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Combining PGD and PGS to Select Embryos Increases Pregnancy Rate But Results in Fewer Transfers

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NEW YORK (GenomeWeb) – In one of the largest studies of combined preimplantation genetic diagnosis (PGD) and screening (PGS) to date, researchers in Italy have found that testing embryos for inherited diseases and aneuploidies in parallel prior to transferring them into the uterus resulted in higher pregnancy rates per transfer than testing for genetic diseases alone.

The study was published in Human Reproduction this week after preliminary results were presented a year ago at the European Society of Human Reproduction and Embryology annual meeting in Finland.

"We strongly believe that when [a] biopsy needs to be performed in order to prevent the transmission of an inheritable disease, it should be mandatory to analyze also the genetic status of the blastocyst, avoiding useless and/or harmful embryo transfers in this particular category of patients," the researchers, led by Maria Giulia Minasi at the Center for Reproductive Medicine at the European Hospital in Rome and Francesco Fiorentino at Genoma Molecular Genetics Laboratories, wrote.

However, the double-testing also led to fewer women having an embryo suitable for transfer available than doing PGD alone, and patients should be counseled about this adequately, they noted.

Also, other researchers caution that some embryos testing positive for aneuploidy in PGS can still develop into healthy babies, and some clinics do transfer them for that reason.

PGD has been used for several years to select for transfer embryos that are free of a specific monogenic disorder or a chromosomal rearrangement that runs in a family, such as cystic fibrosis or Duchenne muscular dystrophy. In addition, PGS can be used to screen embryos for chromosomal defects such as aneuploidy. Both procedures require a biopsy from an early embryo that can be taken at different stages of development.

The Italian team wanted to investigate whether combining PGD and PGS increases pregnancy rates per transfer and clinical outcomes compared to PGD alone. They performed both PGD and PGS on a single trophoectoderm biopsy, which removes up to 10 cells at the blastocyst stage and is less invasive than a biopsy performed at an earlier stage.

For their study, the researchers tracked the outcomes for 1,122 blastocyst embryos obtained in 304 cycles from almost 230 couples between October 2011 and May 2016. After whole-genome amplification of the DNA from the biopsied cells, using Illumina's SurePlex DNA Amplification System, multiplex PCR was performed to diagnose specific monogenic genetic diseases.

Embryos shown to be disease-free by PGD were further tested for aneuploidy by array-CGH-based PGS, using 24sure V3 microarrays from Illumina on the same amplified DNA sample. Only embryos free of aneuploidy were subsequently transferred.

After PGD alone, 625, or 56 percent, of blastocysts were considered transferable, while 36 percent were deemed non-transferable, and the remainder had mosaic or no results.

However, after PGS, the number of transferable embryos was cut in half, to 309, or 27.5 percent of all blastocysts.

Looking at the number of cycles, after PGD, 71 percent of cycles, or 217, had embryos available that were considered transferable, but following subsequent PGS, only 183 cycles, or 60 percent of cycles, had transferable embryos.

In total, 218 embryos were transferred to 167 patients in 202 transfer procedures. At the time the study was submitted for publication, 70 healthy babies had been born and 13 pregnancies were still ongoing.

Overall, 49 percent of the transfers in the study resulted in clinical pregnancies, which the authors said was higher than in a previous study from 2006 in which they only performed PGD, not PGS. In that study, 427 embryos were transferred in 211 procedures, and just 34 percent of the transfers resulted in clinical pregnancies.

Minasi, who is the laboratory director of the Center for Reproductive Medicine, said that the recent study, while not the first, is one of the largest tracking the outcome of combined PGD and PGS for embryo selection.

Her center, which is part of a private hospital, treats approximately 1,500 couples per year, among them about 150 for whom it performs PGD because their children are at risk of inheriting a genetic disease.

The center started performing the double analysis in 2011 for some PGD patients and switched to offering it to all PGD patients in 2012. Most patients decide in favor of the PGD/PGS analysis, she said, despite the additional price tag — while PGD alone costs around €7,000, PGD and PGS together cost approximately €10,000. Only one patient, who was young and therefore at low risk of having an aneuploid embryo, opted for PGD alone for economic reasons, she added.

The downside of the combined PGD/PGS analysis is that it decreases the number of cycles that have embryos unaffected by genetic disease or aneuploidy — in the study, from 71 percent to 60 percent — which can be devastating for patients. "When patients arrive here, they spend a lot of money, they wait for a long time, because it's a long procedure," Minasi said. "After all this time, which can be three to four months, we sometimes have to call them and tell them 'I'm sorry, we don't have anything for you'." That risk, she said, needs to be explained clearly in advance.

Minasi said several other centers in Italy also perform the double PGD/PGS analysis, but some countries have restrictions on PGS, though they do permit PGD for couples at risk of genetic diseases.

And while there is still some discussion about whether PGS alone for families not at risk of a specific disease improves pregnancy rates and live births, there is less controversy about adding PGS to PGD when a biopsy is already taken for PGD, she said.

Her center does perform PGS alone on blastocysts for about 70 percent of couples treated but the practice varies between reproductive clinics in Italy, she said.

Joris Vermeesch, chair of the Department of Human Genetics at the University of Leuven in Belgium, said his group, in a smaller study, has also shown that combining PGD and PGS increases the pregnancy success rate per embryo transfer.

He and his colleagues in 2015 published a method for genomewide haplotyping of embryos, called haplarithmisis, that allows them to perform both PGD and PGS in the same assay, and similar approaches called karyomapping can do the same.

Earlier this year, his group published a study in which they used their approach on 373 embryos from 101 cycles to select embryos for transfer. Later this year, Agilent Technologies plans to commercialize the method, Vermeesch added.

He cautioned that some embryos that test positive for aneuploidy in PGS are in fact mosaic and develop into healthy babies when transferred.

That is why his laboratory ranks embryos and does transfer some aneuploid ones when no euploid embryos are available. While this carries the risk of babies with aneuploidies being born, it also increases the chance of a woman to have a healthy baby in the end, instead of no child at all. "The field has to come to terms with how to deal with those embryos and how this affects the baby take-home rate," he said.

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