The process of in vitro fertilization (IVF) often involves genetic screening, which introduces complexity and stress for prospective parents. After embryos are created, preimplantation genetic testing (PGT) classifies their perceived viability, forcing difficult decisions about which ones to transfer. The central question is whether an embryo flagged as having a chromosome abnormality can still develop into a healthy baby. This possibility rests on the concept of an embryo’s natural ability to correct or manage genetic errors, a biological phenomenon that challenges the initial diagnostic labels.
Understanding Aneuploidy and PGT-A
A fundamental concept in embryo genetics is the distinction between euploidy and aneuploidy, which refers to the number of chromosomes present in the cell. A euploid embryo possesses the correct number of 46 chromosomes, arranged in 23 pairs, and is considered genetically normal. Conversely, aneuploidy describes a state where an embryo has an abnormal number of chromosomes, either missing one (monosomy) or having an extra one (trisomy).
To identify these chromosomal states, preimplantation genetic testing for aneuploidy (PGT-A) is performed during the IVF cycle. This testing is conducted on the blastocyst, the embryo stage reached five to seven days after fertilization. A small number of cells are carefully removed from the trophectoderm (TE), the outer layer that will eventually form the placenta.
The genetic material from these trophectoderm cells is analyzed to infer the chromosomal status of the entire embryo. The goal of PGT-A is to select euploid embryos for transfer, as they have the highest probability of resulting in a live birth. Embryos found to be fully aneuploid are not recommended for transfer due to their low developmental potential. A third classification, mosaicism, arises when the tested sample contains a mixture of both euploid and aneuploid cells, which is where the question of self-correction becomes relevant.
The Mechanism Behind Embryo Self-Correction
The term “embryo self-correction” describes the ability of a mosaic embryo to reduce its burden of abnormal cells, a process more accurately termed mosaicism resolution or aneuploid cell depletion. This phenomenon explains why some embryos initially diagnosed as mosaic can develop into healthy, euploid individuals. The mechanisms proposed for this genetic cleanup involve differential cell fate and programmed cell death.
One mechanism is the preferential destruction of aneuploid cells through apoptosis, a form of controlled cell suicide. Studies suggest that chromosomally abnormal cells are less robust and have a slower cell cycle, making them more susceptible to this programmed elimination. This selective apoptosis occurs more intensely within the inner cell mass (ICM), the cluster of cells that will form the fetus, purging the fetal lineage of genetic errors.
Another mechanism is the physical sorting or marginalization of the abnormal cells within the developing blastocyst. As the embryo matures, it differentiates into two distinct cell populations: the ICM and the trophectoderm (TE). Aneuploid cells appear to be preferentially shunted toward the TE layer, which contributes only to the placenta and supporting membranes.
The result of this differential allocation is that the ICM, which forms the fetus, becomes enriched with euploid cells. Conversely, the TE, which is biopsied for PGT-A, retains a higher proportion of aneuploid cells. This explains why a PGT-A result showing mosaicism in the TE does not always mean the fetus itself will be mosaic or abnormal.
Clinical Outcomes and Transfer Decisions
The biological potential for mosaicism resolution translates into complex clinical decision-making, especially when a patient has no euploid embryos available for transfer. Data comparing outcomes of mosaic embryo transfers (METs) to euploid transfers show that mosaic embryos have a lower implantation and live birth rate. While euploid transfers achieve a high live birth rate, METs are associated with a reduced rate and an increased miscarriage rate.
The decision to transfer a mosaic embryo is dependent on the degree and type of aneuploidy detected during PGT-A. Mosaicism is categorized by the percentage of abnormal cells; lower-level mosaicism (less than 50%) generally has a better prognosis than higher-level mosaicism. The specific chromosome involved and whether the abnormality is a whole chromosome or a smaller segmental piece also influence the outcome, with segmental aneuploidies often showing a more favorable prognosis.
Despite the reduced success rates, reports of healthy live births following the transfer of mosaic embryos confirm their developmental potential and the reality of the resolution process. For patients undergoing a MET, genetic counseling is recommended to discuss the risks, which include an elevated chance of a less-favorable outcome. If a mosaic embryo is transferred and a pregnancy is established, follow-up prenatal diagnostic testing, such as chorionic villus sampling (CVS) or amniocentesis, is advised to confirm the genetic status of the developing fetus.