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PGT-A and IVF – why, if and when?

Àlex García-Faura, MD
Fertility Specialist & Sicentific Director
Luca Gianaroli, MD
Specialist in Reproductive Medicine & Scientific Director
Elias Tsakos MD, FRCOG
Medical Director , Embryoclinic
AskYourDoctor-PGT-A-FB
From this video you will find out:
  • What is PGT-A, when should it be recommended and how does it work?
  • What are the main benefits of undergoing PGT-A during IVF treatment?
  • What factors should couples consider when deciding whether to pursue PGT-A?
  • What are the potential risks or limitations associated with PGT-A?

PGT-A and IVF – why, if and when?

During this event featuring 3 Fertility Experts Dr Àlex García-Faura, Scientific Director at Institut Marquès, Spain; Dr Luca Gianaroli, Scientific Director at S.I.S.Me. R., Italy and Dr Elias Tsakos MD, FRCOG, Medical Director at Embryoclinic discssed PGT-A (Pre-implantation genetic testing for aneuploidy) and addressed questions from the audience.

The event was hosted by: Professor Alan Thornhill, Fertility Expert & Coach, Founder of The Fertility Guy

Preimplantation Genetic Testing for Aneuploidy (PGT-A), is a procedure used to examine embryos for chromosomal abnormalities, meaning when there are missing or have extra chromosomes before implantation. It is used to help with identifying euploid embryos which means embryos with the correct number of chromosomes. Distingushing normal embryos from abnormal ones is increasing the chances of successful pregnancy and can reduce the risk of miscarriage.

PGT-A is recommended in cases where there is an increased risk of chromosomal abnormalities, e.g. women of advanced maternal age, recurrent miscarriages, or failed IVF cycles. It is also performed in couples who already have some preexisting genetic conditions or those with a history of chromosomal abnormalities in previous pregnancies.

- Questions and Answers

Can you briefly explain what PGT-A is?

Dr Luca Gianaroli, S.I.S.Mer: I think that we have to go back at least 20 or 30 years when we were trying to understand which embryos were best to be transferred. Suddenly, it became known that some or many of the embryos we were transferring were not implanted because they were chromosomally abnormal. The idea of PGT for aneuploidy was designed to remove those embryos that should not be transferred because they are chromosomally abnormal, so they will never implant, or if they implant, they will result in a miscarriage. The technique involves a biopsy, similar to what we do in most medical specialties, removing a few cells and then conducting a genetic analysis to confirm whether the embryo is viable or not. The state of the art is that at the moment, we can predict the viability of an embryo based solely on the normality of its nuclear DNA, nothing else.

So, it’s already a significant improvement. We should not be concerned if what we call a normal embryo, a euploid embryo, once it is transferred, could still face the risk of not being able to implant with the technology that we have at the moment. This has proven to be an improvement, reducing the time to pregnancy. And alas will tell us more about the results. So, this is the state of the art, and this is the most advantageous selection criteria that we now have in routine IVF.

Dr Àlex García-Faura, Institut Marquès: I think that this test should be used when we expect a high risk of abnormal or chromosomally abnormal embryos, especially depending on the patient’s age. We know that this risk starts to increase at around 35 years old, where it’s about 50%. It’s high in a 35-year-old patient. When we move up to 38, we might be around 70% of abnormal embryos coming from her eggs, and once we get up to 40, between 40 and 43, we might be in the range between 85 or 95% of normal embryos, especially when we get up to 43 or 44-year-old patients. I think that the first group of patients that probably would need or require this test are those patients trying to conceive through IVF, between those over 38 years old.

The second group would be younger patients or any patients who have had previous transfers in optimal conditions. By optimal, I mean high-quality day-5 embryos and a perfect endometrium protocol and still have had a repeated failure or repeated miscarriage, even if getting in optimal conditions on the day of the transfer. So, probably these would be the two major groups. There’s also a smaller group, which is when we do know that there is also a high risk coming from the male factor. So, we might expect in oligospermia or severe male factor a higher risk of abnormal embryos. That would be a smaller group but still an important group of patients that could have repeated miscarriages or repeated failure if they don’t undergo PGT-A. The final group that we might be able to discuss later on is just because the patient wants to make sure she’s transferring a normal embryo. I think that this last group is open for discussion later on.

Dr Elias Tsakos, Embryoclinic:  Just to bring a side of relief to the audience tonight, may I say that before we started, we had a little chat between us, and it seems that we all share the same principles and the same views on PGT-A testing indications, application, and value. I don’t have much more to add to Professor Gianaroli or Dr Àlex García-Faura. All I was going to say is that, apart from specific male factors, I would also include male age as a potential factor. These days, we see more often men in their late 40s and sometimes in their 50s or 60s, so that by itself should be an indication for PGT-A.

With regards to legislation and regulation in Greece, may I say that it’s not brilliant at the moment because it seems that the new data hasn’t been incorporated into the legislation. At the moment, we may only perform PGT-A on women over the age of 40 as a routine. That’s the only absolute indication, and younger women, would have to go through either 2 miscarriages or 3 unsuccessful IVF implantation attempts. I think I probably express the opinion of the majority of fertility specialists in Greece. This is not fair for patients. It’s not fair for a 39-year-old woman to have to undergo 2 or 3 IVFs and experience 2 miscarriages before she qualifies for a test that’s proven to be effective in her age group. Especially when she’s also going to privately pay for this test because this test, in Greece, is not compensated by public or private insurance and so forth. I’m very much an advocate for the freedom to choose, and especially when it’s based on scientific data.

