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Studies Provide Conflicting Results on Impact of Preimplantation Genetic Screening


SAN FRANCISCO (GenomeWeb) – Two studies analyzing the impact of preimplantation genetic screening for chromosomal aneuploidies seem to reach different conclusions.

A prospective study published in the journal Human Reproduction by researchers from the Vrije Universiteit Brussels in Belgium found no difference in the live birth rate among women who opted for preimplantation chromosomal aneuploidy testing while undergoing in vitro fertilization versus those who chose not to have testing. Meantime, a retrospective analysis published in Fertility and Sterility conducted by Natera found that around 45 percent of women who opted for testing and 65 percent who ultimately had embryos implanted, had live births.

Analyzing embryos for chromosomal aneuploidies prior to implantation is a relatively new technique, adopted in just the past several years. Previously, embryos were chosen based on their morphology — how they looked under a microscope. But, growing evidence that chromosomal aneuploidy is a likely cause of IVF failure — leading either to an unsuccessful implantation or to miscarriage — plus advances in genomic technologies, have led researchers to test methods for analyzing embryos for chromosomal aneuploidies prior to implantation.

A number of firms already market such tests, including Illumina, which sells its VeriSeq PGS reagent kit to be run on a sequencing instrument. It has been working with Reprogenetics, which was acquired by CooperSurgical in 2015, to conduct a clinical trial of the assay, although results have not yet been published. Natera, meanwhile, offers its own test using a microarray platform. Good Start Genetics, now owned by Invitae, also offers an NGS-based PGS test based on technology it licensed from Johns Hopkins University.

Despite the rapid growth in the field, "from a patient's point of view, the data is very confusing," said Zev Williams, chief of the division of reproductive endocrinology and infertility at Columbia University Medical Center. Williams was not affiliated with either recently published study, but has been developing a PGS method on Oxford Nanopore's MinIon platform. 

Some studies have shown that testing embryos for chromosomal aneuploidies prior to implantation can make a big difference, but others have been less convincing. And since testing in the US is not covered by insurance, cost continues to be burden.

Karen Sermon, a professor within VUB's reproduction and genetics research group, said that these factors were what led to the decision to do a prospective evaluation of the technology. At the time the study was conceived in 2010, the gold standard was to use array CGH technology and to screen polar bodies rather than embryos. In addition, she said, the group targeted patients in the 36-year to 40-year age range.

In the study, 205 participants had chromosome screening with Illumina's 24sure array and 50, or 24 percent, had a live birth within one year. Of the 191 participants who did not have chromosomal screening, 45, or 24 percent, had a live birth.

The participants in the screening arm of the study also had fewer embryos transferred — 73 percent of participants versus 90 percent of participants. In addition, screening led to fewer miscarriages — 14, or 7 percent, compared to 27, or 14 percent — and to fewer twin births — 5, or 3 percent, compared to 10, or 6 percent.

"There was no significant difference in birth rate" between the two groups, Shermon said. "At the end of the day, that came down to there were less embryos that were deemed transferrable" in the group that was screened.

The Natera study, by contrast, looked retrospectively at women who had opted to receive its Spectrum test, which is based on a SNP microarray. The study analyzed 974 women, aged 20 to 46, who received IVF treatment and opted for screening. The researchers also analyzed embryos as opposed to polar bodies, which are now more commonly tested and likely to be a more accurate representation of what's going on in the pregnancy, according to Williams.  

In total, 952 embryo retrieval procedures were performed and 665 transfers performed. For some women, embryos were unable to be retrieved or testing resulted in no euploid, viable embryos.

The overall birth rate among all women was 45 percent. Looking just at women for whom testing resulted in an embryo transfer, the live birth rate was 65 percent.

The Natera team compared their results with data available from the Society for Assisted Reproductive Technology, finding that SNP-based PGS resulted in a higher embryo implantation rate, pregnancy rate, and live birth rates compared to not testing, for all age groups. For instance, for women between the age of 35 and 37, the researchers reported that testing resulted in a greater than 70 percent live birth rate per embryo transfer compared to just under 50 percent for women who are not tested.

Michelle Kiehl, director of the fertility program at Natera, and one of the study's authors, said that one reason for not comparing women who opted for testing to those who did not is that there were significant differences between the two groups that would not have made a comparison accurate. For instance, in order to run the Spectrum test, embryos are grown for five to six days. Women with a low ovarian reserve have a lower chance of growing a viable embryo, so those women often opted to not have testing. In addition, those women typically had fresh embryos transferred as opposed to frozen embryos, creating other differences that wouldn't make for a good comparison, Kiehl said.

Williams said that although the studies on the surface seem to provide contradictory results, the "devil's in the details, and there are a few critical differences between the studies that make them hard to compare."

Although the Natera study used techniques that are more commonly used today — analyzing SNPs and testing embryos — "there's always a concern with retrospective studies" and who chooses to get tested. "If it is only patients with more embryos or a better prognosis, then it's not surprising that they had a better outcome," he said. Nonetheless, he said, "there's consensus [in the field] that aneuploidy is a significant cause of failure of embryos to implant and for miscarriage."

What's not settled, Williams said, is the tradeoffs of testing. Aside from testing accuracy, he said, it's important to know whether the testing process harms the embryo in the process. In addition, he said, it's also not clear the patient population that would receive the most benefit from testing. "It's a complex area both for those of us in the field and for patients," he said. "There's a lot of subtlety in figuring out who to test and who testing will help."

Sermon said that her group's next steps are to continue to analyze the data. "We generated a large database, and so we can go data mining," she said. For instance, although the group did not find a difference in the birth rate between women who were tested and those who were not, the team did find that the women who had testing prior to implantation had a lower rate of miscarriage.

Sermon said that the group also plans to evaluate the types of chromosomal abnormalities that were found as well as the clinical effects of the drugs that stimulate ovaries during IVF cycles and whether the dosing has an impact on pregnancy and birth rates.

Natera, meantime, is working on developing an NGS-based version of its test. Kiehl declined to disclose details of the test, but said it would be a targeted NGS test that would enable them to also analyze abnormalities such as uniparental disomy and complex aneuploidies, and to trace inheritance patterns.