A Systematic Assessment of Statements on UK Fertility Centre Websites

BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from

Claims for fertility interventions: a systematic assessment of statements on UK fertility centre websites.

ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2016-013940

Article Type: Research

Date Submitted by the Author: 18-Aug-2016

Complete List of Authors: Spencer, Elizabeth; University of Oxford, Primary Care Health Sciences Mahtani, Kamal; University of Oxford, Department of Primary Health Care Sciences Goldacre, bben; University of Oxford, Primary Health Care Heneghan, Carl; Oxford University, Primary Health Care

Primary Subject Communication Heading:

Secondary Subject Heading: Reproductive medicine

fertility, evidence-based medicine, patient information, Reproductive Keywords: medicine < GYNAECOLOGY

http://bmjopen.bmj.com/

on October 4, 2021 by guest. Protected copyright.

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 1 of 32 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from

1 2 3 4 Claims for fertility interventions: a systematic assessment of statements on UK 5 6 fertility centre websites. 7 8 9 Spencer EA1, Mahtani KR1, Goldacre B1, Heneghan C1 10 11 12 13 Corresponding author 14 [email protected] 15 For peer review only 16 17 1 18 Centre for Evidence-Based Medicine, 19 20 Nuffield Department of Primary Care Health Sciences, University of Oxford, Radcliffe Primary Care 21 Building, Radcliffe Observatory Quarter, Woodstock Road, Oxford OX2 6GG 22 23 Tel. 01865 289300 24 25 26 27 28 29 30 31 32 33 34

35 http://bmjopen.bmj.com/ 36 37 38 39 40 41 42

43 on October 4, 2021 by guest. Protected copyright. 44 45 46 47

48 49 50 Word count, excluding title page, abstract, references, figures and tables = 2,805 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 32 BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from

1 2 3 ABSTRACT 4 5 6 7 Background 8 9 10 Fertility services in the UK are offered by over 200 HFEA-registered NHS and private clinics. Whilst IVF 11 12 and ICSI form part of NICE guidance many further interventions are offered. We aimed to record claims 13 of benefit for interventions offered by fertility centres via information on the centres’ websites, and 14 15 record what evidenceFor was cited peer for these claims. review only 16 17 18 19 Methods 20 21 22 We obtained from HFEA a list of all UK centres providing fertility treatments and examined their 23 24 websites. We listed fertility interventions offered in addition to standard IVF and ICSI, and recorded 25 statements about interventions that claimed or implied improvements in fertility in healthy women. We 26 27 recorded which claims were quantified, and the evidence cited in support of the claims. Two reviewers 28 29 extracted data from websites. We accessed websites from 21 December 2015 to 31 March 2016. 30 31 32 Results 33 34

35 http://bmjopen.bmj.com/ 36 We found 233 websites for HFEA-registered fertility treatment centres, of which 152 (65%) were 37 excluded as duplicates or satellite centres, two were andrology clinics and five were unavailable or 38 39 under construction websites. In total, 74 fertility centre websites, incorporating 1,401 web-pages, were 40 41 examined for claims. We found 282 claims of benefit relating to 42 different fertility interventions made 42 by 60 of the 74 centres, (median 3 per website; range 0 to 10). Quantification was given for 79 (28%) of

43 on October 4, 2021 by guest. Protected copyright. 44 the claims. 16 published references were cited 21 times on 13 of the 74 websites. 45 46 47 48 Conclusions 49 50 51 Many fertility centres in the UK offer a range of treatments in addition to standard IVF procedures, and 52 53 for many of these interventions claims of benefit are made. In most cases the claims are not quantified 54 and evidence is not cited to support the claims. There is a need for more information on interventions to 55 56 be made available by fertility centres, to support well informed treatment decisions. 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 32 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from

1 2 3 Strengths and limitation of this study 4 5 6 • We accessed all HFEA registered fertility centre websites available in the UK that provide IVF and 7 8 treatment information 9 10 • Two reviewers assessed the websites assessed all of the extracted claims and resolved issues by 11 12 discussion 13 • Different reviewers may disagree in categorising some statements as claims, but it is unlikely 14 15 that the patternFor of findings peer would change review substantially. only 16 17 • Web pages are subject to change over time, and a different set of reviewers might locate further 18 19 intervention claims that we missed. 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34

35 http://bmjopen.bmj.com/ 36 37 38 39 40 41 42

43 on October 4, 2021 by guest. Protected copyright. 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4 of 32 BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from

1 2 3 4 5 BACKGROUND 6 7 8 9 Approximately 1 in 7 UK couples have problems conceiving, [1] and increasing age is one factor that 10 contributes to this. Approximately 98% of women, aged between 19 to 26 years, and having regular 11 12 intercourse, will conceive naturally within two years. However, this figure drops to 90% for women aged 13 14 between 35 to 39 years. [2] Other factors that can affect fertility include ovulatory, tubal, uterine or 15 For peer review only 16 peritoneal disorders as well as male related factors. However, in approximately 25% of couples, there is 17 no identified cause of the infertility. [1] 18 19 20 21 Current UK NICE guidelines advocate that women with unexplained infertility, who have not conceived 22 after two years of regular sexual intercourse, be offered NHS treatment. This may be through medical, 23 24 surgical or assisted conception techniques. For women under 40 years of age, the latter includes 3 full 25 26 cycles of in vitro fertilisation (IVF), with or without intra-cytoplasmic sperm injection (ICSI). [3] 27 28 29 In general, fertility treatments include an array of interventions that seek to aid conception, or treat 30 31 infertility, or subfertility, with the specific aim of increasing the live birth rate or the pregnancy rate 32 33 (sometimes called “clinical pregnancy rate”) as well as conception or survival of cultured embryos or 34 blastocysts. Treatments often involve ovulation stimulation and monitoring, in vitro fertilisation itself 35 http://bmjopen.bmj.com/ 36 (sometimes via intracytoplasmic injection ICSI) and replacement of resulting embryos or blastocysts into 37 38 the uterus. 39 40 41 In addition to these standard treatments, a range of additional investigations and treatments may be 42

43 offered at UK fertility treatment centres. All centres, whether they provide private, NHS or both types of on October 4, 2021 by guest. Protected copyright. 44 45 services, are registered with the Human Fertilisation and Embryology Authority (HFEA), the independent 46 regulator that oversees fertility treatment and research in the UK. [4] However, despite this regulation it 47 48 has been suggested that some of these interventions - offered beyond routine IVF - may not best serve 49 50 patients, as they are not based on evidence of effectiveness, are costly, and some clinics might be using 51 52 IVF techniques that have not been stringently tested. [5] Furthermore, the HFEA recommends that some 53 treatments, such as reproductive immunology, are only used in the context of clinical trials.[6] 54 55 Given the concerns over the evidence base underpinning fertility treatments as well as the implications 56 57 for couples undergoing these treatments, and the resources needed to fund them, we set out to 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 5 of 32 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from

1 2 3 systematically identify and document claims made by UK fertility centres on the effectiveness of 4 5 treatments offered on their websites as the first information source for individuals. We went on to 6 7 identify the evidence that the centres use to support their claims. Finally, using this information, we 8 9 have conducted a follow up study examining the credibility of the claim statements when compared 10 with the published evidence of effectiveness. 11 12 13 14 METHODS 15 For peer review only 16 17 Identification of fertility claims 18 19 We obtained a list of all UK centres providing fertility treatments from the HFEA website [4]. No centres 20 were excluded. Where it was clear that a primary fertility centre had satellite centres offering 21 22 treatments, we restricted our searching for claims to their main website. We examined the websites for 23 24 each of these centres and for each intervention additional to IVF that was offered. We extracted 25 26 statements that suggested or claimed improvements in fertility in healthy women. These included 27 statements relating to increased conception rate, increased rate of “clinical pregnancy”, or relating to 28 29 increased live birth rate. 30 31 32 Inclusion and exclusion criteria for claims 33 34 We defined a claim as a statement that implicitly or explicitly asserted that an intervention provides 35 http://bmjopen.bmj.com/ 36 enhanced effectiveness in relation to either increased conception rate, implantation rate, pregnancy 37 38 rate, or live birth rate. A list was made of all claims identified on the first website. In the websites 39 accessed subsequently, these claims were all searched for, and additional claims identified were added 40 41 to the list. In this way the list of claims increased as the search continued through the list of fertility 42

