During this webinar, Vladimiro Silva, PharmD, Embryologist, CEO, Founder & IVF Lab Director at Ferticentro, Portugal, discussed one of the most common questions that many patients ask before starting IVF treatment: What to do if you are afraid of having a baby with genetic diseases after IVF?
Doctor Silva started by explaining that the situation of having a child with genetic diseases is one of everybody’s worst fear, especially if you’re going through IVF. You’re already going through a very stressful treatment and process, and you’re wondering what if, on top of that, you’ll have a baby affected by the genetic disease. Therefore, Dr Silva explained how IVF is used to prevent genetic diseases, what tools are available in the market and what can be done about it.
IVF is one of the most used strategies to avoid genetic diseases. There are multiple strategies available and in fact. IVF can be used for many purposes, the first one is the prevention of the transmission of known genetic diseases like monogenic diseases, for example, Huntington’s disease, cystic fibrosis, and spinal muscular atrophy, there are hundreds of thousands of genetic diseases that can be transmitted if you are a carrier. IVF is a way of preventing that from happening, IVF is also used to screen for genetic risks. The most known are the age-related risks because above the age of 35, women tend to produce abnormal eggs. The number of abnormal eggs increases with age, the most known genetic condition that increases especially after the age of 35 is trisomy 21 called Down syndrome, but many other diseases can be identified via IVF. The fact that there are chromosomal imbalances and problems at that level could also lead to treatment failure.
In the third box, we can also name the screening for rare diseases, this is a completely different set of tests for genetic diseases. The genetic carrier tests are important between both members of a couple but they can also be very important when selecting an egg or a sperm donor or in a double donation treatment. There are always pros and cons to this option. IVF can also be used to treat severe diseases, we can even find HLA-compatible embryos that will allow us to treat babies for whom there is no other alternative.
When we talk about prevention, we are talking about the PGT-M (Preimplantation Genetic Testing for monogenic/single gene disorders), and PGT-SR (Preimplantation Genetic Testing for Structural Chromosomal Rearrangements). The screening for age-related diseases in people, for example, who have normal karyotypes and are not affected by any known disease is called PGT-A (Pre-implantation Genetic Testing for Aneuploidies). Aneuploidies are numerical chromosomal abnormalities.
We have the Genetic Carrier Screening tests, and nowadays, there are many packs available from many companies in the market. Some of them are screening for 300 diseases, other ones for 600 diseases or 200 diseases. When we’re talking about HLA compatibility, for example, a baby can be a bone marrow donor for his sibling, brother, or sister who has a very serious disease.
PGT-M stands for Pre-implantation Genetic Testing for Monogenic Diseases. Monogenic disease means a disease that only impacts one gene, which is a very small portion of our DNA, it is extremely tiny, but problems at its level can cause major health issues and very serious diseases. PGT-M is used to:
The difference between an autosomal dominant and a recessive disorder is that if the disease is autosomal dominant, one copy of the gene is enough for us to have the disease, if the disease is recessive, we can have one copy of the disease and still be completely healthy, but if we have a child and someone is carrying that same genetic disease then there is a 25% chance of having an affected child because both partners can transmit the affected gene. These are very often rather complex situations like Huntington’s disease, Neurofibromatosis, Cystic Fibrosis, etc.
It all starts with doing genetic tests, identifying the issue knowing exactly what to look for, then we have to do the PGT-M to prepare for the procedure, and then we create the embryos, we take them until day-5 or day- 6, sometimes even day-7 and then we make a little hole in the embryo, we pick up some cells, and we analyse those cells genetically. We only transfer back embryos that are considered to be genetically normal.
This used to be called Pre-implementation Genetic Screening (PGS) because we are screening for genetic risks. Normally, these are age-related. The difference between the diagnosis and the screening is that in screening you don’t know if the problem is there, but you’re trying to see if that explains any possible previous failure or if you want to prevent the failure because that patient is at risk to have a problem. The most classical indication for this kind of treatment is advanced maternal age.
Unfortunately, having a euploid embryo is not the synonym for having a pregnancy even when we transfer euploid embryos, we don’t have a 100% guarantee of pregnancy probability. PGT-A is most often done with NGS (Next Generation Sequencing), which is the most modern technique, and nowadays, we analyse all 24 chromosomes, and this technique allows us to quantify each one of them and see if they have the quantity of each chromosome is normal or if there is an extra or a missing chromosome.
