This week IVF for the treatment of infertility has been in the spotlight following the BBC Panorama programme on Monday 28th November. The programme looked at “add ons” that some clinics offer. However, in my opinion, it was an example of extremely poor journalism, a misrepresentation of what happens in the majority of IVF units and an amazing misunderstanding of the data, that I am surprised was published in the BMJ in its current form – particularly given the comments of the paper’s reviewers (see below). Furthermore, this sort of journalism serves only to frighten patients, who are already very anxious, rather than provide a true representation of the fertility sector. I fully agree that it is only right that treatments that bring new life into the world are carefully scrutinised to make sure they are safe and effective and we do have a strict, yet permissive regulator in the HFEA and a large number of published guidelines, scientific advisory papers and policy and practice papers published in the UK by The National Institute for Health and Care Excellence (NICE), The Royal College of Obstetricians and Gynaecologists (RCOG) and The British Fertility Society (BFS).
The Panorama programme commissioned a piece of research by Professor Carl Heneghan and his team at Centre for Evidence-Based Medicine, Nuffield Department Primary Care Health Sciences, University of Oxford, which has been published as an open access paper by BMJ On Line entitled Lack of evidence for interventions offered in UK fertility centres (BMJ 2016; 355 doi: http://dx.doi.org/10.1136/bmj.i6295) also published on the day of the Panorama programme.
As Chair of the BFS, I was approached several months ago by the Panorama team for an interview about “add ons”. I had a lengthy preliminary discussion with the producer Joseph McAuley and the interviewer Dr Deborah Cohen, who also works for the BMJ and has a position in Kellogg College, Oxford University. They advised me of the Heneghan study, on which they based their programme and which I asked to see but they declined to send it to me. Nonetheless I felt it important to be interviewed in order to be able to present a balanced over-view of fertility practices in the UK, how they are regulated and also to make the point that if there was better NHS funding of treatments, desperate couples would not be forced into the private sector. In the end, I was given less than 30 seconds air time and there was no opportunity provided in the programme for an official view from the sector; furthermore the HFEA had declined to be interviewed.
The BMJ paper looked at information provided on the websites of all IVF centres in the UK and suggests that many investigations and procedures are presented that are extra to the standard IVF treatment, are not properly referenced and may not be evidence based. This is not necessarily a reflection either of what is told to patients who attend those clinics or the written information and other advice that they may be given. Nonetheless this is a wake-up call for us all in needing to ensure that we present clear, reliable and accurate data on our websites and that we do not make unvalidated claims.
I felt very sorry for Dr George Ndukwe, of the Zita West clinic who was filmed secretly by journalists posing as patients for the programme. I have no doubt that both he, Zita West and the rest of her team believe passionately in what they do and have the best interests of their patients at heart. Both the BFS and RCOG have written guidelines on immunology and have advised against the use of intralipid therapy (which incidentally appeared on 3 of the websites examined). Yet the undercover filming left a very bad taste and it would have been much better to have interviewed Dr Ndukwe, who I believe to be an honourable physician and to have challenged him directly, thereby giving him the right to reply.
I felt that the Panorama programme displayed the worst form of journalism and has seriously let both it and the BBC down given that it is heralded as the BBC’s flagship investigative programme. Throughout the programme Deborah Cohen repeatedly stated that “26 of the 27” add-ons cited in Heneghan’s paper were not evidence based and Heneghan himself said that “It was one of the worst examples I’ve ever seen in healthcare. …… Some of these treatments are of no benefit to you whatsoever and some of them are harmful. Only one treatment, called an endometrial scratch, was supported by moderate quality evidence that it would help….”
Also, to quote the BBC: “Long-standing industry critic and fertility pioneer Professor Robert Winston told Panorama that he thinks most add-ons are unnecessary. “So many of them are not justified.”
I wonder how many of those who commented on this paper have actually read it? Figure 1 lists the 41 items looked at of which 27 have been termed interventions. It needs to be pointed out that 14 appeared on only once, 5 on twice, 4 on three times and 2 on four times – often on the same website – in other words the majority of websites did not contain “add-ons” of concern.