43 centres. on October 4, 2021 by guest. Protected copyright. 44 45 46 We excluded claims of effectiveness for: 47 48 ● IVF itself and its associated standard treatment ICSI 49 50 ● Freezing of sperm or eggs 51 ● Donation of sperm or eggs 52 53 ● Nutrition advice, acupuncture or hypnotherapy 54 55 ● Interventions in women with pre-existing disease such as diabetes or diagnosed conditions such 56 57 as polycystic ovarian syndrome, or neurological conditions such as spinal cord injury 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 6 of 32 BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from

1 2 3 ● Genetic testing of inherited disorders 4 5 ● Interventions for women experiencing recurrent miscarriage. 6 7 8 Data extraction 9 10 Two reviewers (ES and CH) independently listed interventions offered and extracted claims for the 11 12 interventions. We accessed websites from 21 December 2015 to 31 March 2016, and accessed each 13 14 website on one date only. When a website cited external evidence and provided a link to this, we 15 recorded this link.For We extracted peer a copy of the reviewclaims, and a list of the only webpages viewed into a single 16 17 Google data sheet. We recorded methodological issues and important contextual information relating to 18 19 claims into the data sheet and analysed some of the emerging themes. 20 21 22 We counted the number of web pages accessed, the total number of claims per site, the presence or 23 24 absence of quantification of the benefits for a given claim, and the number of external references cited 25 26 to justify claims. Clarification of the presence of a claim was achieved through discussion between the 27 reviewers (ES and CH). For each intervention, we then collated all of the claims and counted the number 28 29 of fertility centres making a claim of benefit. We counted the number of websites giving a quantification 30 31 of effect for a claim they made, how many websites cited an external reference for their claim and how 32 many references were cited. Using the citations given on the websites we attempted to identify and 33 34 locate the published references cited by the fertility centres. 35 http://bmjopen.bmj.com/ 36 37 38 RESULTS 39 We identified 233 websites for HFEA-registered fertility treatment centres (websites searched 40 41 December 2016), of which 152 (65%) were duplicates or satellite centres (information on these sites 42

43 referred directly to one of the cohort of included websites). Of the 81 sites we reviewed four (4.9%) on October 4, 2021 by guest. Protected copyright. 44 45 were unavailable; two (2.5 %) were andrology clinics and one website (1.2%) was under construction. 46 Therefore we included a total cohort of 74 (30%) separate websites of centres providing IVF services in 47 48 the UK (See Fig 1 and Web Table 1). 49 50 51 Across these 74 sites we searched 1,401 webpages (median 16 per website; range 1 to 60) that related 52 53 to treatment interventions meeting our inclusion criteria. We found 282 claims of benefit relating to 54 55 fertility interventions made by 60 of the 74 centres (median 3 per website; range 0 to 10). 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 7 of 32 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from

1 2 3 Examples of claims statements are shown in Web Table 2. Some of the claims were moderately direct, 4 5 stating that the intervention increased the likelihood, optimised or increased the chance, of conception 6 7 or pregnancy. For example: "A pre-treatment scan gives the clinician the information they need to decide 8 9 on the most appropriate treatment pathway for you. This allows the team to optimise your chances of 10 achieving a pregnancy." and "Special tests may identify couples who are at risk of these problems. 11 12 Treatment which stimulates the proper immune response (immuno-modulation) in the mother may then 13 14 improve the chances of a successful pregnancy." Rarely, a claim stated that there was a benefit relating 15 to live birth, for example:For "Intralipid peer infusion therapyreview can help to stabilise only your immune system and 16 17 increase your chances of having a baby....It is safe, non-invasive and may help to increase your chance of 18 19 success." Many of the claims were more indirect, suggesting a generalised benefit or improvement, for 20 21 example: "Hyaluranon may also help to isolate mature sperm for use in ICSI (intracytoplasmic sperm 22 injection) cycles helping to increase fertilisation rates". 23 24 25 26 The interventions additional to standard IVF offered on the websites are shown in Web Table 3. 27 Quantification was given for 79 (28%) of the 282 claims. As an example, “chance of an embryo 28 29 transferred to the womb making a baby was found to be increased by more than 50%.” In conjunction 30 31 with the 282 claims, a total of 16 unique references were cited 21 times on 13 of the 74 websites. Web 32 33 Table 4 shows the citations found on the websites and the corresponding references identified, by 34 intervention offered, and shows the category for the highest level of evidence cited. References 35 http://bmjopen.bmj.com/ 36 supported six interventions: IMSI (4 unique publications); endometrial scratching (6 unique publications 37 38 cited in 7 instances by 4 websites); Embryoglue (3 unique references cited in 8 instances by 6 websites); 39 assisted hatching (1 reference cited once on one website); vitrification of human eggs and 40 41 embryos/EVES technique (1 reference cited once on one website) and Embryoscope (1 reference cited 42

43 once on one website). on October 4, 2021 by guest. Protected copyright. 44 45 46 Of the 16 cited references, four were systematic reviews [7, 8, 9, 10]. One was a meta-analysis [11], two 47 48 were randomised trials [12, 13]. Four were reports of prospective observational studies [14-17] and one 49 50 was a report of a non-randomised parallel group intervention study [18]. Two were reports of 51 retrospective cohort studies [19, 20] and two were conference abstracts, of which we were only able to 52 53 locate one [21]. 61 (82%) of the 74 websites provided no references. On the 13 websites that did, the 54 55 number of references cited ranged from one (five sites) to nine references (one site: 56 57 http://cheshirewomenshealth-fertility.co.uk/). 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 8 of 32 BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from

1 2 3 The 282 claims made related to 42 different interventions (Figure 2): eight of these were tests (shown in 4 5 the table on a blue background), six were interventions considered part of NICE recommendations 6 7 (shown on a yellow background), two were classified on reanalysis as not meeting our inclusion criteria 8 9 (nutrition four claims and natural cycle IVF one claim, shown on a purple background) and 26 10 interventions or techniques were classified as additional to standard IVF treatments. Figure 2 shows that 11 12 the five most commonly made claims were for blastocyst culture, ICSI, endometrial scratching, 13 14 Embryoglue and IUI, accounting for 110 (39%) of the overall claims. 15 The eight tests forFor which claims peer were made included review an ovarian reserve only test/AMH and antral follicle 16 17 count, thyroid antibodies, hysterosalpingogram, semen analysis and chromosome tests. For all these 18 19 tests except immunology testing, NICE gives guidance, [2] which was not referred to by any of the 20 21 websites. 22 23 24 Six interventions for which claims were made are also referred to in current NICE recommendations [22] 25 26 and not referred to by the website in relation to claims: intrauterine insemination (IUI) [NICE 27 28 recommendation 1.2.1.2]; intracytoplasmic injection (ICSI) [NICE recommendation 1.11.1.2, cycle 29 monitoring, ovulation induction and cycle monitoring [NICE recommendation 1.5.5.3, 1.5.4.2, 1.12.3.4 30 31 and 1.12.4] and egg freezing and sperm freezing [NICE recommendation 1.16.1 Cryopreservation of 32 33 semen, oocytes and embryos]. NICE guidance on cryopreservation relates to patients preparing to 34 undergo chemotherapy or radiotherapy when it is likely to affect their fertility [NICE recommendation 35 http://bmjopen.bmj.com/ 36 1.16.1.1] and is therefore in most cases not relevant to cryopreservation in non-cancer patients seeking 37 38 help with fertility. 39 40 41 DISCUSSION 42

