Preimplantation Genetic Testing (PGT) is used in IVF to check the chromosomes or specific genes of a developing embryo. All cells in our body have 46 chromosomes: two copies of 23 chromosomes—one set from the egg and one from the sperm. (With the exception of the “sex cells” which have 23 chromosomes from the egg and 23 from the sperm.). Our chromosomes contain all the DNA that we need for life. But embryos with the wrong number of chromosomes are quite common, and increasingly so as females age.
What causes issues (aneuploidies) with chromosomes?
We are born with all the eggs we’re ever going to have and, over time, they’re exposed to all sorts of damaging (but mostly unavoidable) influences: fevers, infections, stress, toxins and chemicals. Human cells, including eggs, are fragile, and this exposure can lead to mistakes in the DNA of eggs, called chromosomal abnormalities. When a person with eggs is under 35 years of age, less than 30 percent of their eggs are abnormal. After age 35, this number starts to climb and once over 40 years old, over 70 percent of eggs may be abnormal. About 90 percent of chromosomal abnormalities in human embryos come from eggs.
It's not just eggs that can have DNA abnormalities. Sperm can carry aneuploidies too—but these are less common. One explanation is that because new sperm are continuously produced in the testes (unlike eggs which don’t regenerate, so their quality and quantity decline over time), they are exposed to less DNA damage. An embryo that develops today is a product of new sperm (at most, three months old) and an older egg (which has existed since birth).
What happens to embryos with chromosomal abnormalities?
When an egg or sperm with chromosomal abnormalities come together inside a human body in spontaneous conception and the egg is fertilized, most of the time, we don’t even know about it. If the egg has several chromosomal abnormalities, then it might not even fertilize or develop into a blastocyst, resulting in menstruation and therefore no outward indication that anything was amiss (you’re just not pregnant that cycle). Some abnormalities may result in an embryo that does implant, and the person becomes pregnant, but will inevitably miscarry. We know that chromosomal abnormalities are the most common cause of miscarriage and miscarriage tissue testing can help confirm this in individual cases.
Generally (but not always), embryos that are missing chromosomes will likely not reach the implantation phase (resulting in a negative pregnancy test), and embryos with additional chromosomes will reach a pregnancy but lead to a miscarriage (which might present as a chemical pregnancy, or first trimester loss). There are only three chromosomal abnormalities that can reach a live birth (Trisomy 13, Trisomy 18 and Trisomy 21, a.k.a., Down Syndrome).
Things work differently in IVF
Eggs are fertilized by sperm in vitro (outside the body) and grow in the lab for several days until they are transferred into a uterus.
Embryos that are chromosomally normal (euploid) look no different than embryos that are abnormal (aneuploid) under a microscope. Embryologists cannot use imaging techniques to select embryos that are normal and have the best chance of implanting and resulting in a healthy baby. This is where PGT is especially helpful.
What is the difference between PGT testing and embryo grading?
Embryo grading is a visual assessment prior to transfer to determine which embryo might have the most success of developing into a viable pregnancy. (Read more on embryo grading, here.) It provides a different set of data from PGT testing (and because it’s a visual assessment, it can be quite subjective). PGT testing is a chromosomal evaluation based on embryo biopsy (making it more invasive, but also potentially providing more concrete answers). Having a good or bad result on one test, does not necessarily mean you will have the same result on the other. For example, you can have an embryo that is graded highly (i.e. it looks good), but it also has Trisomy 21—which would be undetectable with just a visual embryo grading evaluation. When undergoing IVF all embryos are graded as part of the process, but PGT testing is an optional test to provide more information prior to transfer.
What are the different types of PGT testing?
There are three types of PGT: PGT-A, PGT-SR and PGT-M. Each is used to detect different potential abnormalities, but depending on your own DNA, you likely will not need (or qualify for) all three.
What is PGT-A?
Preimplantation Genetic Testing for Aneuploidy (PGT-A), tests for Aneuploid embryos. This is by far the most common PGT test that is routinely done in IVF labs. If an embryo has the correct number of chromosomes, we call it Euploid, but if the embryo has extra or missing chromosomes, we call it Aneuploid. PGT-A tests preimplantation embryos to check if they have the correct number of chromosomes and screens for large chromosomal imbalances.
PGT-A can be used by any IVF patient who wants to be sure that they are transferring a euploid embryo. It is commonly recommended:
- When the egg provider is over 35
- If there is low quality or quantity of sperm
- When there is previous IVF failure
- When there are previous miscarriages
It is important to remember that PGT-A is a screening test and not a treatment—it doesn’t create a euploid embryo, but simply identifies them to allow only chromosomally normal embryos to be transferred. The decision to add PGT-A testing during your IVF cycle should be made between your clinician and yourself.
What is PGT-SR?
