As the resolution and accuracy of diagnostic techniques for preimplantation genetic testing for aneuploidy (PGT-A) are improving, more mosaic embryos are being identified. Several studies have provided evidence that mosaic embryos have reproductive potential for implantation and healthy live birth. Notably, mosaic embryos with less than 50% aneuploidy have yielded a live birth rate similar to euploid embryos. This concept has led to a major shift in current PGT-A practice, but further evidence and theoretically relevant data are required. Proper guidelines for selecting mosaic embryos suitable for transfer will reduce the number of discarded embryos and increase the chances of successful embryo transfer. We present an updated review of clinical outcomes and practice recommendations for the transfer of mosaic embryos using PGT-A.
In the field of preimplantation genetic testing for aneuploidy (PGT-A), mosaicism was first identified 25 years ago in a validation study, where it was thought to be caused by an insufficient trophectoderm (TE) sample size [
Mosaic embryos have the potential to implant and develop into genetically normal babies [
However, arguments for and against transferring mosaic embryos still exist [
Mosaicism is the presence of more than one genotypically distinct cell population within a single zygote [
Mosaicism can be classified into four types based on cell lineage and the timing of mitotic errors in the blastocyst stage [
Mosaicism may not be associated with maternal age [
A high proportion of mosaic embryos was found in couples with low sperm concentrations [
Technical laboratory factors may affect the quality of a biopsy and thus may affect the occurrence of mosaicism within the TE. The differences in platform specificity and sensitivity, the protocols for DNA amplification, and the threshold settings established for interpretation can lead to differences in the proportion of mosaicism and the number of euploid embryos to transfer [
Multiple factors determine the fate and viability of mosaic embryos, such as the degree of mosaicism in the biopsied sample, the specific type and number of chromosomes involved, and the type of mosaicism.
In 2016, the position statement of the PGDIS recommended priorities for mosaic embryo transfers based on the specific chromosome involved and the level of mosaicism [
Despite these diverse ranking approaches, attempts to provide clinical recommendations for patients may yet be in early stages. Uncertainty remains regarding related factors affecting the clinical outcome data of mosaic embryo transfer. Some studies have suggested differences in live-birth rates based on the type and level of mosaicism [
Chromosomal mosaicism has been defined as low-level mosaicism if abnormal cells are in the 30%–50% range and high-level mosaicism if abnormal cells are in the 50%–70% range using the NGS validation algorithm [
The clinical outcomes of mosaicism can be highly dependent on the chromosomes involved. Autosomes were ranked in order of their risk of placental insufficiency, intrauterine growth restriction, and uniparental disomy (UPD). The mosaic trisomy 16 chromosome is commonly affected in preimplantation embryos and leads to a high risk of abnormal perinatal outcomes, such as intrauterine growth restriction, preterm birth, and hypertensive disorders [
Grati et al. [
Most monosomies arise from mitotic errors and most trisomies result from nondisjunction during maternal meiotic errors [
When duplication or deletion errors occur in a small portion of DNA during mitotic division, the embryo will have a mosaic of the segmental error, allowing some cells to have a normal copy number of chromosomes and others to have segmental deletion or duplication of the chromosomes [
Regarding chromosome type, large chromosomes such as chromosomes 1 to 9 are prone to breakage, resulting in segmental mosaicism [
Segmental aneuploidies originate because of mitotic errors during preimplantation development [
Several studies found reduced pregnancy capacity in mosaic embryos that had three or more chromosomes involved [
A recent statement by the American Society for Reproductive Medicine highlighted the importance of patient education prior to PGT-A [
Patients should be informed about the risk of mosaicism in a biopsy specimen, the complexities of the various possible outcomes after transfer of a mosaic embryo, and the need for close prenatal monitoring, including amniocentesis. Until definitive data is available, patients should be advised to go through additional cycles if possible to obtain euploid embryos instead of transferring a mosaic embryo. A schematic prioritization of mosaic embryos according to clinical outcomes is shown in
If a pregnancy has been confirmed after mosaic embryo transfer, prenatal diagnosis is recommended to identify fetal chromosomes and other genetic conditions. Although evidence-based guidance for prenatal testing after mosaic embryo transfer is still lacking, most practice statements consistently recommend amniocentesis as the gold standard for prenatal diagnosis [
Although interest in mosaic embryo transfers is increasing, the debate over whether mosaic embryos can be transferred is ongoing. In practice, the identification of mosaic subgroups that are viable and worthy of transfer is very important, but it is also vital to inform patients that the data on postnatal and neonatal outcomes following mosaic embryo transfers are still limited and that clinical outcomes have been mixed. We emphasize the need for further research on the genetic and clinical outcomes of mosaic embryo transfers. Large-scale multicenter studies would be of particular value in collecting data for the risk evaluation of mosaic embryo transfers and could potentially reduce the disposal of viable embryos for implantation and live births.
