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.
IVF & genetic diseases – types of tests
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:
- avoid the chance of having a child with an inherited genetic disorder by analysing embryos before transfer and identifying those that do not carry the altered disease-causing gene
- it is intended for patients who are known to carry serious genetic diseases (either autosomal dominant (means that one gene is enough to cause the disease) or recessive (means we can be a carrier of that disease and not have the disease
- custom-designed test for every patient
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.
- PGT-A is a genetic test performed on embryos to screen for numerical chromosomal abnormalities (aneuploidies – embryos with extra or missing chromosomes)
- embryos with extra or missing chromosomes often fail to implant and lead to miscarriage or, in some cases, they are compatible with life and can lead to a birth of a child with a genetic condition
- embryos found to be chromosomally normal are referred to as euploid as opposed to aneuploid and are most likely to lead to a successful pregnancy
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.
- chromosomal abnormalities are detected before the embryos are transferred to allow patients to make informed decisions about their treatment
- PGT-A doesn’t make embryos better, however, it gives us information, and it gives us the capacity to select the best embryo
- PGT-A can reduce the number of cycles needed to obtain a pregnancy
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.
Genetic Carrier Screening
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.
HLA compatible embryos
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.