Debatt – del 2: Blastocyst vs dag 2-3

Steven Mansell

Vi har tidligere hatt en diskusjon gående med OUS vedrørende bevisene for blastocystdyrkning og i hvilken grad dette ser ut til å gi bedre resultater enn dyrkning til dag 2 og 3. Da kommentaren ble lang og relativt omfattende publiserer vi den her som et nytt blogginnlegg og referer til forrige blogpost og OUS respons.

Artikkelen er fortsatt på engelsk da det er embryolog Steven Mansell som skriver.


 

I firmly believe that our main objective as professionals in this field is to best serve the needs of our patients. In this, we must strive continuously to ensure the information we release into the public arena is rooted in fact. This, I believe, is the best means by which the public electing to use our services can make an informed decision as to what is best for them. I have spent the last couple of weeks contacting international experts in the field of embryology to try to respond to this article in a manner that will address the points highlighted by the authors in a factual manner.

Blastocyst culture as an ‘add-on’

The UK paper regarding ‘add-on treatments’ within the fertility industry discussed blastocyst culture in the context of a service that attracted an additional charge. However, this did not reflect the practices of all clinics in the UK. Furthermore, this is not relevant to the fertility industry in Norway, given that no clinics here charge extra for this service. Some public hospitals actually now provide blastocyst culture entirely as standard. Lastly, the paper by Heneghan et al ., 2016 (https://www.bmj.com/content/bmj/355/bmj.i6295.full.pdf) also included a number of other IVF techniques, including surgical sperm retrieval  (SSR), which cannot be described as an add-on as it is a necessity for the treatment of men with severe male factor infertility, notably Azoospermia. The point highlighted in the original blog is not reflective of the Norwegian fertility industry as it currently stands. As such, my aim in responding to the blog stems wholly from the inherent duty of care we all have to patients to ensure accurate and unambiguous information is made available to them. It is my contention that the original blog post does not achieve that high standard of care owed to patients.

Take home baby rate

One of the most significant comments provided against my response that blastocyst transfer results in higher pregnancy rates were that couples want babies, not just a pregnancy. What the author neglected to mention is that in the meta-analysis referenced in the original blog, the very first conclusion indicated that blastocyst transfer resulted in a higher live birth rate compared to cleavage stage (day2/3) transfer. I provide the actual quote from the referenced paper for the author’s reference; “The live birth rate following fresh transfer was higher in the blastocyst transfer group (odds ratio (OR) 1.48, 95% confidence interval (CI) 1.20 to 1.82; 13 RCTs, 1630 women, I2 = 45%, low-quality evidence) following fresh transfer. This suggests that if 29% of women achieve a live birth after fresh cleavage stage transfer, between 32% and 42% would do so after fresh blastocyst stage transfer. “ The author is correct in stating the level of evidence is indeed low quality (only 13 randomized controlled studies, RCTs), however, the evidence to suggest cumulative pregnancy rates are no different (which was the author’s pivotal argument) is of even lower quality. In the paper by Glujovsky et al., (https://www.ncbi.nlm.nih.gov/pubmed/27357126 ) only 5 RCT regarding cumulative pregnancy rates were included. Therefore, the author’s assertion that there is no difference in cumulative pregnancy between blastocyst and cleavage stage embryo transfer is based on weaker evidence than that of live birth rate or clinical pregnancy rates following blastocyst transfer.

Cumulative pregnancy rates as a measure of success

The author is correct in concluding that cumulative pregnancy rates are the historical ‘gold standard’ for assessing IVF outcome. However, as professionals in this field, we know there are many ways to assess IVF outcomes e.g. live birth per cycle started, clinical pregnancy rate/ transfer etc. However, it is of vital importance that we focus on what it is we are trying to assess. Furthermore, the method used needs to be examined for its effectiveness by the context of the case in question. I believe a better way to assess success is by looking at implantation rate per embryo transferred. The implantation rate is an important indicator of the overall laboratory performance and is reflective of the culture conditions of the lab. However, it can also be influenced by uterine receptivity and the different policies for embryo transfer in different centers e.g. cleavage vs. blastocyst transfer, single vs. double embryo transfer (Vienna consensus https://www.rbmojournal.com/article/S1472-6483(17)30268-7/pdf).  The implantation rate is calculated by the number of gestational sacs, with heart activity, observed by ultrasound divided by the number of embryos transferred, multiplied by 100

The Vienna consensus set up in 2017 by a team of international experts have set key performance indicators  (KPI) for a number of stages of the IVF process. One such KPI is implantation rate. Interestingly the KPI values for cleavage stage vs blastocyst stage implantation rates are different, with a higher implantation rate expected for blastocyst transfer (competency value of ≥25% vs ≥35%, cleavage vs blastocyst transfer). If, as the author suggests, there were no difference in cleavage vs blastocyst transfer then these would be similar.

Viable embryos being lost due to extended culture

The author is correct in saying that no one knows for certain if viable embryos may be lost during extended culture. However, we do have a good idea of how many viable embryos should reach day 5 and lower rates are reflective of poor laboratory culture conditions and techniques. This once again has been set out by the Vienna consensus and states a competent laboratory should expect ≥40% of all fertilized eggs to reach blastocyst stage. At Medicus, I monitor our blastocyst development rates daily to ensure we are meeting these standards. At present we have a 52% blastocyst formation rate and a 44% blastocyst utilization rate. Based on an average patient age of 38 years this is very good and meets the criteria of the Vienna consensus. Therefore, I feel confident based on our data from our blastocyst culture program that a viable embryo should reach day 5.