43 on October 4, 2021 by guest. Protected copyright. 44 45 Summary of findings 46 Our findings demonstrate that whilst many claims were made on the benefits of fertility treatments, 47 48 there was a lack of supporting evidence cited, with the majority of the websites providing no sources for 49 50 claims made. From 74 websites and reviewing 1,401 web pages from UK based centres providing IVF 51 52 treatments, we found a substantial number of claims (282) of effectiveness for interventions additional 53 to standard IVF treatment. Despite 282 claims made across these 74 websites, we identified only 13 54 55 websites where any references were included, which referred to just 16 unique published references. Of 56 57 these 16 references cited, only five were high level systematic review evidence; the remaining 12 were 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 9 of 32 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from

1 2 3 either small prospective or retrospective studies, including two conference abstract reports which 4 5 include only limited information. 6 7 8 Strengths and Weaknesses 9 10 We attempted to execute replicable methods but there are some limitations worth noting. Whilst our 11 12 list of websites was provided by the UK regulator, web pages do change, and a different set of reviewers 13 14 might locate further intervention claims that we missed, not least because on some sites it is not 15 straightforward toFor locate all treatmentspeer offered. review Different reviewers onlymay disagree in categorising some 16 17 statements as claims, and it is possible that a repeat of our analysis would record a different number of 18 19 claims, but it is unlikely that the pattern of findings would change substantially. In this study we 20 examined only the evidence cited by these websites, we did not examine all available evidence on the 21 22 safety and effectiveness of the interventions for which claims were made. We have therefore followed 23 24 this work with further research to examine the published evidence relating to fertility interventions 25 26 identified in this study as being currently offered by regulated clinics, and to investigate whether the 27 claims of benefit can be substantiated. 28 29 30 31 Context of previous findings 32 33 34 Previous studies have shown that couples undergoing reproductive treatment are not well informed, 35 http://bmjopen.bmj.com/ 36 particularly when it comes to the risks of treatment. [23] A Dutch questionnaire survey of 1,499 couples 37 38 concluded that information provision for infertile couples is currently poor and in need of improvement: 39 on average only half were aware of national fertility guideline based recommendations, [24] and 40 41 strategies to improve uptake of guidelines had so far proved to be ineffective. [25] Surveys have also 42

43 shown that the success rates of reproductive treatments are often overestimated, and that IVF couples on October 4, 2021 by guest. Protected copyright. 44 45 often want to decide independently whether or not the particular risks and burden of interventions are 46 acceptable. [25, 26] Qualitative studies have also shown that many women start IVF treatment with 47 48 unrealistic expectations of the effectiveness of treatments. [27] 49 50 51 A survey of women undergoing fertility treatments in university hospitals and private fertility clinics in 52 53 Canada reported that most women “wanted to share knowledge equally with their doctors about 54 55 possible fertility treatments.” About half the woman wanted to make decisions mostly by themselves, 56 57 [28] which emphasizes the importance of high quality online information and access to relevant 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 10 of 32 BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from

1 2 3 evidence. Previous work has found there is insufficient information on the web for couples to 4 5 adequately inform themselves about available treatment options; but also that the overwhelming 6 7 majority of infertile couples use the internet to look for information relevant to their situation; and 8 9 those that do want a better understanding of fertility problems. [29] This survey of 163 couples with 10 fertility problems in Holland reported that many couples felt the internet improved their knowledge 11 12 about fertility treatments and facilitated decision-making [30] However, similar to our findings, an 13 14 analysis of the Society for Assisted Reproductive Technology websites in the US reported that the 15 majority did not meetFor the American peer Medical Associationreview (AMA) Internet only health information guidelines. 16 17 [30] Furthermore, that analysis of 263 sites found that the “quality of the hospital centers' websites was 18 19 better than that of private clinics”. 20 21 22 Implications 23 24 Current NICE guidance on fertility treatments, under “Principles of Care: Providing Information”, states 25 26 that: “people should have the opportunity to make informed decisions regarding their care and 27 treatment via access to evidence-based information.” [22] The best current evidence shows that the 28 29 information provided to potential patients on fertility centre websites is likely to be a primary 30 31 information source for most individuals seeking medical help with fertility. This information should 32 33 therefore ideally be of high quality, provide evidence for claims, and state its limitations. This is currently 34 not the case. Whereas in the UK it is mandatory for fertility clinics to publish their success rates, there is 35 http://bmjopen.bmj.com/ 36 no requirement to cite national guidance or relevant evidence. It may be that there is a need for 37 38 regulatory oversight of the evidence on fertility clinics provided to couples through the web to ensure 39 accuracy and timeliness of the information. Ideally, regulatory bodies should require that information 40 41 provided on these websites is accurate, reflects the highest level of available evidence, and links to 42

43 national guidance where appropriate. on October 4, 2021 by guest. Protected copyright. 44 45 46 Conclusions 47 48 Many fertility centres in the UK offer a range of treatments in addition to standard IVF procedures, and 49 50 for many of these interventions claims are made, implying or stating a benefit. In most cases these 51 claims are made without referring to any evidence to support them. Fertility treatment centres should 52 53 provide information based on the best available evidence, citing sources including NICE guidance where 54 55 appropriate, and should state the limitations of what is known about interventions offered. The fertility 56 57 regulator takes an active role on ensuring data for success rates is correct and correctly reported; they 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 11 of 32 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from

1 2 3 could, and in our view should, do the same for evidence given by clinics to patients about the benefits 4 5 and risks of interventions. 6 7 8 ACKNOWLEDGMENTS 9 10 We thank Deborah Cohen and Joseph MacCauley of the BBC for their helpful discussion in formulating the protocol 11 and the manuscripts 12 COMPETING INTERESTS 13 14 ES has no competing interests. Carl Heneghan has received expenses from the WHO and holds grant 15 For peer review only 16 funding from the NIHR, the NIHR School of Primary Care Research and the WHO. BG has received 17 18 research funding from the Wellcome Trust, the NIHR School of Primary Care Research, the Laura and 19 John Arnold Foundation, NHS England, and the Health Foundation; he receives personal income from 20 21 speaking and writing for lay audiences on problems in science. 22 23 FUNDING 24 This project received no specific funding. Carl Heneghan receives funding from the National Institute of 25 26 Health Research (NIHR) School of Primary Care Research; BG has received research funding from the 27 28 Wellcome Trust, the NIHR School of Primary Care Research, the Laura and John Arnold Foundation, NHS 29 30 England, and the Health Foundation; and Kamal Mahtani is funded by a NIHR clinical lectureship. 31 32 33 CONTRIBUTIONS 34

35 CH and ES conceived the study design, extracted and analysed the data. BG, KM, CH and ES all http://bmjopen.bmj.com/ 36 37 contributed to the methods, and the writing of the manuscript. All authors approved the final draft 38 39 40 DATA SHARING AGREEMENT 41 42 A copy of the full web table of data extraction of each website is available upon request from the

43 on October 4, 2021 by guest. Protected copyright. corresponding author 44 45 46 47 48

49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 12 of 32 BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from

1 2 3 REFERENCE LIST 4 5 6 7 [1] http://cks.nice.org.uk/infertility#!topicsummary NICE National Institute for Health and Care 8 Excellence. Clinical Knowledge Summaries. Infertility. Last revised April 2013. 9 10 [2] https://www.nice.org.uk/guidance/cg156/chapter/Recommendations#initial-advice-to-people- 11 12 concerned-about-delays-in-conception Accessed 18 August 2016. NICE guidelines [CG156] Fertility 13 14 problems: assessment and treatment. Published date: February 2013 Last updated: August 2016. 1.2 15 Initial advice to peopleFor concerned peer about delays review in conception. only 16 17 [3] https://www.nice.org.uk/guidance/cg156/chapter/Recommendations#initial-advice-to-people- 18 19 concerned-about-delays-in-conception Accessed 18 August 2016. NICE guidelines [CG156] Fertility 20 problems: assessment and treatment. 2013 1.11 Access criteria for IVF. 1.11.1 Criteria for referral for IVF 21 22 1.11.1.3 [new 2013] 23 24 [4] http://www.hfea.gov.uk/ Accessed 18 August 2016. HFEA Human Fertilisation and Embryology 25 26 Authority. 27 [5] Some clinics using techniques not stringently tested. http://www.dailymail.co.uk/health/article- 28 29 3592661/The-great-IVF-rip-Clinics-preying-anxious-couples-selling-add-ons-not-work-harmful.html 30 31 Accessed 18 August 2016. Daily Mail. The great IVF rip-off. 32 33 [6] http://www.hfea.gov.uk/fertility-treatment-options-reproductive-immunology.html Accessed 18 34 August 2016. HFEA. Reproductive immunology - Natural killer cells - Fertility. 35 http://bmjopen.bmj.com/ 36 [7] Nastri CO, Lensen SF, Gibreel A, Raine-Fenning N, Ferriani RA, Bhattacharya S, Martins WP. 37 38 Endometrial injury in women undergoing assisted reproductive techniques. Cochrane Database of 39 Systematic Reviews 2015, Issue 3. Art. No.: CD009517. DOI: 10.1002/14651858.CD009517.pub3 40 41 [8] Potdar N, Gelbaya T, Nardo LG. Endometrial injury to overcome recurrent embryo implantation 42

