Should you do PGT-A if you are over 35?

Vladimiro Silva, PharmD
Embryologist, CEO, Founder & IVF Lab Director at Ferticentro, Ferticentro

Category:
Advanced Maternal Age, Genetics PGS / PGT-A

From this video you will find out:

Is PGT-A recommended in all patients over 35?
Why is PGT-A useful and above what age?
Are there risks to the embryo(s) from the PGT process?
What are the benefits of PGT-A?
What other tests can be useful?

Should you do PGT-A if you are over 35?

Who should use PGT-A?

During this webinar session, Dr Vladimiro Silva, Founder & IVF Lab Director at Ferticentro, Coimbra, Portugal has talked about PGT-A. The main question that has been discussed was: Should you do PGT-A if you are over 35? According to Dr Vladimiro Silva, it’s one of the questions we hear very often in our daily routine. Some people say that we always should do PGT-A. Dr Silva started his presentation by explaining what PGT-A means, it’s the acronym for Pre-implementation Genetic Testing for Aneuploidies, this test is used to see whether you have the right number of chromosomes on your embryos. We know that the probability of having an abnormal embryo increases with age. The most known abnormality of this kind is Trisomy 21, and it increases with female age. That is why the question of doing this genetic screening after the age of 35 is a recurrent topic. The answer is very easy, it depends. There is no clear answer to this question. Every patient is different, the risks are different, and we need to assess multiple factors.

IVF & Genetic Diseases

IVF, in reality, is one of the most used strategies to avoid genetic diseases. There are multiple strategies to prevent the transmission of these genetic diseases, and so Pre-implantation Genetic Screening, so-called PGT-A, is just one of them. We use IVF to prevent genetic diseases in many ways. If you know that you have a certain disease, IVF can prevent the transmission of such genetic disease, that’s the case of monogenic diseases, this has nothing to do with PGT-A. Sometimes patients ask what kind of disease am I preventing, but this is for diseases that run in your family, you know you are a carrier for those diseases and so on. Another thing that we use IVF for is to screen for genetic risks, that’s where PGT-A comes in, it’s age-related risks, balanced translocations so sometimes you’re a carrier of a balanced abnormality that wouldn’t cause any disease or any problem with you but can cause problems while you are forming your eggs and sperm. This is one of the risks we need to address. Next, Dr Silva discussed the Carrier Genetic Test and explained that all of us are carriers of rare genetic diseases, and there are tests that we can do to see if we have the risk of transmitting genetic diseases. If our partner is a carrier for the very rare genetic disease, there will be a 25% chance of transmission. There are also more complicated situations where we can try to obtain embryos that are HLA compatible, for example, to allow for a bone marrow transplantation on a sibling because we already have an affected child or a child with a serious disease. Those embryos can be used to create a compatible sibling. For prevention, we use PGT-M (Pre-implantation Genetic Test for Monogenic Diseases), and PGT-SR (Pre-implantation Genetic Test for Structural Rearrangements). For screening, we have PGT-A. The Carrier Screening Tests are being done on the patient’s blood, not on the embryos, and we can screen for packs of 400, 300 or 200 diseases. There are multiple offers in the market. Then we have the Pre-implantation Genetic Testing for HLA.

PGT-M

This has nothing to do with age, so if you are a carrier of a disease such as Huntington’s disease, Neurofibromatosis, Cystic fibrosis, etc., this means that you were born like this, and the risk of transmitting that disease onto your child will always be 50%. If the disease is autosomal recessive, you need your partner to also transmit the same gene for the same disease. If the disease is autosomal dominant, the mere fact that one of you transmits the gene can already cause the disease, so the incidence is 50% for autosomal dominant diseases and 25% for recessive diseases. This is intended by patients who are known to carry these serious genetic diseases that run in their families, etc. These tests have to be custom-designed for every patient, they are quite complex to establish.

