If only there was a straightforward answer. 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.
…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).
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.
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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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.