43 failure: a systematic review and meta-analysis. Reprod Biomed Online. 2012 Dec;25(6):561-71 on October 4, 2021 by guest. Protected copyright. 44 45 [9] Bontekoe S, Blake D, Heineman MJ, Williams EC, Johnson N. Adherence compounds in embryo 46 transfer media for assisted reproductive technologies. Cochrane Database Syst Rev. 2010;7:CD007421 47 48 [10] Carney SK, Das S, Blake D, Farquhar C, Seif MM, Nelson L. Assisted hatching on assisted conception 49 50 (in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI)). Cochrane Database of Systematic 51 52 Reviews 2012, Issue 12. Art. No.: CD001894. DOI: 10.1002/14651858.CD001894.pub5. 53 [11] Souza Setti A, Ferreira RC, Paes de Almeida Ferreira Braga D, de Cássia Sávio Figueira R, Iaconelli A 54 55 Jr, Borges E Jr. Intracytoplasmic sperm injection outcome versus intracytoplasmic morphologically 56 57 selected sperm injection outcome: a meta-analysis. Reprod Biomed Online. 2010 21(4):450-5. 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 13 of 32 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from

1 2 3 [12] Antinori M, Licata E, Dani G, Cerusico F, Versaci C, d’Angelo D, Antinori S. Intracytoplasmic 4 5 morphologically selected sperm injection: a prospective randomized trial. Reproductive Biomedicine 6 7 online. 2008; Vol 16 No 6: 835-841 8 9 [13] Karimzadh MA et al. Endometrial local injury improves the pregnancy rate among recurrent 10 implantation failure patients undergoing in vitro fertilisation/intra cytoplasmic sperm injection:a 11 12 randomised clinical trial. Aust N Z J Obstet Gynaecol. 2009 Dec;49(6):677-80 13 14 15 [14] Barash A, DekelFor N, Fieldust peer S, Segal I, Schechtman review E, Granot I.Local only injury to the endometrium 16 17 doubles the incidence of successful pregnancies in patients undergoing in vitro fertilization.Fertil Steril. 18 19 2003 Jun;79(6):1317-22. 20 [15] Bartoov B, Berkovitz A, Eltes F, Kogosowski A, Menezo Y, Barak Y. Real-Time fine morphology of 21 22 motile human sperm cells is associated with IVFICSI outcome..J Androly 2002; 23:1-8 23 24 [16] Gnainsky Y et al. Local injury of the endometrium induces an inflammatory response that promotes 25 26 successful implantation. Fertil Steril 2010 Nov;94(6):2030-6 27 [17] Zhou L, Li R, Wang R, Huang HX, Zhong K. Local injury to the endometrium in controlled ovarian 28 29 hyper stimulation cycles improves implantation rates. Fertil Steril. 2008 May;89(5):1166-76 30 31 [18] Bartoov B, Berkovitz A, Eltes F, Kogosowski A, Menezo Y, Barak Y Pregnancy rates are higher with 32 33 intracytoplasmic morphologically selected sperm injection than with conventional intracytoplasmic 34 injection.Fertil Steril 2003 Dec;80(6):1413-9 35 http://bmjopen.bmj.com/ 36 [19] Chian RC, Huang JY, Tan SL, Lucena E, Saa A, Rojas A, Ruvalcaba Castellón LA, García Amador MI, 37 38 Montoya Sarmiento JE. Obstetric and perinatal outcome in 200 infants conceived from vitrified oocytes. 39 Reprod Biomed Online. 2008 May;16(5):608-10 40 41 [20] Meseguer M1, Rubio I, Cruz M, Basile N, Marcos J, Requena A. Embryo incubation and selection in a 42

43 time-lapse monitoring system improves pregnancy outcome compared with a standard incubator:a on October 4, 2021 by guest. Protected copyright. 44 45 retrospective cohort study. Fertil Steril. 2012 Dec;98(6):1481-9.e10. doi: 46 10.1016/j.fertnstert.2012.08.016 47 48 [21] Sun HX, Hu YL, Zhang NY, Wang B. A retrospective clinical study on effects of hyaluronan-containing 49 50 transfer medium on implantation, pregnancy and delivery. IFFS 2010 (conference poster abstract, 51 52 available at http://www.kup.at/kup/pdf/9085.pdf, page 66/147. Accessed August 2016) 53 [22] https://www.nice.org.uk/guidance/cg156?unlid=373307668201622815432 Accessed 18 August 54 55 2016. NICE guidelines [CG156] Fertility problems: assessment and treatment. Published February 2013, 56 57 last updated August 2016. 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 14 of 32 BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from

1 2 3 [23] Rauprich O, Berns E, Vollmann J. Information provision and decision-making in assisted 4 5 reproduction treatment: results from a survey in Germany. Hum Reprod. 2011;26: 2382–2391. 6 7 [24] Mourad SM, R.P.M.G. H, Cox-Witbraad T, R.P.T.M. G, W.L.D.M. N, Kremer JAM. Information 8 9 provision in fertility care: a call for improvement. Hum Reprod. 2009;24: 1420–1426. 10 [25] Mourad SM, Hermens RPMG, Liefers J, Akkermans RP, Zielhuis GA, Adang E, et al. A multi-faceted 11 12 strategy to improve the use of national fertility guidelines; a cluster-randomized controlled trial. Hum 13 14 Reprod. 2011;26: 817–826. 15 [26] Stoebel-RichterFor Y, Yve S-R, peer Kristina G, Ada review B, Elmar B, Kerstin W. onlyWhat Do You Know about 16 17 Reproductive Medicine? – Results of a German Representative Survey. PLoS One. 2012;7: e50113. 18 19 [27] Peddie VL. A qualitative study of women’s decision-making at the end of IVF treatment. Hum 20 21 Reprod. 2005;20: 1944–1951. 22 [28] Stewart DE, Rosen B, Irvine J, Ritvo P, Shapiro H, Murphy J, et al. The disconnect: infertility patients’ 23 24 information and the role they wish to play in decision making. Medscape Womens Health. 2001;6: 1. 25 26 [29] Haagen EC. Current Internet use and preferences of IVF and ICSI patients. Hum Reprod. 2003;18: 27 28 2073–2078. 29 [30] Huang JYJ, Discepola F, Al-Fozan H, Tulandi T. Quality of fertility clinic websites. Fertil Steril. 30 31 2005;83: 538–544. 32 33 34

35 http://bmjopen.bmj.com/ 36 37 38 39 40 41 42

43 on October 4, 2021 by guest. Protected copyright. 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from

Page 15 of 32 BMJ Open Figure 1. Flowchart of 233 websites identified as HFEA-registered 1 websites included in the fertility treatment centers 2 analysis 3 4 5 152 websites excluded for being 6 duplicates or satellite centres 7 8 For peer review only 9 81 websites reviewed 10 11 12