Preimplantation Genetic Testing for Structural Rearrangements (PGT-SR) is a type of PGT-A that is used specifically for patients who have a chromosomal rearrangement themselves (translocation). This means that the egg or sperm provider (who is otherwise healthy because they have the right amount of DNA) has a difference in the arrangement of their chromosomes. (You would only know this about yourself if you underwent karyotype (chromosome) testing, but this is not routinely done, and usually only in the context of recurrent pregnancy loss.) If you are a known carrier of a chromosomal rearrangement, PGT-SR is recommended.
What is PGT-M?
Preimplantation Genetic Testing for Monogenic Conditions (PGT-M) is a test for patients who are at risk of having a child with a single-gene disease, such as cystic fibrosis or spinal muscular atrophy. If someone is a carrier of a dominant gene, there is a 50 percent chance that any pregnancy will have it as well. Generally, anyone with a dominant gene is aware of it as they would have a diagnosis. If someone is a carrier of a recessive gene, only if their partner is also a carrier is there a 25 percent chance of a pregnancy having a double mutation and having it as well. Nowadays it’s quite easy to screen yourself to identify if you are a carrier of a recessive gene, in which case it’s important to make sure your complement (sperm or egg) is not also a carrier. If they are, then PGT-M would be a good test to include in your protocol so that no embryos with a double mutation get transferred.
When do you get a PGT test?
If you are thinking about using PGT, it is a great idea to talk to a genetic counselor first. This is an excellent way to learn more about PGT-A (including risks, limitations and benefits) and specifically, the types of results you can expect. In the IVF process, PGT tests are done after fertilization in the blastocyst stage (typically day five or day six).
Igenomix offers free pre-PGT-A webinars for patients. If you believe PGT-SR or PGT-M are indicated, please contact an Igenomix genetic counselor at firstname.lastname@example.org or your own healthcare provider for additional information.
How is a PGT test done and how long does it take?
After fertilization your embryos will grow in the IVF lab to the blastocyst stage. The embryologist will then take a small biopsy from the outer layer of the blastocyst (called trophoectoderm; the part that will be become the placenta), and then freezes the biopsy and the embryo. The embryo is kept safe at the IVF clinic and the biopsy is sent to a genetic testing lab.
Once the biopsies are received at the genetic testing lab, it takes about one to two weeks for the results to be sent back to the IVF clinic (for PGT-M, the process is more involved before the biopsy, so can take longer overall, although the timeline for receiving test results remains the same).
What are the possible results from a PGT test?
A euploid result indicates that no chromosomal copy number abnormalities were detected in the embryo biopsy. The embryo is expected to have the typical number of 46 chromosomes necessary for normal growth and development. Euploid embryos have the highest chances of reproductive success and are recommended for transfer when doing IVF.
Aneuploid or abnormal results indicate that a chromosomal copy number change was detected in the embryo biopsy. Aneuploidy is reported when there is a trisomy (three copies) or monosomy (a single copy) of a chromosome or chromosome segment. The reproductive potential of uniformly aneuploid embryos is very low so, currently, they are not recommended for transfer when doing IVF.
This result indicates an imbalance of a chromosome segment (a piece of the chromosome, rather than the entire chromosome) was detected in the embryo biopsy. Embryos with this result can be considered for transfer, though the recommendation is to do further genetic counselling to determine if this is right for you.
An embryo biopsy involves sampling a few cells from the trophoectoderm of the blastocyst embryo. If all the cells have the same result, then they are labelled as abnormal (aneuploid) or normal (euploid). If most of the cells are abnormal (but some are normal) it would be labelled as high-level mosaicism, and if most of the cells are normal (but some are abnormal) it would be labelled as low-level mosaicism.
The level of mosaicism may vary in each biopsy and cannot predict the true level of mosaicism in the entire embryo. Embryos reported as low mosaic have been shown to have significant reproductive potential; some studies suggesting almost as high as euploid embryos. Embryos reported as high mosaic may have some reproductive potential but with lower implantation rates and higher risk of miscarriage in comparison with euploid and low mosaic embryos. Further genetic counseling is strongly recommended for mosaic results.
If a result could not be obtained for the biopsy, then essentially it is unclear what the underlying chromosomes of the embryo truly are. A no-result outcome does not necessarily mean abnormal and outcome rates vary between genetic testing labs and IVF clinics—at Igenomix, the average no-result rate is two percent, so this not a common result. You will need to discuss this situation with your doctor which might include transferring the embryo (but selecting the PGT-A normal embryos first), not transferring it, or thawing the embryo for a repeat biopsy.
Aneuploid rates tend to increase with female age, but the other results (mosaicism, segmental) are age independent.
It’s recommended you discuss with your clinicians, prior to undergoing PGT-A results, how the results are handled in your clinic as it can vary widely. For example, some clinics will only transfer euploid embryos, while others may transfer no results, low-level mosaicism and even high-mosaicism embryos.
What happens after I have my PGT results?
PGT results will be used by your IVF clinic to help determine which embryos have the best chance of a healthy pregnancy. If you would like genetic counseling to help understand your results, the genetic testing provider should be able to assist you with this. Igenomix offers complimentary results counseling for all PGT patients.