Blastocyst culture as personalized treatment

This leads me on to the notion that blastocyst culture is personalized treatment. I would like to make clear that blastocyst culture is in no way personalized treatment; it is a routine procedure in the vast majority of clinics globally.

I contacted the Human Fertility and Embryology Authority to provide me with some information regarding blastocyst transfer in the UK.  From their latest data in 2014, over 40% of transfers were blastocysts in 2013 compared to 12% in 2008 and there was a steady upward trend in blastocyst transfer over cleavage stage. This indicates that blastocyst culture is more or less a standard procedure and the notion that somehow growing to blastocyst is a personalized treatment is not substantiated. In my opinion, personalized treatment begins prior to the creation of the embryo. Once the embryo is created you are stuck with what you have. Blastocyst culture will not make a bad embryo more viable.

Fewer embryos to freeze.

In the original blog, there was great emphasis placed on blastocyst culture resulting in fewer embryos to freeze. As I mentioned in my previous response this is because we are eliminating embryos that do not have the potential to progress further. I subsequently decided to contact two experts in the field of embryology to get their opinion to help address this issue. Both of which provided some really useful points which I would like to share.

Point 1: Fewer embryos are a good thing!

Let’s say you start with 10 embryos and grow them to day 3. Roughly 95% will make it to this stage and you pick 1-2 from 9,5 embryos. At this stage, you have 1 in 10, maybe a 2 in 10 chance of picking the right embryo. However, if you grow to blastocyst you may “lose” 40-50% of the embryos because they will not continue past day 3. Now you have 4-5 embryos to pick from narrowing the chances of picking the correct embryo for transfer. Given that blastocyst grading is so much more informative and given that the embryonic genome will not become active past day 3, consider if an embryologist picks an embryo that looks great on day 3 but is, in fact, part of the 40-50% of embryos that couldn’t make it to day 5. This would result in twice as many embryo transfers to go through the cleavage frozen embryos to basically select the same productive blastocyst that would filter out naturally in culture. Furthermore, freezing cleavage stage embryos can also be detrimental because the survival rate of a day 2/3 embryo can be lower given that losing 1 or 2 cells can equal 10-50% of the entire embryo. If you lost 1-2 cells in a blastocyst you would lose less then 3% of the embryo. The main message is that fewer embryos are not a bad thing, as it helps embryologists ‘weed out’ non-viable embryos reducing the number of transfers prior to success.

Point 2: Fewer embryos mean fewer failed transfers.

As a result of having more embryos frozen on day 3, some of which are potentially ‘non-viable’, couples may require more embryo transfers before achieving a pregnancy. One of the experts I spoke to pointed me to data indicating the likelihood of success at fertility treatment actually reduces as the number of unsuccessful transfers increased. This was not due to the reduced likelihood of pregnancy over multiple transfers (cumulative pregnancy rate), but in most part, due to the emotional and financial burdens, infertility treatment places on couples. In a paper by Dodge et al 2017(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5306407/pdf/10815_2016_Article_839.pdf), the authors observed that as the number of unsuccessful transfers increase the higher the likelihood of couples to discontinue their treatment. They showed that by the third transfer roughly 21% of all couples (6534 couples) did not continue with their treatment. This was, of course, age-dependent as younger couples were less likely to discontinue treatment compared to older couples due to a better prognosis.

At Medicus, we are very fortunate to have a fantastic therapist, Mari Heger, who helps our couple deal with some of these emotional struggles. I asked Mari to give her professional opinion regarding the struggles many couples go through when undertaking infertility treatment. This is her response:

“Par som kommer til IVF behandling har forsøkt å bli gravid i opptil flere år på egenhånd. De har allerede kjent på nederlag, sorg og utilstrekkelighet. I oppstarten av en IVF prosess opplever mange et nytt håp om å lykkes, bli gravid og få et barn. Vi vet at det er intenst å være i en IVF prosess, det er sterke, dype og høyst reelle følelser involvert. Målet om barn er utenfor egen kontroll og påvirkning, det kan forsterke fortvilelse og maktesløshet. Disse følelsene gjør noe med kroppen og kan påvirke livskvaliteten i negativ retning. Par i IVF forsøk er villige til å gjøre alt for å nå det store målet, men på et tidspunkt kan noen oppleve at det sier stopp. Psyken og kroppen orker ikke mer. Hvert forsøk med negativt svar blir en ekstra påkjenning. Håpet som holder dem oppe og som hjelper dem med å mobilisere, blir svekket. Det gjør det vanskeligere å reise seg for å gå i gang med et nytt forsøk. Det er vondt å se par som ikke orker å stå i det, selv om vi vet at de kan bli gravide om de fortsetter.”

I mitt arbeid som fertilitetsterapeut ser jeg tydelige endringer i tankene knyttet til håp og mobilisering hos de som må gjennom flere mislykkede forsøk. For hvert forsøk som gir negativt svar krever det mer å fortsette. Jeg oppfordrer alle par til å være åpen om prosessen, vonde følelser blir verre hvis man samtidig er alene om dem. Støtte fra nettverk og tett oppfølging fra klinikken er særdeles viktig for at par skal klare å stå prosessen fullt ut. Tid er en av store utfordringer parene møter på, livet blir satt på vent. Det påvirker tankene og følelsen, og hvordan de har det.”

The main message I would like to emphasize is that as embryologists we need to think about the stress that fertility treatment places on our patients and to be sure that what we are transferring or freezing has a good chance of resulting in a live birth. This can be achieved in some part by ensuring the embryos are capable of progressing past day 3.

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