See BMJ article graphical representation of the number of claim statements found on 74 fertility treatment websites, by intervention offered (total claims=276), (E A Spencer et al. BMJ Open 2016;6:e013940).
Those working in the field of reproductive medicine will soon see that many of these so called “add-ons” are in fact standard investigations and procedures that are required in certain circumstances. Unfortunately every test and procedure has to be paid for and some which are essential for the proper management of patients coming through for treatment. Again, if the NHS provided better funding this situation would not arise. Indeed I am currently chairing the newly formed NHS England IVF Pricing Development Expert Advisory Group which is exploring a national tariff for IVF. But even now each individual clinic has the freedom to choose what they include within their package of care (e.g. which drugs, culture media, incubator and any “add-ons” etc…) and then have to budget appropriately within the allocated envelope of funding – whether NHS or private.
Furthermore we all know how difficult it is to obtain funding for research in reproductive medicine. Interventions are based on the most up to date knowledge available and there is a huge amount of research taking place that is published, presented at conferences and open to peer review. IVF itself was not proven with randomised trials in the same way that drugs, for example, are tested. In the 1970s, Bob Edwards and Patrick Steptoe tried the IVF technique for eight years before they were successful and received almost no support from the medical research establishment. Even now it is very difficult to get funding for fertility research, yet despite this we are still doing ground breaking work here in the UK. Therefore many of the evolving treatments find their way into clinical practice before they have been subjected to the full rigour of the clinical studies that we would ideally like. As long as we are ensuring that our patients are fully informed and not causing harm, we have to use the evidence available to keep exploring new ways to improve outcomes.
Let us now look at each of the “add ons” cited in the BMJ paper, I have re-arranged them into investigations and procedures and, for those not working in the field, I have added a brief description, although the limit of this article does not enable me to provide a full academic appraisal of each:
Pre-treatment investigations that have a clear role
• Ovarian reserve test/ anti-mullerian hormone and antral follicle count – essential to perform one or other in order to determine appropriate protocol for ovarian stimulation.
• Thyroid antibodies – evidence that thyroid dysfunction influences fertility so a test of thyroid function as a baseline and antibodies in some cases is required.
• Hysteroscopy – may be required if there is concern about the endometrial cavity, usually offered if problems have been identified in other tests.
• Dummy/mock embryo transfer – a simple procedure to ensure that the cervix can be cannulated, especially if there has been a history of surgery to the cervix.
Pre-treatment investigations that have an uncertain role
• Sperm DNA test – this is still being assessed and evidence for benefit is not clear. Not routinely recommended in BFS guidelines.
• Cytokine testing (Th1, Th2) and treatment – role less clear; not a routine test.
• Autoimmunity to the HCG receptor – role less clear; not a routine test.
Other treatments which may have a role in defined situations
• Ovulation induction cycle monitoring – mandatory when providing drugs to stimulate the ovaries.
• Intrauterine insemination (IUI) – there has been much debate about IUI, with mixed evidence and NICE guidelines that many disagree with. The treatment can be considered with appropriate advice and counselling and is required when donor sperm is being used.
• Natural cycle IVF / Modified natural cycle IVF (gentle/light IVF) – there are some advocates for this approach, which can be employed given clear guidance about success rates. True natural cycle IVF offers lower success rates but avoids the use of drugs, which some prefer. Otherwise all IVF should employ the lowest effective dose to stimulate the ovaries.
Standard components of the IVF cycle, that should not be considered as add-ons
• Surgical sperm retrieval – necessary for men with an obstruction, e.g. after vasectomy – otherwise there is no sperm!
• Intra-cytoplasmic sperm injection (ICSI) – standard procedure when there is a significant male factor – no longer debatable.
• Blastocyst culture – has clearly been shown to offer advantages and is not an “add-on”.