Nowadays, we have 2 types of PGT-A, invasive PGT-A where we do the whole in the embryo and non-invasive PGT-A (niPGT). In niPGT instead of doing a hole in the embryo, we are analysing the culture media where embryos are cultured because there is free DNA available in the culture media. By analysing that DNA, there is a correspondence of more than 80%, in some cases, more than 90% of the genetic characteristics of the embryo. Thanks to this method, we don’t need to touch the embryo, and we still can say whether that embryo is viable or not. It’s still experimental, but it is certainly the future and looks like a very promising technique.
One study from the Igenomix lab showed the incidence of aneuploid and euploid blastocysts according to maternal age. As it was shown, we start with 36.9% when we are at the top of our fertility and then with the progression of maternal age, we see that percentage is increasing, and at the age of 43, 76% of the embryos are carrying a genetic abnormality, it’s not 100%, so this kind of gives hope for many patients however we have to think that to have a viable embryo you will need 7 blastocysts to have 1 that is viable. That’s what this 76% means, having 7 blastocysts at the age of 43 or 44 is a very huge number. PGT-A is an important tool in modern IVF clinics, and it is strongly recommended, especially after 39.
PGT-SR stands for Preimplantation Genetic Testing for Chromosomal Structural Rearrangements. These are karyotype abnormalities like balanced translocations, inversions, and chromosomal rearrangements that can be inherited or may occur spontaneously (de novo). It is estimated that 1 in every 500 people carry a balanced reciprocal translocation. As they are balanced, people don’t have any health conditions, they don’t have any physical characteristics that make this distinction. Most of these people are unaware of their balance translocation carrier status, and they live a normal healthy life, they only find out that they are carriers of these abnormalities when they are trying to have a baby, and they have repeated miscarriages, or they have faced infertility, and when we ask them to do a karyotype, we detect it.
Such patients are at a very high risk to produce embryos with unbalanced chromosomal rearrangements, this usually does not lead to a successful pregnancy, normally it’s a miscarriage or a negative pregnancy result, but it is not impossible having a child with a genetic abnormality. Therefore, using PGT-SR will naturally increase the chances of having a successful pregnancy, and we can make sure that only the embryos with the correct balance and the embryos that have a normal karyotype are transferred, and naturally, this leads to a higher pregnancy rate.
Humans are carrying multiple genetic diseases, there is probably not a single human being who is not a carrier of a genetic disease. The risk only exists if we have a baby with a person who carries the same disease when we are talking about recessive diseases, not dominant diseases. Then the big question is: is it worth knowing the truth? That’s a debate, it’s something that we do a lot, but patients must take very well-informed decisions about this issue.
If we look at a graph from Igenomixs, we can see that if the father and the mother is a carriers of a certain disease, 25% of their children will be healthy because neither of them will be passing the affected gene. 50% of their children will be receiving one copy of the normal gene and one copy of the abnormal gene, it could be the mothers or the fathers, but 25% of them, this is theoretical, will receive the affected genes both from their father and their mother. These are risks we want to avoid.
We have 2 types of screening tests, 1 that screens for up to 570 diseases and another one that screens for more than 2200 diseases. It is very important for people to understand, that 55% of human beings are a carrier for at least 1 mutation from the 570, and 67% are carriers for more than 2 200. As Dr Silva explained, At Ferticentro, they’ve never found a person that is not a carrier of any disease after doing the Genetic Screening Test. The mean number of mutations per individual is 2.7 when we test for 2 200 diseases and 1.7 when we test for 570 diseases. These are rare diseases, some of them are rarer than others, and these are, for example, Cystic Fibrosis, Spinal Muscular Atrophy, sickle cell anaemia, Fragile X syndrome, Thalassemia, and the proportion of carriers is quite high. If you are a carrier of cystic fibrosis, you have a 25% chance of having a baby with a person who is also a carrier, and if that happens, you will have a 25% chance of having a baby with cystic fibrosis.