Can you tell us what are your indications are for PGT-A?

Dr Luca Gianaroli, S.I.S.Mer: I think that the indication is every subcategory of patients that has a higher risk of not getting what they want, that means a healthy baby. All the indications that have been given by the colleagues, they are all right, but that also depends on the quality of the center. If you have a very high percentage of clinical pregnancies or deliveries in your center, it’s enough that they fail 2 or 3 times a normal embryo transfer for which an indication can be given, even in a young couple. If your results are not as good, maybe it’s a repeated IVF failure.

It would mean that they need more cycles before they enter the program. I think that the main factor plays a very important role because if you look into the sperm with a FISH analysis, so you look into the chromosomes of the sperm, you see that many times, these men with very poor sperm quality also have a high percentage of chromosomally abnormal sperm that will contribute to chromosomal abnormalities or to chromosomal defects in the newborn. If you have very severe male factor, the Down syndrome risk is multiplied by 3 or 4 according to the quality of the sperm, independently of the age of the mother. There are signals quite clear for which everything that is getting out from the normal range maybe should, in one way or another, have a selection of the embryos to make an embryo transfer where an embryo is unavailable to implant is almost a more, let’s say, a bad clinical practice. You shouldn’t do that. And at the moment, PGT-A is one of the most powerful instruments that we have in our hands to remove reproductive circuit those embryos that would never implant. So, they should not be transferred.

Who would you not offer PGT-A testing to? What would that patient be?

Dr Àlex García-Faura, Institut Marquès: I think that the first group of patients is patients that do not even need IVF. Sometimes some patients are moving up to IVF too fast just because some of the easy techniques do have a low efficiency or a low pregnancy rate. Perhaps not in Europe, but in some other parts of the world, you see scientific works with a mean age of 27. For these groups, they should try natural or should try with easier techniques like artificial insemination. They don’t even need to go up to IVF to be able to do PGT-A.

I think that we cannot only focus on the medical part, but we need to focus on the emotional part, and I think that’s quite important too. It’s not the same to attend to a patient who has not even tried to conceive or to get pregnant or a patient who has had 4 previous spontaneous miscarriages without any artificial reproductive technique. The impact or the risk of having again another miscarriage in a patient that has had a previous pregnancy interruption because there was a chromosomal abnormality, even if they were very young and with no risk, I think that we cannot say no just because of the medical part. Sometimes, we need to listen and make sure that the patient from an emotional point of view couldn’t stand another miscarriage that could have been prevented or another baby with a chromosomal abnormality that could have been tested and avoided. We’re setting only the medical criteria, but I think that we do all agree that first of all, we need to listen and then we need to talk.

Dr Luca Gianaroli, S.I.S.Mer: There is a group of patients that sometimes they are missed out, mainly those with again, male factor where chromosomal analysis has not been done. I’m talking about karyotype and peripheral karyotype. You find that at least 5% of them have translocations. This is not PGT-A, but again, if you look at the translocated males, the chance for them to have an aneuploid embryo is extremely low, depending on the location.

It would be extremely important that when we have a severe male factor and the origin of this is not well known, that we karyotype the patients. And if we find any abnormalities, the karyotype, PGT-A, not only for the translocation but PGT-A in general should be done because we will find a lot of chromosomal abnormalities that do not refer specifically to the translocated chromosomes, and that will again decrease the chance of pregnancy. So PGT-A should always be back-to-back when we have problems like karyotype anomalies or even when we have monogenic problems. So when we have genetic diseases, it would be a pity to transfer an embryo that is safe for the disease that we are looking for, cystic fibrosis, hemophilia, and then we have chromosomal abnormalities that bring them to a miscarriage or even worse to a Down syndrome baby. So this is another strong indication for PGT-A.

Dr Elias Tsakos, Embryoclinic: I fully agree with what’s been said already, I would add egg donation patients where perhaps PGT-A would not be indicated, provided that the male partner who’s providing the sperm is of normal age, which is probably under the age of 45 to start with, with no severe male factor that would indicate further analysis. Egg donation is a group of patients that I would not consider a PGT-A straight line. Having said that, you know, we’ve all seen egg donation cycles failing. It’s a small percentage, although we’re spoiled with egg donation success rates, with cumulative success rates reaching up to 90% per egg donation cycle, I think for those unexpected failures, especially if there’s a suspicion of potential male contribution to a genetic anomaly, I think it may be indicated.

What kind of results might we expect from PGT-A testing, if you can cover what percentage of sample embryos, do you expect to get a result, or not?

Dr Elias Tsakos, Embryoclinic: There are 4 types of results I would expect. One is a normal result, so that’s a normal euploid embryo. Second is an abnormal result, so black and white, abnormal, totally abnormal result. Then we have the gray area, and gray could be either light gray or dark gray, and I’m referring to mosaics at this stage. And then there’s a small possibility, but existent, of no result, so unable to get a result from the lab. And that’s why I mean, the types of results that may be expected, in my opinion, are part of the complexity of PGT-A. It is one of the reasons why PGT-A probably got a bad name, especially with the regulators, especially if the regulators, don’t consult fertility specialists very closely. And I think as fertility specialists, we have to put a lot of effort into counseling our patients, our couples, and our single women before PGT-A is performed to cover those potential possibilities.