• Preimplantation genetic diagnosis (PGD) / Preimplantation genetic diagnosis for aneuploidy screening (PGD-A) – two terms for the same thing, different from PGS and used in defined situations when there is a known genetic problem
• Frozen embryo transfer – not debatable. If there are frozen embryos from the fresh cycle they will require transfer at some stage.
• Vitrification of eggs and embryos – generally considered better than slow freezing.
• Egg/embryo freezing – necessary if there are surplus embryos from the fresh cycle. Egg / embryo freezing for fertility preservation may be required prior to chemotherapy. There is a debate about social egg freezing.
• Sperm freezing – necessary for fertility preservation prior to chemotherapy or after surgical sperm retrieval.
• Ovarian tissue freezing – an alternative to egg freezing for pre-cancer therapy fertility preservation.
• Segmented IVF – role less clear. There has been a suggestion that deferring embryo transfer from the stimulated cycle to a subsequent frozen embryo replacement cycle may be beneficial. Currently the subject of a large RCT in the UK.
Add-ons during treatment that may have a role
• Endometrial scratching – may have a role, especially in repeated implantation failure. A scientific opinion paper published this month by the RCOG explores the effect of endometrial scratch on pregnancy outcomes in women who have experienced recurrent implantation failure and there is convincing evidence of benefit. The current evidence on the value of the procedure in women undergoing their first IVF cycle is lacking and this is the subject of a large RCT in the UK.
• Time lapse embryo imaging (including Primo vision and Embryoscope) – the use of time lapse imaging has been the subject of much interest. There are many embryologists who believe that the information provided may help inform couples about the overall prospects of their embryos even if this does not translate into an improvement in pregnancy rates; some have found a reduction in miscarriage rates and there is no evidence of harm. On the other hand there are those who are sceptical about its use and believe there is no benefit. This is a clear situation where a full explanation is required. For those clinics who offer time lapse routinely to all patients, the price should be included within the envelope of the treatment cycle.
• Adherence compounds (Embryoglue) – a 2015 Cochrane review has actually suggested benefit in live birth rates.
Add-ons during treatment that are of uncertain benefit and/or undergoing evaluation
• Endometrial receptivity array (ERA) – a new technique, not widely offered; requires more research. Promising preliminary data from Spain.
• AneVivo – this is offered in one centre, who state that this permeable medical device allows fertilisation of eggs and sperm in an “optimal maternal environment” with encouraging preliminary results. But also states that the process “might offer no improvement in efficacy and might add unecssaery costs to patients”.
• Oral antioxidant treatment – The Cochrane review states that there is low quality evidence of benefit for supplementation in subfertile men to improve live birth rates.
• Preimplantation genetic screening (PGS V1) / Preimplantation genetic screening (PGS V2) array comparative genomic hybridisation – still being debated and researched; thought by many to have a role in defined situations. Actively being evaluated and new data from large studies anticipated fairly soon.
• Embryogen – a specific culture medium, which appears to require more formal evaluation.
• Intracytoplasmic morphologically selected sperm injection (IMSI) – fine tunes sperm selection for ICSI, is not harmful and may still prove to be beneficial.
• SpermSlow – a semi viscous medium containing Hyaluronan for slowing down the movement an individual sperm. There is currently a very large trial under way to assess optimising the selection of sperm for ICSI.
Add-ons during treatment that are of unproven or no benefit
• Intralipid infusion – A scientific opinion paper published this month by the RCOG calls for more high quality research into the role of natural killer cells in fertility The paper clarifies that uNK cells are different from peripheral blood (PB) natural killer (NK) cells, and that measurements of the latter are of limited value in aiding our understanding of the role of uNK cells in reproductive failure. The paper states that despite much research, the role of uNK cells in pregnancy remains uncertain. The use of intravenous immunoglobulin (IVIg) is not supported by the current evidence and, since it may have serious adverse effects, should not be used.
• Quad therapy – is a combination of medications used to aid luteal support and address “immunological” problems, which requires more formal evaluation.
• Assisted hatching – no longer thought to improve outcome.
• Aspirin – no longer thought to improve outcome.
• Artificial oocyte activation – no longer thought to improve outcome.