PGT-A

Screening for genetic risks that are age-related is done with PGT-A. The big question is whether it is worth doing it after the age of 35, is it worth doing at any age or maybe later? PGT-A was formerly known as PGS (Pre-plantation Genetic Screening). PGT-A is a genetic test performed on embryos to screen for numerical chromosomal abnormalities called aneuploidies, so embryos with an extra or a missing chromosome. The embryos with this extra or missing chromosome often fail to implant, so the most likely scenario when you transfer one of these embryos into the uterus is that you have a negative pregnancy result. They can also lead to a miscarriage, or in some situations’ implantation can be successful, these embryos sometimes are even compatible with life which would lead to the birth of a child with a genetic condition. The most well-known of these conditions is Trisomy 21, but there are others such as Trisomy 13, Trisomy 18, there are multiple diseases that can happen. Embryos are found to be chromosomally normal, referred to as euploid, that’s what we want when we do these tests, and these are most likely to lead to a successful pregnancy. At Ferticentro and in all main clinics worldwide, we do pre-implementation genetic testing with Next Generation Sequencing (NGS) allows us to analyse all 24 chromosomes. We know that we humans have 23 pairs of chromosomes, so we have a pair of chromosomes 1,2, 3, 4, 5 until chromosome 22, and so the 23rd pair of chromosomes are the sex chromosomes. If you are a man, you have an X and a Y chromosome if you are a female, you have two XX chromosomes. This is why we say that we have 24 different types of chromosomes, and so we do the NGS to analyze the quantity of these chromosomes. Chromosomal abnormalities are in these cases are detected before embryo transfer, and this will allow patients to make informed decisions about their treatment. Dr Silva emphasized that:

PGT-A will not make your embryos better, it will not give you a better chance of pregnancy, this is all about information. It gives us information on our capacity to select the best embryo it can, so we can identify the embryos that are most likely to originate in pregnancy, but it will not transform a bad embryo into a good one, it is very important. If we always have embryos with the wrong number of chromosomes, this could mean that we might consider egg donation instead or sperm donation if it comes from the male side.

We can identify the embryos that are most likely to implant, this will reduce the number of cycles needed to obtain a pregnancy. Once again, if the embryo is not viable, it is not the PGT-A that will transform it into a viable embryo.

PGT-A & age

So should we do PGT-A above the age of 35? Statistics published by the Igenomix group, one of the most well-known genetics labs in the world, show and they do a lot of investigating, a lot of research on this, that the incidence of the new applied blastocyst increases with maternal age. We know that when we start at the age of 35, we see that 36 to 40% of the embryos are aneuploid, they have a wrong number of chromosomes, and that number starts to rise, and it rises very steeply, especially after the age of 38 by the age of 38-39 we already have 61% of the embryos being carriers of genetic abnormalities. At the age of 43 or 44, we have 76% of the embryos carrying abnormalities. In Portugal, the IVF authorities have established that there is an indication for PGT-A after the age of 39, which is more or less when we are at around 61%. According to Dr Silva, it’s a good threshold because that’s when you have the majority of the embryos being carriers for chromosomal abnormalities. People are asking why not test it at any age if the chance is different from 0, why shouldn’t we do it, it is arguable that this could be an acceptable approach. Naturally, the more we know about our embryos the better, and Dr Silva finds PGT-A very useful, and if it was legally and financially possible, he would recommend testing all the embryos.

As an embryologist, I always prefer to transfer embryos that are tested, as a clinic, we need to know where to focus when we have a negative result after transferring a tested embryo. It has a completely different meaning than when we have a negative result after transferring a non-tested embryo. We have to balance that need for information with the real benefit for the patient. We know that if we look into statistics of the PGT-A, we will see that roughly speaking, 70% of pregnancy rates, in all studies published, which is more or less the same that we get below the age of 35. It’s not much of a difference, so why do an invasive procedure to the embryos that can lead to a 2% embryo loss with embryo vitrification itself can have another 2 or 3% embryo lost. We would be losing possibly healthy embryos because of these extra procedures, we would also be adding extra costs to the process.