Dr Luca Gianaroli, S.I.S.Mer: Embryo biopsy technically is a surgical procedure, and as any surgical procedure needs to be done by expert people, and to be an expert, you need to have a learning curve that will put you in training via models, animal trials, or whatever. First of all, let’s say that embryo biopsy has to be done by expert people. The second thing is that, in general, in any branch of medicine, when you talk about add-ons, you consider add-ons as an improvement of the technique. Only in Reproductive Medicine recently, add-ons have been considered from a negative point of view because it’s something that people are doing just to increase not only the result but to have some economic return.

This has been said in many scientific papers and many discussions. What I want to stress is that PGT-A is not an add-on. If it’s done properly, if it’s done consciously, if it’s done scientifically, correctly, it’s a big help to reduce time to pregnancy and to avoid unnecessary embryo transfers. That means cost, stress, and economic burden to the patients. I’m saying this because I want to remove PGT-A from a negative viewpoint of being an add-on that has been offered only to get some extra advantage to the clinic. This is completely false. Scientific data show this clearly. So, it has to be done properly. To conclude, it has to be done by professional people, but it is a help for couples, not an add-on to look for extra money for the clinics.

99% of the embryos will survive, and if those do not survive, they will probably not survive even if a biopsy is not been done. And secondly, the answer is covering more than 98-99%. And if you have no answer, this does not prevent you from not doing another biopsy. I think that we are going to publish an embryo that has been biopsied 3 times because it was the only embryo that the patient had, and she asked us to do this even if we explained to her that nobody has published up to now 3 embryos biopsies in the same embryos, and now she’s delivering a normal healthy baby. So, as far as, again, you are doing this professionally with the right person, the biopsy by itself would not harm the embryo.

Dr Elias Tsakos, Embryoclinic: I fully agree with Prof.Gianaroli. I would only add, if I may, that getting 99% survival is, of course, a top-quality lab and top-quality embryologist and also selecting top-quality blastocysts for freezing. I think this is a very important point, and may I express a little bit of, my own personal bitterness. In our lab and most of the labs, in all of the labs I’ve worked in the last 30 years that I’ve been in the field, our embryologists have been very selective about what they put in the storage. And that has caused a lot of issues sometimes with patients when they say, “Oh, how come I only have 3 blastocysts out of 7 eggs?” and so forth. So, I think, we could all agree that we only freeze, we only grade blastocysts, and only good-quality or top-quality blastocysts are utilized.

Dr Àlex García-Faura, Institut Marquès: I think we do all agree the embryos that will not survive will be the abnormal ones. Before, after, and during the biopsy, usually, there are the aneuploid ones that will get blocked. I think that’s because of the chromosomal abnormality. And referring to the results that we might have, I think that right now, and especially in the UK, you have an extra result that I still don’t know if it’s an add-on or that we will be able to use, which is this coming from one side or the other one. We can get to know right now whether this chromosomal abnormality if there is only 1, is coming from sperm or is coming from the egg. I think that we do know that most of the trisomies, and that’s quite standard, are coming from the egg, most of them. And most of the segmental, so a part of the chromosome is lacking, most of them are coming from the male factor. But we do know that some labs now are offering, and I think that we still need some extra evidence to make sure that this is okay, but I think it’s quite important when we do have both a male and an egg factor to get this information, whether the majority of the embryos are abnormal because of the egg or the majority of these embryos are abnormal because of sperm before deciding to change to egg donation or sperm donation.

Are there any downsides of taking these tests (PGT-A)? Why aren’t they part of the standard protocol?

Dr. Àlex García-Faura, Institut Marquès: I think that the first thing we should say is if it was for free, probably we would do it more often. That’s the worst side effect. I think it’s the cost, and some patients who could have the possibility to have 2 or 3 attempts sometimes won’t because they need to afford PGT-A added to the IVF treatment. I think it’s quite important to say that the most expensive treatment is transferring an abnormal embryo that will never lead to a delivery. So, when patients say, “What’s the worst part of it?” I say, “Sorry, the worst part is the economic part.” But just need to think that it’s still worse to keep on freezing and transferring to 3, 4, or 5 high-quality blastocysts if all of them are abnormal. That’s really more expensive than any PGT-A fees that you can get in any clinic. We know what we’re looking at, the medical part, but I think that talking about money is also important for patients. And the other thing is that we cannot do the transfer immediately. We need to freeze the embryos. There’s going to be a few weeks’ delay, but of course, this will also give us the possibility in the following cycle to do the optimal protocol to increase the implantation rate. 

Are there any downsides to taking these tests (PGT-A)? Why aren’t they part of the standard protocol?

Dr. Àlex García-Faura, Institut Marquès: I think that the first thing we should say is if it was for free, probably we would do it more often. That’s the worst side effect. I think it’s the cost and some patients that could have the possibility to have 2 or 3 attempts sometimes won’t because they need to afford PGT-A added to the IVF treatment. I think it’s quite important to say that the most expensive treatment is transferring an abnormal embryo that will never lead to a delivery. So, when patients say, “What’s the worst part of it?” I say, “Sorry, the worst part is the economical part.” But just need to think that it’s still worse to keep on freezing and transferring to 3, 4, 5 high-quality blastocysts if all of them are abnormal. That’s really more expensive than any PGT-A fees that you can get in any clinic. We know what we’re looking at, the medical part, but I think that talking about money is also important for patients. And the other thing is that we cannot do the transfer immediately. We need to freeze the embryos. There’s going to be a few weeks’ delay, but of course, this will also give us the possibility on the following cycle to do the optimal protocol to increase implantation rate.

