PGT-A: Does testing a few cells tell us what is going on for the whole embryo?

Preimplantation genetic testing for aneuploidy is a type of genetic test for embryos. It is used as a guide in order to determine which embryo to transfer first, if someone has more than one available after their in vitro fertilization process. It is not considered a diagnostic test, and there are limitations to what it can tell us. One limitation is that the test is performed on cells of the embryo that will become the future placenta but not the future baby. Often the genetics of the placenta and baby are going to be the same, but there are times where that is not the case. It is difficult to predict when those times are occurring. In this post, we will go into more detail about the test and the general overview of the types of results that are possible.

How is Preimplantation Genetic Testing Performed?

Preimplantation genetic testing is performed on embryos created during an in-vitro fertilization (IVF) cycle. An embryo is created after an egg is fertilized by a sperm (step 1. in the picture to the right). An embryo will go from having 2 cells, to 4 cells, to 8 cells, until about 200 cells by day 5 or 6 of development. Once there are about 200 cells, a few are removed from the embryo and sent to a genetic testing laboratory to be tested for chromosomal differences. The result is then used to predict what is going on for the rest of the embryo, as there is no way to test every single cell of an embryo. If that was done, then the embryo would not be able to continue to grow and develop given when cells are removed, they are not able to be put back.

When the embryo is biopsied, it can be described as looking like a ball. The cells on the external portion of the embryo or outer layer are called the trophectoderm. These are the cells that are removed and otherwise would have gone on to make up the placenta. The cells clustering inside of the ball are called the inner cell mass, and they will go on to make the future baby.

What is the point of PGT-A?

PGT-A is counting the number of chromosomes the cells have because chromosomes hold all of our DNA. There is supposed to be a total of 46 chromosomes, any more or any less means that there is not the typical amount of DNA which can cause implantation failure, miscarriage, or health complications for a person. Check out our blog on chromosomes. The goal of PGT-A is to implant the embryo with the lowest chance to have a chromosomal condition in order to improve implantation rates and reduce miscarriage as well as reduce the possibility of a pregnancy with a chromosomal condition.

Reasonably, there is the question of whether the few cells that are biopsied from the outer portion of the embryo actually represent what is going on for the embryo as a whole, particularly the cells that are going to become the baby. Studies have been conducted to address this question with embryos that have been donated for this research.

How do researchers determine if the few cells tested actually let us know what is going on for the embryo as a whole?

The researchers in the studies biopsy the outer portion of the embryo as is done with typical PGT-A, but they will also biopsy other parts of the embryo, including the cells that will become the future baby. The goal of the studies is to determine if the initial biopsy result matches the other parts of the embryo, particularly those of the future baby.

What the studies have found is that it ultimately depends on the initial result of whether or not you can use that result to predict what is going on for the future baby’s cells.

So what are the possible initial results? For PGT-A, there are three main categories of results. There is normal (science term is “euploid”), abnormal (aneuploid), or mosaic. The results refer only to the few cells that were sent for biopsy. While the term “abnormal” can be difficult to receive, it is important to keep in mind the point of testing. It is only intended to help with selecting which embryo to transfer. It is not meant to devalue anyone’s embryos.

When the result is “normal” or “euploid”:

When the initial result is normal, the studies found that over 90% of the time, the rest of the embryo will also be normal. Check out the studies below for the exact concordance rate. Concordance rate means how often the result from the trophectoderm matched the result of the inner cell mass. Embryos with normal results typically are prioritized for transfer because it is likely the whole embryo has normal chromosomes and has the best chance to result as an ongoing pregnancy compared to other results.

When the result is “abnormal” or “aneuploid”:

For abnormal results involving full extra or missing chromosomes, the studies also found over 90% of the time, the rest of the embryo was also abnormal. Therefore, these embryos are typically deprioritized because adverse outcomes like miscarriage are more likely to occur.

It is important to note that the studies did not find that the results matched 100% of the time, so the PGT-A results are a guide to what is going on for the rest of the embryo, but they are not absolute. Testing only a few cells is a limitation of PGT-A.

For abnormal results that involve a part of the chromosome that is extra or missing (referred to as a segmental abnormality), the studies found that the initial result less often predicted what was going on for the rest of the embryo. Depending on the study, the concordance rates can be from 40-76%.

When the result is “mosaic”:

Lastly, for mosaic results, the studies also found that it is difficult to determine what is going on for the rest of the embryo. There can be a few different reasons for a mosaic result, one of which may be that some chromosomes are considered normal and other chromosomes are considered abnormal. Some clinics and providers have policies in which a mosaic result may be an option to transfer, but with the understanding that it is less clear if the rest of the embryo cells have normal or abnormal chromosomes.

To Conclude:

Making a decision of whether or not to transfer an embryo based on PGT-A results can be difficult given the test is not perfect. PGT-A serves to be a guide in the decision making process. Your healthcare providers such as reproductive endocrinologists and infertility specialists (REIs) and genetic counselors are also available as a resource. PGT-A results are not considered diagnostic results, and confirmatory testing can be considered while pregnant or after a baby is born. PGT-A is an optional test, so some people decide not to have the evaluation. Other people feel that the results have been helpful in navigating embryo selection. As is the case in other areas of healthcare, the decision is tremendously personal.

Resources:

• Capalbo, Antonio et al. “Mosaic human preimplantation embryos and their developmental potential in a prospective, non-selection clinical trial.” American journal of human genetics vol. 108,12 (2021): 2238-2247. doi:10.1016/j.ajhg.2021.11.002

• Victor, Andrea R et al. “Assessment of aneuploidy concordance between clinical trophectoderm biopsy and blastocyst.” Human reproduction (Oxford, England) vol. 34,1 (2019): 181-192. doi:10.1093/humrep/dey327

• Kim, Julia et al. “The concordance rates of an initial trophectoderm biopsy with the rest of the embryo using PGTseq, a targeted next-generation sequencing platform for preimplantation genetic testing-aneuploidy.” Fertility and sterility vol. 117,2 (2022): 315-323. doi:10.1016/j.fertnstert.2021.10.011

• Grkovic, Steve et al. “Clinical re-biopsy of segmental gains-the primary source of preimplantation genetic testing false positives.” Journal of assisted reproduction and genetics vol. 39,6 (2022): 1313-1322. doi:10.1007/s10815-022-02487-z

• Marin, Diego et al. “Preimplantation genetic testing for aneuploidy: A review of published blastocyst reanalysis concordance data.” Prenatal diagnosis vol. 41,5 (2021): 545-553. doi:10.1002/pd.5828

• Vanneste, Evelyne et al. “Chromosome instability is common in human cleavage-stage embryos.” Nature medicine vol. 15,5 (2009): 577-83. doi:10.1038/nm.1924

* This blog constitutes general information about genetic testing and medical screening. This blog does not offer or provide medical advice or diagnosis, and nothing in this blog should be construed as medical advice or diagnosis. Do not rely on the information in this blog/article to make medical management decisions. Please consult with a medical professional before making those decisions. Do not delay in seeking professional medical advice if you think you have a medical concern. Do not disregard professional medical advice based on any information received in this blog.