Is a day 5 embryo transfer better than a day 2 or 3 embryo transfer ?

Blastocyst

Myth : A day 5 embryo transfer (blastocyst transfer) is better than day 2 to 3 embryo transfer (cleavage stage embryo transfer).

Fact : When  blastocyst transfer was introduced a decade back , there was a lot of hype surrounding it. It is of course amazing to watch a human embryo grow into a blastocyst invitro ; and it is very reassuring to know that the cell culture media and laboratory culture conditions in the IVF lab have improved so much that we can routinely grow embryos to Day 5. But is it really useful from the patient’s point of view ? A few IVF centres initially claimed that pregnancy rate increased tremendously with blastocyst transfer when compared to cleavage stage embryo transfer. One such example is this paper (PMID:10856474) from the very famous CCRM in which they claimed a 70 % implantation rate (with heart tone) with the transfer of two good quality blastocysts. But as time went on and when enough clinical evidence accumulated based on several Randomised Clinical Trials (RCTs) , it became clear that as usual overenthusiastic researchers have made a mountain out of a molehill !

 Before going into the details, here is a brief summary about human embryo development:

A human embryo starts its development as a zygote. A zygote is the initial cell which is formed when an egg and a sperm fuse with each other. It carries the genetic material from both the parents. Approximately at around 30 hours after fertilization a zygote divides into two cells and the cells are called blastomeres. On the third day of fertilization a zygote usually contains 8 blastomeres. A cleavage stage embryo transfer is usually performed at this stage. The zygote further divides and at around day 5 of fertilization it contains around 70-100 cells. From this time onwards a zygote is called a blastocyst. The blastocyst contains an inner cell mass (ICM) which subsequently forms the embryo and an outer layer of cells called trophoblast which develops into the placenta. The meeting of egg and the sperm takes place in the fallopian tube and the embryo thus formed resides in the fallopian tube for upto 4 days. The gentle contractions of the fallopian tube pushes the embryo towards the uterus and the embryo reaches the uterus usually at around day 4-5 of fertilization; that is in the blastocyst stage.

 If an embryo reaches the uterus when it is a blastocyst , then isn’t it logical to transfer the embryo produced in vitro back to the uterus during the same time period , so that the synchrony between the endometrium and the embryo is not lost ? Also , when embryos are allowed to develop in vitro , not all of them develop into blastocysts. Many embryos arrest during the initial developmental stages. If this is the case , then doesn’t doing a blastocyst transfer ensures that you transfer only embryos which are viable enough to develop into a baby when compared to cleavage stage embryo transfer ? Won’t better embryo selection improve pregnancy rates ? All these logical questions led to the development and propagation of blastocyst transfer with great expectations. It was assumed ( quite logically !) that a blastocyst transfer will lead to a dramatic improvement in IVF pregnancy rates. But logical reasoning is not always enough to decipher biological secrets ! Blastocyst transfer ultimately proved to be no better than a cleavage stage embryo transfer.

A recent analysis of 23 RCTs showed that transfer of cleavage stage embryos resulted in a higher clinical pregnancy rates than blastocyst transfer (PMID:22786480). But the live birth rate is slightly higher in the blastocyst transfer group when compared to the cleavage stage embryo transfer group.

The results are surprising ! There are two reasons for the study results favouring a cleavage stage embryo transfer in terms of higher clinical pregnancy rate:

1) A blastocyst transfer can lead to higher embryo transfer cancellation rate. Not all the embryos develop into a blastocyst and the blastocyst formation rate are less for women of advanced maternal age ; women with poor ovarian reserve ; and women with poor embryo quality. Such women are at higher risk of cycle cancellation if none of their embryos reach the blastocyst stage.

2) More embryos are available for freezing if the embryos are frozen at the cleavage stage,  and hence there are more chances for performing subsequent frozen embryo transfer (which improves the cumulative pregnancy rate).

This means that your odds of getting pregnant are higher if you are doing a cleavage stage embryo transfer. It is wise to opt for cleavage stage embryo transfer if you have only a few embryos for transfer ; or if you are of advanced maternal age. Further advances have to be made and more evidence is actually needed to prove that a blastocyst transfer is really better than a day 3 embryo transfer . Until then , the claim that a day 5 embryo transfer is better than cleavage stage embryo transfer is just a logical fallacy !