We cannot transfer the embryo on that cycle. We need to wait for the next one. But of course, this will lead us also to an optimal endometrial protocol for endometrial.

Dr Luca Gianaroli, S.I.S.Mer: What Alex said is the best scenario. The worst scenario is without having a PGT-A, a patient over 38 has a high chance to have a miscarriage. A miscarriage is a waste of time, a waste of energy, and many times this patient just drops out from a program, and this is the worst thing that could happen to an infertile couple that have looked for a baby for many, many years, just to abandon based on a miscarriage. I feel guilty every time I see a miscarriage after PGT-A has not been performed because I know that that couple is going to pay such a high price, that the major risk is that they abandon the program, and this is our fault, not suggesting them PGT-A.

I think that Alex is right, the major downside is the cost, but let me imply that we should have an agreement among clinics and also industries because we know very well that the cost is not mainly driven by clinics but is mainly driven by genetic laboratories and the industries. So, maybe we should find a solution for which this is going to be cheaper. It’s going to be not safer because it’s already safe enough. It’s going to be cheaper. We need to use this tool for many categories of patients that deserve it without the constriction of the cost. That is the reality.

Dr Elias Tsakos, Embryoclinic: I fully agree with both of my colleagues. I mean, the only thing I would add is that the cost is a downside if it’s not applied properly. If it is applied properly, I do not believe that the cost is a downside because if you take into account exactly what Professor Gianaroli said and what Dr Faura – Garcia said, that every time a patient is having a miscarriage, to be honest, I feel very guilty, not just guilty, when I know I could have prevented it. In Greece, it’s even more frustrating because we are bound by law. We have a 39-year-old woman with a very low ovarian reserve. We managed to create maybe 2 blastocysts with a husband who is in the mid-50s with terrible sperm.

We know that the chance of chromosomal anomaly is probably as high as 80%, and this woman has a miscarriage and then she drops out of IVF altogether. And it’s happened to me many times. I’m grateful to Professor Gianaroli who brought this up. As a fertility specialist, we have feelings as well. And what I find is that the older we get, the more feelings we have. And it’s very frustrating for a doctor not to be able to provide the very best possible treatment to their patients with a technology that’s been there for longer than 25 years, 30 years.

I have had a number of different transfers, some successful, some not successful, but I’m in Sweden and it’s not allowed to do PGT-A testing here. Do you think it’s worth traveling overseas taking those embryos overseas, and testing them? How would you convince someone to bring those embryos over and test them?

Dr Àlex García-Faura, Institut Marquès: When we look at cumulative life birth rates, we cannot tell that PGT-A will increase the possibility of a live birth rate if we transfer all the embryos one by one. That’s why some countries, like France, won’t even allow PGT-A at all. If Dr Tsakos was frustrated, just think of our colleagues in France who are not allowed to do any PGT-A at all. I think that the main point is time to deliver and avoid unnecessary treatments. As we said, if we can select the embryo itself that has the possibility for pregnancy and delivery and avoid transferring these embryos that won’t even implant or will lead us to early miscarriage or monosomy or trisomy during pregnancy.

I think it’s worth it to test the embryos and avoid 5, 6, and 7 unnecessary transfers that will never lead us to the birth of a healthy baby. I think that we cannot tell that if we transfer them all one by one, we will increase the overall newborn rate, but some of these patients will get exhausted and will abandon after the third, fourth, or fifth transfer are exhausted physically, emotionally, and economically. I think it’s important to avoid these unnecessary treatments because we might get a high rate of dropout patients who will abandon just because they are exhausted for any reason and still haven’t had the possibility to transfer the only euploid embryo that they had in that group.

If there is only 1 blastocyst from the cycle, does it make sense to do PGT-A?

Dr Luca Gianaroli, S.I.S.Mer: I think it does, based on what we just heard about the unnecessary embryo transfer. If you have a chromosomally normal embryo, honestly, from a medical point of view, don’t you consider it completely unethical to transfer an embryo that you know will never be able to succeed in terms of full-term pregnancy? And in the meantime, I’d like to underline what Alex just said. If you look inside our cryobanks, how many euploid embryos are sitting there without us knowing that they’re euploid because the patient just disappeared? They didn’t leave the clinic; that is acceptable. They left the reproductive program that they had in their mind, abandoning the concept of being parents. On the basis of the fact that they have done a certain number of embryo transfers for nothing, I think this is an ethical issue that should be deeply discussed because we are responsible for those patients who abandon the program, leaving in our bank euploid embryos that could lead to a normal, healthy baby. On the basis of this, I think even if only one embryo has the right to be tested, the point I want to make is that we should think differently. We should reverse the paradigm and say, “Madam, because of your age, because of your history, because of your clinical problems, we need you to give us a certain number of embryos, and among them, you will have 1 or 2 or 3 embryos transferred because they will be normal.