There are also mosaic embryos that we should keep in mind, it’s never an easy decision. In Dr Silva’s opinion, the Portuguese approach is acceptable. The age of 39 is an understandable threshold, we could lower it a bit to 38 or 37, or if you already had 3 negative results, then it is advisable to do PGT-A. Also, it should be indicated if you had previous miscarriages or a previous pregnancy with aneuploidy, a baby diagnosed with a genetic disease. If we can isolate those cases, then the rest of the patients are very unlikely to have problems. Possibly the 39-year-old threshold will be more appropriate than 35 because, at the age of 35, we have a 37 to 40% probability of having an abnormal embryo. Once again, Dr Silva highlighted that if he could test all the embryos, it would be better, but when we weigh the pros and the cons, the benefits with the financial costs for the patients. We have to understand that the 60% that we get at the age of 39 is probably a more sensible approach.

PGT-A & clinical outcomes

Other statistics from Igenomix show the comparison of implantation rates in a group of patients that did PGT-A and in a group of patients that just transferred the embryos without testing them. On the left side, the probability of pregnancy is relatively stable through all the groups, there is a slight drop in pregnancy rates, but not a very significant one. When we don’t use PGT-A, the drop is more clear, and then the differences are bigger. Why does it happen? It’s because PGT-A doesn’t improve the quality of the embryos, but it does help select the best embryos. The difference between these two groups is that while here we are still transferring embryos that were not tested, and we are transferring a lot of aneuploid embryos, and on the other hand, you see the embryos transferred that have been tested. PGT-A helps us to remove the difference between these. It helps us focus on the embryos that have a real potential to implant and lower the number of embryo transfers needed to obtain a pregnancy. When we look at the statistics at the delivery rates, we see the same thing. You are more likely to have a miscarriage if you are transferring an embryo with the wrong number of chromosomes, this is completely clear. With the increase in the miscarriage rate, there is indeed a decrease in the delivery rate.

PGT-SR

PGT-SR is a very specific type of PGT-A, it’s for patients that carry karyotype abnormalities. The karyotype is kind of a formula of your genetic constitution, and sometimes people can be a carrier either because they inherited it or it occurred spontaneously in those chromosomal rearrangements. It is estimated that 1 in every 500 persons can carry a balance at reciprocal translocation patients are unaware of this, they don’t have the slightest idea, they only discover it when they are trying to get pregnant and are not getting pregnant, and they don’t know why. Then we do a Karyotype, we identify that, but patients live otherwise normal healthy lives. Knowing that carrier status is very important, but again the only thing we can do is to test the embryos, we cannot modify them. If all the embryos carry abnormalities, it’s not possible to do anything. There are multiple types of balanced rearrangements like duplications, deletions, inversions, so this is a very specific type of situation.

Genetic Carrier Screening

We’re all carriers for something, and if you have a baby with someone who is a carrier of the same mutation, you have a 25% chance of having an affected child. This is an example of how these diseases are transmitted. Multiple tests in the market can screen for these diseases, for example, Igenomix has 2 tests, one where they screen for 570 diseases and the other with more than 2 200 diseases. The chance of finding a carrier is 55% or 67% in the largest of the tests. This is something that is done to understand whether people are carriers of recessive genetic diseases, this is has nothing to do with aneuploidy, this has to do with the number of chromosomes in an embryo. The most common monogenic disorders detected with Genetic Carrier Screening are Cystic fibrosis, Spinal Muscular atrophy, Sickle-cell anaemia, Fragile-X syndrome, Beta thalassaemia, etc., there are lots of diseases, probably you’ve never heard of any of those, which is a good sign. The question is whether this is Pandora’s box or not. Once you know that you’re a carrier for something, you will always have to do this test. If you try again and then if you have a brother or a sister who is also trying to have babies, you probably should share that information with them because there is a very good chance that they are also carriers, but possibly you don’t want to share the fact that you are doing IVF with them and being tested or maybe that you are doing egg donation and are being tested to see if you are compatible with an egg donor. This causes a lot of ethical dilemmas. Sometimes it’s preferable not to be involved in all this kind of madness where we need to do a lot of tests. It’s completely indisputable that it gives you more safety, it lowers the risks significantly. However, you have to be very well informed and prepared to cope with having this information.

