Analysis

Lack of evidence for interventions offered in UK fertility centres

BMJ 2016; 355 doi: https://doi.org/10.1136/bmj.i6295 (Published 28 November 2016) Cite this as: BMJ 2016;355:i6295

Re: Lack of evidence for interventions offered in UK fertility centres

Continuing to deliver: The evidence base for PGS

We read the BMJ manuscript by Heneghan and co-workers [1] - a study commissioned by the BBC - and watched the subsequent Panorama programme made by BMJ associate editor Deborah Cohen, with considerable interest.

The purpose of this letter is to respond specifically to the comments made about preimplantation genetic screening (PGS) also known as preimplantation genetic for aneuploidy (PGD-A), one of the three so-called “add on” treatments highlighted in the programme and among the 41 in the manuscript. We would like to draw the reader to the current extensive evidence base that supports the efficacy of PGS/PGD-A. At time of writing at least 20 retrospective studies and 4 RCTs provide evidence that PGS, if performed to a high standard, can, and does, improve IVF success for some patient groups [2-5.] We accept that these studies are open to criticism (indeed this could be applied to any study) and we thus continue to support more advanced investigations, both randomised and retrospective. After careful consideration however, the CoGEN forum [6] has distributed guidelines for the sensible use of PGS based on the balance of the available evidence. The overwhelming opinion among the IVF community is acceptance of the evidence that, for certain patient groups, offering PGS is more beneficial than not offering it.

The Panorama programme mentions that only one add-on treatment has an evidence base behind it, but fails to mention that this is the case for PGS. Without this caveat, it gives the impression of viewing PGS as completely unsupported by published evidence, which is misleading. We also question the wisdom of only highlighting the opinion of one lab, known opponents of PGS, without providing balance by also presenting the evidence base in favour of PGS.

We are strong advocates of evidence based medicine (EBM) and thus subscribe to the view that medical practice should be supported by “well designed and well conducted studies” - the widely accepted definition of EBM. We point out however that the quality of study design is relatively easy to assess by reading a manuscript. Whether the study has been well conducted however is considerably more difficult. The 10 year old Mastenbroek study [7] (the only one cited in the Panorama programme) is a clear example: if one mines the evidence provided in the manuscript it gives a clear indication that it is their practice of cleavage stage embryo biopsy, not the screening for chromosome abnormalities per se, that led to reduced IVF success and pregnancy rates. What the Mastenbroek study and its follow-ups gave the world therefore was the evidence base to question the use of cleavage stage embryo biopsy for PGS, not to discontinue PGS completely. Indeed questions remain to this day about the extent to which the reduction in IVF caused by the use of cleavage stage biopsy was a generic issue or specific to the individuals performing the trial. In any event, PGS has moved on in the last 6 years to using trophectoderm biopsy – an improved procedure - and whole karyotype screening (array CGH, qPCR and next generation sequencing) – a totally different and more accurate chromosome assessment techniques, these are the ones that provide evidence for its benefit. Even today however PGS remains a complex procedure, not only requiring a robust genetic test, but, critically, the need for high quality embryological practice.

Where we would like to engage in dialogue with the Oxford group is how EBM should be viewed and interpreted in the context of reproductive medicine (and for PGS specifically). In a field where the outcome measure is the likelihood of achieving a live birth of a healthy child, we point out that there are countless individual components that can, in our collected experience, have a profound effect on IVF success. To assess each individually by randomised controlled trials (RCTs) would be prohibitively costly both in terms of time and money. A possible consequence might be that patients would be denied the opportunity to consider the highest quality treatment until the trial was published (and no doubt criticised further), which would be far too late for many. The ESTEEEM trial8 is a good example where this has yet to be published because of criticisms of its recruitment strategy, mixed skill variance and now out of date technology as the field has moved away from array CGH and towards sequencing.