The BMJ Open Access enables us to see the referees’ reports, which are worth reading:
The first Reviewer, Professor Cynthia Farquhar from Auckland, New Zealand is also the Coordinating Editor of the Cochrane Menstrual Disorders and Subfertility Group and Co-Chair of the Cochrane Steering Group. She states that “This is an interesting approach to highlight the lack of evidence for much of what is being offered to fertility patients from fertility clinics in the United Kingdom. I am sure that this is no worse than other centres in Europe, the US and in Australia and NZ. The problem with the evidence in much of the literature is widespread confusion about the outcomes and the best way of reporting them. Many studies only report clinical pregnancy rate which is inadequate for a number of reasons but mostly because of the difference from live birth rate. …… The second problem is the denominator as per embryo transfer is common but many treatments don’t get to the stage of an embryo transfer and the denominator is smaller and using a smaller denominator overinflates the size of the benefit. And some treatments reduce the number of embryos such as preimplantation genetic diagnosis (at least the 1.0 version and the jury is still out for the PGS 2.0 as no satisfactory RCT done yet) ….. Many of the studies have undeclared COIs. But I don’t have much evidence for this as they are not required to be disclosed. But with companies doing their own studies on new stuff such as GM-CSF and time lapse systems and ERA then there are fairly obvious opportunity for bias. …… Re the gaps in the Cochrane reviews – we are aware of several of these and in fact do have titles in progress for GMCSF, freeze all cycles, intralipid, the intravaginal incubator and ERA. It is just hard to keep up with all the new and slightly unusual interventions that keep on popping up. This paper is very useful and will help us set next year’s priorities for our group and reminds us that women need this information…..”
The second reviewer, Dr Sue Avery, Director of Birmingham Women’s Fertility Centre is spot on when she states “This paper addresses an important and controversial issue. The majority of patients requiring IVF and other forms of assisted conception either have to or choose to fund their own treatment, and a number of adjuncts have been developed with variable quantity and quality of evidence, which must inevitably, also be paid for. Given the emotive nature of this treatment there is considerable potential for exploitation, intentional or unintentional. The authors of this paper are aiming to address the quality of evidence associated with “add-ons”, and to make suggestions as to how this problem could be addressed by the regulator. This is very welcome.
“However, the paper loses some of its power due to the inclusion of treatments that fall outside of the scope of “add-ons”. The methodology has led them to five interventions for which there may be some evidence of improvement in live birth rates. One of these is intrauterine insemination in a natural cycle. This is an alternative treatment, rather than an “add-on”, and usually not one applied to the population who require IVF, and certainly not one intended to increase live birth rate. Ovulation induction and cycle monitoring, which is included in the overall list of add-ons, is similarly a different treatment modality, and not an “Add-on”. …… percutaneous epididymal sperm aspiration/ testicular sperm extraction. Again, this is not an “add-on” as such, but an essential element of treatment for men with obstructive azoospermia or testicular failure. It attracts an additional cost, but only for those for whom it is essential.
“Hysteroscopy is a diagnostic procedure. NICE guidance runs as follows: Women should not be offered hysteroscopy on its own as part of the initial investigation unless clinically indicated because the effectiveness of surgical treatment of uterine abnormalities on improving pregnancy rates has not been established.  Hysteroscopy is not intended to increase pregnancy rates in the sense of other add-ons. There may be some dispute with regard to the significance of uterine abnormalities, but it still does not fit the definition of an “add-on”. It is a quite separate procedure from the IVF, and is usually part of the process of understanding why natural conception has not taken place.
“Other treatments included in the list, which are not intended to increase live birth rate, but serve another practical purpose, include ovarian tissue freezing, a means of fertility preservation, similarly egg, embryo and sperm freezing, and vitrification, which is merely an alternative method of cryopreservation. Sperm freezing is essential in the use of donated sperm, for screening purposes, and may also be used where the male partner is likely to have difficulties providing a sample on the day of treatment, not to increase the live birth rate. Pre-implantation genetic diagnosis (PGD), as opposed to pre-implantation genetic screening (PGS), is intended to avoid the birth of children with serious genetic diseases/conditions, not to improve the live birth rates.
