In this session, Dr. Evangelos Papanikolaou, MD, PhD, Founder of Assisting Nature, Thessaloniki, Greece has been discussing RIF patients cases and talked about preimplantation genetic diagnosis and when it is indicated.
The causes, as we’ve discussed earlier, are mainly the incapability of the egg to divide those 46 chromosomes into 2 pairs of 23. There is eternal incapability of the egg to divide strictly into those 2 parts to become a polar body. In the past, there were a lot of discussions about whether high stimulation might be the cause. And there were some papers back in 200-2004 regarding this issue. The truth is that the higher the stimulation the doctor retrieves more not mature eggs that at the end may divide into a blastocyst, but this blastocyst will be abnormal. The problem is not per se the drugs, the high stimulation, but that we retrieve all the eggs, all the follicles that we have in the ovaries and in the end we up with higher aneuploidy rate in that particular patient, but you should always to remember that if you’re a good responder If I’m a good responder and I produce a lot of eggs at the end, I increase my chances of having normal eggs and in the end having normal embryos. High stimulation is not the real causative agent, but only it can change this result statistically. That’s why we need rational stimulation, so produce as many eggs as we can without any harm to your health, and we know that the perfect number of eggs is around fifteen. If we have more than this, there’s no benefit, less than this will cause lower pregnancy chances. So the maximum of eggs is around 15, and we should aim for this number if it’s possible.
The oldest woman where we had 1 euploid embryo and live birth was 45. The chances of having a euploid embryo at the age of 45, as you know, it’s less than 1%. If you have 100 ladies at 45, in the end, one of them will become pregnant.
With NGS, which is the technique that we perform our biopsy, the cost is 1,000 EUR for the biopsy itself, in Greece, plus 250 EUR per embryo. If you have one blastocyst, then you will pay 1,250 Euros. If you have 4 blastocysts, you will pay 2000 EUR.
We do not biopsy everything, of course. The blastocyst should be above B or A to be tested. The problem here is that those blastocysts were already on day-6, which means that they were already very late in development. If you have a day-6 blastocyst, and it is perfect, the chances of this blastocyst to be euploid is around 10%, so it does not mean that if you have an excellent blastocyst on day-6, that this blastocyst is normal. In this particular couple, the problem might arise either from the high number of eggs, maybe you have PCOS, or from the poor quality of the sperm or the poor quality of the stimulation. If they retrieved the eggs earlier, then you might end up with this late development as the blastocyst stage.
Mosaic means that if the blastocyst has 100 cells, 20 of them might be abnormal and 18 normal, or the opposite 18 might be abnormal and 20 normal.
Mosaicism, in some way, is a normal procedure in the development of the blastocyst. It looks strange, but actually, it is a normal procedure. So the embryo tries to avoid the abnormal cells because mistakes do happen in the best families. They try to abort those abnormal cells to the trophectoderm, unfortunately, we do the biopsy, so actually, the trophectoderm sometimes might be the protection shield for the embryo itself where abnormal cells are deposited. This is the explanation of mosaicism.
The criteria that we use to select a mosaic embryo is that if we have less than 10% of mosaicism and specific chromosomes, our geneticist advises for them to be transferred. You can find this information in our leaflets on the Internet.
I talked about 5 or 6 embryos, in total, from different IVF to define that someone has recurrent implantation failure.
So actually, we only need 1, as you know, the more we have if we are over 42, of course, the better chances for finding euploid embryos. On the other hand, if you’re 42 and your AMH is low, and if you take medications, but you won’t produce more than 2 eggs, we can do several natural cycles. We can deposit 2 or 3 blastocysts after 9 natural cycles, for example, and to do genetic testing on the 3 blastocysts after 1 year of trying that should be the maximum, so a doctor needs to put the threshold for how long you should try and out of this 2-3 blastocysts if you’re lucky, you can have a normal blastocyst. At the age of 42, this probability is around 15%.
There is no reason for fresh transfer anymore. As we know, the endometrium is always better outside the simulation. On the other hand and NGS is an excellent technique at the moment for identifying abnormalities. The only reason to perform it the old way with micro ways of PGS is when I have frozen embryos, for example, from another trial or another center, and I do transfer them to another center, and I want to know if I have 4 blastocysts, for example. Let’s say I have 7 blastocysts in another center, and I transfer 4 of them and I have no pregnancy and I don’t want to continue, and I still have those 3 blastocysts. If I want to know if these 3 blastocysts are genetically normal, only then we can do this old way of PGS on day-5 and transfer them the next day on day-6.
It’s up to you, and you should have a thorough discussion with your fertility specialist and your senior embryologist. Let’s say you have 10 blastocysts, then we would freeze, let’s say 4 of the blastocysts without doing PGS, and we do NGS on the rest of them, waiting for the result. I don’t agree with doing a fresh embryo transfer, and in women, especially in a woman like you with PCOS, it is malpractice.
I don’t think that all these additives, in the end, can improve the quality of the eggs.
I think that in the coming years, we will have a real pharmaceutical agent that makes these mitotic errors not to happen anymore in the egg, and a lot of women within the next 50 years will not need any IVF because they would produce euploid eggs and euploid embryos.
Sometimes it’s the sperm, and sometimes it’s the egg, so they don’t know if the eggs don’t look really well if they’re dark with a lot of micro vacuoles. They can say that this lady does not produce good eggs from the beginning and say they would not expect to have good blastocyst, whatever is the fertilization rate. On the other hand, if the sperm is bad, especially morphologically, they are looking at it for 1 or 2 hours to identify morphologically good sperm, then they inject it into the egg, which indicates a male factor. Until the day-3, the embryos develop with the machinery of the egg, and only after day-3 it comes from both the female and male genetics, so the combine and work together to divide into a blastocyst. We say many times that if after day-3, we don’t have a blastocyst, it indicates bad sperm. But we don’t say this if the embryologist sees that the eggs are bad morphologically from the beginning. You were young when you had those 4 IVFs and getting only 4 blastocysts is a very bad number. I cannot give more explanations having only this information, but definitely, you should do the genetic testing of your embryos in your next cycle or one after that, and only then you can decide if going for egg or sperm donation is an option. Do not decide that after 1 abnormal genetic testing right away because it can only be a bad coincidence of a bad cycle.
Yes, with sperm it is much easier. Firstly because if the embryologist is experienced, she or he can choose a good morphological sperm. So the first one is the selection per se on the day of ICSI. Another thing that we can do is PICSI, we do sometimes select morphologically better sperm. We can, of course, give some antioxidants to help the sperm morphology, but I sometimes laugh because if someone is still smoking, and he’s taking all those antioxidants, it is useless to take all this medication, there is no improvement of the sperm.
I don’t believe that we have better quality embryos with any of these protocols and the best protocol is when we prepare it individually for the patient. From the studies that we’ve done on patients from the same category, let’s say women who are less than 39 with both protocols, the percentage of the euploid embryos is the same. I don’t think that there is any interference in the protocol with the genetic quality in the end.
The optimal size for the follicle to be triggered is 17-20. But keep in mind that one doctor will measure it 17, and the other one 21. There is a lot of deviation from doctor to doctor. However, answering your question, I think that the follicle that is more than 22 or 24 does not have a chance to produce a good quality embryo.
90% of empty follicles, it’s a mistake of the patient or the doctor or the ovulation triggering injection. Empty follicle syndrome (EFS) is what we call when we have empty follicles repeatedly, it happens very rarely.