HLA compatible embryos

We do genetic testings to find HLA compatible embryos. This is something we do for certain diseases, we need to find a compatible stem cell donor, and the only solution is to have a genetically compatible sibling. This is something that requires approval from the National IVF authorities, those are very complicated cases, we have done those with success in the past, but it’s always very complicated and kind of stressful. Sometimes we need a lot of embryos to be lucky enough to find a compatible one, but at the end of the day, what we all want is a healthy child, and so this is what we’re here for.

Who should use PGT-A? - Questions and Answers

After 35, we have fewer embryos obtained, and if we do PGT-A, we might have 1 embryo biopsied to transfer. What if it is a mosaic? Professor N. Gleicher has proven a lot of diagnostic mistakes in that matter. What do you think?

This is one of our main concerns. First, it is true that the older the patient gets, the lower is the number of eggs and hence the lower is the number of embryos. At the same time, we are more likely to find abnormal embryos, so we need to do this in a more advanced stage because this is not about justifying the need for the procedure. We can even do it if we just have one embryo because this is about having information to decide on our reproductive future. I would say that the number of embryos is not very important, what’s important is to be able to decide. If we could decide without PGT-A it would be preferable, but it’s a useful tool. Regarding mosaicism, there are multiple cell lines in the embryo, there can be more than one cell line, and when we are doing PGT-A, we are making a hole in the embryo, which is like a ball, and we make a small hole. We retrieve 5 or 6 cells, those cells are then analysed, we take those cells of the embryo from a part called trophectoderm, which we find to be representative of the embryo. Many studies have concluded that they are representative, but we can never exclude the possibility there is another cell line inside the rest of the embryo not included in the biopsy and could be normal and take over the embryo that can still have an implantation potential. Some studies have been done with embryos that were considered to be abnormal and ended up implanting and originating in normal babies because those were mosaic embryos. Those are rare, the probability of that happening is low. When we transfer a mosaic embryo, there are a lot of concerns, one of them is, for example, if you transfer a Trisomy 21 embryo based on the assumption that it could be a mosaic, that’s a very high risk. Trisomy 21 is compatible with life, as we all know, so if that’s not the case, you can have a handicapped child. On the other hand, if you have, for example, a Trisomy 4 embryo that is not compatible with life, then you can maybe take the risk if you don’t have any other embryos because it would either be a negative result or a miscarriage, but you will never have a child born with a Trisomy 4 because that’s not compatible with life. We need to address every situation carefully because transferring an embryo carrying an abnormality that is compatible with life is a very huge risk, and so the possibility that it could be a mosaic doesn’t justify the risk, in my opinion. On the other hand, if it is an embryo that carries an abnormality that is not compatible with life, you have nothing to lose, you can risk the embryo transfer in the worst-case scenario, you will get a negative result or a miscarriage. Although having a miscarriage could cause problems in subsequent pregnancies, this also needs to be addressed carefully. However, if there is no alternative if that’s the only embryo available, then it’s either that or nothing, so maybe it’s justifiable. I haven’t included it in the presentation, but we now also have a new way of doing Pre-implementation Genetic Tests that looks very promising. It is called Non-invasive Preimplantation Genetic Testing, instead of making a hole in the embryo and retrieving 5 or 6 cells, we are analysing the free DNA that lies in the embryo culture media. That DNA is theoretically representative of the whole embryo. In principle, it should be a better representation of the different cell lines that might be present in the embryos. The issue with Non-invasive PGT-A is that we’re still in the early days of non-invasive PGT-A, it’s relatively soon to generalize its utilization and the concordance between the trophectoderm and the free DNA, and the culture media is only around 85 possibly 90%. It’s a very promising technique, we are implementing it in our labs, but it’s still not the same as doing, let’s say, a classical PGT-A, but that’s a way of addressing this mosaicism issue.

