EmbryoScope Archives - Fertility Fact Checker

Which is better: A day three or day five embryo transfer?

For some the answer will lie in the standard protocol of the clinic; for others it might be dictated by how many embryos they have. Regardless of how you get to your answer, it seems there are costs and benefits for both. Whilst there appear to be the seemingly obvious advantages of a day five transfer – that being the embryo has already grown and survived five days instead of three and therefore theoretically healthier, there are some distinct disadvantages. Plus if it was simply that conclusive that a day five transfer is the gold standard, than surely all the fertility clinics would be doing them as standard?

What happens during a day three transfer…

A day three transfer is when the embryo is transferred back into your uterus on the third day after fertilisation (with egg pick up and fertilisation happening on day zero). A day three embryo is considered to be in cleavage stage and the cells are still small in number and easy to count. There are all sorts of different grading systems but ideally a day three embryo has eight cells (though this number can vary between seven to nine cells and I am sure there are some stories out there of a four cell, day three embryo successfully implanting). According to the Centre for Disease Control (CDC) who publishes a huge amount of data on IVF success rates, in the U.S. in the year 2012 45.9% of non donor embryo’s were transferred on day three. For the record, 44.5% were transferred on day five, 4.5% on day two, 2.3% day four and 0.1% on day one.

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…and a day five transfer

A transfer on day five, or sometimes day six means that the embryo is transferred on day five or six post fertilisation. An embryo at this stage has turned into a blastocyst and is getting ready for implantation. Cell differentiation is also beginning meaning that is there are now two different types of cells – one that will become the placenta and one that will become the fetus. Embryos cannot be grown in the lab for longer than this because the embryos are soon start hatching out of their shell and need your endometrium for implantation.

The case for a day five transfer

One of the main arguments for doing day five transfers is that only the strongest embryos have survived until this point and therefore are more likely to be chromosomally normal and hence develop into that take home baby. That is a fair point. According to data collected by the CDC, across all age groups, and particularly in women under 40, there were higher success rates for day five embryo transfers when compared with day three embryos – and not an insignificant amount. In their 2012 report, for women under 40 a day five transfer typically had about a 12% improved success rate than a day three transfer (interestingly though, a recent Cochrane review didn’t put the improved success rates so high, reporting that for the limited amount of studies that reported such figures, they only found there was only an increase in live birth rate of between 1 – 11% and no difference in miscarriage rates (1)) .

This means that for any one transfer, you can be more confident that your embryo will implant, which in turn means that lower numbers of embryos should be transferred, ideally one at a time. This carries the added benefit of theoretically reducing the chance of twins and triplets. Although multiples seem, and for many women still would be, a blessing, it does carry with it its own set of risks such as premature birth, higher chances of preeclampsia and lower birth weights which in turn can impair the overall health of the baby. Therefore if transferring on day five means that less embryo’s will be transferred each time, this ultimately results in better outcomes for both mum and baby.

Another reason some clinics prefer to complete a day five transfer is so that when the transfer is completed and the embryo is your uterus it is in a location more aligned with where the embryo would be expected to be in a natural cycle. Although fertilisation can happen anywhere along reproductive tract, most of the time it happens in the fallopian tube at the end closest to the ovary. The embryo then spends the next few days travelling down the fallopian tube, not reaching the uterus until day five. It is believed that when transfers occur on day two or three that the embryo is placed in the uterus too prematurely. These two different locations of the fallopian tube and the uterus also provide a different nutritional environment to the embryo catering to its differing developmental needs (1).

Day 3 or Day 5 - different paths to the same place? — Day 3 or Day 5 – different paths to the same place?

The case against a day five transfer

Whilst reading the above you are probably already drafting up arguments for your doctor on why they should be doing a day five transfer, it is important to remember that there are two sides to every coin.

A recent Cochrane review found that women who are waiting for a day five embryo transfer have lower transfer rates then women who have day three transfers (1). That is, ‘success rates’ aside, for a significant proportion of women, embryos arrest on day four which means that they would have been able to have a day three transfer, but unfortunately none survived to the blastocyst day five stage. Whilst it has been suggested that this may be better on a woman’s mental health because women don’t have to survive through the two week wait with an ‘inferior’ embryo that may not implant at all, surely most women would rather be ‘in the game’ and still with very reasonable chances of a BFP than not make a transfer at all? And as they say, just because the embryo wasn’t able to grow in a laboratory who is to say that it wouldn’t have grown ‘in vivo’, or in you to be less latin about it.

