‘Lack of evidence for interventions offered in UK fertility centres’ paper challenged

BMJ publishes response from the fertility sector

The BMJ published my response to its paper entitled ‘Lack of evidence for interventions offered in UK fertility centres’. The letter is co-authored by some of the UK’s leading fertility specialists.

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

To The Editor, BMJ

Dear Dr Godlee

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

We are writing to express our concern regarding the papers by Heneghan et al, (2016) and Spencer et al (2016) owing to their lack of scientific robustness.

We would like to state at the outset that we oppose the provision of procedures or treatments that do not have a scientific basis and we welcome the initiative by the Human Fertilisation and Embryology Authority (HFEA), which has been endorsed by the British Fertility Society (BFS), to introduce a grading scheme for “add-ons”.

Spencer, Heneghan and colleagues have unfortunately obscured their important message by mixing various categories of treatment, not all of which come under the category of “add-ons”. Indeed, a number are accepted components of routine treatment. The papers have grouped together three categories of care: (i) necessary investigations (e.g. assessment of ovarian reserve, which is vital in determining correct dosage of ovarian stimulation drugs to optimise outcome and ensure patient safety), (ii) essential treatments (e.g. surgical sperm retrieval) and (iii) interventions that can be termed “add-ons” – namely an addition to a pathway of care, whether as an additional drug or therapeutic procedure. Many of the items identified have a clearly defined role in specific situations; e.g. for a man with a physical blockage sperm has to be extracted surgically, frozen and used in an IVF cycle combined with intra-cytoplasmic sperm injection (ICSI). For this group of patients, without those interventions (which are clearly not “add-ons”) IVF cannot happen and looking for improved outcomes is irrelevant. Therefore, the papers are inherently flawed as the basis upon which they are structured is clinically and scientifically unsound.

The BMJ disregarded key points made by one of the referees which should have alerted the authors to fundamental flaws in their enquiry: Quoting Dr Avery’s review “For this paper to have the intended impact, the authors need to decide whether to include all procedures for which centres are charging a fee, or whether as the title suggests, they are going to stick to add-ons, specifically those for which claims of increased live birth rates are made.……., in its current form it [the paper] could easily be dismissed by those it targets as having been written by those with no understanding of the field or the technology ….” It is clear that no specialists in reproductive medicine were involved which is why the authors misunderstood and misinterpreted their task. To quote one co-author this is a clear example of “Bad Science” (Goldacre, 2009).

We are fully aware there may be “add-ons” that are not evidence-based, either because the research has not yet been carried out, or because they have been found to be ineffective (Harper et al 2017). The use of intralipid is one such example. This has been clearly stated by the BFS (Nardo et al 2014) and Royal College of Obstetricians and Gynaecologists (RCOG 2016) and so it is perfectly legitimate to criticise a clinic for offering intralipid. However, when it is only 3 clinics (4%) offering this intervention on their websites, it should be clearly stated that this is not mainstream practice or representative of the whole sector.

Treatments that appear more frequently on websites, such as ICSI and blastocyst culture, and the “add-ons” such as embryoglue and endoscratch do have an evidence base. We can present an analysis of each of the 41 items which clarifies the evidence for many and against some. However, it is important to recognise that, although live birth rate is the key outcome measure recommended by the HFEA and something patients need to know, using live birth as the sole indicator of an evidence base oversimplifies a hugely complex process and fails to recognise the significant scientific research underlying decisions to bring treatments into clinical practice.

We are under no illusion that there are sections of the sector that are commercially driven and offering invalidated, costly “add-ons”. Clinics are inspected and called to account by the HFEA, resulting in greater regulation of the fertility sector than any other area of medicine. Furthermore, the HFEA inspectors examine all written information and consent forms that are given to patients, which will always be a truer reflection of clinical practice than the summaries on websites. In the conclusion of the publications, the authors’ own criteria were not fulfilled. The authors were asked “to carry out an independent review of the evidence for fertility treatments additional to IVF”, which they did not do. They only looked at websites and took no account of information provided to or understood by patients at consultations or in the clinics’ written literature. Whether patient literature should be referenced is an interesting concept, as not even that produced by NICE includes references. Nonetheless, we are absolutely clear that websites must provide accurate information that does not mislead patients.