In the case of egg donation, we start to test the husband, we will see if the husband is a carrier of 3 or 4 diseases, for instance, and then we will test the donor, we already have the DNA from the donor, and we will test her for those same diseases to see if she’s a carrier of the same diseases as the husband or not. The problem is whether this is Pandora’s box or not because when we decide on doing this test, we will be receiving important information that we are healthy carriers for 3, 4 or 5 diseases, we need to test the donor for these diseases because we know that the risk exists. It’s very relevant information that you will also have to give to your children because if you are a carrier of some disease, there is a 50% chance that your son is also a carrier, that’s relevant information for his or her reproductive future.
This method is only used in very dramatic situations where the only way to heal a child with a very severe disease is by finding a compatible stem cell donor, and many often the only solution is to have a genetically compatible sibling. This is a very complex situation from an ethical point of view, these situations require approval by The National IVF authorities, as Dr Silva mentioned, he had 1 of these cases at Ferticentro, luckily it went well but this is extremely difficult to make, we depend on our luck a lot and we might need a lot of embryos to be able to find 1 or 2 that are compatible because at the end of the day what we all want is a healthy child.
Related reading:
My advice here is to take the embryos to day-5 because day-3 is a very informative day, we know a lot about the embryos already, it’s a very relevant day for us to understand whether these embryos are viable or not, but at the age of 41, it is really important to take them to day-5.
I would advise doing PGT-A in these circumstances because by doing PGT-A, we understand whether these embryos are viable or not.
I will use the statistics that I was pointing out in my presentation, we know that at 41, 73% of the embryos are not going to be viable. This is what nature gives us, it’s 73% of the blastocysts, but not all day-3 embryos reach the blastocyst stage. First, we need to see how many of these will reach the blastocyst stage, and then we know that 73% of them, roughly speaking 1 in every 7 or 6 are not viable of those blastocysts. If you want to be statistically sure, you’d need about 7 blastocysts, which is a lot. Do a few embryo banking cycles, take your embryos to day-5, do the PGT-A, then decide accordingly.
It’s kind of the same sometimes. It’s just the name of the technique. If you have a balanced translocation, this means that we know what we’re looking for, and then we should use targeted probes because when we are doing a PGT-A, we are screening for the whole chromosomes. It’s the same way when we are doing PGT-SR, we are targeting the chromosomes that are potentially affected by the translocation. I sincerely doubt that they didn’t look more carefully at the affected chromosomes because that wouldn’t happen, so answering the question, you have a very clear indication for PGT-SR with probes and specific for the chromosomes affected by the translocation.
First, 5AA is a morphological classification, it had its importance in the past, that was all we had, and so we talked a lot about morphology. These days, we’re not caring so much about morphology as we did before, we’re more focused on video morpho kinetics, meaning video-time-lapse imaging of the embryos. We even have artificial intelligence algorithms that help us with that.
The most important aspect is the fact that both embryos are euploid. However, we know that as age advances, the other parts of the embryo become more fragile. There are studies about mitochondrial DNA, and it was suggested that mitochondria are a part of the cell that produces energy. There are very interesting studies where scientists were replacing the mitochondria from a 40-year-old woman with the mitochondria of an egg donor, and then those embryos gained a lot of capacity, they obtained a lot of euploid embryos. That is because this is not all about the DNA in the nucleus, this is also about the strength of the egg, the strength of the embryo. I would say the embryo from the 30-year-old has a significantly better prognosis than the one from the 40-year-old.
The fact that they are both euploid makes them good prognosis embryos. In the study that I showed, they didn’t even find statistically significant differences between the probability of implantation from both of them.
NGS is more sensitive and more accurate. In the past, we were using a technique called FISH, then it was a CTTA Microarray, and now it’s NGS, which is the most powerful tool that science has at this very moment. I don’t think any of the main groups all over the world use other techniques than NGS.
Apart from my balanced translocation (discovered on karyotype), should we do Carrier Genetic Test tests in case there are other genetic issues? I had 11 aneuploid and 1 high mosaic, and 0 euploid embryos.
I don’t think the CGT makes sense. Those are completely unrelated things. The CGT is a test for people that are carriers for recessive genetic diseases, this is not non-related with a balanced translocation. You can do CGT to identify that, but that has nothing to do with your other problem. You’re having 11 aneuploids, 1 high mosaic, 0 euploid embryos. Possibly the high mosaic would be the solution, but it’s a very complex issue. There are sometimes multiple cell lines in the embryos, and we risk selecting the wrong one, and so on.