 How many embryos do we need to reach this point? We roughly know, and that implies that we need a large amount of eggs. Are you prepared to do 1, 2, or 3 oocyte recoveries to reach 4 or 5 blastocysts and among them discover that 1 or 2 are viable for transfer? This is the engagement that we should have with the couples. Stop saying you’ve got 30% per cycle, 40% per cycle. This doesn’t mean anything. We need to reverse the paradigm and say to them, “You want 70%, 60% of delivery? We need 3 normal blastocysts. That means you have to give us 6, 7, 8 blastocysts. That means that you need to give us 30, or 40 eggs. It doesn’t matter how many oocyte recoveries we need, as long as you give us 30 or 40 eggs.” If we are able to explain to patients that this is the way to go, now we are getting very close to an oncologist. If one of us, touching wood, has been told that we have cancer and we need 66 chemotherapy cycles, there is no reason to do only 1 cycle because we will never get rid of the cancer and we have all the collateral effects, all the negative effects, losing hair, vomiting, whatever. All of us have been told, “You have cancer, you need 6 chemotherapy cycles,” all of us will do it, and we need to convince the patient the same way.

Is ICSI compatible with PGT-A?  Lots of clinics will say it’s mandatory for PGT-A. What’s your feeling about doing it if somebody doesn’t have a male factor problem they would normally have in conventional IVF? Is that still compatible with PGT-A in your practice at least?

Dr Elias Tsakos, Embryoclinic: Yes, it is.

Dr Àlex García-Faura, Institut Marquès: We only do ICSI.

Dr Luca Gianaroli, S.I.S.Mer: I agree. For PGT-A, we do ICSI.

I had 1 euploid embryo left but it didn’t work. We had multiple euploid embryos transferred on different cycles. What would you have done to try to improve our chances?

Dr Àlex García-Faura, Institut Marquès: I think that right now we can say that the gold standard or what we all would like to transfer is a single euploid high-quality embryo. That would be the optimal condition for any clinician or any patient. And I think that also in clinical trials, that’s what we are trying to look at, not this profile of patients that have had one single high-quality blastocyst transferred. But of course, sometimes it fails. We know that probably the newborn rate, the possibility of getting up to delivery depending on the clinics might be between 60 and 65% per 1 single blastocyst. And this is, of course, in relation to repeated implantation failure, as I said before, in optimal conditions. But of course, what is repeated implantation failure for the clinician and what is repeated implantation failure for the patient? So, our patients, on the first attempt with a high-quality normal embryo, will say, “We need to do something. No, it didn’t work. What can we do? Can we get several add-ons that Dr Gianaroli just explained before?

I think we need to be honest and true when we call repeated miscarriage or repeated implantation failure because we have more than one. So, first of all, we need to tell the patient that it’s normal just for statistics that having a single embryo transfer that has been tested is not a disaster and that we do not need to start undergoing invasive, expensive, and sometimes with low scientific evidence tests just because they had one single transfer in optimal conditions that didn’t work. I think that with euploid embryos and, as I said, with a beautiful lining and everything okay and all the parameters correct, of course, if we do have a second attempt in this optimal condition and with a euploid embryo, probably we need to start doing some tests related to the uterine cavity, and I’m talking about morphology. Some of the tests that have been used in Europe in recent years and that unfortunately do not have strong scientific evidence and sometimes also some studies related to autoimmunity or thrombophilia that are quite easy to do and that have scientific evidence to support that this might help us better understand why did we have repeated miscarriage or repeated failure.

What’s your policy on transferring Mosaic embryos in your clinic? 

Dr Elias Tsakos, Embryoclinic:  I mean, firstly, we have spoken about it. We have counseled our patients beforehand so that they’re a little bit prepared for this potential possibility. Secondly, we give priority to the euploid, to the normal embryos, and usually, we have good results with those. And then, if it comes down to the remaining embryo being Mosaic, then we assess it, we look at it again, we have a multidisciplinary meeting with the embryologists, the clinicians, the genetics lab, the patients, and then we decide if it’s a low-grade mosaic, we may consider transferring it. If not, then we put it on hold. It has to do also with the option given to the patients whether they would consider another stimulation to solve the problem at the time. All in all, we leave them for last. If the low-grade mosaicism and the patients are not willing to undergo another stimulation, then following very careful second counseling, we may consider transfer.

Dr Luca Gianaroli, S.I.S.Mer: First of all, I’d like to remind you that when we were using the previous technique, that was microarray, and when you were not able to detect mosaicism and you looked at the big registries, European registries, national registries, you don’t see any difference in terms of the risk of chromosomally abnormal embryos that have been implanted and that have gone to term or that have been miscarried. This does mean that the importance of mosaicism is very limited. It goes down to 2-3%. So, if we have an answer regarding mosaicism from the genetic lab that involves a high majority of the cells, those chromosomes that could lead to miscarriage or a trisomy, and I’m referring to chromosomes 16, 21, 22, 13, and 18, we will not transfer.

All the rest, I think it makes sense to transfer, as long as the patient is aware that the chance of pregnancy is diminishing and maybe the chance of miscarriage is increased. I think this is the right way to say because, once again, when we look at the 100,000 cycles of microarray, you compare to the 100,000 of the new generation cycles that have been done. You don’t have an increase in malformations and chromosomal abnormality rates. My point is that we have emphasized from the clinical point of view the mosaicism as a sort of biological, I don’t want to say artifact, but a biological event that is not confirmed by the clinical event of a normal pregnancy. In other words, I would not be worried.