Had the authors sought the input of specialists in reproductive medicine they would have been able to write scientifically sound papers and contributed to a debate (and associated work by the HFEA and BFS) already underway in the sector. To place an article in the public domain that is highly inaccurate and misrepresents the fertility sector is both misleading and deeply unhelpful to patients.

We strongly believe that these papers should not have been published in their current form. Whilst we welcome scrutiny that contributes accurate analysis and informs the mechanisms by which future advances should be brought into clinical practice, our concern is that this should be conducted in a scientifically robust manner that provides clarity to the topic. Given the rapid advances in reproductive medicine, such work is vital and contributes to the natural evolution of the sector’s regulatory machinery. It is important that we work together to promote ethical and innovative patient care.

The key objectives of the BFS are to promote high quality clinical practice and high quality research. To this end, we would be happy to collaborate with the authors to ensure that their research results in valid conclusions.

Yours sincerely

Adam Balen, MD, DSc, FRCOG.
Professor of Reproductive Medicine and Surgery, Leeds &
Chair of The British Fertility Society (BFS).

Lesley Regan, MD DSc FRCOG FACOG
President of the RCOG,
Professor& Head of Department of Obstetrics and Gynaecology, Imperial College & St Mary’s Hospital,London

Sue Avery PhD FRCPath PGDipLaw – referee of the original paper.
Consultant Embryologist & Director of Birmingham Women’s Fertility Centre.

Peter Braude OBE, FRCOG, FRSB, FMedSci
Emeritus Professor of Obstetrics and Gynaecology, King’s College London

Ian Cooke FMedSci, FRCOG, FRANZCOG (Hon.)
Former Chairman, former President of the British Fertility Society and current Chairman of Trustees
Director of Education, International Federation of Fertility Societies, 2004-2011
Emeritus Professor, University of Sheffield

Grace Dugdale BSc, MA.
Reproductive biologist, London

Susan Seenan, Chief Executive, Fertility Network UK
(The UK support organisation for people with infertility)

Yacoub Khalaf MSc MD FRCOG
Consultant Gynaecologist & Sub-Specialist in Reproductive Medicine and Surgery,
Director of the Assisted Conception Unit & Centre for Pre-implantation Genetic Diagnosis, Guys & St Thomas’ Hospital, London
Member of The HFEA.

Anthony J Rutherford FRCOG
Consultant in Reproductive Medicine & Gynaecological Surgery, Leeds.
Past Chair of The British Fertility Society.
Member of The HFEA.

Peter R. Brinsden MB BS FRCOG
Past-President of the British Fertility Society
Former Medical Director Bourn Hall clinic, Cambridge.

Tim Child MA MD MRCOG
Associate Professor, University of Oxford
Medical Director, Oxford Fertility.

Henry Leese PhD, FRCOG
Professor Emeritus Reproductive Biology, Hull York Medical School
President of The British Fertility Society.

Alison Murdoch MD, FRCOG
Professor of Reproductive Medicine, Newcastle &
Past Chair of The British Fertility Society.

Allan Pacey MBE, PhD, FRCOG ,
Professor of Andrology, Sheffield University.
Past Chair of The British Fertility Society.

Mark Hamilton MD FRCOG
Consultant in Reproductive Medicine, Aberdeen Maternity Hospital.
Past Chair of The British Fertility Society.

David Adamson, MD, FRCSC, FACOG, FACS
Chair, International Committee Monitoring Assisted Reproduction Technology
Past President, American Society for Reproductive Medicine

Bart CJM Fauser, MD, PhD,
Professor of Reproductive Medicine & Gynecology, Utrecht, The Netherlands
Chair WHO Global Guidelines Taskforce for the Management of Infertility.

And (in alphabetical order)

Hossam Abdalla MD, FRCOG
Director & Person Responsible of the Lister Fertility Clinic, London
Past Member of The HFEA.