“Finally, the mention of the ovarian tumours as a risk relating to ICSI should be clarified, as this is identified by NICE as being potentially associated with IVF and ICSI, and not specific to ICSI, as the paper implies. 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, other than IVF, 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. The message they seek to purvey is undoubtedly both important and sound when the argument is narrowed down. However, in its current form it could easily be dismissed by those it targets as having been written by those with no understanding of the field or the technology (something that would actually be a strength if the paper were rationalised.) The conclusions with regard to possible actions by NICE and the HFEA are sound, and anticipate a move by the HFEA to return to live births as a headline figure as opposed to pregnancy rates. For the sake of patients this subject should be aired, and I hope the authors will understand that my comments are intended to strengthen their argument.”
In summary, in my opinion, at least 20 of the so called “add-ons” are either part of standard treatment, or of potential benefit and many of the others are being carefully evaluated in clinical trials. The Panorama programme repeatedly said that 26 out of 27 were of no value. They obviously did not feel the need to obtain clarification from any specialists in reproductive medicine, which significantly weakens the whole thrust of their argument and reflects extremely poor journalism. Furthermore Dr Avery’s comments to the authors make this abundantly clear and have been ignored. This is not to say that the world of IVF medicine has no room for improvement, of course it does. It is simply a question of providing a balanced appraisal of the evidence.
Infertility is a disease caused by a large number of different conditions and there are three patients involved in one treatment: the father, the mother, and the embryo, all requiring consideration and adding complexity to the drive for evidence-based medicine. The field of reproductive medicine and IVF is evolving continuously and now there are more than 6 million babies in the world who have been born from IVF. The rapid advancement of science in this area means there will always be work to do to assess how quickly to bring new treatments into clinical practice.
Sadly there is insufficient funding provided by the NHS. Furthermore the amount of funding varies widely around the country – there really is a “post code lottery” and a huge amount of unfairness. Overall, this year has seen sustained disinvestment in England. Only 17% of clinical commissioning groups (CCGs) fund 3 cycles, another 17% fund 2 cycles, 63% fund only one cycle and 3% currently fund no treatment at all. Things have got better in Scotland, with three full cycles being funded and the rest of the UK now has to catch up. What many don’t realise is that IVF treatment isn’t as costly as you think and the results are improving all the time. The British Fertility Society (BFS) has been campaigning for a long time together with the national patient group Fertility Network UK and the Fertility Fairness campaign to try to improve the situation in the UK.
Unlike patients with cancer, diabetes or heart disease, many people are therefore required to self-fund their treatment and this is when it can be confusing as the information provided by different clinics can vary quite a bit. The funding landscape was the much needed context missing from the media coverage this week, which conflated evidence-based medicine with treatment costs. New treatments are always being evaluated and it is important that patients receive full information about everything that is offered. That includes the current evidence for benefit and whether there are any side effects or risks associated with it – and also how much it might cost. It may be true that some clinics are charging for treatments that aren’t yet fully proven and this needs to be explained fully to patients.
It is the role of the BFS and of healthcare professionals to support and provide reliable information on any treatment being considered. There are some treatments that still need more research into their effectiveness and so they need to be properly explained. The sector recognises this and the national regulator, the Human Fertilisation & Embryology Authority (HFEA) is currently developing a system to allow patients to easily understand how much evidence there is behind the treatments on offer. It isn’t necessarily wrong to offer these new approaches provided full information is provided. Those looking after fertility patients have their best interests at heart. The BFS produces a number of patient information leaflets offering up-to-date information and explanations of complex scientific topics, based upon comprehensive policy and practice papers:
If people would like to support infertile couples in accessing the very best treatments without breaking the bank, we strongly recommend campaigning for the NHS to observe the NICE guidelines in funding treatment. We also encourage our senior politicians in the Commons and the Lords to support our quest to improve the situation for our patients. This is the real scandal in the world of infertility medicine.
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