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Never Do a Day 3 Embryo Transfer

ACFS was not able to say this 5-6 years ago, but if your embryos were not able to reach the blastocyst stage (day 5) in ACFS-ART laboratory culture system, than they would not have made it in you if they were transferred at an earlier stage (day 3).

The same is true of frozen embryos, if they do not survive the freeze/thaw process (vitrification) at ACFS, than they would not have survived in a fresh transfer. There are clinics that disagree with these conclusions but the overall experience at ACFS is quite the opposite. We have not done a day 3-embryo transfer for the last 4-5 years; and as shown from our data, we feel very comfortable with our freeze/thaw (or vitrification) program; which is a very critical part of doing PGS-chromosome testingSome clinics still will do a day 3 transfer because they are not comfortable with growing embryos out to day 5 (advanced blastocyst culture); or tell their patients "it is better to transfer on day 3" because the uterus is the “better” or natural environment.  ACFS respectfully disagrees. We also believe it is more cost effective to see if the embryos make it to day 5; if they do not, ACFS feels that they would not have made it in you either; and at least you would not have to pay for possible multiple embryo transfers and "anxiously and hopefully" wait for the results of a pregnancy test; not to mention "those" progesterone shots and/or gel.

One of the principal causes for In Vitro Fertilization (IVF) to not be successful is the failure of the embryo(s) to implant in the uterus after transfer. There are many “reasons” why this may be; but numerous modifications and advancements in the IVF culture media have been developed to improve the chances of implantation. One of significant breakthroughs is in blastocyst culture, the other is chromosome testing or PGS.

Many embryos transfers are done on day 3 after egg collection in a fresh cycle. Some embryos do well in culture while others do not. It is hard to tell which type of embryos you have. If embryos are cultured in the laboratory for a longer period of time (day 5-6), they may develop further to the blastocyst stage. At this stage the embryo has differentiated and is made up of more than 100 cells and it is possible to identify groups of cells that will make up the placenta (trophectoderm cells) and the fetus (stem cells) or what’s called the ICM or inner call mass.

Day 5 Blastocyst

A nice looking day 5 blastocyst with an ICM, inner cell mass or stem cells, a blastocyst cavity (C) and a ring of outer cells, known as trophectoderm, that will develop into the future placenta.
Day 6 Hatching Blastocyst

Picture of a very nice looking day 6 "hatching" blastocyst. This is where the blastocyst begins to break out of its shell (zona pellucida), getting ready for implantation on cycle day 6-1/2 from fertilization.

Growing embryos in the laboratory is a difficult process and the longer that they remain in culture the greater is the chance that some or all of the embryos produced by the In Vitro Fertilization (IVF) process will not survive. Or that is the argument some clinics try to make. At ACFS, we have the opposite experience. In an excellent IVF laboratory with an experienced and skilled embryologist, many embryos do survive to day 5-6 or the blastocyst stage and are believed to have a greater chance of implanting. Again, ACFS was not able to say this 5-6 years ago, but if your embryos were not able to reach the blastocyst stage (day 5) in ACFS-ART laboratory culture system, than they would not have made it in you if they were transferred at an earlier stage (day 3).

But something much bigger changed our minds in how this new technology should be used:

First, ACFS was driven to be successful on each patient’s first attempt at IVF (for many obvious reasons).

Second, with the new technology of PGS to test each embryo to see if it was chromosomally normal, we had a number of biopsied day 3 embryos that made “beautiful” day 5 embryos or blastocysts but came back chromosomally abnormal. There had been speculation that embryos could “self-correct” but there was no scientific proof of that. With patients’ permission and informed consent, ACFS asked to re-biopsy these abnormal day 5 blastocysts to see what percentage of them, if any, had “self-corrected”. In collaboration with 3 other clinics we found that in the first 24 day 5-6 embryos re-biopsied, 64% had “self-corrected” and were read as normal. ACFS, along with 3 other major clinics, published what we believed at the time to be the first scientific paper showing the embryos could “self-correct” by day 5-6 of development. That was the last time ACFS did day 3 embryo transfers or biopsies. However, this change demanded and pushed ACFS to get proficient with culturing embryos out to the blastocyst stage.

Using new and advanced blastocyst culture methods, ACFS’ ability to grow embryos to the blastocyst stage had significantly improved. Said differently, only the "best of the best" embryos make it to the blastocyst stage. Since blastocysts are "very good embryos" they tend to freeze and thaw very well. On the other hand, good day 3 embryos also freeze and thaw well. However, for the last 5-6+ years, ACFS has cultured all their patients’ embryos to the blastocyst stage with excellent results.  ACFS can say we confidence, that if your embryos do not make it to day 5-6 in ACFS in-vitro culture environment, they would not have been successful even if transferred on day 3.  Since only the “best of the best” make it to the blastocyst stage, that is very important information to have, because by not waiting to see if day 3 embryos can make it to the blastocyst stage, you may be doing a lot of transfers that will not be successful. Obviously, some day 3 embryo transfers can be successful but in ACFS opinion, those would have been the embryos that would have progressed to day 5-6 anyway; but unfortunately, you can not identify them in advance.

