Current opinion on preimplantation genetic screening (PGS)
Joyce Harper, Progress Educational TrustReader in Human Genetics and Embryology, UCL Centre for PGD, Institute for Women's Health, University College London; Chair of the ESHRE PGD Consortium
16 July 2009
Preimplantation genetic screening (PGS) for aneuploidy was first reported by Verlinsky et al (1995) and Munne et al (1995). Both of these initial studies analysed polar bodies. The aim of the technique is to help determine the best IVF embryo for transfer on the grounds of the polar body or embryo's chromosomes, by performing biopsy and analysis of the chromosomes using fluorescent in situ hybridisation (FISH). There have been hundreds of papers on the use of PGS. It is well known that for patients with advanced maternal age, there is an increased risk of chromosome abnormalities in the embryos they produce. Therefore this has been the main indication for PGS, but other indications include repeated IVF failure, repeated miscarriage (with normal karyotypes in the parents) and severe male factor infertility. As with many new technologies brought into the IVF clinic, there has been little evidence-based medicine to show that PGS increases delivery rates. At the late breaking news at the 2007 European Society of Human Reproduction and Embryology (ESHRE) annual meeting, Mastenbroek reported that their randomised controlled trial (RCT) on PGS showed that the treatment group had a lower delivery rate compared to the control group (Mastenbroek et al, 2007). Since then the debate about the validity of PGS has been rife.
In 2007, as chair of the ESHRE PGD Consortium, I was asked if the Consortium steering committee could write a position statement on the use of PGS. The steering committee could not come to a consensus and so a position statement was never issued. The majority of the committee felt that further RCTs were required to convince the world whether PGS did or did not improve delivery rates (Harper et al, 2008). Since 2007, the British Fertility Society (BFS), the American Society for Reproductive Medicine (ASRM) and the American College of Obstetricians and Gynecologists (ACOG) have all issued statements that PGS should not be offered clinically. Several times at ESHRE 2009, I asked the audience how many were routinely performing PGS and many groups said they were.
There are now nine RCTs applied to both good (Staessens et al, 2008, Meyer et al, 2009, Jansen et al, 2008, Mersereau et al, 2008) and poor (Staessens et al, 2004, Stevens et al, 2004, Debrock et al, 2007, Hardarson et al, 2008, Mastenbroek et al, 2007) prognosis patients which have all shown that PGS has not improved the delivery rate, compared to a control group, and some of these studies show it has decreased the delivery rate. Almost all of these studies have been applied to cleavage stage embryos and FISH to study 5-12 chromosomes except Jansen et al (2008) who performed trophectoderm biopsy. Performing the biopsy at cleavage stages has a biological problem as this is the stage when human embryos show high levels of chromosome abnormalities (Harper et al, 1995, Munne et al, 1995) and so analysis of one cell from these embryos is not representative of the rest of the embryo. Many embryos are 'mosaic' - different cells may have different chromosomal complements - which may well self correct to give a normal embryo, but mosaicism creates a problem for PGS.
I reported the latest data of the ESHRE PGD Consortium at ESHRE 2009 in Amsterdam. The data shows that the majority of PGD cycles reported to the Consortium are for PGS (more than all of the other indications added together), but the latest data collection only includes cycles performed to the end of 2007, and so we have yet to see the 'Mastenbroek' effect. It will be interesting to see what the next data collection shows.
At the 2009 ESHRE meeting, I organised a post-congress course on the use of arrays in PGS. Several groups and companies reported on their development and clinical application of array CGH (comparative genomic hybridisation - which just looks at the chromosomes) or SNP arrays (single nucleotide polymorphism - which can look at the chromosomes and genes) for PGS. I summarised the session with three questions: 1) Are the arrays validated? 2) At what stage should we do the biopsy? 3) Have we done the necessary RCTs to determine if PGS will result in improved delivery rates?
The arrays are being validated using a variety of single cells from normal and aneuploid cell lines and also polar bodies, blastomeres and trophectoderm cells. Cleavage stage biopsy is a good option for PGD for inherited disorders as it allows analysis of the paternal and maternal genes/chromosomes and a fresh transfer, but it may not be the optimal stage to biopsy for PGS (as described above). Therefore the third question needs to be answered by performing RCTs on either polar bodies (first and second) or trophectoderm.