Dr Àlex García-Faura, Institut Marquès: I completely agree with both of them. I think that, first of all, we need to tell patients that probably we are transferring Mosaic embryos that are classified in the euploid group. When we say 10%, 20%, or 50% of the cells are abnormal, we’re not going to be taking 100 cells, so probably we’ll be taking only 8 cells or 10 cells. Every lab and every clinic should settle the cutoff point for mosaicism, but first of all, let patients know that some of these embryos, of course, will be Mosaics and it doesn’t have any impact. And referring to low-risk mosaicism, I don’t go deep on that, but just saying that with low-risk mosaicism, the delivery rate of a euploid embryo is 40%, so it’s quite a high possibility compared to the 60-65% of a euploid embryo. I think, I don’t know if it’s worth it to transfer, but it’s worth it to discuss and have time enough to tell the patient what this means instead of just saying the risk of having an abnormal or aneuploid baby. Avoiding these high-risk chromosomes 13, 18, 21, that’s for sure that no patient will accept to get this transferred. But with all the other ones, I think it’s very important for each clinic to settle depending on the experience of the clinic and the miscarriage rate on euploid embryos. Each clinic should decide to raise or get down the cutoff point for mosaicism to make sure that we can transfer it.

You mentioned potentially being able to look at the origin of the abnormality, coming from either sperm or egg. Could you say a little bit about that and what those tests might look like?

Dr Àlex García-Faura, Institut Marquès: I think that especially for this group of patients where there’s a low risk for aneuploidy, a young mother, and a male patient that doesn’t have any sperm problem, and especially for these patients that have had repeated failure and repeated miscarriage and we really do not why. I think that getting to know if they do have a high group of high rate of aneuploidy is important, but see that we do not know why because it shouldn’t come from the egg because it’s a 25-year-old patient and it should not come from the sperm because sperm quality is fantastic, and even FISH or DNA fragmentation tests are completely normal. We do know that still it might be something that we don’t know why it’s raising the risk for aneuploidy, coming from sperm or coming from the eggs, usually, it happens with the male factor, no even if with a normal sperm count and sometimes even with the normal FISH test that Dr. Gianaroli told before, there’s still 40% of these patients that might have the risk of a higher aneuploidy rate even of the older test that has been done before abnormal.

Getting to know if this risk of these chromosomal abnormalities is coming from sperm or from the egg, and especially for these patients that all the embryos are abnormal euploid, I think it’s quite important to get to know which one should we change or go to egg or sperm donation. And it would be, I’m not saying it’s the standard, I think we do all know that some laboratories will give us this opportunity, but I think there’s still a lot of research that has to be done. But I think it can be interesting for this group of patients to help decide whether we should change the eggs or the sperm.

You’ve got a long research history in this, can you tell us what the future looks like for a non-invasive test PGT-A testing (niPGT-A)? 

Dr Luca Gianaroli, S.I.S.Mer: Non-invasive PGT-A has been tried for many years. We tried it with blastocyst fluid, which is semi-invasive, and now there is this new wave of checking the quality of the embryo via the spent media. At the moment, the concordance rate, which means an agreement of the result with a gold standard technique that at this moment, and I disagree anyway, the gold standard is the trophectoderm biopsy, is still 88-90%. What does it mean? That one out of 10 analyses is not telling the patient the truth. Would you accept in your life to have a diagnosis that fails one time out of 10? The answer would be no. I would never accept this as a test. As far as we don’t call it a diagnosis but we call it, as you have said, a way to prioritize the embryo to be transferred, it is acceptable. But we have to keep in mind that it is not a diagnostic test.

The diagnostic test is always the test that is coming as close as possible to reality, and at the moment, we only have the invasive technique. Now, if we say that the invasive technique is safe because it’s performed properly if I want to have a diagnosis of my embryos, I would go for the invasive technique. If I have a young patient and I have 10 blastocysts and I want to prioritize them and since all of them look morphologically equal, I would prefer that one that is telling me that in the spent medium, it’s okay. Fine, it’s not a diagnosis, it’s not a test, it’s a prioritization system. So, as long as the patients understand this very clearly, I have nothing against it. But don’t call them PGT, don’t call them tests, they are not tests, they are just priority tests.

What can change in terms of costs and pricing models to make PGT-A more accessible?

Dr Elias Tsakos, Embryoclinic: It’s a very difficult one, we all know that even in Europe, there’s a huge variation in costs. It’s very difficult for me to speak on behalf of other European countries, apart from Greece. The cost of IVF in Greece has been the same in the last 20 to 25 years, and I was very happy to hear Alex say that they usually do ICSI as a routine. That’s more or less what we do as well, and most people don’t agree with that, don’t accept it, or don’t do it, so I’m glad you do it. What I don’t know is whether you charge extra for it or not. We don’t. Spain and Greece, share a common, I think, common ethos and common wish to give the very best to patients. To conclude, I would say that in Greece, we don’t charge extra for any laboratory technique that would potentially increase the chance of the patient getting pregnant. There’s no different price for ICSI versus IVF. IVF with ICSI is the same package, and also, if we need to do anything extra in the lab, like blastocyst culture, like assisted hatching, like time-lapse, like EmbryoGlue, there’s no extra charge.

