The intended purpose of preimplantation genetic testing for aneuploidy (PGT-A) is to screen for chromosomally normal embryos. This means an embryo with 46 chromosomes and no overt missing or extra pieces, otherwise known as deletions or duplications. This is because, in theory, chromosomally normal embryos are thought to have a better reproductive outcome than embryos that are chromosomally abnormal. However, according to the American Society for Reproductive Medicine, the value of PGT-A as a universal screen for all patients undergoing in vitro fertilization (IVF) has not been established.
Before I go on, let me define a few terms:
The trophectoderm is the area of the embryo that will become the supporting structures of the pregnancy, such as the placenta
The inner cell mass is the area of the embryo which will develop into the fetus
A blastocyst refers to the developmental stage at which PGT is done, typically five to six days after fertilization
The above image was taken from Gleicher, N., Metzger, J., Croft, G. et al. A single trophectoderm biopsy at blastocyst stage is mathematically unable to determine embryo ploidy accurately enough for clinical use. Reprod Biol Endocrinol 15, 33 (2017). https://doi.org/10.1186/s12958-017-0251-8.
When the blastocyst is ~100 to 200 cells, ~5 to 10 cells are biopsied from the trophectoderm. Cells are NOT biopsied from the inner cell mass. The reason this is important is because your test results only pertain to the sample that was analyzed by the lab. Therefore, there's no guaranteed that the cells biopsied are an exact match for the chromosomal makeup of the remaining embryo.
It's also important to know that PGT-A cannot detect all clinically significant findings including but not limited to small chromosomal deletions or duplications, single gene disorders, congenital malformations, multifactorial conditions, autism or intellectual disabilities. Because PGT-A can only assess aneuploidy status, which is associated primarily with the viability (or nonviability) of an embryo, current evidence does not support its use to predict long-term health issues aside from those related to aneuploidies.
Potential PGT-A results can include:
Euploid: in which the embryo is determined to have the correct number of chromosomes.
Aneuploid: in which the embryo has the incorrect number of chromosomes. "Trisomy" means there are three copies of a chromosome in a specific set of chromosomes instead of two. Most non-sex trisomies (1-22) are not compatible with life. Notable exceptions include trisomy 21, 18, and 13, which may be to varying degrees. "Monosomy" means there is one copy of a chromosome in a specific set instead of two. All non-sex monosomies (1-22) are not compatible with life.
Complex abnormal: in which there are two or more chromosome sets affected with an abnormality. This is believed to be the result of abnormal cell division after fertilization.
Segmental deletions or duplications: in which there is a piece of a chromosome that is extra or missing. They are believed to occur in ~8% of cases. As stated above, PGT-A cannot detect all genetic deletions and duplications.
Mosaicism: describes an embryo in which there is the presence of more than one chromosomally distinct cell line.
The above image was taken from https://www.differencebetween.com/difference-between-chimera-and-mosaic/.
Aside from true mosaicism, there are several other proposed contributors to and explanations for what is termed mosaicism. Recent studies have reported incidences of mosaicism ranging from 2-26%. Mosaicism in the trophectoderm may be indicative of aneuploidy, euploidy, or mosaicism in the inner cell mass. A mosaic embryo may result in no implantation, a miscarriage, a child with no health issues, or a child born with a variable clinical presentation, ranging from mild to profound intellectual and physical disability. The severity of the findings depends on the level and location of mosaicism and the chromosome material involved. Mosaic embryos can be categorized into “low-level” and “high-level” depending on whether they were seen to have between 20-40% mosaic cells or 40-80% mosaic cells, respectively. Low-level mosaic embryos have been reported to generally have a better reproductive outcome than high-level mosaic embryos. As of 2023, there have been over 2,700 documented embryos transferred with mosaic results, leading to a gradual but increasing acceptance of the transfer of embryos with mosaic results as a viable option for patients. Mosaicism identified in the preimplantation embryo has thus far not been definitively associated with a significantly increased risk of an adverse fetal or neonatal outcome. To date, studies on mosaic embryo transfers have focused on prenatal and newborn outcomes; no longitudinal studies have been performed to assess long-term outcomes beyond the neonatal period. Ultimately, more data are needed to clarify whether certain mosaic findings are clinically relevant to an embryo’s reproductive potential.
No result/inconclusive: occurs when no information can be reported on a specific embryo. This occurs in 2.5 to 3% of cases. This can be the result of biopsy sampling or genetic testing errors. Re-biopsy may be an option in this case as is the option to transfer the embryo with no additional testing or discarding the embryo. Studies have suggested that embryos with originally inconclusive results are not more likely to be aneuploid upon re-biopsy. It is recommended that you discuss the potential negative impact on success rates when an embryo is rebiopsied.
Triploidy: describes when an embryo has an entire extra set of chromosomes, thus 69 instead of 46. Triploidy is believed to occur in ~2% of all embryos. Those affected can have intrauterine growth retardation and congenital anomalies; ultimately triploidy is not compatible with life.
Because PGT is considered a screening rather than diagnostic test, prenatal diagnosis via chorionic villi sampling or amniocentesis is recommended following PGT. Something to note is that, in the case of mosaicism seen at trophectoderm biopsy, a normal result on prenatal testing does not rule out the possibility of chromosome abnormalities in non-tested tissues.
Attempts have been made to prioritize embryos with different types of mosaic PGT-A results concerning their success rate and perceived risk. Ultimately, an evidence-based approach has not been developed. As such, the decision to transfer a given embryo rests in the hands of you and your physician.
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