My first 3 IVFs with ICSI cycles were with juvenile sperm, and ultimately we had no embryos to freeze and no live birth. Now we have good sperm (from mTESE), in our first IVF cycle, 2 embryos were transferred, 2 births, one healthy, and one had chromosome abnormality (rare ALGS) and lived 10 months. We also had 4 frozen embryos. Three were transferred separately and all failed. I have 1 frozen embryo left. Now we’re starting a new IVF cycle, egg collection will be done tomorrow. I am 35, given our history, should I PGT-A test embryos, including the frozen embryo?

Yes, when we work with TESE sperm, there is always a slightly increased risk of having a genetically abnormal embryo, but still, the vast majority of genetic abnormalities come from the egg, not from the sperm. This is statistics, nature works like that. On the other hand, since you are only 35 I would say that in principle you’re on the good side of statistics or at least it shouldn’t be too bad for you. I honestly don’t exactly know what this genetic disease was, but if it was identified, then you will need a genetics consultation so we can address the risk of recurrence to see if you’re at an increased risk to have the same problem again or if it was just a random event that can happen to everyone, meaning just bad luck. Having 1 embryo I would test it, and if you’ll be doing another new cycle, I would also test the embryos because you have done a lot of cycles. This is the example that I was talking about in my presentation, you’ve 3 IVF cycles, you’ve done a lot of embryo transfers with negative results, so there is a clear indication for Pre-implantation Genetic Testing. I would do it. This may have nothing to do with PGT-A that would have been normal in a PGT-A test. It will require a genetic consultation to see if there is any risk of having the same issue again, at first sight, I would say no, it seems like a random event, but I’m not a genetic specialist but based on these results and the bad experience you had with so many difficulties I would advise PGT-A before transferring either the previous embryo or the new ones.

Can a previously frozen embryo be transferred alongside a fresh embryo?

Yes, we can warm the embryo, do the biopsy, we have to freeze it again and then we can wait for the PGT-A result. If the embryo is normal, we can warm it again and transfer it alongside the fresh embryo. However, again if we are doing PGT-A, we’re not working with fresh embryos, we are always working with frozen embryos because PGT-A requires that, especially if we work with Next Generation Sequencing (NGS), we need about 2 to 3 weeks to have the genetic results depending on where we are. We need to obtain the embryo, do the biopsy, vitrify/freeze them, then thaw the embryo and do the embryo transfer if the embryo is normal. We can thaw the frozen embryo, do the biopsy, at the same time with the fresh embryos that are being collected and freeze them all again. Even for Non-invasive Preimplantation Genetic Testing, we can do that. We can warm the embryo, culture it for at least 8 hours, there would be enough free DNA in the culture medium for us to analyse it and have an opinion, so that’s also one of the possibilities.

Would the double freezing on the current embryo not cause any deterioration?

There is a risk associated with it, we’ve done that multiple times we have a lot of embryos that were frozen twice or, in some cases, 3 times and the babies are born still. However, the more we manipulate it, the more we touch the embryo, the riskier it gets. I don’t have statistics for that, but it will lower the implantation potential of the embryo, but it’s a balance between what you get from testing the embryos and what you lose from testing them. In a case such as this, I would test it.

If the stimulation medication is too high, can this affect embryos, and could this cause damage?

This is a controversial question because until 5 or 6 years ago, more or less, we all thought that stimulation that was too high would decrease the quality of the eggs. Having too many eggs would be bad and could lower the pregnancy rates. More recent studies have been published in the last few years, and apparently, the pregnancy likelihood continuously increases even with a very high number of eggs. In principle, we don’t know, but the most recent research indicates that it shouldn’t affect embryos. We have to balance this with the risk for the patient, we don’t want the patient hyperstimulated, we need to trigger the ovulation with the agonist, a special drug that prevents ovarian hyperstimulation syndrome, if we do that, we cannot transfer the embryo in that cycle. We have to freeze the embryos and so on. My advice, especially if you’re older than 35, is to do a strong stimulation trigger with an agonist like Decapeptyl, then take the embryos to day-5 if you meet the criteria, do PGT-A, freeze the embryos and transfer the euploid ones

Did you say PGT-A has to be done only on frozen embryos? Is it a minimum of 3 weeks process to wait for the result before the transfer can be made?