Some clinics feel that the uterus is the natural or “better” environment than the IVF laboratory. ACFS respectfully disagrees and strongly feels that in our culture system; all good embryos, regardless of the patients’ age, can develop successfully to the blastocyst stage. And if they do not, they would not have been successful if transferred on day 3. Based on our long and extensive experience with embryo culture, Arizona Center for Fertility Studies strongly recommends growing all embryos to the blastocyst stage (day 5).  In our experience, ACFS gets much higher pregnancy rates with a day 5 blastocyst transfer. A couple should understand that there are a few animal studies that have raised concerns about neonatal problems such as increased birth weight and fetal abnormalities. There is no evidence at the present time of similar problems following the transfer of human blastocysts.

As a result of our experience over the last several years doing 23-chromosome microarray; and now what seems to be conclusive evidence that embryos can "self-correct", Arizona Center for Fertility Studies strongly recommends growing all embryos to the blastocyst stage and doing chromosome testing or PGS on all day 5-blastocysts using laser-directed TE (trophectoderm) biopsy techniques.  This means that after the blastocyst is biopsied, it will undergo cryopreservation and be transferred in a subsequent or following cycle. Although this means that the couple will need to wait a cycle to do the transfer, there are a number of advantages of growing embryos to the blastocyst stage and doing chromosome testing or PGS as opposed to a day 3 embryo transfer or day 3 embryo biopsy for chromosome testing:

1. First and foremost, it eliminates dealing with the possibility of "self-correction", which Arizona Center for Fertility Studies has observed happens more commonly than would be expected. Arizona Center for Fertility Studies was in a unique situation to be able to re-biopsy normal appearing day 5-6 blastocysts at no charge. Most clinics are not able to do this and if they are doing day 3 embryo transfer and/or biopsies and the chromosomes come back abnormal, they have to discard the embryos because without re-biopsy there is no way to know if they "self-corrected" and it is too risky to just assume they did. Although Arizona Center for Fertility Studies strongly recommends day 5-6 TE biopsy for PDG/PGS with subsequent FET, the couple will not have to worry about discarding "normal" embryos.

2. Another reason to culture embryos out to day 5-6 then do chromosome testing or PGS is that there is evidence to suggest that embryos do better in group culture through the blastocyst stage than to be separated on day 3, which they have to be to if a day 3 embryo transfer and/or biopsy is done.

3. Additionally, day 3 biopsy has an increased chance of failed amplification (see below) because only one cell is being removed. With a blastocyst or TE biopsy you can safely remove 3-4 cells, which eliminates the risk of failed amplification and gives a more accurate interpretation for chromosome testing or PGS.

4. Also, by doing blastocyst culture and cryopreservation, with subsequent FET, the patient can be stimulated more aggressively to make more eggs/embryos and be triggered with lupron, rather than with hCG, and significantly reduce the risk of ovarian hyperstimulation syndrome (OHSS).

5. Finally, the couple only pays for embryo transfer if the embryos reach the blastocyst stage and/or come back chromosomally normal. If a day 3 embryo transfer and/or biopsy are done, all embryos need to eventually undergo a transfer and/or biopsy, since you do not know which ones will develop into blastocysts. With blastocyst culture or growing all embryos to day 5-6, if the embryos do not reach the blastocyst stage, which is of course not a good sign and very unlikely at ACFS, at least you are not paying for possible multiple embryo transfers and/or chromosome testing of embryos that could not survive pass day 3 or the cleavage stage.

6. This actually worked to ACFS advantage because we were starting to realize that frozen embryo transfers were showing up to 30% higher pregnancy rates and significantly reduced the risks of ovarian hyperstimulation syndrome (OHSS) allowing ACFS to use more aggressive stimulation protocols that proved instrumental in recovering increased quality and quantity of eggs with resulting higher numbers of “quality” embryos for transfer and more remaining to cryopreserve.

In Arizona Center for Fertility Studies experience, all these advantages collectedly added up to higher success rates when growing all embryos to the blastocyst stage and doing chromosome screening or PGS. It is the reason Arizona Center for Fertility Studies now strongly recommends growing all embryos to the blastocyst stage, doing PGS, cryopreservation and subsequent next cycle frozen embryo transfer or FET.

ACFS no longer does day-3 fresh embryo transfer or biopsies for chromosome testing.  And since only the "best of the best" embryos make it to day 5; if embryos do not make it to the blastocyst stage (stage 5) than no biopsy is done and the patient not only knows the answer sooner rather than waiting for the results of the day 3 biopsy; but also saves a considerable amount of money by not doing a transfer. ACFS has not done day 3 transfers in the last 4-5 years with or without chromosome testing.

The "easy" job at ACFS is to get good day 5 blastocysts, even in reproductively older women. ACFS is very good at that and can control the whole thing-from ovarian stimulation (COH), fertilization using ICSI, blastocyst culture developing the embryos to day 5, the freeze-thaw process (vitrification) and uterine transfer. Where we "lose" control is whether or not the embryos are chromosomally normal. That is out of ACFS control. Therefore, it is ACFS thinking, "If you can not control it than maximize it".

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