The why, the how and the when of PGS 2.0: current practices and expert opinions of fertility specialists, molecular biologists, and embryologists

Sermon, Karen; Capalbo, Antonio; Cohen, Jacques; Coonen, Edith; Rycke, Martine De; Vos, Anick De; Delhanty, Joy D. A.; Fiorentino, Francesco; Gleicher, Norbert; Griesinger, G.; Grifo, James A.; Handyside, Alan H.; Harper, Joyce; Kokkali, Georgia; Mastenbroek, Sebastiaan; Meldrum, David R.; Meseguer, Marcos; Montag, Markus; Munné, Santiago; Rienzi, Laura; Rubio, Carmen; Scott, Katherine; Scott, Richard T.; Simón, Carlos; Swain, Jason E.; Treff, Nathan R.; Ubaldi, Filippo Maria; Vassena, Rita; Vermeesch, Joris Robert; Verpoest, Willem; Wells, Dagan; Geraedts, J. P. M.

doi:10.1093/molehr/gaw034

Cited by 125 publications

(83 citation statements)

References 77 publications

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“…Blastocyst biopsy was described already in 1990 [23], but has only recently known a high flight and is now introduced in a growing number of PGD centres [11,24]. The advent of better-adapted culture systems yielding more blastocysts per treatment cycle paved the way for this type of biopsy.…”

Section: Blastocyst Biopsymentioning

confidence: 99%

“…It would be the uterus to make the ultimate selection, and not PGS. Because PGS is only a selection method, it would never increase the live birth rate for that given cohort [66]. Proponents of PGS argue that PGS is able to decrease the time to pregnancy, as no time is lost in transferring embryos with no chance of implantation, and that it will decrease miscarriage rates [66].…”

Section: Biological and Technical Variables Influencing Pgs Efficacymentioning

confidence: 99%

“…These trial characteristics lead to a distortion of the real a priori benefit for patients, as they do not represent those patients that for instance do not obtain blastocysts for analysis, or only have abnormal embryos and therefore do not even reach embryo transfer. Although these three RCTs were on specific patient categories, they are often cited as demonstrating PGS efficacy for all IVF patients [62,66,71,72].…”

Section: Pgs and Its Troubled Relationship With Evidence-based Medicinementioning

confidence: 99%

“…This was made possible by the introduction of a highly efficient type of cryopreservation, called vitrification, which allows recovery of nearly 100% of frozen blastocysts. Not only does vitrification allow the spreading of embryo transfer over several cycles avoiding the need for embryo selection in the fresh cycle, it also gives the molecular biologists extra time for the analysis of the samples [11]. However, history repeated and PGS2.0 was widely implemented without the support of well-designed RCTs [12].…”

Section: Introductionmentioning

confidence: 99%

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Preimplantation Genetic Screening

Sermon¹

2017

obm genet

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The main aim of PGS has always been to improve IVF outcome, especially in patient groups assumed to have higher rates of chromosomally abnormal embryos, such as patients of advanced maternal age. In that sense, PGS is quite different from other types of screening as discussed in other papers in this issue. Today it bears no doubt that blastocysts found to be uniformly aneuploid in a biopsy will fail to implant, or worse, will implant and lead to a pregnancy and birth carrying a major chromosomal abnormality, such as trisomy 21. However, it has been argued that a cohort of embryos cannot be improved, and that PGS is only a selection method for which efficiency has not been proven. PGS would never increase the live birth rate for that given cohort, even with a 100% efficiency rate of embryo cryopreservation. The current debate on whether PGS should be applied and to which patients it should be offered has shifted from the effect on live birth rates towards other outcomes such as the reduction of transfers and of miscarriages. Taking the undeniable higher cost of IVF into account when PGS is included, what is the benefit to the patient? The views on this question differ on whether PGS is an additional source of income for the IVF clinic and may or may not balance the extra cost for cryopreservation and embryo transfer for the patients, or whether society pays for IVF treatments and may decide not to want to invest in a medical act that does not improve the primary goal of IVF, i.e. having a healthy child. PGS is also often presented as diminishing patient anxiety and stress through decreasing unnecessary embryos transfers and miscarriages, although no data on this

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Section: Blastocyst Biopsymentioning

confidence: 99%

Section: Biological and Technical Variables Influencing Pgs Efficacymentioning

confidence: 99%

Section: Pgs and Its Troubled Relationship With Evidence-based Medicinementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Preimplantation Genetic Screening

Sermon¹

2017

obm genet

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“…This is an important step to standardize reporting of PGS. A survey by Sermon et al conducted among 12 wellestablished molecular biologists found that only two participants report the mosaicism level back to practitioners [23]. It will also be important for practitioners to understand the implications of having only mosaic embryos available for transfer.…”

mentioning

confidence: 99%

Mosaicism: throwing the baby out with the bath water?

Vega

Jindal

2016

J Assist Reprod Genet

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With the advent of next-generation sequencing (NGS), cytogenetic laboratories now have the ability to detect low-level mosaicism in the trophectoderm of blastocysts [1]. An abstract presented by Dagan Wells, PhD, and his collaborators at the European Society for Human Reproduction and Embryology (ESHRE) Meeting titled: BEvidence that differences between embryology laboratories can influence the rate of mitotic errors, leading to increased chromosomal mosaicism, with significant implications for IVF success rates,^was well-received. In this study, the authors retrospectively analyzed 623 blastocysts from seven fertility clinics and suggested that under different laboratory conditions, the same embryo can have different mosaicism rates ranging from 32 to 60 % [2]. The abstract focuses on mosaicism-introduced post-fertilization (mitotic non-disjunction of the embryo) and therefore during laboratory culture, rather than due to meiotic nondisjunction of the oocyte.The concept that laboratory conditions may cause postfertilization aneuploidy or mosaicism in embryos is provocative. This could explain the large dissimilarities seen in aneuploidy rates among different clinical trials and why some embryology laboratories see a decrease in their live birth rates per cycle start when performing preimplantation genetic screening (PGS) due to no euploid embryo being available for transfer [3][4][5]. Munne et al. first described a possible increase in postfertilization mosaicism when comparing different embryology laboratories [6]. More recently, it has been shown that embryos with better morphological scores have fewer chromosomal errors [7,8]. What specific embryo culture conditions can impact embryo morphology and possibly ploidy status? According to a recent systematic review and meta-analysis of randomized controlled trials (RCTs), culture at 5 % vs. 20 % oxygen concentration increased the number of high/top morphology embryos at the cleavage stage (RR = 1.2, 95 % CI 1.1-1.3) [9]. Different culture media with different recommended pH ranges support blastocyst development in culture, but the optimal pH level has not been established [10,11]; animal models suggest that strict control of pH at different developmental stages improves embryo quality [12]. A recent RCT showed that embryos cultured at 37°C have higher blastulation rates (60.1 vs. 51.6 %, p 0.03) and form more usable blastocysts (48.1 vs. 41.2 %, p 0.03) when compared to embryos cultured at 36°C [13], indicating the need for strictly controlled temperature of incubators and heated surfaces in the laboratory. If we follow this same principle, variations in the biopsy technique such as location of biopsy in the trophectoderm, due to segregation of abnormal cell lines, and/or number of cells removed, may impact the level of mosaicism reported [14]. We know that controlling for these variables by strict adherence to protocols and training of staff lead to comparable and reproducible outcomes with no difference in aneuploidy rates [15].If indeed there is variation amo...

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