The mosaicism sometimes can deceive us while analysing the embryo, but we also know that typically at least until a certain percentage of mosaicism, meaning embryos with more than one cell line, we can identify the normal cell line. It can overlap the abnormal cell line, and so these low mosaic embryos could implant and become normal babies. Even last week, I received the result of an amniocentesis from one of those embryos we were very afraid of, but luckily everything is fine, and we’re waiting for a perfect baby girl. It was a mosaic embryo with 30 or 40% of mosaicism.
The CGT test has nothing to do with balanced translocation, those are completely different issues, and you can test for that. I would suggest focusing on the main issue, which is the balanced translocation. Possibly you could think about that donation, I mean egg donation is certainly an alternative that I would consider very seriously. I wouldn’t be doing CGT because you already have something to worry about, and you don’t need to out that you’re a carrier for 3 or 4 diseases and your partner from another 2 or 3, so that would be an unnecessary additional complication.
It will depend on your age and other factors. If you are below 30, it will be around 6-7%. If you are over 40, it could be more about 18-19%. These miscarriages are not of genetic cause. These miscarriages are caused by other factors, other than the genetics of the embryo. When a female age advances, several factors increase the probability of having a problem like hypertension, pre-eclampsia, gestational diabetes. There are lots of issues associated with a pregnancy at a later age, it is independent of the genetic quality of the embryo and those we cannot divide.
We don’t recommend this for donor embryos because, as I showed, the probability of having a chromosomally normal baby in the egg donor is very high. In principle, we have seen that the probability of pregnancy is not that different with and without PGT-A because a lot of the embryos are normal, so I wouldn’t recommend it for egg donation cycles.
On the other hand, in this particular case, you had 3 different egg donors, 2 different clinics, 8 egg donation cycles, it’s a lot. I don’t think PGT-A would have made any difference because between all of this, you certainly had viable embryos. Either the problem comes from your husband because we’re talking a lot about the egg quality, but sperm quality is also a very important factor. It could have something to do with the implantation conditions. There are multiple tests that we can do to try to identify the possible recurrent implantation failure causes.
It’s too much to be just a lack of luck, there should be something that justifies these failures, you need to study it very carefully because something is keeping you from getting pregnant, and your doctors still haven’t found the reason, which is something that also happens to us. This is something we cannot fully control.
It’s very unlikely. If you had a normal antiphospholipid test, it’s very unlikely. I’m not a specialist in this field, but these rare conditions can happen, I would say that other factors are far more likely to justify this than these extremely unusual explanations. I’m not saying that it is impossible because nobody can say that, but it does seem unlikely.
This is an experimental scoring system, it’s not something that is used as a daily routine. One of the labs that we work with is Igenomix, they use that. It gives us an indication of the embryo capacity to divide and implant itself. It’s sort of measures the energy of the embryos because there is a difference between an old and young embryo. The activity of the mitochondria can play a role that is proven and consensual. The only thing that’s not proven and consensual is whether the MitoScore can reflect that point.
We can use that indicator, we should prioritize the embryos with the highest ranking, but we cannot put too much hope on this indicator because we don’t know its real value.
As far as I know, no there is no specific test for PGT-A in autism or the spectrum of autism diseases, unfortunately, this is not something that we can control.
Perhaps, we should pay a little attention to the endometrium because you had 2 cycles with your own eggs. Now you’re 41, so you probably started at a younger age, and you started 10 years ago at 31, so you were still very young, in principle it was a good prognosis factor, so these two initial cycles, assuming that they were done before the age of 35, they were already like egg donation cycles.
I would say that between your own cycles, which were like egg donation cycles, between the natural attempts at the very young age, 2 cycles with egg donors, I wouldn’t start a new cycle without assessing the endometrium.
Some tests are available that can check the implantation window, the microbiome, the screening for infectious diseases in the endometrium, uterine malformations and abnormalities, there could be several factors and also systemic issues like immune diseases, haematological disorders, those are rarer. There is some debate, for example, whether thrombophilia, one of the most classical haematological disorders, should even be part of the evaluation, but without further clarification, I don’t think it makes sense to move on with another attempt, at least without making it clear this could be just bad luck.
