Fertility • March 24, 2018

Blastocyst culture vs day 2-3, which is best?

Steven Mansell

Embryologist, PhD

A few days ago, a PhD student at Oslo University Hospital published a blog post where she discussed the evidence for blastocyst cultivation vs. day 2-3. Her conclusion was that the evidence is not good enough for culturing to blastocyst.

We at Medicus routinely culture to blastocyst and have a different understanding of the matter and have commented on the matter directly on OUS's blog. We also reproduce the matter here on our blog. The matter is written by our embryologist (PhD) Steven Mansell in English as this is his native language.

I am writing this response purely because I was perplexed to read the way this article was presented to couples reading it. The argument regarding cleavage stage (day 2 or day 3) versus blastocyst (day 5) embryo transfer is one that has been ongoing for many years. However, it is generally accepted in the scientific community that blastocyst transfer results in a higher pregnancy rate. In my opinion, this argument needs to be put to rest and the best interests of our couples need to be taken into account. We as embryologists have a duty to provide the best quality care and help our couples achieve their desired goal of having a family quickly and safely. In this response, I would like to address a number of issues that the author has highlighted in her blog post and I would strongly advise her to pay closer attention to the details within the papers she is referencing here. Particularly since attention to detail is the key requirement for good research and a good embryologist.

Issue 1: Norwegian private clinics charging for blastocyst

The author states that many private clinics charge more for blastocyst culture suggesting it will be more expensive for the couples. We at Medicus, and as far as I'm aware no private clinic in Norway charges extra for blastocyst culture. If they do, I would advise couples to seek another clinic, as this is unjustified. I also felt this comment was a poorly constructed attempt to vilify the private sector whose sole interest is to provide the best of quality care for our patients.

Issue 2: Fewer embryos to freeze

The author states that there will be fewer embryos to freeze down. This is actually accurate. Not every embryo has the capacity to reach the blastocyst stage and therefore create a baby due to inherent abnormalities within the embryo itself. One of the main purposes of growing to blastocyst stage is to exclude embryos that cannot progress further. By freezing on day 2 or 3 you may inadvertently freeze down embryos that would inherently never become a viable pregnancy. This not only provides the lab with more work and resources but also gives false hope to couples. Furthermore, I would be inclined to question the type of freezing method routinely used. If a clinic is currently doing slow freezing over vitrification, the survival rate after thawing is pretty poor, typically 60-70% compared to vitrification (~95%). Therefore, even though many embryos may have been frozen down, let's say 10 embryos, only 6 or 7 will survive and that's with a good slow freeze program. For any couples reading this response, I would recommend you to ask your clinic which method they are using. If their freezing program is not vitrification I would ask why as the survival rate after thawing with vitrification is ~95% or higher in a good clinic.

Issue 3: Cancellation rates are higher.

This is true, however, once again this is because we are removing embryos that cannot progress further than day 3. This is also obviously dependent on the blastocyst culture conditions and the general quality of embryology within the clinic. But for the sake of argument let's say these were completely optimized and the typical blastocyst formation rate was over 50%. Is it better to put back an average looking embryo on day 3 and allow that woman to wait two weeks to find out it hadn't progressed, or is it better culture for 2 more days to see if it didn't form a blastocyst and cancel the cycle, thereby preventing that anxious and emotional 2-week wait? Furthermore, freezing of embryos that would not reach the blastocyst stage means additional lab resources and time. The time that could be better spent training and implementing new techniques to improve success rates within the lab.

Issue 4: No difference in pregnancy rate.

I would suggest that the author reads the paper quoted in her blog in more detail. The paper actually says, and I quote; "The clinical pregnancy rate was also higher in the blastocyst transfer group, following fresh transfer”. It goes on to provide a statistic saying that if 36% of women fall pregnant after cleavage stage embryo transfer, around 39% to 46% of women would achieve a clinical pregnancy after a fresh blastocyst transfer. Furthermore the Human Fertilization and Embryo Authority of the UK (HFEA), one of the strictest regulatory bodies in the field of reproductive medicine, states in their patient guide entitled “Decision to make about your embryos”, that blastocyst transfer will provide patients with a higher chance of falling pregnant over a day 2 or day 3 transfer. I strongly urge readers to click on this link to view their recommendations. This advice is based on the HFEA's latest national statistics and can be found on page 32 of theirs 'Fertility Treatments - trends and figures' document. This document showed a ~16% increase in pregnancy rates per single embryo transfer for all ages after blastocyst transfer. Once again I would urge readers of this blog to look at this document.