In terms of cost, all I can say is that in Greece, and certainly in my clinic, and in the clinics I worked in the last 25 years, there’s the same price for IVF, and that price has not increased in the last 20-25 years, despite inflation and all that. In this context, it’s not how much it costs, it’s whether it’s cost-effective or not, and before we answer that, we have to answer whether it’s medically indicated or not and whether it is going to give us one of those three advantages that PGT-A should have, which is to improve the implantation, the pregnancy rate per embryo transfer, decrease the miscarriage rate, and thirdly, shorten the time to pregnancy. If the answer to those questions is yes, then yes, it is cost-effective, and that is the approach that I have as a doctor, and that we have in my clinic.

Dr Àlex García-Faura, Institut Marquès: Do you know what an iPhone is? Do you think iPhone prices are dropping? Why? Because every single year, there’s an upgrade that makes a better camera, higher pixels, higher RAM, a better phone, and who’s going to use an iPhone 4 today? No one. So, I think the same thing is happening and has been happening through these 20 years of PGT-A, starting on day 3 biopsy, arrays, NGS, etc.

Unfortunately, and that’s not because of the clinicians, this has to do with the labs, and not because it’s fancy, it’s because it’s effective. I think the main difference, I’m sorry, I didn’t want to just make a joke, but just to make people understand why these prices are not going to drop down. I think it’s easier to tell it this way. It’s not because it’s fancy, it’s because we can get more information, more accurate, and it’s going to help us teach the patients where the problem is and what are the possibilities of pregnancy and new birth with this group of embryos that the patient has. I think that the pricing will stay there. It’s been there for 20 years, and it’s going to be there for an extra 10-20 years, but of course, we will reduce probably the risk, the non-informative rate, and all of them will be in, and we will be able then not only to test chromosomes, but we will be able to test 10 genes, and then we’ll be able to test 100 genes. There’s always going to be extra stuff to add to PGT-A, so I think it’s not going to get down.

What do you think is required to make this test (PGT-A) a standard?

Dr Àlex García-Faura, Institut Marquès: I think that we always need to tell patients, every single patient, that this is a standard, or could be a standard, and could be an option. Not because we could get legal prosecution, that’s what’s happening in the US, that you need to tell the patient that PGT-A exists, even if the patient doesn’t need PGT-A. Because if you don’t and there is the birth of an abnormal baby, you can get in jail. That’s the American model, and I’m happy that in Europe, this is not going to happen, not because of the risk for the clinician, but for the risk of the patient.

We need to be true and tell IVF is standard, and PGT-A is standard. Do you want to do it? Or can you afford it? And I think you need it or I think the risk or the benefit of undergoing PGT-A is not worth it from an economical point of view. However I think that PGT-A is becoming a routine in several clinics and several countries. Even in egg donation, some clinics will report up to 50% of PGT-A. That might be excessive for a clinician, but probably it’s not excessive for every single patient who had the consent form and decided that they really wanted to get the benefits from PGT-A after getting all the information.

Dr Elias Tsakos, Embryoclinic: I would like to address a little bit of the issue of the technology of non-invasive testing. I think there is a place in that, and not only because my team has been involved in a wonderful multicenter study that was presented in ASRM and hopefully now will be published in Fertility and Sterility. But I think that 90% is pretty good going, and I think there is a tendency in medicine, I agree it’s a surgical procedure, it’s a microsurgical procedure, and as a surgeon, as a background, I can say that the tendency is to move to non-invasive or to less invasive surgeries. And we’ve seen this with laparotomies moving on to laparoscopy, and then moving on to robotics, and we’ve seen it with amniocentesis and then moving on to non-invasive prenatal testing. So, my feeling, and my scientific hunch, is probably saying that non-invasive testing is here to stay, and maybe will be complementing invasive PGT-A. I think if the scientific community, at least in this part of the world, in Europe, agrees on the place of genetic testing, whether it’s non-invasive or invasive, it doesn’t really matter. I think at the end of the day, our patients will benefit from that.

I would point out the value, and I would definitely try to address the indications, and those indications have really been mentioned. For those patients where there’s a clear indication, this test is cost-effective, because the worst that can happen to a patient, in my opinion, is not just failing the IVF, is dropping out of the IVF program altogether, is having a dire complication, because abnormal embryos can still cause an ectopic pregnancy, they can still risk the integrity of a woman’s uterus, and they can risk the inability of not having children in the future. So, cost-effectiveness I would focus on more than the actual cost itself.

Dr Àlex García-Faura, Institut Marquès: I’m sure we will see these robotics applied to PGT-A and any other micromanipulation techniques. As Luca said, it’s not only the technique, but it’s the one who’s doing the biopsy. Now that everything is managed by micromanipulators, probably in 5 to 10 years, you’ll say, “Yes, I want my embryos in Barcelona to get the biopsy done by this biologist who lives in the USA,” and this biologist will be at home with the PlayStation just doing the biopsy to my embryos in Barcelona. This might reduce or increase costs, depending on who’s going to do the biopsy and how many embryos you can do in one single day staying at home. Robotics will get into that field, and it might reduce or increase costs. We still need to see what’s going to happen with that, but I’m sure we’re going to see it.

What’s the benefit of doing ICSI if there’s no male factor? 