No potential conflict of interest relevant to this article was reported.
Conceptualization: ISK. Writing–original draft: EJY. Writing–review & editing: all authors.
A list of professional medical society guidelines and recommendations regarding mosaic embryo transfer
Variable | PGDIS 2016 [ |
CoGEN 2017 [ |
Grati 2018 [ |
PGDIS 2019 [ |
ASRM 2020 [ |
PGDIS 2021 [ |
---|---|---|---|---|---|---|
More favorable clinical outcomes in euploid than mosaic embryos | Yes | Yes | Yes | Yes | Yes | Yes |
More favorable clinical outcomes in low than high levels of mosaicism | Not assessed | Yes (20%-40% vs. 40%–70%) | Not assessed | Yes (<40% vs. >40%) | Yes (but controversial) | Yes |
Specific chromosome(s) involved | Lowest priority: chr 13, 18, 21 | Lowest priority: chr 13, 18, 21, 22 | Lowest priority: chr 13, 18, 21 and 45, X | Embryos mosaic for chromosomes that are associated with potential for uniparental disomy, severe intrauterine growth restriction, or liveborn syndromes may be given lower priority. | Some studies have found risky outcomes depending on the specific chromosome numbers involved; while others have reported that mosaic aneuploidies involving most chromosomes have pregnancies and live births with an abnormal phenotype. | No specific comments |
Lesser priority: potential for uniparental disomy (chr 14, 15), intrauterine growth restriction (chr 2, 7, 16) | Low priority: uniparental disomy (chr 14, 15), intrauterine growth restriction (chr 2, 7, 16) | Lesser priority: potential for uniparental disomy (chr 14, 15), intrauterine growth restriction (chr 2, 7, 16) | ||||
More favorable clinical outcomes in monosomies than trisomies | Yes | Yes | Yes | Yes | Yes | Yes |
Different clinical outcomes between mosaic types (segmental vs. whole chromosome vs. complex | Not assessed | In the case of complex mosaicism, transfer is not recommended | Not assessed | Not assessed | Controversial | Yes |
Recommendation of prenatal test method | Amniocentesis | Amniocentesis | Amniocentesis | Amniocentesis | Amniocentesis | Amniocentesis |
Special considerations | If a decision is made to transfer a non-complex, low-level mosaic embryo, one can prioritize selection based on the specific chromosome involved. | If a decision is made to transfer embryos mosaic for a single chromosome, one can prioritize selection primarily based on the level of mosaicism and then the specific chromosome involved. | Before transfer of mosaic embryos, comprehensive genetic counseling should be provided. | The relative percentage of mosaicism seems to be a better predictor of outcome than the specific chromosomes involved. |
PGDIS, Preimplantation Genetic Diagnosis International Society; CoGEN, Congress on Controversies in Preconception, Preimplantation and Prenatal Genetic Diagnosis; ASRM, American Society for Reproductive Medicine; Chr, chromosome.
Schematic prioritization of mosaic embryo classified according to favorable clinical outcomes
Priority | Percentage of mosaicism | Monosomy vs. trisomy | Segmental vs. whole chromosome | Specific chromosomes involved | Number of Chr involved (single vs. double vs. complex) |
---|---|---|---|---|---|
Low clinical risk | Low (<50%) | Monosomy | Segmental | Chr 1, 3, 4, 5, 6, 10, 12, 17, 19, 20, 22, X, Y | Single |
High clinical risk | High (>50%) | Trisomy | Whole | Chr 13, 18, 21: best-avoided | Complex |
Chr 6, 7, 11, 14, 15, 20: UPD risk | |||||
Chr 2, 16: IUGR risk | |||||
Chr 8, 9: aneuploidy viability |
Chr, chromosome; UPD, uniparental disomy; IUGR, intrauterine growth restriction