A Defense of PGS

A Defense of PGS

An article recently published in The Cut column of New York Magazine has captured the attention of the fertility and genetic testing community. Titled “A New Last Chance”, the article questioned the utility of preimplantation genetic screening (PGS) – a technique which data from the CDC and SART, along with the results of several randomized controlled trials (RCTs), have all shown to be effective in increasing live birth rates and decreasing miscarriage rates for women pursuing in vitro fertilization. Unfortunately, the article failed to provide a full picture of the science surrounding PGS.

A defense of this valuable technique was provided to IVF centers by two of the most respected experts in the field, Santiago Munne, PhD and Mark Hughes, MD, PhD. For those of you considering using PGS in your IVF cycle I am presenting their defense.

What evidence do we have to support our use of PGS?

Several RCTs have found clinical benefit in PGS: An analysis published by the CDC in 2016 found decreased miscarriage rates (for patients >35 y.o.) and increased live birth rates (for patients >37 y.o.) with IVF and PGS. A 2017 article in Fertility and Sterility (Rubio et. al.) concluded that PGS was “superior” to controls for clinical outcome at first transfer, decreased miscarriage rates, and shortened time to pregnancy for women >38 y.o. In our own experience, we routinely work with centers who see IVF+PGS success rates of up to 60%.

Does technology matter when we’re discussing PGS?

Testing performed during the timeframe referenced in this article would not have been on next-generation sequencing (NGS), which we now know has the highest sensitivity. High resolution PGS (hr-PGS) via NGS, which offers a unique ability to detect mosaicism. Mosaic embryos contain a mix of both normal and abnormal cells, which originate after fertilization and early in post-fertilization embryo growth and development. PGS was initially developed to identify meiotic errors of the gamete that produced uniformly aneuploid embryos, but recent technology breakthroughs in hr-PGS allow the detection of post-meiotic (mitotic) genomic events. The article did not differentiate between mosaic embryos and fully abnormal ones, which is an important distinction when comparing clinical outcomes, especially since mosaic embryos may have been called abnormal by previous technologies. The quoted 24 babies from the Rome center were not meiotic aneuploid but mosaic, and the 7 analyzed by Gleicher et al were analyzed with an older technique that could not have differentiated aneuploid from mosaics. Data has shown that mosaic embryos – specifically those with a lower level of mosaicism – can successfully implant and lead to healthy live births. By detecting both low and high levels of mosaicism, we can make the most informed decisions around embryo prioritization for transfer. The article quoted a recent publication of Dr. Munne as saying that “more than 100 such babies have been born”. The article forgot to include the important distinction that this statistic referred to mosaic embryos – not those identified as abnormal. We are, in fact, not surprised whatsoever that these mosaic embryos produced healthy babies.

The article implied that, because PGS requires biopsy, it may be harmful to the embryos. Is this true?

Similar to many aspects of medicine, the results of a PGS test can be complicated by external factors. Embryo biopsies are challenging procedures requiring great technical skill and expertise. The article focused on FISH/aCGH technologies and day 3 biopsies, which Scott and Treff (2017) have shown to be associated with reduced success rates. We’ve come a long way since the days of FISH, aCGH, and day 3 biopsy, including the use of laser tools and thousands of data points from NGS. These advances have impacted the quality of PGS and the references made by the article are out of date. Data show a statistically significant difference in ongoing pregnancy and miscarriage rates between aCGH and NGS (aCGH: 50% OPR, 11% miscarriage; NGS: 60% OPR, 6% miscarriage). We know today that day 5 biopsy and single, frozen embryo transfer ultimately have the highest success rates. Moving forward, it will be important for the field to focus on quality control and standardization of biopsy technique.

What does all of this mean for PGS and its role in IVF success?

PGS is designed to help patients and providers better understand the options they face, and prioritize embryos with the highest chance of success for transfer. Genetic testing labs do not make transfer recommendations nor do they discard embryos. The article strongly implied that PGS is designed to ‘eliminate’ embryos, which is never the goal or intent. Using genetic testing to prioritize embryos allows patients to more safely approach IVF by selecting one embryo for single-embryo transfer. This is another point the article failed to acknowledge; single embryo transfer is widely accepted, and recognized by the ASRM, as the safest approach given the reduced chance of multiples and the associated costs and complications of twin, triplet, or higher order pregnancies. [Cost on the order of 4 – 10x increase]. While no genetic test is perfect, the strongest assessment of an NPV for PGS was shown to be 4% by Scott et. al. in 2012. It’s important to note, however, that the PGS in this analysis was performed via SNP methods now considered inferior to today’s NGS methodology. PGS is also an important tool for those who suffer recurrent pregnancy loss – and the incredible emotional and physical toll their experience causes. A test which is able to decrease the risk of miscarriage for these women holds tremendous value.

We are confident in the ability of PGS to assist in selection of the embryo most likely to lead to success, and ultimately contribute to building a healthy family.

Santiago Munne, PhD and Mark Hughes, MD, PhD

Please see RPMG’s Single Transfer, Safer Pregnancy, Healthier Baby protocol.

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