Women who complete day five transfers also generally have less embryo’s to freeze (1). Athough as we previously discussed, per transfer there may be up to around 12% higher success rates for a day five transfer, you are still far from being guaranteed that take home baby and may need to do subsequent frozen embryo transfers. Unfortunately for some though, by growing embryos to day five, several may have been lost getting them to grow in the laboratory to that stage. This in turn means that you have to go through the financial expense, emotional exhaustion and physical discomfort of going through the whole IVF process rather than ‘just’ a frozen embryo transfer.

The above two points (not making to transfer and having less embryos to freeze) contributes to the interesting point also highlighted in the Cochrane Review. That is although the pregnancy rate of each transfer may be higher for day five transfers the cumulative pregnancy rates for day three transfers were in fact higher. The cumulative pregnancy rate is the overall pregnancy rate when all the embryos produced have been used. Although the chances of success per transfer is lower, per cycle they are in fact higher for women who transfer on day three. This is an interesting point and one that is hard to take a step back and appreciate when each transfer feels like it is taking everything from you and you just want that positive result NOW.

Day five transfers have also been associated with higher rates of monozygotic twinning (when the one embryo splits and implants as two foetuses) and is also associated with higher rates of males being born (not that I’m attributing that to being a negative per se, but it lends itself to the fact that some sort of artificial elimination process is occurring, though I am aware that in mother nature slightly more males are born also). Day five transfers have also been associated with premature births when compared to day three transfers with the researchers hypothesising that by growing the embryos in culture for longer periods of time that this is possibly associated with subsequent placental development and functioning (2)

Additionally, it is women who are typically ‘good responders’ who are able to grow large numbers of embryos to day five. These women seem to produce good embryos regardless of what developmental stage they are at.

With the development of better monitoring systems for early embryo development the need to ‘wait it out’ for a day five embryo also reduces. The embryoscope for example enables laboratory staff to check that embryo development is ‘normal’ at every minute of the day. Who knows, perhaps by having these milestones noted it may one day prove to be more useful to predicting an embryos health than if it was able to develop into a blastocyst in the laboratory.

The Rebutal

However, just like the theory that day five embryos are inherently superior than day three embryos is the main reason to try for a blastocyst transfer, the theory that embryos thrive better inside you than in a laboratory is the main reason to support a day three transfer. This still may be so, though there are no guarantees of this and if an embryo is chromosomally abnormal it is not going to survive regardless of where it is.

The argument that embryos are better in your uterus rather than in a laboratory dish is also becoming less convincing as technologies develop. For instance, the culture that laboratories grow embryos in are becoming more tailored and there are now two different types of culture that can be used and changed depending on the age and hence nutritional requirements of the embryo (1). This should mean that fewer embryos perish at around that day three stage in the laboratory. Similarly, incubators are becoming more and more advanced and capable of maintaining the ideal temperature, gas composition and pressure for growing the embryos to day five removing the need for them to be transferred back into a living uterus as soon as possible.

To sum it up…

Whilst day five transfers have higher per transfer success rates, this needs to be weighed up against lower cumulative success rates and less embryos available for use in the future. But perhaps the biggest factor that women need to accept is the ‘what if’ factor. For despite all the advances in fertility treatments there is still a lot that is unknown. For a woman that had no embryos to transfer on day five, or only one or two, who is to say that any number of embryos wouldn’t have implanted if transferred on day three?

The answer as to which day is better to transfer on isn’t cut and dry and as patients we rely on the specialised skills of the laboratory staff and our doctors to make that decision for us. As improved monitoring techniques mean that healthier day three embryos can be selected and better culture means that more embryos survive to day five perhaps the answer to the question isn’t as polarising as first thought.

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References

1. Glujovsky, D., Blake, D., Bardach, A., Farquhar, C. (2012). Cleavage stage versus blastocyst stage embryo transfer in assisted reproductive technology (Review). The Cochrane Library, Issue 7.

2. Dar, S., Librach, C., Gunby, J., Bissonnette, F. and Cowan, L. (2013). Increased risk of preterm birth in singleton pregnancies after blastocyst versus Day 3 embryo transfer: Canadian ART Register (CARTR) analysis. Human Reproduction, 28 (4) 924–928.

9 Things You Should Know About the EmbryoScope

The EmbryoScope seems to be the latest ‘big thing’ in the fertility clinics and is being offered by more and more clinics to more and more women. Although it seems there are definitely benefits to using the EmbryoScope it may not be useful to everyone. Here are 9 things you need to know before deciding with your doctors whether or not to use the EmbryoScope:

It is a new type of incubator

Essentially, EmbryoScope is the trade name for a type of incubator that uses time-lapse photography to continuously monitor the embryo as it grows in the laboratory.