Not exactly, so PGT-A can be done on fresh embryos, but then we have to freeze the embryos. We fertilize the eggs, we take the embryos until day5,-6,-7, we do the biopsy, and we freeze the embryos on that day, then we wait for about 2-3 weeks for the results from the genetics lab and then we can schedule the transfer. In the past, people were doing a biopsy on day-3 and the embryo transfer on day-5 or day-6. That was too risky for the embryo, and we were only taking 1 or 2 cells from a day-3 embryo that has 8 cells. It was too aggressive for the embryos, the embryo degeneration rates were high, and it was not as informative as NGS biopsy, not only because NGS is way more accurate, and so it gives us better information, but also because it’s based on the higher number of cells. Therefore, that has been completely abundant, so we only work with frozen cycles when doing Pre-implantation Genetic Testing.

I have had 8 donor egg transfers with 3 different donors. From these, two chemical pregnancies, the rest failed implantation. Before the age of 45, I had a natural pregnancy with a missed miscarriage. I am now 50, my partner is 37, we have had many tests, all normal, Karyotype is normal, no explained reason for failure, my partner also had FISH, DNA fragmentation, Meiosis tests – all normal. If you were to do one more cycle of donor egg IVF, would you recommend doing PGT-A in our case? Bearing in mind, we would only be able to do one or possibly two more transfers maximum due to age and finances. Is there any other test or HLA, other donor matching, screening you would recommend?

It’s a lot of embryo transfers, and so in Portugal, this wouldn’t be possible because we can only treat patients up to the age of 49 years and 364 days, the day you turn 50, you are no longer illegible to do a treatment. In other countries, this could still be possible. I don’t know anything about the quality of the embryos, but with 3 different egg donors, 8 embryo transfers, I guess it is very likely that at least some of these embryos were viable. Perhaps, you should focus on the window of implantation, on the endometrial factors rather than the quality of the embryos. I mean, you can do PGT-A because the problem can also come from the male partner, we can try to consider the possibility that these problems can also come from the male partner, and so in that sense doing PGT-A is acceptable, I would recommend it. However, I would think it seems more likely that the issue is on the uterine side than on the embryo side. Having so many failures, I would do PGT-A.

For a low-grade embryo, is there a chance for that embryo to be healthy?

There is because there are studies that have shown that the way we grade embryos is not as effective as we thought it is a few years ago. For example, there was this research paper from some Italian investigators, from Antonio Capaldo, where the embryos were tested for PGT-A, according to morphology, they were assessing the probability of the embryo being normal or abnormal according to its respective classification. There is not much difference, even a poor quality embryo has a 54% chance of being normal. This is incredible and shows how low is our capacity to identify just based on morphology along with the implantation potential of an embryo. These days morphology is becoming something of the past, we are more focused on morphokinetics parameters, from video timelines, artificial intelligence, it’s giving its first steps in understanding whether the embryos are viable or not based on factors that are invisible to the human eye, but that is possible to be detected by the computer. Even between day-5 and day-6, there are no significant differences. Between the different ways, we grade the embryos, there are also no differences. The take-home message is that a low-grade embryo is a classification in the lab, it is kind of the old way of looking into embryos. From that study with almost 1000 embryos, the chance for that embryo to be healthy is more or less the same as for a high rate embryo. What we have learned from the past, from our classification, is that from the moment we have a blastocyst, this is a good embryo, so forming a blastocyst is already a very important step, and then the quality of that blastocyst is more or less time-sensitive. There is variability between operators, two different people assessing the same embryo can have different opinions, and so I would say we prefer to have high-quality embryos, we always feel more comfortable with that, we’re working in this field for 20 years. We are very happy when we have these good quality embryos, but apparently, there is not much difference.

What are the complications, if any, of having an early miscarriage in a future pregnancy?