Also at the 2009 ESHRE conference, Professor Joep Geraedts, the
outgoing chairman, announced that ESHRE would be undertaking its first ever
clinical trial - a two stage study developed to assess the efficacy of PGS using polar body biopsy and analysis of 24 chromosomes using array technology. The first part of the study aims to determine if the technique of polar body biopsy and analysis of 24 chromosomes by array CGH is feasible. Two centres that have extensive polar body and PGS experience (Markus Montag, Hans van der Ven, University of Bonn, Germany and Cristina Magli and Luca Gianaroli, SISMER, Italy) are analysing the first and second polar bodies from a variety of patients who have agreed to be in the study. Any abnormal oocytes will also be examined to see whether the polar body abnormalities can really be used to predict that the oocyte will be abnormal. If the proof of principle part of the study is successful, the second part of the study will involve a multi centre RCT involving at least six centres in different EU countries, to determine if PGS gives an increased delivery rate in women of advanced maternal age. It was decided to run the trial on polar bodies as this will allow for a fresh transfer, the biopsy is less invasive and hopefully the results will be more reliable than cleavage or blastocyst biopsy as mosaicism will not affect the results. Dagan Wells (Oxford) is developing a blastocyst biopsy clinical trial for PGS with vitrification of the biopsied blastocysts to give time for the analysis.
The UK's Human Fertilisation and Embryology Authority (HFEA) has reviewed the regulation of PGS and now no longer require clinics to offer PGS just for the criteria stated above (advanced maternal age, etc). Instead, they have placed the onus on clinics, requiring them to validate the use of PGS for each category of patient and to warn patients that PGS is an unproven technique in need of further research. If the RCTs show no improvement in delivery rates, it may be time to put PGS behind us, but if they show that PGS improves delivery rates this will be a major step forward for IVF treatment. We need to learn from the PGS experience to ensure that we rigorously test new techniques before we introduce them into clinical practice.
1. Debrock S, Melotte C, Vermeesch J, et al. Preimplantation genetic screening (PGS) for aneuploidy in embryos after in vitro fertilization (IVF) does not improve reproductive outcome in women over 35: a prospective controlled randomized study. Fertil Steril 2007; 88:S237.
2. Hardarson T, Hanson C, Lundin K, et al. Preimplantation genetic screening in women of advance maternal age decrease in clinical pregnancy rate: a randomized controlled trial. Human Reprod 2008; 23:2806-2812.
3. Harper JC, Coonen E, Handyside AH, et al. Mosaicism of autosomes and sex chromosomes in morphologically normal, monospermic preimplantation human embryos. Prenat Diagn 1995; 15:41-49.
4. Harper J. Sermon K, Geraedts J, et al. What next for preimplantation genetic screening? Hum Reprod 2008; 23:478-480.
5. Jansen RP, Bowman MC, de Boer KA, et al. What next for preimplantation screening (PGS)? Experience with blastocyst biopsy and testing for aneuploidy. Hum Reprod 2008; 23:1476-1478.
6. Mastenbroek S, Twisk M, van Echten-Arends J, et al. In vitro fertilization with preimplantation genetic screening.
N Engl J Med 2007; 357:9-17.
7. Mersereau JE, Pergament E, Zhang X, et al. Preimplantation genetic screening to improve in vitro fertilization pregnancy rates: a prospective randomized controlled trial. Fertil Steril. 2008;90:1287-9
8. Meyer, L, Klipstein, S, Hazlett, W et al. A prospective randomized controlled trial of preimplantation genetic screening in the "good prognosis" patient. Fertil Steril 2009; 91:1731-1738.
9. MunnÈ S, Sultan KM, Weier HU, et al. Assessment of numeric abnormalities of X, Y, 18, and 16 chromosomes in preimplantation human embryos before transfer. Am J Obstet Gynecol. 1995;172(4 Pt 1):1191-9.
10. Staessen C, Platteau P, Van Assche E, et al. Comparison of blastocyst transfer with or without preimplantation genetic diagnosis for aneuploidy screening in couples with advance maternal age: a prospective randomize controlled trial. Hum Reprod 2004; 19:2849-2858.
11. Staessen C, Verpoest W, Donoso P, et al. Preimplantation genetic screening does not improve delivery rate in women under the age of 36 following single-embryo transfer. Hum Reprod 2008; 23:2818-2825.
12. Stevens J, Wale P, Surrey ES, Schoolcraft WB. Is aneuploidy screening for patients aged 35 or over beneficial? A prospective randomized trial. Fertil Steril 2004; 82(Suppl. 2):249
12. Verlinsky, Y, Cieslak, J, Freidine,M et al. Pregnancies following pre-conception diagnosis of common aneuploidies by fluorescent in-situ hybridization. Mol Hum Reprod 1995;1:265-269.
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Reproduced from BioNews with permission, a web- and email-based source of news, information and comment on assisted reproduction and human genetics, published by Progress Educational Trust.