The author does state that there is no difference in cumulative pregnancy rates between cleavage and blastocyst stage embryo transfer, and this is also stated in the paper she referenced. This is true, but why? So let's think about it. In a cohort of 200 women, 100 will have day 3 transfer and 100 will have blastocyst transfer. Now let's say these patients are between 18 and 35 years old and all have 1 egg collection. The blastocyst group had fewer embryos to freeze as not all embryos reach the blastocyst stage while the cleavage stage embryos have more embryos frozen down. Statistically, ~ 50% of the women in each group have the potential to achieve a pregnancy per embryo transfer. In the blastocyst group, 40 patients achieved a pregnancy after the first transfer and 10 patients achieved a pregnancy in their second transfer with all embryos used up in the 2 transfers due to fewer embryos being frozen down. To calculate the cumulative pregnancy rate we take the number of patients achieving a pregnancy after the first transfer plus the number of patients achieving a pregnancy after subsequent transfers (frozen embryo transfers) and divide by the total number of women who had an egg collection. Therefore it would be (40+10)/100, and this is multiplied by 100 to give a cumulative pregnancy rate of 50%.

Now let's compare cleavage stage. We know that cleavage stage transfer has roughly a 14% less rate of pregnancy per transfer in this age group (HFEA statistics). This means that in the first cycle 35 women will achieve a pregnancy in the first cycle, 9 in the second and for the sake of the argument, the rest fall pregnant (6 women) in the third. Therefore the cumulative pregnancy rate would be (35+9+6)/100*100 which equals 50%.

The cumulative pregnancy rate isn't different but the time for all the women who could potentially achieve a pregnancy is longer. Consequently, these women would have to go through additional cycles in order to achieve a pregnancy compared to those receiving a blastocyst transfer. This means more days off work for the patient, increased medication usage, more doctor appointments and increased emotional stress for the couple. The example given here is a gross simplification of the process and I admit that. However, what we also need to think about are the women in this cohort who had embryos that would never create a viable pregnancy. In the blastocyst group, many of those women would have had their first cycle canceled and would begin on their next treatment cycle. While those in the cleavage stage group would have had non-viable embryos frozen down for subsequent frozen embryo transfers. In this group, those patients may have to undergo many more frozen cycles without success before starting a fresh treatment. This not only wastes the couple's time but could reduce the success rate of future cycles as the patient's age increases.

Issue 5: The proposed study into the difference between cleavage and blastocyst stage pregnancy rates.

As a person from a scientific background with a Ph.D. and a post-doctoral fellowship in the field of reproductive medicine, I am completely for research in this field. However, I do have concerns about the study that is proposed here. For this study to be credible it is important that the institution in question should have a well-established blastocyst program with good blastocyst formation rates and a successful vitrification program. Although I do not wish to draw conclusions I cannot help but question the lack of blastocyst culture experience based on the content of this blog. Therefore I would have to evaluate the data published here with a more skeptical view over data published from a clinic with an optimized blastocyst program.

Summary

In summary, blastocyst transfer has been proven to result in higher pregnancy rates per transfer. Blastocyst culture programs can have fewer embryos to freeze down and higher cancellation rates but this is because the main purpose of this culture is to eliminate embryos that cannot develop past day 3 and therefore do not have the potential to create a viable pregnancy. Cumulative pregnancy rates are not different, however, the number of cycles required to achieve a pregnancy is fewer saving the couple time, money and emotional stress. As an additional note, the main argument I am often presented with is that 'the uterus is a better incubator'. My response is typically that of a physiologist. The uterus is a better incubator for a blastocyst as the environment of the uterus is optimal for blastocyst development. However, the fallopian tubes are a better incubator for cleavage stage embryos as this is the sight of optimal embryo development for the first 4 days after fertilization. By replacing a cleavage stage embryo, especially a day 2 embryo, into the uterus we are artificially forcing that embryo to develop in suboptimal conditions. The culture media in the lab, although not perfect, is designed to support different stages of embryo development.

Lastly in a country that does not allow genetic testing of embryos prior to transfer to prevent multiple failed transfers or transmission of hereditary diseases, that does not allow egg donation, that does not allow routine vitrification of eggs and does not allow surrogacy, I feel scientific resources could be better allocated to investigate these areas in order to bring Norway up to the same standard as many other European countries. I feel it's time to follow suit of countries such as the UK who have legalized many treatments such as 3 parents embryo cycles after rigorous research and public opinion, to provide world-class treatment to many couples desperate to fulfill their dream of becoming parents. So let's put these dated arguments to rest and focus on the bigger picture.