If you have to do a Dilation and curettage (D&C), it’s an aggression to the uterus, there could be infections, you could be triggering immune factors. The less we manipulate the uterus, the better. Sometimes having a miscarriage can be a problem if the miscarriage goes away spontaneously. Then in principle, it shouldn’t be an issue, but there are situations where we get remnants from the past pregnancy we have to do procedures to remove them, so if we can choose, it’s preferable not to have a miscarriage if that’s something we can avoid, we should do everything in our hands to avoid that.

Is Non-invasive PGT-A possible to do already? Or how soon before it is available e.g. in Europe, Spain?

We are about to start doing it, we are still validating it with Igenomix, the genetics lab with whom we work, it’s a process. Some places all over the world are validating this, it’s a new technique. We have to prove that we can have a good correlation between the results of the trophectoderm and the free DNA in the culture media, once we prove that and we need a certain number of cycles to prove that, we can start doing it. Yes, it is now available, we can do it at our clinic, we expect to be doing it in about a month or so, but there are clinics in Europe, including Spain, where that is already available. Not only in Spain, in other countries as well. I don’t have a list of places, but there are a lot of countries where that is already available.

Would PGT-A show any male factor issues in donor IVF if we have already done FISH, DNA fragmentation, Meiosis tests and they were all normal?

With PGT-A, we cannot know whether the problem comes from the male or the female, but we can tell if the problem is there or not. We will never know what was the cause, if there is any cause, but we can say whether that chromosomal constitution is normal or not. If the question is, if a man who has done FISH, DNA fragmentation, and other tests can have genetically abnormal embryos, then yes, it is possible. That is the issue with male fertility. We have millions of spermatozoa, and we are only testing a few ones in all of these tests. We can have percentages probabilities, and so on, but at the end of the day, what counts are what was the sperm that entered the egg, and that wasn’t tested because if we were to test it, we would have to destroy it and so we wouldn’t be able to use it. The issue is that these issues usually don’t affect 100% of the spermatozoa, and that’s where the problem is.

You’ve mentioned that having a miscarriage with D&C could trigger an immune response. I was diagnosed with hypothyroid after my missed miscarriage, I was treated for 6 months, then it was normal. Could this be an ongoing reason that impacts the following 8 failed IVF transfers? What tests/ treatment may be an option if this is the case?

Sometimes it’s problems with the thyroid that cause the miscarriages, not the other way around. It’s more likely that a thyroid imbalance can cause a miscarriage than the other things. At the same time, immune diseases can cause miscarriages, and we know for a fact that people that are carriers of immune diseases very often have more than one immune disease, and those diseases can increase the risk of miscarriage. On the other hand, they are invasive in exposing the uterus to other genes, cells like in egg donation cycles, and so on. We know that can trigger immune factors that can ultimately cause some other problems. Everything is true, so yes, doing multiple treatments can trigger immune responses that can lead to miscarriages. Performing intrauterine procedures can trigger immune responses that can lead to miscarriage, having immune hyperactivity can cause miscarriages that need to be treated. It’s kind of a vicious cycle that is difficult to abandon. There are many protocols, doctors can certainly help you in the process, but typically we treat it with steroids with heparin and aspirin in different regimes and protocols, and that’s what medicine has to offer. There is nothing else we can do.

If there is a good outcome with multiple embryos, would the clinic’s usual ‘graded’ quality be the best approach to selecting which embryos to transfer? The clinic has advised transferring 2 embryos to give a better chance of pregnancy. With or without PGT-A, is that a sensible thing to do? Does a double embryo transfer improve pregnancy chances?

