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What to do if you are afraid of having a baby with genetic diseases after IVF?

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

Genetics PGS / PGT-A

From this video you will find out:
  • IVF & genetic diseases – what can be done to prevent them?
  • What is PGT-M, and when is it recommended?
  • What types of chromosome abnormalities does PGT-A screen for?
  • Why is PGT-A so useful?
  • How does PGT-SR work, and how can it increase the chances of a successful pregnancy?
  • Why is Genetic Carrier Screening useful?
  • What are the most common monogenic disorders detected with Carrier Genetic Test (CGT)?
  • How does Preimplantation Genetic Diagnosis (PGT) and HLA Matching work?

Does IVF cause genetic disorders?

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?

Does IVF cause genetic disorders? - Questions and Answers

I’m 41, and I’m doing embryo banking. I have 4 day-3 of frozen embryos, and I had an egg collection yesterday. I am waiting to see how the two embryos we got are evolving. They don’t do genetic testing at that clinic and recommend freezing on day-3 if you only have a few embryos. How many more embryos would you recommend adding up before transfer? We were thinking to do a couple of more cycles, but not sure if it’s enough. I have a very low AMH, and I get 2, 3 at one time.

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.

I have a balanced translocation, but my clinic only did PGT-A, not PGT-SR, what is the reason?

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.

Is there a difference in embryo quality if both embryos are euploid grade 5 AA, but 1 is from a 30-year-old and 1 is from a 40-year-old?

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.

What’s the difference between NGS and other PGT-A options? Is it about specific chromosome abnormalities that NGS checks for, and not PGT-A, or something else? Those issues are not detected by regular PGT-A? How common are those?

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.

How common is it to have a miscarriage with an NGS tested good quality embryo?

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.

I am 50, my husband is 37, we have done 8 donor egg transfers with grade A blastocysts from 3 different donors at 2 different clinics. We have had every test possible on both sides, all normal, with no explanation of failure. I had a natural pregnancy at 45, but it was a missed miscarriage. We never had done PGT-A, would you recommend this for donor embryos or any other tests?

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.

Could the cause be hidden antiphospholipid syndrome?

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.

What is MitoScore, is it related to mitochondria of the day-5 embryo?

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.

Are Autism Spectrum Disorders (ASDs), Asperger’s syndrome detectable in any screenings?

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.

I’m 41, and my husband is 47. We started this journey 10 years ago, we had 1 cycle with my own eggs (no luck), 2 cycles with frozen egg donors (no luck), 2 cycles with embryo donors (no success). What would you advise in our situation?

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.

Have you ever heard about some couples transferring aneuploidies? I’ve read an article about it.

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.

Is there a risk of losing viable embryos due to a wrong diagnosis of aneuploidy? Is there a difference between NGS and Array CGH

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.

I had a miscarriage at week 7 with a euploid NGS tested embryo. Are there any tests I should do before the next cycle? ERA, EMMA, ALICE are done? HCG was 168 on day 12, maybe it was a bit low from the start?

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.

Do you think that time-lapse incubators would replace embryo testing in the future as a non-invasive technique?

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.

What is the concordance between trophectoderm and ICM in embryo tests?

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.

Vladimiro Silva, PharmD

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.
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Caroline Kulczycka

Caroline Kulczycka

Caroline Kulczycka is managing 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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