COMMENTS · 4

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Andreas July 14, 2018

Hi. My wife and I have now completed 2 fresh attempts and 2 tin attempts at Riksen. We feel like we are not heard at all when we ask questions about why 2-day embryos are put back every time. We have both read up on IVF and are surprised by the way we are received at Riksen. There is absolutely no personalized treatment that we have been involved in. An assembly line feeling is what we are left with. And when we ask about the possibility of using a short protocol and growing to blastocysts, we are dismissed without any good reason as to why. We have justified our wish with what Steven Mansell has gone through here previously. Not least his point that the uterus is intended for blastocysts, not 2-day embryos. Yet we are not heard for any of what we put forward. Overall, we are left with the impression that the numbers presented by Riksen are mostly based on luck, and not science. We want to be heard, but we are NOT.

1 answer SVAR
- Magnus Finset Sørdal Aug 14, 2018
  
  Hi Andreas, sorry for the late reply here on the blog. As you can see from the discussion we have had with OUS, we have different views on this. You are welcome to contact us if you would like to talk about any experiments with us.
  
  SVAR
Steven Mansell Jun 14, 2018

Hi Trine, I've written a response to your response in this new blogpost: https://medicus.no/debatt-del-2-blastocyst-vs-dag-2-3/

SVAR
Trine Skuland March 27, 2018

We thank Medicus and Steven Mansell for the comments on our blog post. It is very nice to have a response, but it would have been nice if we could stick to the professional debate and not question each other's competence.

When it comes to Mansell's professional comments, there seem to be some misunderstandings. Mansell is right that the pregnancy rate may be higher with blastocyst transfer than day 2 embryo transfer when looking at each individual embryo transfer. However, we want to look more closely at what is most important to our patients, namely the overall "take home baby rate", i.e. the chance that a couple will have a child after the treatment in its entirety. Couples want babies, not pregnancies, and our treatment offer is 3 fresh cycles, as well as any attempts at conception - not one embryo transfer. For our patients, what is most important is therefore what the cumulative birth rate is for these cycles, and it is this unit of measurement that is the gold standard when we look at treatment results. This is also something that the Cochrane report that the blog referred to has looked at. They point to the low quality of randomized controlled trials (RCTs), because many of them do not report birth rate, cumulative birth rate and miscarriages. In our study, we therefore want to look at these factors so that we have a solid evidence base for which patients will benefit from blastocyst culture and which will benefit more from day 2 insertion. This will give us an optimal starting point for providing each individual couple with personalized treatment.

Furthermore, there are many unanswered questions when it comes to blastocyst culture. The most important issue is whether prolonged culture is a win-win situation. To what extent does embryo selection improve with blastocyst culture and to what extent does this impair embryo development? The balance between these two is central when comparing day 2/3 and blastocyst culture, and no one yet knows where this balance lies. There is no point in winning selection if more viable embryos are dropped before reaching the blastocyst stage, and vice versa. This fundamental issue is crucial for both the number of embryos that can be frozen and how many transfers must be canceled. Again; it is the cumulative birth rate that is the outcome that makes the most sense to look at, and here there is no evidence that blastocyst culture is better.

We will invite other clinics to join the study. In this way, we can create a framework for multi-center clinical trials so that reproductive medicine can once again become a field based on high-quality evidence. There are many examples of additional treatments in assisted reproduction that have been used on a large scale without evidence that this is to the benefit of patients, and there are many clinics in Europe that charge extra for such additional treatments. At Oslo University Hospital, we have an international perspective and Mansell has probably noticed the English media coverage of the referenced article in the British Medical Journal, where they looked at additional costs for IVF treatment. One of these was £800 (approx. 8000 NOK) for blastocyst culture. In Norway, this may not be a separate cost, but rather included in the total price of a standard treatment. The main point here is that treatments offered at any fertility clinic must have convincing and well-documented effects - which is often not the case because methods are generally introduced prematurely.

The Department of Reproductive Medicine at Oslo University Hospital has a very good starting point for conducting randomized, controlled clinical trials. We are one of the largest IVF clinics in Europe in terms of the number of cycles and we have a professionally skilled staff. Several of our employees have worked at fertility clinics in, among others, the UK, Greece, Sweden, Spain, the USA and Japan, and therefore have broad experience with various cultivation methods and advanced techniques within assisted reproduction. With this, we welcome all clinics that share the same interest to collaborate with us towards the goal of more evidence-based reproductive medicine!

SVAR

Blastocyst culture vs day 2-3, which is best?

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