Dr Elias Tsakos, Embryoclinic: Male factor is not the only indication for doing ICSI. That’s the bottom line. I’ve been around for more than 30 years in this field now, and I have very fresh memories of failures, unexpected fertilization failures, not having enough embryos to transfer after difficult stimulation, and so forth. I think there are a lot more indications for ICSI than male factor, and nowadays, our patients tend to get much older. The average age of our patients with own eggs in my clinic is very near 39 years old. We cannot risk poor fertilization or no fertilization, and then only to find out that we have to repeat a cycle The patients come to our clinics for the best possible outcome, and I think that if you dig deeply, you always find an indication for ICSI. If not, always invariably.

Dr Àlex García-Faura, Institut Marquès: I think that finally each lab has to decide how it works, and of course, when you get to the ICSI routine for every single egg, and you get all the eggs in this routine… I know that when we get sometimes 25 or 35 eggs from a patient, the biologist might want to kill me. But of course, it works, and we know in our clinic, in our lab, it’s the way it works, and we do have an extremely high fertilization rate. In some patients, I’m sure that IVF would work, but ICSI too. That’s why probably we’re doing ICSI. It might be a little bit more difficult, it might take some time from our biologist, but it’s the routine that we got into the lab, not doing IVF, and we only do ICSI. It’s easier to get in this one single routine for the whole clinic, and it works.  I think that’s the main reason, and I’m not saying that IVF might not work in patients where there’s not a male factor. Is that what we decide in our lab.

Dr Elias Tsakos, Embryoclinic: I would just add that in my personal practice, the biggest relief was when we introduced, about 10 years ago, the fact that ICSI is not paid extra. Since we’ve done that, we felt the relief that our patients understand that we’re going to give them the best possible outcome without risking the individual couple, which in my opinion, is a good proportion of our population with abnormal fertilization or no fertilization with IVF. Since we’ve done that, to be honest, I can’t remember a single patient or a single couple who said, “Oh, okay, I know it’s included in the price, but I would prefer if you did IVF.†It was a huge relief when we managed to offer this as a free service for our patients.

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Authors
Picture of Àlex García-Faura, MD

Àlex García-Faura, MD

Àlex García-Faura, MD, graduated in Medicine & Surgery in 1999 from the University of Barcelona. He has spent 15 years as a breast cancer specialist and oncofertility consultant at Institut Marquès Barcelona and is the current Scientific Director of the centre. In this role, and as a Director of the Scientific Committee, his time is focused on clinical research, management, and quality in healthcare. As a consultant specialising in breast cancer he sits on the Corachán Clinic Tumor Committee, and is the current Director of the Oncology and Reproductive Medicine Unit at Institut Marquès, counseling patients from all over the world who wish to undergo IVF treatment after cancer.
Picture of Elias Tsakos MD, FRCOG

Elias Tsakos MD, FRCOG

Dr Elias Tsakos, FRCOG, is a Medical Director of Embryoclinic - Assisted Reproduction Clinic in Thessaloniki, Greece. He has received extensive and certified training in the United Kingdom and is a Fellow of the Royal College of Obstetrics & Gynaecology. Dr Tsakos is also a Board Member Representative of the Royal College for Greece and Cyprus and a Board Member of the Hellenic Society of Assisted Reproduction. He is a Member of the British, European and American Fertility Societies (BFS, ESHRE, ASRM). Dr Tsakos has been living and working in Thessaloniki, Greece, since 1999.
Picture of Luca Gianaroli, MD

Luca Gianaroli, MD

Dr Luca Gianaroli has been a specialist in Reproductive Medicine since the end of the 1970s. He is the Scientific Director of S.I.S.Me.R. (Italian Society for the Study of Reproductive Medicine) and he holds the position of Scientific Director of I.I.A.R.G., the International Institutes of Advanced Reproduction and Genetics and of IIRM SA. He is also an Honorary Professor at the School of Biosciences of the University of Kent. Dr Gianaroli is an active member of several international scientific societies in which he has covered and currently covers roles of primary importance, he has served as Chairman of the Italian Society of Reproduction and of the European Society of Human Reproduction and Embryology (ESHRE). He is a member of the ESHRE Certification Committee, and he is the coordinator of the Steering Committee of the ESHRE ART Centre Certification Program. Dr Gianaroli is author of more than 250 papers in international scientific journals and publisher or co-publisher of 9 books. Throughout his professional career, he collaborated with several Italian universities (Università degli Studi di Teramo, Università degli Studi di Modena e Reggio Emilia, Università degli Studi di Trieste, Università degli Studi di Roma Tor Vergata, Università di Bologna).
Event Moderator
Picture of Professor Alan Thornhill

Professor Alan Thornhill

Professor Alan Thornhill is a fertility expert with over 25 years of experience and more than 100 scientific publications in IVF. Specifically, he’s a clinical scientist (specialising in embryology and genetics). Uniquely, he’s worked in IVF and diagnostic laboratories, research, clinical and business management, and even with the UK’s fertility regulator. Working in US and UK-based IVF clinics and consulting globally, he’s been involved in the IVF journeys of thousands of couples (both professionally and personally). He’s helped and advised patients, friends and strangers with issues including low sperm count, sperm and egg donation, genetic testing, surrogacy, treatment overseas and more. He currently works in the biotech industry, and his personal mission is to provide his unique brand of fertility coaching to people in need of help.
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