Ian Aird MB ChB, FRCOG
Consultant Gynaecologist and Person Responsible
Gateshead Fertility Unit, Queen Elizabeth Hospital Gateshead

Valentine Akande PhD MRCOG
Lead Clinician & Person Responsible
Bristol Centre for Reproductive Medicine

Richard A Anderson PhD, FRCOG
Elsie Inglis Professor of Clinical Reproductive Sciences
Head of Section, Obstetrics and Gynaecology, University of Edinburgh,
MRC Centre for Reproductive Health

Harish Bhandari MD MRCOG
Subspeciality Trainee in Reproductive Medicine, Newcastle

N. Ellissa Baskind MD MRCOG
Subspeciality Trainee in Reproductive Medicine, Leeds Teaching Hospitals

Joshua D Blazek PhD
CooperGenomics, Genesis Genetics

Virginia N Bolton MA, PhD
Consultant Embryologist, Honorary Senior Lecturer, KCL
Assisted Conception Unit, Guy’s & St Thomas’ Hospital,
Treasurer of The British Fertility Society

Rachel Cutting MBE, MSc
Consultant Embryologist, Sheffield University Hospitals
Former Chair of The Association of Clinical Embryologists

Dr Melanie Davies MA MRCP FRCOG
Consultant in Reproductive Medicine, HFEA Person Responsible, University College London Hospitals

C Janine Elson MD, FRCOG,
Consultant Gynaecologist and Subspecialist in Reproductive Medicine and Surgery,
Associate Medical Director CARE Fertility Group

Professor Simon Fishel PhD (Cantab) FRSB
Founder, President and Head of R&D for CARE Fertility.

Darren K Griffin PhD, DSc, FRSA, FRSB, FRCPath
Professor of Genetics, School of Biosciences, University of Kent
President of the International Chromosome and Genome Society

Jamie Grifo MD PhD
Professor and Director New York University Fertility Center, New York, USA

Stephen Harbottle PhD
Consultant Clinical Embryologist,
HFEA Person Responsible, Cambridge University Fertility Centre
Chair of the Association of Clinical Embryologists

James Hopkisson MBBS MD MRCOG
Associate Professor, & Sub Specialist in Reproductive Medicine, Nottingham University Hospital; Person Responsible Nurture Fertility

Kanna Jayaprakasan MD MRCOG PhD
Hon. Associate Professor & Subspecialist in Reproductive Medicine,
HFEA Person Responsible, Derby Fertility Unit, Royal Derby Hospital, Derby.

Jason Kasraie PhD
Consultant Embryologist & Andrologist
HFEA Person Responsible, Shropshire & Mid-Wales Fertility Centre
Chair Elect of the Association of Clinical Embryologists

Charles Kingsland MD FRCOG
Professor of Reproductive Medicine
Liverpool Women’s Hospital

Jackson C Kirkman-Brown MBE PhD,
Reader & NIHR/HEE Senior Clinical Fellow in Healthcare Science, College of Medical & Dental Sciences, The University of Birmingham.

Stuart Lavery MBBCh MSc MRCOG
Consultant Gynaecologist, Person Responsible IVF Unit, Hammersmith Hospital
Honorary Senior Lecturer, Imperial College, London.

Christine Leary BSc, PhD, FRCPath
Consultant Embryologist,
The Hull IVF Unit, Hull Royal Infirmary

Sheena E. M. Lewis BSc PhD CBiol FRSB
Emeritus Professor Andrology,
Queen’s University Belfast,
Chair British Andrology Society,
Member of HFEA SCAAC Committee

Gillian Lockwood FRCOG DPhil MA (Oxon)
Medical Director, Midland Fertility

Jane MacDougall FRCOG MD MEd
Consultant Reproductive Medicine, Cambridge University Hospitals,
Head of School, EOE Postgraduate School Obstetrics & Gynaecology, Director of Studies Clinical Medicine, Newnham College Cambridge

Kevin McEleny PhD, FRCS (Urol)
Consultant Urological Surgeon & Andrologist, Newcastle

Alison McTavish RGN, RN
Manager Aberdeen Fertility Centre,
Past Secretary of BRITISH FERTILITY SOCIETY and Chair of Senior Infertility Nurses Group

Enda McVeigh FRCOG
Consultant in Reproductive Medicine, Oxford

Nick S. Macklon MD, FRCOG
Professor of Obstetrics and Gynaecology
University of Southampton
Scientific Director, Complete Fertility Centre.