I would prefer to do PGT-A instead of trusting the morphology. As I’ve explained before, morphology is becoming something of the past, it’s still the easiest to use the tool, at least we can try to use video time-lapse like the EmbryoScope or other morphokinetic classification systems, not only morphology. If the only thing we have is morphology, then we have to use morphology. However, if we can use other more informative and accurate methods, I would prefer to do it. Transferring 2 embryos at the same time, at our clinics, we always advise one regardless of the patient’s age or other things, we always say it’s preferable to transfer 1 because of the risk of multiple pregnancies. We wouldn’t agree to transfer 2. When we have patients that have done a lot of treatments and had always negative results or if the embryos are not that good, we might consider advising them to transfer 2. The probability of implementation in principle is an individual probability, so each embryo has its probability of implanting. In that sense, transferring 2 increases the chances of having a pregnancy on that particular embryo transfer. On the other hand, there are cases, rare situations, especially KIR/HLA C incompatibility cases, where transferring more than 1 embryo can trigger immune responses that can be deleterious and can harm the chances of pregnancy. Those are extremely rare situations. For the vast majority of cases transferring 2 embryos increases the chance of having a pregnancy in that embryo transfer, but after transferring all the embryos in multiple embryo transfers, the number of implanted embryos should be the same, and the risks are lower. Our advice would be to transfer just 1, and if possible, test it with PGT-A.

I am 38, the partner is 30 with high DNA fragmentation caused by varicocele which has been solved with embolization 6 months ago. We had 4 failed transfers and going through 5th cycle now. Should we do PGT-A, on average, we get 2 good embryos per cycle.

The answer is yes because you had 4 failed embryo transfers, this is a lot. We have 2 factors, the age because you’re 38, we’ve seen during my presentation that at this age, roughly 60% of the eggs have an abnormal constitution, so having made 4 embryo transfers, statistically speaking, we should have 1 viable embryo. If we have just a bit of bad luck, we might not have any, because these are very low numbers. PGT-A would give you a better notion of whether your embryos are viable or not. Having 2 good embryos per cycle probably would make the decision easier. The role of DNA fragmentation and varicocele is hard to tell, but in principle, this should solve the problem or at least improve the situation significantly. Normally, the issues caused by DNA fragmentation are not detected in the PGT-A tests, so having a high DNA fragmentation index is not an indication to do PGT-A, but I would suggest doing PGT-A because you had 4 failed embryo transfers, not because of the DNA fragmentation test from your partner.

Would KIR/HLA matching be recommended if doing a new donor egg IVF cycle after 8 failed previous transfers?

Normally having 8 failed previous transfers leaves us on the desperation level, so whatever tests we might do, we can try to do it. I don’t think it’s very likely, but still, that can happen because you’ve tried with 3 different donors, you would be extremely unlucky to have all 3 donors incompatible with you and being KIR AA with donors, your husband being C2 and the donors all of them having the C2 gene. We all know that after an initial situation where that hyperimmune response is triggered, it could be difficult to lose that adverse environment inside the uterus. At this point, having 8 embryo transfers, I think it’s worth taking a look at it but not losing too much time. You’re already 50, and so you shouldn’t waste a lot of time with things that are not very likely to give any result, you can also decide just to use a prophylactic protocol to treat you as if you were a carrier of an HLA incompatibility and so that would also be an option. That’s something for you to discuss with your doctors, we can’t help without having more details.

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Authors

Vladimiro Silva, PharmD

Vladimiro Silva, PharmD, embryologist, CEO, founder and IVF Lab Director at Ferticentro and Procriar, two of the leading IVF centres in Portugal. Doctor of Pharmacy, Faculty of Pharmacy, University of Coimbra. MSc in Health Economics, Faculty of Economy, University of Coimbra. Post-graduated in Health Services Management, Faculty of Economy, University of Porto. Post-graduated in Clinical Analysis, Faculty of Pharmacy, University of Porto. Author of hundreds of lectures, oral communications, posters and scientific articles in Portugal and abroad. Vladimiro Silva speaks: English, French, Spanish, Italian and Portuguese.

Event Moderator

Caroline Kulczycka

Caroline Kulczycka is managing MyIVFAnswers.com and has been hosting IVFWEBINARS dedicated to patients struggling with infertility since 2020. She's highly motivated and believes that educating patients so that they can make informed decisions is essential in their IVF journey. In the past, she has been working as an International Patient Coordinator, where she was helping and directing patients on their right path. She also worked in the tourism industry, and dealt with international customers on a daily basis, including working abroad. In her free time, you’ll find her travelling, biking, learning new things, or spending time outdoors.

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