryo that will form a blastocyst and implant.
  4. Current developments beyond morphological criteria have looked into metabolic parameters of embryos in culture media.All these techniques are not yet routinely applied because of lack of precision in addition to their complexity and costs. So, what is the best and most simple option for embryo selection?
Seeing that examination of zygotes-embryo/ morphology-cleavage status is only predictive to a limited extent, why not opt for blastocyst culture?

Several prospective randomized studies have showed that blastocyst transfer can results in a higher likelihood of becoming pregnant when compared with day 2/3 ET. It is observed that after 5 days of growth as much as 40% of embryos fail to develop to the blastocyst stage. With the introduction of the time lapse technology, it is frequently observed that day 2 or day 3 embryos stop their development even though they fulfill all the morphokinetic criteria that are reported to predict further normal development. Thus waiting for the embryos to reach the blastocyst stage decrease the number of abnormal embryos leaving the labs with the ones that are most likely to develop into a healthy baby.

A question to those performing routinely blastocyst culture:
--> what is your Expected Gametes Performance (EGP) and do you perform IMSI (i.e. selection of the best sperm using MSOME to positively impact on the late paternal effect, which is neither detectable nor predictable or influenceable by using time-lapse systems)?

What does EGP mean?
We believe that urgent action is needed as to the current grouping of the women in so-called responder-groups (Low / Poor, Normal, High).
The reason: an accurate and uniform definition of these "responder"- groups and a holistic view of the different components that may influence a fertility treatment are still missing!

Typically, the responder-groups reflect the expected number of oocytes for a specific age group after hormonal stimulation and egg retrieval. Sperm quality, fertilization rate and embryo developmental potential have not been taken into account here.

For us it is therefore clear that it is not sufficient to determine the number of oocytes in order to provide the couples with meaningful predictions regarding the possible success of the treatment. What matters is to view together female and male factors and give a prognosis based on blastocyst outcome.

If a lab cannot specify its individual EGP based on its used stimulation protocol and culture system, it should not start discussing other fancy techniques such as preimplantation genetic screening (PGS), which is said to further increase success.
And if a lab has its individual EGP also reflected in high success rates of establishing viable single pregnancies after eSET: how do they classify a viable embryo and how many of those are eligible for PGS, if applied because of believed additional benefit?

Furthermore, is the lab able to freeze surplus embryos, also those which seem to be arrested in development or show slow growth? Such embryos can give viable pregnancies if managed properly. However, such embryos might not be suitable for further screening using PGS. In certain cases, such as with advanced maternal age or a severe sperm factor, many embryos are rather slow growing or not good for a biopsy.

Is recurrent implantation failure maybe due to the fact that inferior lab conditions are present (day 2/3 transfer), or other conditions such as a severe sperm-factor (e.g. not using IMSI), suboptimal endometrium (e.g. ET on day 2/3 into a non-physiologic environment; insufficient progesterone substitution), allergy on culture media, to name but a few, are not factored in?

Is recurrent miscarriage next to possible aneuploidy of embryos, due to e.g. suboptimal hormonal supplementation?
How are embryos classified? According to the Istanbul consensus workshop of embryo assessment from 2010, using the classic Gardner criteria, through external/ internal validations or through time-lapse analysis or through a combination of reported classifications? And if with the additional help of time-lapse, why?

Are we not already confused enough with all the other reported criteria? Would someone choose let`s say a 2CC blastocyst (it could also be an early blastocyst) with good time-lapse classification over a 4AA blastocyst which does not fulfil published criteria for ET? And who would biopsy a 2CC (or early blastocyst)? Would both be transferred with the 4AA being biopsied – well, then a cryo-ET would be needed. Is the lab willing and able to freeze the other 2CC (or early blastocyst) which fulfils time-lapse criteria; would it discard it because being classified as non-viable or disregarded as a blastocyst at all; or would it keep the embryo in culture until day 6 and then see what happens? What is the implantation rate of such embryos? Would an eSET be better instead of transferring both? Would the second embryo negatively influence implantation if both would be transferred? And if, which one would negatively influence the others potential?....Whatch this space.

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