There is a tendency nowadays, especially in the United States, where patients decide to transfer aneuploid embryos, it’s a long shot, they do that because they hope that somewhere in the middle of the embryo there could be a normal cell line that takes over the embryo and overlaps the abnormal cell line. This is something that can happen in a very small percentage of embryos, and I think it is something that you can do, but you should do it in a very informed way.
There are even articles and strategies to prioritize which aneuploid embryos should be transferred first. Some embryos are not compatible with life, so if you transfer those, either you have a negative result, or you have a pregnancy, and then you should do a prenatal diagnosis like chorial biopsy or amniocentesis. Then some embryos are aneuploid, but they are compatible with life and could lead to the birth of a handicapped child, for example, trisomy 21, 18, 13, so it’s very important to be careful with this, make informed decisions, have good genetic counselling before doing it and then select which embryos can be transferred or not because maybe they are all compatible with life.
It’s a question of making that decision knowing that chances are little. They are not just theoretical because in scientific literature, we have a few cases where that was done, and normal babies have been born, but the likelihood of that happening is extremely low. The reason there are articles about that is that those are situations are so rare.
Yes, NGS is much more powerful than Array CGH, I don’t think Array CGH is still used these days, it was a technique that has been replaced.
The wrong diagnosis of aneuploidy can happen. There is no such thing as a perfect technique to identify viable embryos. We all know that even NGS has around 98% of the capacity to identify its results. If we have 2 cell lines and we are unlucky enough and only collect cells from the bad cell line, yes, we can lose an embryo to a wrong diagnosis of aneuploidy. This is not very likely to happen, but theoretically speaking, it can happen.
Those would be my first line suggestions. Then we should look for immune factors, which is a very complex topic since many tests can be done. We would also need to look into the uterus because sometimes there are fibroids, malformations, adenomyosis, there are local uterine factors that can affect that and then check for the less common things like those immune and haematological factors. It also depends on when did the miscarriage happen, it could be an infection, I mean many things can cause that.
A miscarriage at week 7 is early, and it should be more associated with immune factors or haematological disorders, but this is difficult. We would have to take a deep look at it, and because I believe that your doctors have certainly told you the same, we don’t know what to think in these situations.
The HCG was a bit low, but we have babies born from values lower than this, so sometimes it starts slow, but then it starts rising. One of our patients have a baby from an HCG of 16, I would prefer to see 500 or 600, but 168, we have hundreds of babies born that started with this level of beta-HCG, but we don’t know.
The answer is no. They give us very important and very relevant information. We were the pioneers of the Embryoscope in Portugal, we do 100% of our treatments in the Embryoscope at both clinics, and so we are very fierce defenders of this technology. However, we have to know what we can do with it, and what we can’t do. We’ve been using it for almost 9 years now, so we have a lot of experience with this. I believe that with artificial intelligence involved in the process, it is a very essential tool, it will help us a lot, it will optimize the culture conditions for the embryos, and so it’s a wonderful breakthrough. However, testing the embryos will always be more accurate, especially if non-invasive PGT-A develops, as we all expect it to, and I think we will end up with a very powerful method to identify viable embryos without doing biopsies on the embryos, which is significant.
These are parts of the blastocyst, the trophectoderm, it’s where we are doing the biopsies nowadays, and the inner cell mass, which is another part of the embryo. It is believed that the trophectoderm is more representative of the real genetic potential of the embryo, and the level of mosaicism in the inner cellular mass is higher. These are all theories. Nowadays, we’re all focusing on the trophectoderm because there is more variability in the inner cell mass. It is not a question of concordance, we’ve never done such tests. There are studies on that, but in principle, it’s about what part of the blastocyst is more representative of the real genetic potential of that embryo, and that part is the trophectoderm.
Even now, when we are talking about non-invasive PGT-A we are comparing the culture media with the trophectoderm biopsy because we know that’s the part that represents the embryo better.
I would say, and this would be kind of a bold statement, that if the concordance between both of these parts of the blastocyst is very high, this means that there is also mosaicism in the trophectoderm, which is not good. In the past, we were doing biopsies of the inner cell mass, but these days, we are focusing on the trophectoderm and there is a reason for it. I’m not the author nor a specialist on that, but after a lot of studies, we have found that the trophectoderm is more representative and related to the information that we need.
