The Actual Effectiveness of Preimplantation Genetic Screening (PGS): Response to NYMag

This response to New York Magazine ‘The Cut’ article titled “A New Last Chance” was republished from Natera® with permission from Michelle Kiehl, MS, ELD, TS, Director of Fertility Program Development. For more information, please visit natera.com

Recently, New York Magazine featured an article in The Cut column, titled “A New Last Chance.” The article raised questions about the effectiveness of preimplantation genetic screening (PGS) in conjunction with in vitro fertilization (IVF). We are contacting our valued partners because this article failed to discuss the more recent advancements in the field of assisted reproductive technology (ART) and the benefits of PGS, which are clearly supported in the literature and outcome data from SART and CDC.

The points below address the shortcomings of this article and may assist you with patient questions about the utility of preimplantation genetic screening.

Data Supporting the Use of PGS:

  • A recent randomized controlled trial (RCT) published by the CDC found increased live birth rates and decreased miscarriage rates for women of advanced maternal age (>37 years and >35 years, respectively) using IVF
    and PGS.1
  • Reported transfers using Spectrum PGS have a 62% clinical pregnancy rate (fetal heart tones), and is higher than non-PGS outcomes reported by SART, 2014.2
  • A subset of data from two large centers using Spectrum PGS shows a clinical pregnancy rate per transfer of 70% and a livebirth rate per transfer of 65% (in preparation for publication).

Advances in Embryo Biopsy Technique:

  • The article cites Scott el al, 2013 to support that embryo biopsy at the cleavage stage can cause harm and reduce implantation potential. However, data from the same publication showed that biopsies performed at the
    blastocyst stage, with techniques commonly used today, have no negative impact on implantation potential.3

The nature of mosaicism in embryos:

  • The article discusses the possibility of moving away from PGS due to the presence of mosaicism in embryos. Mosaicism refers to when there is more than one cell line in a given embryo and occurs by abnormal cell division (mitotic error) early on in the developing embryo.
  • The majority of PGS today is performed on trophectoderm (TE) cells from blastocyst-staged embryos. Data published in Molecular Human Reproduction showed a 96% concordance between TE and inner cell mass (ICM) by SNP microarray with bioinformatics,4 demonstrating the utility of PGS, even in the face of mosaicism.
  • To date, the rate of mosaicism within the TE has yet to be established. Some PGS tests report mosaicism, based on a lab-specific threshold for calling mosaicism which can impact the decision to transfer an embryo. Ultimately, it is the personal decision of the patient and clinic whether it is appropriate to consider transferring an embryo that has been reported as mosaic.
  • Mosaicism is not reported on the Spectrum platform. When a lower confidence call is reported, one of the possible explanations is mosaicism. However, the testing algorithms do not differentiate mosaicism from other
    factors such as uneven amplification, poor quality DNA, or a combination of all of the above.

PGS technologies – there is a difference:

  • The majority of PGS referenced in the article used array comparative genomic hybridization (aCGH), a microarray platform shown to have more false positives and detection limitations compared to newer technologies.5
  • Spectrum PGS, performed using SNP microarrays and bioinformatics (Parental Support), is a proprietary platform available only through Natera.6 In addition to the chromosome abnormalities typically detected on other
    platforms (whole chromosome aneuploidy, deletions, and duplications), Spectrum also offers a more comprehensive screening including:

    • Uniparental disomy, which can cause genetic syndromes like Angelman/Prader-Willi syndrome
    • Haploidy and all forms of triploidy,7 which can result in partial molar pregnancy when paternal in origin
    • Parental source of aneuploidy, which can help tailor medical care
    • Parentage and sample contamination
    • Individual “confidence calls,” i.e. expected accuracy, which are typically ≥ 99%

PGS is Designed to Improve the Chance of a Healthy Pregnancy:

24-chromosome PGS is a tool that aids patients and physicians in choosing an embryo most likely to have a correct chromosome complement and improves the chances of achieving a successful pregnancy.

Several statements in the article failed to address the number of positive advancements in assisted reproductive technologies (ART) and PGS over the last several years:

  • Data shows that implantation rates using PGS are >50% across all age groups.2
  • PGS enables elective single embryo transfer (eSET), which reduces complications associated with multiple-gestation pregnancies.
  • PGS is also especially valuable to patients with recurrent pregnancy loss (RPL) as it decreases the chances for experiencing an additional miscarriage.8

IVF carries an incredible physical and emotional toll for patients. Natera, a leader in reproductive genetics and innovation, is committed to providing high quality tests and services to support your patients in their reproductive journey. If your patients have questions or concerns about the utility of PGS, we highly recommend they utilize our complimentary pre- and post-test genetic information sessions to better understand the benefits and limitations of Spectrum PGS.

If you have further questions, please contact your local IVF sales specialist to set up time with our team of physicians and board-certified genetic counselors. Additional patient and provider resources and educational materials are available on our website: www.natera.com

References:

  1. Chang J, Boulet SL, Jeng G, Flowers L, Kissin DM. Outcomes of in vitro fertilization with preimplantation genetic diagnosis: an analysis of the United States Assisted Reproductive Technology Surveillance Data, 2011–2012. Fertility and sterility. 2016;105(2):394-400. doi:10.1016/j.fertnstert.2015.10.018.
  2. SART National Summary Report (https://www.sartcorsonline.com/rptCSR_PublicMultYear.aspx?reportingYear=2014)
  3. Scott RT Jr, Upham KM, Forman EJ, Zhao T, Treff NR. Cleavage-stage biopsy significantly impairs human embryonic implantation potential while blastocyst biopsy does not: a randomized and paired clinical trial. Fertility and sterility. 2013:100(3):624-30. doi:10.1016/j.fertnstert.2013.04.039.
  4. Johnson DS, Cinnioglu C, Ross R, et al. Comprehensive analysis of karyotypic mosaicism between trophectoderm and inner cell mass. Molecular Human Reproduction. 2010;16(12):944-949. doi:10.1093/molehr/gaq062.
  5. A. Siegel, P. R. Brezina, A. T. Benner, L. Du, M. Gunn, W. G. Kearns. 23-chromosome single nucleotide polymorphism (SNP) microarray detects genomic aberrations that may be missed by comparative genomic hybridization (CGH) arrays in preimplantation genetic screening (PGS) Fertility and Sterility. 2011: 96(3):S224.
  6. Johnson DS, Gemelos G, Baner J, et al. Preclinical validation of a microarray method for full molecular karyotyping of blastomeres in a 24-h protocol. Human Reproduction (Oxford, England). 2010;25(4):1066-1075.doi:10.1093/humrep/dep452.
  7. K.J. Doody, K. Merrion, M.K. Maisenbacher, D. Kijacic, M. Kiehl. Triploidy – a critical yet underdiagnosed embryo abnormality: review of data from preimplantation genetic screening via single nucleotide polymorphism microarrays with bioinformatics. Fertility and sterility. 2016:106(3):e159.
  8. Brooke Hodes-Wertz, Jamie Grifo, et al. Idiopathic recurrent miscarriage is caused mostly by aneuploid embryos.Fertility and sterility. 2012 0015-0282. doi:10.1016/j.fertnstert.2012.05.025.
  9. McCoy RC, Demko Z, Ryan A, Banjevic M, Hill M, Sigurjonsson S, et al. Common variants spanning PLK4 are associated with mitotic-origin aneuploidy in human embryos. Science. 2015;348(6231):235–238. pmid:25859044