In traditional IVF, the sperm and egg are mixed together in a dish, hopefully the magic happens and the sperm fertilises the egg, or, if you are doing ICSI, the embryologist will inject the egg with the sperm, again, hopefully the magic happens and the eggs fertilise. The fertilised eggs, now embryos, are in their ‘dish’, surrounded by a ‘culture’ which is a substance that supports the growth of the embryos. The embryos are then placed in an incubator. The incubator enables the embryos to be locked away in an environment controlled for temperature, humidity, pH and gases (such as carbon dioxide, oxygen and nitrogen). About once a day the incubator is opened to monitor fertilisation rates, embryo morphology – that is what they look like, monitoring how many cells are there, if the cells dividing appropriately, if there is fragmentation and if the nuclei are behaving appropriately, just to name a few of the markers that are monitored. Each time the incubator is opened the highly controlled environment the embryo is in is disturbed. Therefore, it makes sense that the least amount of times the incubator can be opened the better.

By monitoring embryos in this way, the only information that technicians have on what has happened over the past 24 hours is what you can see at that very point in time. It provides a ‘snapshot’ so to speak. Cells can divide at different rates, can reverse the number of cells they have and nuclei can come and go over a 24 hour period. These events can be easily missed if only checking on the embryos once a day. All these events are also known to have significant impact on implantation rates and ongoing success of an embryo, therefore if extra information can be provided on early cell development it will be easier to choose the best embryos capable of ‘going the distance’.

What the EmbryoScope does is allows many photos (amount of photos per hour can be chosen by your laboratory) to be continuously taken of the embryos without them needing to be taken out of the incubator and disturbed. This ensures that the environment they are contained in is kept constant at its optimal settings. It also enables much more information to be collected on how your embyros have behaved over the last 24 hours and in theory the embryo that has shown the most favourable development and seems to be the best can be chosen.

2. Your embryos are kept at the ideal conditions for more time

The people that make the EmbryoScope, Virtolife report that the EmbryoScope incubator can hold up to 72 embryos – that is six clients can store up to twelve embryos at a time. This makes the EmbryoScope much smaller than a standard incubator. Because of this the environment inside the incubator is able to return to the ideal pH, temperature and gas levels at a much quicker rate when it has been disturbed. This is important because although the embryos do not need to be taken out to monitor them, the doors of the incubator do still need to be opened from time to time to place new dishes in or change culture media and the quicker the embryos can be returned to that ideal environment the less they are disturbed leaving them to grow into happy and healthy day 3 or 5 embryos!

3. Early evidence says that it can increase your chances of an ongoing pregnancy.

OK, so this is perhaps the thing that we want to know the most. One recent study (1) compared the ongoing pregnancy rates for women with embryos that were grown in a standard incubator against the pregnancy rates for women who had embryos grown in the EmbryoScope. What they found was that for women with embryos incubated in the EmbryoScope, there was a higher rate of ongoing pregnancy (54% for women with embryos grown in the Embryoscope versus 45% for women who used a traditional incubator) for each transfer. They were also shown to have lower early pregnancy losses and higher implantation rates, though interestingly the pregnancy rate was not statistically different. What this possibly indicates is that although there may be no statistical difference in getting that initial BFP by using the EmbryoScope and the information that is collected on your embryos early development, it allows for healthier embryos to be selected that are capable of going the distance and that are less likely to be abnormal which typically results in early miscarriage.

4. The culture that the embryos are in in the EmbryoScope is different (and some say better).

The culture system your embryos are grown in are different when using the EmbryoScope then what is used in the traditional incubators. One study (2) looked at if more fertilised eggs would grow to blastocyst when using the EmbyroScope as opposed to just a normal incubator. What they found was more embryos grew to blastocyst stage in the EmbryoScope then in the normal incubator. Remember the EmbryoScope is mostly being used as a monitoring system to pick out good embryos – and it can’t magically turn a bad embryo good – it just hopefully helps laboratory staff pick the best one to transfer. Therefore the fact that the study found more blastocysts were produced is kind of interesting, because up until now the EmbryoScope wasn’t expected to change the development of the embryos. The scientists who conducted this experiment thought of a couple of reasons for this result. One was that, as we have already discussed, the environment in the EmbryoScope was able to return to those ideal conditions much faster than a traditional incubator and the other reason was that culture system and EmbryoScope slides were different and possibly better at supporting growth to blastocyst then traditional incubator culture and equipment.

5. Its still only experimental.

Although there does seem to be some promising data coming out supporting the EmbryoScope it is still a new technology. A recent metaanalysis published in the ‘The Journal of Assisted Reproduction and Genetics’ (3) warns that despite the initial optimism, the data is insufficient to warrant the extra cost to prospective parents. In fact they were only able to find four studies that investigated using time lapse monitoring of embryos and the impact of using this method for selection on ongoing pregnancy rates. Needless to say, as always it seems in fertility research, more studies would be beneficial. Saying that though, all technologies and advances are new at some stage, so as long as your doctor isn’t concerned that there could be any disadvantages and if your clinic is one of the ones that provides the use of EmbryoScope free of charge, then surely there are not costs to trying?