In conclusion therefore, we would like to offer the hand of collaboration to the Oxford group in the hope of working together to consider the evidence base that supports IVF innovations in general (and PGS in particular) in its unique setting. Together we feel we can consider the relative value of single centre and retrospective studies and the possible pitfalls surrounding relying on RCTs alone. As a final point, we also ask the community to consider the implications of not implementing PGS, for instance the harm that could be caused to a patient who has an adverse outcome (e.g. trisomic conceptus), assuming that they could, and would, have chosen to avoid this, had PGS been offered.

We all want every patient entering an IVF clinic to be given the highest possible chance of a healthy live birth. The national average in the UK is ~28%, which is 50% lower than some clinics offering PGS and publishing their data on single embryo transfer only. We feel that with an open minded, pragmatic approach to EBM, we can elevate success rates further.

1. Heneghan C and colleagues. Lack of evidence for interventions offered in UK fertility centres BMJ 2016;355:i6295

2. Lee E, Illingworth P, Wilton L, Chambers GM. (2014). 'The clinical effectiveness of preimplantation genetic diagnosis for aneuploidy in all 24 chromosomes (PGD-A): systematic review'. Hum Reprod. 30(2):473-83.

3. Dahdouh EM, Balayla J, García-Velasco JA. (2015). 'Comprehensive chromosome screening improves embryo selection: a meta-analysis.'
Fertil Steril. 104(6):1503-12.

4. Chen M, Wei S, Hu J, Quan S. (2015). 'Can Comprehensive Chromosome Screening Technology Improve IVF/ICSI Outcomes? A Meta-Analysis.'
PLoS One. 15;10(10).

5. Chang J, Boulet SL, Jeng G, et al. (2016). Outcomes of in vitro fertilization with preimplantation genetic diagnosis: an analysis of the United States Assisted Reproductive Technology Surveillance Data, 2011–2012 Fertil Steril. 105(2):394-400.

6. http://www.ivf-worldwide.com/cogen/general/cogen-statement.html

7. Mastenbroek S, Twisk M, van Echten-Arends J, et al (2007). 'In vitro fertilization with preimplantation genetic screening'. N Engl J Med. 5;357(1):9-17 | 05 July 2007

8. https://www.eshre.eu/Data-collection-and-research/ESTEEM/About-ESTEEM.aspx

Competing interests: The corresponding author does not have competing interests (as he is an academic researcher) other than being treasurer of the Preimplantation Genetic Diagnosis International Society (PGDIS) and a collaborator with clinics that perform PGS, including individuals in the other list. The remainder of the author list contains clinicians and PGS practitioners and well as members of laboratories who's business is to process PGS samples.

21 December 2016
Darren Karl Griffin
Professor of Genetics
Simon Fishel, CARE Fertility Group, UK; Tony Gordon, Genesis Genetics, UK, USA; Yuval Yaron, Genetic Institute, Tel Aviv Sourasky Medical Center, Israel; Jamie Grifo, NYU Fertility Center, USA; Ariel Hourvitz, Sackler School of Medicine, Tel Aviv, Israel; Svetlana Rechitsky, Reproductive Genetic Innovations, Illinois, USA; Janine Elson, CARE Fertility Group, UK; Joshua Blazek, Genesis Genetics; Francesco Fiorentino, Genoma Group, Molecular Genetics Laboratories, Rome, Italy; Nathan Treff, Reproductive Medicine Associates of New Jersey, USA; Santiago Munne, Reprogenetics, USA; Milton Leong, McGill University, Montreal, Canada; Andreas Schmutzler, Kiel University and gyn-medicum IVF Center, Goettingen, Germany; Attila Vereczkey, Versys Clinics Human Reproduction Institute, Budapest, Hungary; Tarek Ghobara, University Hospital Coventry and Warwickshire, UK; László Nánássy, Versys Clinics Human Reproduction Institute Hungary; Michael Large, Cooper Genomics, USA; Samir Hamamah, INSERM, Montpellier, France; Robert Anderson, Southern California Center for Reproductive Medicine, USA; Luca Gianaroli, S.I.S.Me.R. Reproductive Medicine Unit, Bologna, Italy Dagan Wells, University of Oxford, NIHR Biomedical Research Centre, UK
University of Kent
School of Biosciences