NEW YORK (GenomeWeb) – To increase the chance of pregnancy and reduce the incidence of miscarriage, more and more fertility clinics have started using preimplantation genetic screening (PGS) to test embryos resulting from in vitro fertilization for chromosomal abnormalities before they are transferred to a woman's uterus.
In most cases, the test yields a clear-cut result: the embryo is either euploid or aneuploid, and transferring a euploid embryo enhances the rate of pregnancy, lowers the risk of miscarriage, and decreases the chance of having a baby with a birth defect.
However, for a small fraction of embryos, testing reveals they are a mosaic, meaning they have a mix of chromosomally normal and abnormal cells, with varying percentages. The field has debated for some time, and there is no consensus yet, whether such embryos should be considered for transfer if a woman has no euploid embryos available, as it might be her only chance to have a child, however, at a risk.
New research by a team in Italy now shows that mosaic embryos can develop into healthy babies, and that the chance of this happening is correlated with the percentage of abnormal cells in the mosaics.
Early results from the ongoing study were presented last week at the European Society of Human Reproduction and Embryology annual meeting in Geneva, Switzerland, by Francesco Fiorentino, CEO and laboratory director at Genoma in Rome.
Two years ago, he and his collaborator Maria Giulia Minasi of the European Hospital in Rome had published a letter in the New England Journal of Medicine in which they showed that eight out of 18 women who had mosaic embryos transferred became pregnant, and six delivered babies, all with a normal karyotype.Â
For the new study, the researchers followed 73 women who had mosaic embryos transferred between 2013 and 2016, all because they did not have any euploid embryos available after IVF treatment and were not willing to perform another cycle. "It was the last chance for these patients," Fiorentino said.
Early in the study, the scientists determined mosaicism by array comparative genomic hybridization (arrayCGH), but later on they switched to a next-generation sequencing-based method, which makes it easier to quantify the degree of mosaicism, he said.
The embryos were cultured to the blastocyst stage and a biopsy was taken from the trophoectoderm, which develops into the placenta, which was followed by PGS.
For their analysis, the researchers classified the embryos into two groups with above or below 50 percent chromosomally abnormal cells.
The embryos with more than half abnormal cells had a miscarriage rate of 10 percent and a live birth rate of almost 17 percent, whereas those with fewer abnormal cells had a miscarriage rate of 7 percent and a live birth rate of almost 40 percent. All pregnancies that went to term resulted in babies with normal karyotype, and there was no significant difference in the pregnancy rate and miscarriage rate between the two groups.
Fiorentino said the study remains open and that his team hopes to add about 50 more women, which would enable them to analyze the level of mosaicsm and its effect on a finer scale.
Not much is known yet about how human mosaic embryos develop into healthy newborns, he said, but a study in mice, published in Nature Communications last year by researchers in the UK and Belgium, suggests that aneuploid cells in the fetal lineage of the embryo are eliminated by apoptosis, whereas aneuploid cells in the placental lineage appear to have a growth disadvantage over euploid cells, so they are quickly outgrown. As long as mosaic embryos have enough euploid cells, the authors wrote, they "have full developmental potential."
Based on the results of the ongoing study, Genoma generally recommends the transfer of mosaic embryos to women who do not have any euploid embryos available, Fiorentino said.
However, in cases where the aneuploidy of the mosaic embryo is potentially viable — mostly trisomy 21, 13, or 18 — the team makes sure to stress to the patient that there is the risk they might have a child with that disorder.
"Of course, we give preference to euploid embryos — this strategy is only used for patients who don't have any euploid embryos available for transfer," Fiorentino said. While this might be the case for any woman, it happens more frequently in patients of advanced maternal age compared to younger women. Preference is also given to embryos with a lower percentage of abnormal cells, he added.
Ultimately, the patient needs to decide what is right for her, Fiorentino said, but the role of the geneticist is becoming more important for explaining the test results and the risks involved.
But not all fertility clinics offer PGS to their patients yet, and there is not much guidance from professional organizations. The exception is the Preimplantation Genetic Diagnosis International Society (PGDIS), which a year ago released a position statement on chromosome mosaicism and preimplantation aneuploidy testing that included guidelines for how to prioritize mosaic embryos for transfer. Until studies like the one from Fiorentino and colleagues clarify the clinical outcome of mosaic embryos, their transfer "should only be considered following expert advice and appropriate genetic counseling of patients," according to the statement.
Mike Large, director of genomic laboratories at CooperGenomics, which provides PGS and other reproductive genetic testing, agreed that it is too early for specific guidelines. "It would be premature to say anything other than 'there is black, white, and gray, and various shades of gray, and we're still trying to figure out what will happen with the gray,'" he said.
CooperGenomics, a unit of CooperSurgical, has conducted its own research of mosaic embryos that were transferred over the last two years, similar to Genoma's study, and has seen very similar results, he said.
Specifically, the company has followed about 75 transfers of embryos with low-level mosaicism, which implanted reasonably well but had an increased miscarriage rate compared to euploid embryos. In addition, it has studied a few dozen cases of embryos with medium- or high-level mosaicism, which implanted at similar levels but had even higher loss rates, he said.
Large pointed out that the technology to detect mosaicism in embryos with confidence, relying on NGS, has only existed for a few years — his lab started using it in the fall of 2014. Prior to that, researchers have probably transferred mosaic embryos unwittingly. "We've been transferring mosaics forever, we just didn't know about it," he said. "Now the technology has gotten to a point where we can see things that we don't quite understand biologically yet."
In the meantime, patients need to decide based on the data available what's best for them. One patient, for example, might want to avoid another miscarriage at all costs and therefore be unwilling to transfer a mosaic embryo, while another patient who is of advanced maternal age and on her last IVF cycle might be willing to take the risk in order to have a baby. "There really is no one-size-fits-all approach," Large said, adding that he agrees with Fiorentino that mosaics could probably be considered a third category of embryos, in addition to truly normal and truly abnormal ones.
"The mission of our field is to give people a healthy and happy family, and we want to take advantage of every opportunity to do that," Large said. "And we're still trying to figure out if mosaics represent an opportunity to do that. For those who don't have other choices, they may very well be."Â