I got a comment from an anonymous commenter on the above article :

The difference between the live birth rates from a cleaving embryo compared to a blastocyst would logically be comparable for populations with a lower incidence of aneuploid embryos (e.g. women <= 35 years of age). Are any of the RCTs which were evaluated specifically targeted at older women with a higher rate of aneuploid embryos? In that scenario, I would anticipate that the live birth rate of blastocyst transfer would be higher. This is, of course, assuming that the skill of the embryologist, the quality of the lab, or the effectiveness of the protocol is not in question. It is well known that all of these critical factors are not equal depending on the chosen facility.

You write – “ The conclusion that the odds of getting pregnant using a cleavage stage embryo transfer may be true in the 23 RCTs, but the true goal is a live birth. Transferring potentially incompetent embryos does not advance one toward this objective. 
 
This excerpt of the review reveals the flaw:
"This review of 25 studies... Disappointingly, only half of the included studies reported miscarriage or live birth rates. Twelve RCTs reported live birth rates and there was evidence of a significant difference in live birth rate per couple favouring blastocyst culture (1510 women, Peto OR 1.40, 95% CI 1.13 to 1.74) (Day 2 to 3: 31%; Day 5 to 6: 38.8%, I2= 40%)." 
 
I cannot imagine a scenario where one would not favor a statistically significant improvement to the live birth rate, and therefore do interpret the data to conclude that there is an advantage to blastocyst transfer.”

and my reply is :

You have put forth a very valid argument – I agree that the goal of any IVF cycle should be live birth ! Since blastocyst transfer has shown a small significant difference in live birth rate it should be logical to conclude that day 5 transfer is better than a day 3 transfer. The authors state that “This means that for a typical rate of 31% in clinics that use early cleavage stage cycles, the rate of live births would increase to 32% to 42% if clinics used blastocyst transfer”. The authors also state that there is no difference in clinical pregnancy rate or miscarriage rates (?) between cleavage stage embryo transfer or blastocyst transfer ! The question, ‘to blastocyst or not ’ is not even necessary in young women with lots of eggs and embryos – of course most clinics will naturally go in for a blastocyst transfer (commercially too it is a better option for them !) The argument whether day 5 ET is better than day 3 ET arises in the case of older women and women with poor ovarian reserve since these are the challenging women who have a guarded prognosis.

My point is that I do not think blastocyst transfer can benefit older women or women with fewer embryos! The odds of achieving a successful pregnancy and live birth via IVF is compromised in older women and in women with poor ovarian reserve  because the amount of eggs obtained and embryos formed is reduced ; and the presence of a high percentage of aneuploid embryos in older women further reduces their chances of success. When you have fewer embryos it is wise to be cautious and transfer the embryos as early as possible to the uterus– after all, the rule of thumb in medicine is ‘first do no harm’ ! It should be kept in mind that even in young woman with good quality embryos , the blastocyst formation rate is just 35-40 %. Will embryos which do not grow to a blastocyst in vitro  achieve a viable pregnancy when transferred in vivo at an earlier stage ? When we do not have a solid answer to this question, isn’t it wise to do a day 3 transfer for women who do not have a good prognosis ?  There is a high risk that their embryos may arrest in vitro if you try to grow them to Day 5, as a result of which there maybe no embryos to transfer at all !

Another important aspect is the emotional impact on patients when they are left with no embryo to transfer ! 40 % of poor prognosis patient’s embryos will not grow to blastocysts ! Patients go through a lot of trouble when doing IVF. When they are left with no embryos to transfer , they can be devastated ! It discourages them and they are likely to give up., You may ask - ‘When there is a risk of reduced live birth rate (1-10% reduction in live birth rate !) after achieving a pregnancy with cleavage stage embryo transfer, why shouldn’t a day 5 transfer be the norm in older women too ?’ Is not getting pregnant better than not having embryos to transfer ? Is not having a live birth better than not getting pregnant at all ? Very hard questions to answer !

 I believe that the cons outweigh the pros of day 5 ET in older women and women with poor ovarian reserve when compared to day 3 ET ! Studies have shown that older women have decreased chance of pregnancy with day 5 ET (I am not aware of any RCTs).  When there is no valid proof in favor of day 5 ET  it is good to stick to  procedures which don’t cause any obvious harm : ) 

I believe that day 5 ET is not better than day 3 ET (I would even say day 3 ET is better for some group of women !) – and I have few  embryos I will definitely avoid day 5 ET !

You have said, “I cannot imagine a scenario where one would not favor a statistically significant improvement to the live birth rate, and therefore do interpret the data to conclude that there is an advantage to blastocyst transfer” . My interpretation is that since the risk of day 5 ET outweighs its advantage, day 3 ET should be preferred until more data is available !

Thanks  for initiating this valuable discussion !