13 7 were not reviewed:http://bmjopen.bmj.com/ 14 4 (4.9%) were unavailable; 15 2 (2.5%) were andrology clinics 16 1 website (1.2%) 17 was under construction. 18 19 20 21 22 on October 4, 2021 by guest. Protected copyright. 23 5 websites were found on 24 detailed examination to 25 comprise satellite services and 26 were therefore excluded from 27 28 74 websites examined for data extraction, given further analysis. 29 an ID and a data sheet created for each ID 30 31 32 33 34 35 36 37 38 39 40 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from

BMJ Open Page 16 of 32

1 2 Figure 2. No. of claims statements found on 74 fertility treatment websites, by intervention offered (total claims=282) 3 Blastocyst culture 4 ICSI 5 Endometrial Scratching EmbryoGlue ® 6 Intrauterine insemination (IUI) 7 Egg/ embryo freezing 8 Chromosome screening/array CGH/preimplantation genetic screening 9 Assisted hatching 10 vitrification of human eggs and embryos/EVES technique ForEmbryoscope peer review only 11 Time lapse embryo imaging (including primo vision) 12 Intracytoplasmic morphologically selected sperm injection (IMSI) Frozen Embryo Transfer (FET); Frozen Embryo Replacement (FER)

13 http://bmjopen.bmj.com/ 14 Surgical sperm retrieval MESA TESA PESE Micro TESE 15 Ovulation induction & cycle monitoring Nutrition 16 Early Embryo Viability Assessment (Eeva™) 17 Sperm freezing 18 Modified natural cycle IVF (Gentle/Light IVF) 19 Ovarian reserve test/AMH & antral follicle count Endometrial Receptivitiy Array (ERA) 20 Intralipid infusion 21 Preimplantation genetic diagnosis PGD on October 4, 2021 by guest. Protected copyright. 22 Hysterosalpingogram, HyCoSy & hysteroscopy 23 Thyroid antibodies 24 Sperm DNA Test/ SpermComet SpermSlow™ 25 PICSI 26 Reproductive Immunology 27 Ovarian tissue Freezing 28 Clotting (thrombophilia) screen 29 Immune testing Cytokine testing (Th1, Th2) 30 Autoimmunity to the HCG receptor 31 Oxidative stress levels in semen (ROS test) 32 Dummy/mock embryo transfer 33 Artificial Oocyte Activation (AOA) 34 Embryogen AneVivo TM 35 Quad therapy 36 Natural cycle IVF 37 Segmented IVF 38 0 5 10 15 20 25 30 39 40 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from

30/12/2015 22/12/2016 Date website accessed accessed Date website

ID1 ID1 (website 21/12/2015 unavailable) ID 9 ID 8 ID 8 21/12/2016 ID 7 ID 7 21/12/2016 ID 6 ID 6 21/12/2016 ID 5 ID 5 21/12/2016 ID 4 ID 4 21/12/2016 ID 3 ID 3 21/12/2016 ID 2 ID 2 21/12/2016 ID 24 ID 24 01/04/2016 ID 23 ID 23 03/01/2016 ID 22 ID 22 03/01/2016 ID 21 ID 21 30/12/2015 ID 20 ID 20 30/12/2015 ID 19 ID 19 30/12/2015 ID 18 ID 17 ID 17 30/12/2015 ID 16 ID 16 29/12/2015 ID 15 ID 15 29/12/2015 ID 14 ID 14 29/12/2015 ID 13 ID 13 23/12/2016 ID 12 ID 12 22/12/2016 ID 11 ID 11 22/12/2016 ID 10 ID 10 22/12/2016 project ID

BMJ Open hospital.html - http://bmjopen.bmj.com/ http://www.cambridge-ivf.org.uk/ http://www.hertsandessexfertility.com/ http://burtonfertility.co.uk/ https://www.nbt.nhs.uk/bcrm http://www.brightonfertility.co.uk/ http://www.thebridgecentre.co.uk/ http://www.nuffieldhealth.com/hospitals/brentwood/fertility http://www.genesisivf.co.uk/ http://www.jessopfertility.org.uk/ http://www.bourn-hall-clinic.co.uk/ http://www.bostonplaceclinic.co.uk/ http://www.bmihealthcare.co.uk/fertility http://www.bhamivf.org.uk/ http://www.heartofengland.nhs.uk/fertility-services/ http://www.bathfertility.com/ crosshouse http://www.healthcentre.org.uk/fertility-treatment/find-clinic- http://www.nth.nhs.uk/services/assisted-reproduction-unit/ http://www.argc.co.uk/ http://www.thehewittfertilitycentre.org.uk/ http://www.andrologysolutions.co.uk/ http://www.carefertility.com/ http://www.ivf.org.uk/ http://www.agoraclinic.co.uk/fertility-screening/ http://www.aberdeenfertility.org.uk/ Web address Web on October 4, 2021 by guest. Protected copyright. For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml For peer review only

Cambridge IVF Cambridge Herts and Essex Fertility Fertility Essex Herts and Burton Fertility Fertility Burton Bristol Centre for Reproductive Medicine Medicine forBristol Centre Reproductive Brighton Fertility Associates Associates FertilityBrighton Bridge Centre Centre Bridge Brentwood Fertility Centre Brentwood Genesis IVF Genesis IVF Jessop Fertility Fertility Jessop Bourn Hall Hall Bourn Boston PlaceBoston BMI Chelsfield Park Assisted Conception Unit AssistedPark Conception BMI Chelsfield Birmingham Women's Hospital Hospital Birmingham Women's Heart of England Fertility Services FertilityServices England Heart of Bath Fertility Centre Centre BathFertility Ayrshire Fertility Unit FertilityAyrshire Assisted Reproduction Univt, University Hospital of Hartlepool Univt, Hartlepool University of Hospital Assisted Reproduction Assisted Reproduction and Gynaecology Centre and Assisted Reproduction Hewitt Fertility Centre Hewitt Centre Fertility Andrology Solutions Andrology Albert House AlbertHouse The Lister Fertility Clinic ListerFertilityThe Clinic Agora Gynaecology and Fertility Centre FertilityCentre and Agora Gynaecology Aberdeen Fertility Centre Aberdeen Name of fertility centre centre fertility Name of Web Table: list of included UK HFEA fertility centres centres fertility HFEA UK included of list Table: Web Page 17 of 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from Page 18 of 32

15/02/2016 02/09/2016 02/03/2016

ID 50 ID 50 18/02/2016 ID 49 ID 49 16/02/2016 ID 48 ID 48 16/02/2016 ID 47 ID 47 15/02/2016 ID 46 ID 46 15/02/2016 ID 45 ID 45 15/02/2016 ID 44 ID 44 15/02/2016 ID 43 ID 42 ID 42 15/02/2016 ID 41 ID 41 15/02/2016 ID 40 ID 40 02/10/2016 ID 39 ID 39 02/09/2016 ID 38 ID 37 ID 37 02/08/2016 ID 36 ID 36 02/08/2016 ID 35 ID 35 02/08/2016 ID 34 ID 34 02/06/2016 ID 33 ID 33 02/05/2016 ID 32 ID 32 02/04/2016 ID 31 ID 31 02/03/2016 ID 30 ID 29 ID 29 02/01/2016 ID 28 ID 28 02/01/2016 ID 27 ID 27 01/12/2016 ID 26 ID 26 01/11/2016 ID 25 ID 25 01/11/2016