Steve Maguiness MD, FRCOG
Consultant in Reproductive Medicine, Hull Royal Infirmary

Abha Maheshwari MBBS, MD, FRCOG
Person Responsible & Clinical Lead Reproductive Medicine, Aberdeen Fertility Centre

Raj Mathur MD, FRCOG
Clinical Lead for Reproductive Medicine, Central Manchester NHS Foundation Trust;
Hon. Senior Lecturer, University of Manchester

Dimitrios Mavrelos MD, MRCOG
Consultant in Reproductive Medicine, University College London Hospital

James Nicopoullos BSc MBBS MD MRCOG DFFP
Consultant Gynaecologist, Subspecialist in Reproductive Medicine & Surgery, Lister Fertility Clinic, London

David Polson MD FRCOG
Medical Director, Manchester Fertility

Nick Raine-Fenning PhD, MRCOG
Consultant in Reproductive Medicine & Associate Professor, Nottingham.

PD Dr. med. habil. Andreas G. Schmutzler
Gynecologist, Specialist in Reproductive Medicine and Lawyer, Lecturer
Kiel University for Gynecology, Reproductive Medicine and Ethics

Jane Stewart, MD, FRCOG.
Consultant in Reproductive Medicine, Newcastle
Secretary of The British Fertility Society

Isabel Traynor BA(hons) RGN,
Nurse Representative British Fertility Society.

Geoffrey H Trew FRCOG.
Consultant in Reproductive Medicine & Surgery, Hammersmith Hospital, London.

Attila Vereczkey, MD, MA
Medical Director of Versys Clinics, Human Reproduction Institute, Budapest Hungary
President of the Hungarian Human Reproduction Society
President of International Society of Periconceptional Medicine

Simon Wood MD, FRCOG.
Consultant in Reproductive Medicine, Countess of Chester NHS Foundation Trust

Ephia Yasmin MD, MRCOG
Consultant Obstetrician and Gynaecologist. Sub specialist in Reproductive Medicine.
Clinical Lead, Reproductive Medicine Unit University College London Hospital, London

References

Goldacre B. Bad Science by, 2009, Harper Perennial ISBN: 9780007284870.

Harper, J, Jackson, E, Sermon, K, Aitken RJ, Harbottle, S, Mocanu, E, Hardarson, T, Mathur, R, Viville, S, Vail, A, Lundin, K Adjuncts in the IVF laboratory: where is the evidence for ‘add-on’ interventions? Human Reproduction (2017 in press).

Heneghan C, Spencer EA, Bobrovitz N, Collins D R J, Nunan D, Plüddemann A, Gbinigie OA, Onakpoya I, O’Sullivan J, Rollinson A, Tompson A, Goldacre B, Mahtani K R. Lack of evidence for interventions offered in UK fertility centres. BMJ 2016; 355 doi: http://dx.doi.org/10.1136/bmj.i6295)

Nardo LG, El-Toukhy T, Stewart J, Balen AH, Potdar N. Adjuvants in IVF: evidence for good clinical practice. On behalf of the British Fertility Society P&P Committee. Human Fertiity, 2014; DOI:10.3109/14647273.2015.985454.

RCOG. The role of natural killer cells in human fertility. RCOG Scientific Impact Paper, number 52, November 2016.

Spencer EA, Mahtani K R, Goldacre B, Heneghan C. Claims for fertility interventions: a systematic assessment of statements on UK fertility centre websites. BMJ 2016; 355:i6295 doi:10.1136/bmj.6295.

The original letter published by the BMJ can be seen by clicking on the link below.

http://www.bmj.com/content/355/bmj.i6295/rr-3

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