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.
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.
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.
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.