- health -

fertility.com/ - BMJ Open centre/ - http://bmjopen.bmj.com/ http://www.lfc.org.uk/ http://www.leicesterfertilitycentre.org.uk/ http://www.kingstonacu.org.uk/ https://www.kch.nhs.uk/service/a-z/acu http://southtees.nhs.uk/services/reproductive-medicine/ http://www.ivfhammersmith.com/ http://www.hullivf.org.uk/ z/f/fertility http://www.homerton.nhs.uk/our-services/services-a- http://hsfc.org.uk/ sted-conception/ http://www.guysandstthomasprivatehealthcare.co.uk/units/assi http://www.gcrm.co.uk/ http://www.gcrmbelfast.com/ http://www.londonwomensclinic.com/ http://www.fertilityexeter.co.uk/ http://www.fertility-academy.co.uk/ https://www.epsom-sthelier.nhs.uk/assisted-conception-unit Z/EdinburghAssistedConceptionProgramme/Pages/default.aspx http://www.nhslothian.scot.nhs.uk/Services/A- http://www.createhealth.org/ http://www.conceptfertility.co.uk/ http://www.completefertility.co.uk/ http://www.city https://www.manchesterfertility.com/ http://www.chelwest.nhs.uk/services/womens services/assisted-conception-unit-acu http://www.uhcw.nhs.uk/ivf http://www.crgh.co.uk/ http://crgw.co.uk/ on October 4, 2021 by guest. Protected copyright. For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml For peer review only

London Fertility London Centre Leicester Fertility Centre FertilityLeicester Centre Kingston Hospital Associated Conception Unit Conception Hospital Associated Kingston King's Hewitt Fertility Centre Fertility HewittKing's Centre James Cook University Hospital Reproductive Medicine Centre Centre Medicine Reproductive University Hospital James Cook IVF Hammersmith IVF Hammersmith Hull IVF IVF Hull Homerton Fertility Centre Fertility Homerton Harley Street Fertility Clinic Clinic Fertility Harley Street Gusy and St Thomas Assisted Conception Unit Assisted Conception Thomas St Gusy and Glasgow Centre for Reproductive Medicine Medicine for Centre Glasgow Reproductive GCRM Belfast GCRM Belfast London Women's Clinic London Fertility Exeter Exeter Fertility Fertility & Gynaecology Academy Gynaecology Fertility & Epsom and St Helier Assisted Conception Unit Assisted Conception Epsom Helier St and Edinburgh Assisted Conception Unit Assisted Conception Edinburgh Create Health Create Health Concept Fertility Fertility Concept Complete Fertility Fertility Complete City Fertility Manchester Fertility Fertility Manchester Chelsea & Westminster Hospital Assisted Conception Unit Assisted Conception Hospital Westminster & Chelsea Centre for Reproductive Medicine, Coventry Coventry Medicine, Centre Reproductive for Centre for Reproductive and Genetic and Health Centre Reproductive for Centre for Reproduction & Gynaecology Wales Gynaecology & Centre Reproduction for 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from

24/02/2016

ID 74 ID 74 14/06/2016 ID 73 ID 73 to access) (unable 14/06/2016 ID 72 ID 72 14/06/2016 ID 71 ID 71 09/06/2016 ID 70 ID 70 09/06/2016 ID 69 ID 69 16/03/2016 ID 68 ID 68 16/03/2016 ID 67 ID 67 16/03/2016 ID 66 ID 66 16/03/2016 ID 65 ID 65 03/09/2016 ID 64 ID 64 03/08/2016 ID 63 ID 63 03/03/2016 ID 62 ID 62 03/02/2016 ID 61 ID 61 03/02/2016 ID 60 ID 60 03/02/2016 ID 59 ID 59 29/02/2016 ID 58 ID 58 29/02/2016 ID 57 ID 57 24/02/2016 ID 56 ID 55 ID 55 23/02/2016 ID 54 ID 54 23/02/2016 ID 53 ID 53 19/02/2016 ID 52 ID 52 23/02/2016 ID 51 ID 51 18/02/2016

BMJ Open

http://bmjopen.bmj.com/ http://www.zitawest.com/ http://www.amandatozer.com/ http://www.fertilityincommunity.org.uk/ http://cheshirewomenshealth-fertility.co.uk/ service-and-assisted-conception-unit/ http://www.cht.nhs.uk/services/clinical-services/fertility- http://www.wessexfertility.com/ http://www.stjudeclinic.com/ http://www.fertilitybristol.com/ tments/ivf/Pages/Home.aspx http://www.plymouthhospitals.nhs.uk/ourservices/clinicaldepar http://www.simply-fertility.com/ http://www.shropshireivf.nhs.uk/ http://www.fertility.salisbury.nhs.uk/Pages/testHome.aspx http://www.reproductivehealthgroup.co.uk/ http://www.rfc.hscni.net/ http://www.nuh.nhs.uk/our-services/services/fertility/ http://www.oxfordfertilityunit.com/ http://www.originfertilitycare.com/ http://www.nurturefertility.co.uk/ http://www.surreyivf.co.uk/ http://www.northmid.nhs.uk/Our-Services/Fertility http://www.acudundee.org/ http://www.newlifeclinic.org.uk/ centre.aspx http://www.newcastle-hospitals.org.uk/services/fertility- http://www.midlandfertility.com/ on October 4, 2021 by guest. Protected copyright. For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml For peer review only

Health Woking Hospital Health Woking

Cheshire Women's Cheshire Health Calderdale Assisted Conception Unit Assisted Conception Calderdale Wessex Fertility Wessex Fertility St Jude's Women's Hospital Women's Hospital Jude's St Fertility Bristol Fertility Bristol South West Centre for Reproductive Medicine Medicine for West Reproductive South Centre Simply Fertility Simply Fertility Shropshire & Mid-Wales Fertility Centre Centre Fertility Mid-Wales & Shropshire Salisbury Fertility Centre FertilitySalisbury Centre Reproductive Health Group Health Reproductive Regional Fertility Centre, Belfast Fertility Centre, Belfast Regional Queens Medical Centre Fertility Unit Unit Centre Fertility Medical Queens Oxford Fertility Unit Oxford Fertility Origin Fertility Care FertilityOrigin Care Nurture Fertility Fertility Nurture Nuffield Nuffield North Middlesex University Hospital Reproductive Medicines Unit Medicines Unit Reproductive University Hospital Middlesex North Ninewells Hospital Assisted Conception Unit Conception Hospital Assisted Ninewells NewLife Fertility Centre NewLife Centre Fertility Newcastle Fertility Centre FertilityNewcastle Centre Midland Fertility Services Fertility Services Midland Zita West Zita West Amanda Tozer Tozer Amanda Fertility in Community Fertility Community in Page 19 of 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from Page 20 of 32

https://www.manchesterfertility.com/ http://www.bourn-hall-clinic.co.uk/ http://www.carefertility.com/ http://www.agoraclinic.co.uk/ http://www.agoraclinic.co.uk/ http://www.nurturefertility.co.uk/ Website and linkWebsite and

ID 15ID ID 4ID ID 2ID ID 2ID ID 29ID ID 57ID Web Table 1)Table Web centre (see centre the fertility the fertility Project ID Project for BMJ Open http://bmjopen.bmj.com/

on October 4, 2021 by guest. Protected copyright. For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml For peer review only "Research has shownmay have positive impactIMSI that a in the following cases: who Men elevated have oflevels fragmentation DNA there haverecurrentWhen been miscarriages implantation Where hasn’t worked on several occasions following ICSI treatment previous embryosWhere developed have poorly high a there’s When number sperm." of abnormal "In general "Ingeneral intrauterine insemination goodis assisteda conception if treatment it is performedto problemovercome of a of lack using sperm ie donor sperm forsevere subfertility,male forwomenand lesbian or single couples. It also successfulis if intercourse is notsuch as occurring in casesnormally of ejaculation dysfunction (ED). Intrauterine insemination issuccessful moderately when for usedmucus cervical hostility when killedsperm are withinIntrauterine cervix. the insemination tends to be less useful thefactor male ifis indication subfertility low numbersie ofor movement sperm in or unexplained infertility." immunologicalreasons failswhy embryo an attach to to the causingwomb develop, and repeated miscarriages. It has been thissuggested that can caused higherby be than levelsnormal of ‘natural killer’ ofcells (a type whiteisof blood that part healthy a cell immune system)and auto-antibodies (antibodies that specific attack organs) and positiveresults reported been have from women treated fortreatment The these. for a positivetestresult involves taking various medicationsgently suppress that thenatural cellkilleractivity in the immune (ID2) system." "this test isthat determineswhethera are increasedyou an at of risk developing blood clots could potentialthat be a of cause miscarriage implantationand (wherefailure the embryo toattach doesn’t the womb develop).and the problemIfis test positive, this be can easilytreated by taking aspirin and/or anticoagulantan (medication that thins the blood) throughout cycle andtreatment pregnancy" earlyyour "A pre-treatment"A scan gives the the clinician information they need to on decide the most appropriate treatment forpathway Thisyou. allowsto the team optimise your "...we good have successa rate for frozen transferbecause procedures, embryo great a chances chances of pregnancy." a achieving Website claim "Immunetesting – there has been lot ofa toresearch to try discover possible Frozen Embryo Transfer Intracytoplasmic morphologically selected sperm injection (IMSI) Intrauterine insemination (IUI) Immune testingImmune Clotting(thrombophilia) screen Ovarian reserve test/AMH and antral follicle count Intervention Table 2.Table Examples ofstatements from recorded claims fertility centre websites accessed 2015December 2016 to March 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from