6. It can cost more money.

If your clinic is not one of those clinics offering it to you free of charge, the extra costs on top of your normal IVF or ICSI charges can be significant. In Australia the extra costs to you can be between $0 to $800… a wide variation! Because there is no Medicare number for this you are also unable to claim any out of pocket expenses. In the UK I have seen quoted surcharges of between £400 –£600. The EmbryoScope, from what I have seen, doesn’t seem to be as widely advertised in America (please correct me if I am wrong!) but when it is used, the cost of it seems to be included into the cost of the IVF cycle and isn’t charged as an extra. Clearly, this is one of those things that needs to be discussed with your clinic.

7. May not be helpful to you if you are a ‘poor responder’.

You may already have the gist, but the idea of the EmbryoScope is to help laboratory staff chose the best embryo out of your batch for you to transfer. Ladies who traditionally don’t have success with IVF cycles generally don’t produce many viable embryos. (This is a big generalisation though!) Therefore if you don’t have many embryos the need to use the EmbryoScope to pick the best one isn’t necessary because you may only have one or two available anyway. In this case it doesn’t really matter what your embryo looked like at every stage because chances are you are going to transfer it regardless. Saying that though, even if you don’t have many embryos and its not going to help your treating team chose the best embryo it still might be helpful to them from a diagnostic point of view. That is they can see exactly where and when the embryo does (or doesn’t!) stop developing normally which might be helpful in planning future treatments.

8. May not be helpful if your clinic grows embryos to Day 5 as routine.

EmbryoScope is mostly used to pick the best embryo up to day 3. For clinics that routinely grow their embryos to blastocyst stage the EmbryoScope may not be considered as important. Though as discussed above, with studies showing that an embryos early development, development that is best seen in the EmbryoScope, having a positive impact on ongoing pregnancy rates, this seems to be a bit of a short sighted reason. Simply getting to blastocyst stage, in whatever shape or form, isn’t necessarily enough to go the distance. It would still be good to know what happened in those early days to chose the best one for transfer.

9. Its going to become more and more useful.

As the EmbryoScope is used more and more, laboratory staff and our doctors are going to be able to learn and collect much more data on embryo development than ever before. This will hopefully let them learn new things about how an embryo develops in the very early stages and its impact on implantation, ongoing pregnancy and the chances of the take home baby we always talk about. One journal article (4) suggests that by watching the appearance of the embryo very closely embryologists can watch out for distinct milestones and markers in the embryo development. By using this information they will then hopefully be able to develop more of a ‘predictive model’ for the embryos success. What they hopefully aim to do is identify by day 2 or 3 which embryos are those destined to become your take home baby by examining how it looks and behaves. By identifying the embryos at this much earlier stage this means that they don’t have to grow to blastocyst in an artificial environment – a situation which is sometimes associated with problems of its own.

Whether or not you chose to use the EmbryoScope is up to you in consultation with your doctor. By discussing things through with your doctor taking into account your own individual circumstances can you make the best informed decision.

References

1. Rubio I., Galan A., Larreategui Z., Ayerdi F., Bellver J., Herrero J. & Meseguer M. 2014. Clinical validation of embryo culture and selection by morphokinetic analysis: a randomized, controlled trial of the EmbryoScope. Fertility & Sterility. 102(5):1287-1294.e5.

2. Speksnijder, C. van de Werken, S.M. de Jong, A.J.A.M. Dons, J.S.E. Laven, E.B. Baart & Erasmus MC . 2011 Abstract: Improved embryo development in a time-lapse incubator system evaluated by randomized comparison of surplus embryo development to the blastocyst stage. Abstracts of the 27th Annual Meeting of ESHRE, Stockholm, Sweden, 3 July – 6 July, 2011 (doi: 10.1093/humrep/26.s1.26)

3. Racowsky, C., Kovacs, P. & Martins, W. 2015. A critical appraisal of time-lapse imaging for embryo selection: where are we and where do we need to go? Journal of Assisted Reproductive Genetics. 32: 1025 – 103

4. Milewski, R., Kuć, P., Kuczyńska, A., & Stankiewicz, B., Łukaszuk, K. & Kuczyński, W. 2015 A predictive model for blastocyst formation based on morphokinetic parameters in time-lapse monitoring of embryo development. Journal of Assisted Reproductive Genetics. 32:571–579