Preimplantation genetic screening is alive and very well: really?

LETTER TO THE EDITOR Preimplantation genetic screening is alive and very well: really? TO THE EDITOR: The September issue featured Views and Reviews on preimplantation genetic screening (PGS), including an editorial by Meldrum et al. (1) declaring PGS ‘‘alive and very well,’’ four reviews of technical aspects of the procedure, and three articles by the Scott group. Unfortunately, lacking was a critical and balanced presentation of the subject. The concept of PGS is not new. It was proven useless in a prior incarnation, although unfortunately only after thousands of women reduced pregnancy chances by using the procedure (2). Now history appears to repeat itself, with many investigators promoting an improved version involving day 5/6 blastocyst trophectoderm biopsy in place of day 3 embryo biopsy and 24-chromosome copy number analysis by various available technologies in place of fluorescence in situ hybridization (FISH). All of the above noted articles uncritically accept that the earlier PGS failure was due to technical shortcomings of day 3 biopsies and chromosomal analyses by FISH. They assume that these shortcomings are remedied by the use of trophectoderm biopsy and new 24-chromosome copy analyses and that PGS now fulfills its presumed destiny of improving IVF outcomes. But what if PGS did not fail because of technical shortcomings? What if it failed because PGS should not be applied indiscriminately to every patient or because embryo selection by PGS statistically simply does not work in older women or in women with low ovarian reserve? Wouldn't we then only repeat the same mistakes all over? Scott's group presented three papers in support of the new PGS. All three papers are fundamentally flawed because their outcome analyses are not based on intent to treat and involve only patients who do reach embryo transfer (ET). With the new PGS, many patients, however, do not: some because their embryos do not make it to days 5/6, others because all tested embryos are aneuploid. Those, quite obviously, are adversely selected. Conversely, those who do make it to ET are favorably selected. Reported results, therefore, are only achieved in a highly favorably selected patient population and should not be considered representative of all IVF. Despite favorable patient selection, Scott et al. still transferred 1.9 and 2.0 embryos, respectively, in PGS and control

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groups. With 2 ET, the authors achieved implantation rates of 66.4% vs. 47.9% and delivery rates of 84.7% vs. 67.5% (3). Results in unselected patients would, however, be very different! PGS may indeed work in patients with best pregnancy chances, as suggested by Scott et al., further increasing pregnancy rates by up to approximately 25%. This is a point we have made before (4). We, however, strongly caution against prematurely concluding that PGS should also be applied to less favorable patients. We are not alone in calling for caution (5). Because of failure to reach ET, poorer prognosis patients will, likely, fail to improve pregnancy chances equally well. In addition, they often are prematurely driven into egg donation after repeatedly not making it to day 5 ET, although they would still have conception chances with day 3 ET (4). Whether PGS in association with routine IVF is, therefore, really alive and very well remains to be seen. Norbert Gleicher, M.D.a Vitaly A. Kushnir, M.D.b David H. Barad, M.D., M.S.c a Center for Human Reproduction and Foundation for Reproductive Medicine; b Center for Human Reproduction; c Center for Human Reproduction and Foundation for Reproductive Medicine, New York, New York September 3, 2013 http://dx.doi.org/10.1016/j.fertnstert.2013.09.019

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Meldrum DR. Introduction: preimplantation genetic screening is alive and very well. Fertil Steril 2013;100:593–4. Mastenbroek S, Twisk M, van der Veen F, Repping S. Preimplantation genetic screening: a systematic review and meta-analysis of RCTs. Hum Reprod Update 2011;17:454–66. Scott RT Jr, Upham KM, Foreman EJ, Hong KH, Scott KL, Taylor D, et al. Blastocyst biopsy with comprehensive chromosome screening and fresh embryo transfer significantly increases in vitro fertilization implantation and delivery rates: a randomized controlled trial. Fertil Steril 2013;100:697–703. Gleicher N, Kim A, Weghofer A, Barad DH. Lessons from elective in vitro fertilization (IVF) in, principally, non-infertile women. Reprod Biol Endocrinol 2012; 10:48. Mastenbroek S. One swallow does not make a summer. Fertil Steril 2013;99: 1206.

VOL. 100 NO. 5 / NOVEMBER 2013