http://www.bostonplaceclinic.co.uk/ http://www.uhcw.nhs.uk/ivf http://www.jessopfertility.org.uk/ http://www.ivf.org.uk/ http://www.ivf.org.uk/ http://www.conceptfertility.co.uk http://www.argc.co.uk/ ID 14ID ID 27ID ID 3 ID ID 3ID ID 32ID ID 16ID ID 7 ID

BMJ Open http://bmjopen.bmj.com/ on October 4, 2021 by guest. Protected copyright. For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml For peer review only more subtle changes duringseen embryo development and identify the best embryos fortransfer. A new time-lapsetechnology called the Embryoscope™ culturing involves embryos in incubator equippedan with microscope, special cameraa computer. and 2011Available since led the to birthit has already of babies. thousands of Eachhealthy individual separately imagedembryo is monitoredand every 15 minutes allowing subtle changes in development This be to detected. allows selection ofembryos with the "In men "Inwithmen obstructive azoospermia a there ishigh very chance of recovering sperm by this method (>90%).In withmen non-obstructive theazoospermiachances sperm ofis 40%.recovering approximately weIf successfulare sperm the retrieving pregnancyat for rate this treatment similar is very thatto of ICSIsperm."withejaculated "hCG hormone producedis a in pregnancy the early there isand it causes evidence that natural suppression system of to in the immune order assist in the implantation of the embryo in the womb.Areceptor of part a that is cell attachesa the to hormoneto have effect.an exists A theory thepresence that of maternal antibodies against hCG or its receptor may affect implantation, leading failure toto pregnancy a orachieve to miscarriage." you producingare too Th1-typemany immune thiscells may also reduce the chancesof successful we and may againimplantation recommend immunosuppression treatment." "Chromosomal oftenabnormalities the are explanation for unsuccessful so pregnancies, theselectingcorrect embryos improve the can chances ofsuccessful a and implantation birth." deal ofdeal our research effort intogoes ways ofidentifying best the very embryos." hormones regulated, it couplesis that likely will be conceive."to able is the probably leading cause of ininfertility pituitary women. the The gland, hypothalamus and some to extent the thyroid gland affectcontrol hormonal of the reproductive organs and defect of in theseany any may result in problems. The fertility followingconditions affectcan control, the hormonal PCOS (polycystic syndrome),ovary hypothyroidism, luteal phase defect. Often once the irregularity correctedis the and most embryosadvanced forthereby increasingtransfer, ofthe chance thetransferring embryos implant." to likely most "Embryoscope recording – information by time-lapse photography allows us assess to "Leaving the embryos to develop ontoFive enables Day the embryologists theselectto "A hormonal"A quiteimbalance is oftenthe of cause in infertility both women. and men It Embryoscope Surgical sperm retrieval MESA PESETESA Micro TESE Thyroid Thyroid antibodies Autoimmunity Autoimmunity to the human chorionic (hCG)gonatrophin receptor Cytokine testing (Th1, Th2) "Th1 Th2 and arecells immune whosecells is for balance vital maintaining pregnancy. If Chromosome / screening preimplantationgenetic screening PGS Blastocyst culture (FET); also Frozen known as Embryo Replacement (FER) Page 21 of 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from

Page 22 of 32

/ http://www.thehewittfertilitycentre.org.uk http://www.andrologysolutions.co.uk/ http://www.londonwomensclinic.com/ http://burtonfertility.co.uk/ http://www.carefertility.com/ http://www.carefertility.com/ http://www.cambridge-ivf.org.uk/ http://www.ivf.org.uk/ ID 6 ID ID 57ID ID 38ID ID 4ID ID 3 ID ID 22ID ID 4ID ID 24ID

BMJ Open http://bmjopen.bmj.com/

." on October 4, 2021 by guest. Protected copyright. For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml For peer review only nutrients, vitality and also utilises specific superfoodsboost really to the nutrients in your body. thebelieve We that food contributeseat we either positively negativelyor to ofthe eachchemistry and cell every – you what are eat! everythingyou When inis "Increased of levels may ROS be reducedwith change a in lifestyle and diet a rich in anti- oxidants, designedto protect oxidativeagainst stress.Randomised placebo controlled studies shown have that supplementsanti-oxidant can reduce ROS levels spermand damage,DNA andrates. improve pregnancy Treatment of infections also reduce can ROS levels. A large randomisedmenstudy withcompared Ureaplasmaor Chlamydia infection with withoutand antibiotics for3 months.Those treated showed significant a fall in ROS levels, improved sperm significant motility and a increase in pregnancy rates" "Studies so suggest far selectedthat embryos with the help ofhaveimaging time-lapse a highof healthy formingchance a sopregnancy, the technology especiallywill be welcome for patients withpoor record a reproductive - womenthat is, who have beenalready unsuccessful and/or those in ofIVF an reproductiveolder age." uterus. It unique is as high a it containsconcentration of hyaluronan, substance a which is occurring naturally in the uterus known to & be ininvolved implantation. Through our own ourat research partnership Nurture, weclinic shownhave sub-groupsmall that a of patients may benefit from using EmbryoGlue ®.saw They a rise dramatic in pregnancy in rates womenover of the age 34who had previously had unsuccessfulmultiple IVF cycles. Our 2012 pregnancyclinical a rateshow results of 555% day transfers inin this stimulates stimulates theproperimmune response (immuno-modulation) mayin the mother then "CARE Fertilityfreezing has been using embryos thevitrification technique (EVES) for a number years. Thisassociated has been withremarkable a rates. increase in pregnancy " (shell)with around the embryo Thislaser.a creates weak a spotit easier makes which for theembryo inside 'hatch' andto implant in your Ifwomb. theembryo cannot escape fromthe be it towillzona never implant able no matter how good The procedure it is. "The chance"The of pregnancy a after hysterosalpingogrameither ora laparoscopy be may slightly higher in the 2 the fertilityafter or test."3 cycles group; this ofis increase an 19%to the previous compared year." improvethe chances ofsuccessful a pregnancy can eithercan threebe done on or fiveday day ofyour treatment." highest pregnancy potential - so-called morphokinetics." "EmbryoGlue "EmbryoGlue ® medium culture a is that is used transferto your toembryos back the ""The dietfertility we talk about onthecourse you will foodsteach about rich in "Microsurgical assisted hatching involves tearsmall making a in pellucidathe zona Nutrition Oxidative stressOxidative levels in semen (ROS test) Time LapseTime Embryo Imaging (see primo vision)/embryoscope EmbryoGlue ® Reproductive ImmunologyReproductive tests "Special identify may couples risk of at who these are problems. whichTreatment Egg Freezing Egg with the EVES technique assisted hatching hysterosalpingogram (womb x ray) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from

