In vitro fertilization (IVF) often includes genetic screening of developing embryos to maximize the chance of a successful pregnancy. This testing identifies embryos with the correct number of chromosomes, which are considered the most viable for transfer. However, advancements in genetic technology have revealed a more complex picture of embryonic development than previously understood. This complexity centers on mosaicism, a condition where an embryo contains a mixture of both normal and abnormal cells. This finding introduces a new layer of consideration for patients and clinicians navigating assisted reproduction.
Defining Embryo Mosaicism
Embryo mosaicism describes a state where a single embryo possesses two or more distinct cell lines with different chromosomal compositions. This contrasts with the historical binary classification of embryos as either entirely normal or entirely abnormal. An embryo is considered euploid if all of its cells contain the correct number of 46 chromosomes, arranged in 23 pairs, offering the highest potential for a healthy pregnancy. Conversely, an aneuploid embryo has an incorrect number of chromosomes in every cell (e.g., trisomy or monosomy). Aneuploidy typically results in implantation failure, miscarriage, or, in rare cases, a genetic syndrome. The mosaic embryo exists on a spectrum between these two states, containing populations of both euploid and aneuploid cells. The resulting genetic variation means that not all cells share the same genetic blueprint, unlike a uniformly euploid or aneuploid embryo.
How Mosaic Embryos Develop
The formation of a mosaic embryo stems from a mitotic error in cell division that occurs after fertilization, typically during the early cleavage stages (around Day 3 or Day 4). This contrasts with uniform aneuploidy, which is usually caused by a meiotic error—an uneven separation of chromosomes in the egg or sperm before conception. During mitosis, a cell should divide into two identical daughter cells. However, a mitotic error, such as non-disjunction or anaphase lag, causes chromosomes to separate unevenly. Non-disjunction results in one daughter cell having an extra chromosome (trisomy) and the other missing one (monosomy), while anaphase lag causes a chromosome to be lost. The timing of this error directly links to the proportion of abnormal cells in the later-stage blastocyst. Errors that happen very early affect a larger number of subsequent cells, resulting in a higher level of mosaicism, while later errors lead to a lower overall percentage of abnormal cells.
Detecting Mosaicism Through Genetic Testing
Mosaicism is detected through Preimplantation Genetic Testing for Aneuploidy (PGT-A), performed during an IVF cycle. This test requires a trophectoderm biopsy, where five to ten cells are sampled from the outer layer of the Day 5 or Day 6 blastocyst. The trophectoderm forms the placenta and other extra-embryonic membranes. The sample is analyzed using Next-Generation Sequencing (NGS) technology, which measures the quantity of DNA for each chromosome. NGS can identify intermediate DNA copy numbers, indicating a mixture of cells with normal and abnormal DNA quantities, leading to a mosaicism diagnosis. PGT-A categorizes the mosaicism level based on the estimated percentage of abnormal cells in the sample. Low-level mosaicism is typically defined as 20% to 40% abnormal cells, while high-level mosaicism is 40% to 80%. This distinction is important because the level of mosaicism is strongly associated with the embryo’s potential for development.
Clinical Implications and Transfer Outcomes
The primary clinical implication for mosaic embryos is that they are generally considered for transfer only after all available euploid embryos have been used. This prioritization reflects the higher and more consistent success rates associated with euploid embryos. However, when no euploid embryos are available, mosaic embryos offer a viable pathway to pregnancy, necessitating a careful discussion with a genetic counselor.
The potential for a mosaic embryo to develop into a healthy live birth is largely attributed to the concept of self-correction and cell lineage allocation. In self-correction, the abnormal cells may be naturally eliminated through a process called apoptosis, or programmed cell death, as the embryo develops. Additionally, the embryo may preferentially confine the aneuploid cells to the trophectoderm, the tissue that becomes the placenta, while the euploid cells form the inner cell mass, which develops into the fetus.
Data on transfer outcomes indicate that mosaic embryos have a reduced, but still significant, chance of resulting in a live birth compared to euploid embryos. For example, some studies report a live birth rate of approximately 46.6% for euploid embryos, compared to around 30.8% to 46.6% for transferred mosaic embryos. This success rate is heavily influenced by the level of mosaicism; low-level mosaic embryos, with less than 50% abnormal cells, have been shown to have live birth rates approaching those of euploid embryos.
The transfer of a mosaic embryo requires careful consideration and thorough pre-transfer genetic counseling to discuss the specific risks based on the chromosome involved and the percentage of mosaicism. Due to the possibility that the mosaicism detected in the trophectoderm could also be present in the fetus, follow-up prenatal diagnostic testing, such as amniocentesis, is often recommended during the pregnancy to confirm the genetic status of the developing fetus.