http://www.genesisivf.co.uk/ http://www.oxfordfertilityunit.com/ hospital.html treatment/find-clinic-crosshouse- http://www.healthcentre.org.uk/fertility- http://www.originfertilitycare.com/ tive-medicine/ http://southtees.nhs.uk/services/reproduc http://www.conceptfertility.co.uk http://www.gcrm.co.uk/ ID 9 ID ID 59ID ID 58ID ID 46ID ID 32ID ID 40ID ID 17ID dometrial scratch”dometrial can BMJ Open http://bmjopen.bmj.com/ on October 4, 2021 by guest. Protected copyright. For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml For peer review only important that theimportantlining that of womb (endometrium)the where the embryo is going to implant favourable.is "Itis important thatbe to aware embryosnot theall survive freezing/thawing process but itaroundis do. typically frozen80% Having a that embryo transferred in a subsequentcan be doneeither with cycle withoutor medication. A recent studyin Oxford has confirmed forrates that success both treatments similar. Once are an embryo has thechanceimplanted, ofsuccessful a outcome does be notto appear differentfrom that otherpregnancy."of IVF any and the embryo itself isn’t tested, but the materials around it.provides It effectively a metabolomics profile for to embryos theirdetermine whatquality, does that mean? This profile of measureis the ofa performance the embryo in sense, and a composedis of the end resultsthe pathways of all reactionsand keep that embryo an andalive developing. better The the metabolomics profile of the betterthe embryo, it is functioning so and its better chances to of the leading fulla pregnancy."term patients participating." "Research indicates may improve pregnancyrates increasingby rates the survival of the thawingeggs after from 65%95%." to "Ovulation induction is recommended for whowomen haven’t yet menopause reached ovulating.butaren’t Depending this on your age, treatment is 10-20% successful. For women whose issue fertility only upanovulation, is to 80%of once ovulate patients induced 50%and begin of those We usingby conceive. ultrasoundwhethersee there to ismaturing.... follicle a wouldWe then use the information ultrasoundfrom your to recommend either natural tablets ovulation, or series a of injections toyour encourage body to mature egg. produce a istreatment This often successful and as usedthe is first option infertilitywhentreating due polycysticto ovarian syndromeor other conditions which inhibit ovulation." "EEVA "EEVA is designed to safely identify which most embryos to are todevelop likely blastocyst stage stage – critical a in embryodevelopment that happenstypically on ‘day’ 56. access With or to information, yourthis unique IVF team can more selectaccurately the best embryo(s) for transfer, thisand could your chances successfulimprove for a pregnancy." Recent studiesRecent suggested have simple procedurethat a called “en balance morewe muchlikelyare – become to pregnant pregnant"stay and "A recently"A completed of PICSItrial pregnancy has delivered a rate of 66% of those "The "The metabolomics procedureone, simplea is be can and donewithin fewa minutes, Endometrial Scratching "For IVF/ICSIan to becycle successful, in addition goodtoembryos itquality is also Egg/ Egg/ embryoFreezing outcomes Metabolomics PICSI vitrification of eggs human and embryos Ovulation Induction & Cycle Monitoring EarlyEmbryo Viability Assessment (Eeva™), a subtype oflapse time embryo imaging Page 23 of 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from Page 24 of 32

http://www.bourn-hall-clinic.co.uk/ http://www.lfc.org.uk/ http://www.bourn-hall-clinic.co.uk/ http://www.createhealth.org/ http://www.ivfhammersmith.com/ http://www.bostonplaceclinic.co.uk/ http://www.gcrm.co.uk/ http://www.shropshireivf.nhs.uk/ ID 50ID ID 15ID ID 33ID ID 45ID ID 14ID ID 64ID ID 15ID ID 40ID BMJ Open http://bmjopen.bmj.com/

." on October 4, 2021 by guest. Protected copyright. For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml For peer review only "The sample"The will be frozen embryologists our by technology, using vitrification an "The SpermComet"The test second-generationis a investigation can the that measure actual damage in individual sperm. It help can us to treat andcouplesdiagnose previously faced with ‘Unexplained Infertility’. 1 in 6troublecouples have conceiving as andmany as 25% of thesetrouble to continueeven when have treatment.undergoing fertility In some clinics men offered only are traditional semen a analysisshould and, this show results,normal then thecouple be diagnosed willwith Infertility’. ‘Unexplained Recent chances chances of baby....It a having safe, non-invasiveis may help and to chance increase your of success." "Inorder for fertilisationsuccessful, be to the sperm must specific release functioninga enzyme Phospholipasecalled (PLCζ) C zeta when it egg. entersThis ofinducesthe waves calcium oscillations across the “activate toit”egg allowing tofertilisation take place. A deficient PLCζ abnormal or may be the causeof low failed very or fertilisation. This can be overcome in some situations ionophore calcium using a solution artificially to the activate egg." advanced fast-freezing whichallows for indefinite almost storage. frozen, Once the be spermthawed can your at withdisposal, highrates very survival from thawing." sperm injection) cycles fertilisationhelping increase to rates" (key-hole surgery).(key-hole This tissueimmature containing eggs is then frozen untilsuitable a time which after be transplanted it may (grafted) back theonovary. to This an is experimentalprocedure with fewa reported livebirths." "A small"A the of wombamount tissuefrom lining (endometrium) be can andsampled analysedfor 200thepresence of over withgenesknown be associated implantation. to Studies shown womenhave this that“window some for is shifted of implantation” either earlier lateror in the menstrual cycle, it or isnarrow. very Furthermore, by theplannedmoving embryo transfer the to appropriatechances time, ofsuccessful "Drug treatment of ovulation has failure high successa Patientsrate. should, however, in mindbear take it may several that months to pregnancy thereisa achieve and no guarantee of success." tests shown have that up 80%towith infertility of men unexplained problems have in implantation improvedare boostof the chances implantation."successful "Hyaluranon may also help isolate to mature sperm for inuse(intracytoplasmic ICSI "Intralipid infusion therapy can help to your stabilise immune system andyour increase Sperm DNA Sperm Test/ SpermComet intralipid infusion Artificial OocyteArtificial Activation (AOA) Sperm freezingSperm SpermSlow™ Ovariantissue Freezing "Several small stripsfrom theoutside of removed of one byare the ovaries laparoscopy endometrial Receptivitiyendometrial (ERA)Array Ovulation induction (see above cell ovulation induction cycle and monitoring) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from

https://www.manchesterfertility.com/ http://www.completefertility.co.uk/ http://www.city-fertility.com/ http://www.londonwomensclinic.com/ http://www.crgh.co.uk/ 30 30 ID 31ID ID 38ID ID 26ID BMJ Open http://bmjopen.bmj.com/ on October 4, 2021 by guest. Protected copyright. For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml For peer review only "Itis medium culture a which newrepresents a assistance for whopatients have environment thanks to permeableAneVivo, a medical device,that fluidallow exchanges betweenthematernal environment and the embryo. Restoring thisstage the to womb may result in increase an in the number ofhigh bothembryos, quality on a morphological level genetic and improve the and success preliminary rate....The results are "encouraging. suffered miscarriages. The medium contains the growth (a signaling factor cytokine proteinthat essentially participatesinthe immunologicalresponse the of organism), which has verifiably a positive influence groupon a ofpatients with recurrent spontaneous (GM-CSF),abortions.... The cytokine which included is in the EmbryoGen medium, improves verifiably thedevelopment of the embryo the placenta and it isand notto threat a the cultivation of Thishuman embryos. broad-acting cytokine creates an environment for the embryosin vitro thatcultivated rather resembles the in vivo environment (under conditions)natural thus and of increases the ability to the embryos implant (sink into the remain endometrium) andimplanted (survive continueand to grow in the endometrium)." "IVF "IVF Lite: A low-dose, single embryo transfer, which therisk ofavoids twins counts and on of healthythe delivery a single baby." "The dummy"The embryo transfer run trial isfor a the processtransfer. of embryo is This necessary to establish whether the actual transfer encounterto likely isdifficulties. It also allows measurementsus take to note deviations and/or any of the uterus. the timeWhen comes forthe embryo transfer actual this allowsinformation us to proceed withthe toleast amount the fragile of embryos.trauma Should we encounter resistance theto passage of the maycatheter we recommendthecervix.to dilate ways The use of dilapan/cervical dilatation facilitatesthe procedureembryo transfer thisand helps tothe pregnancy improve rate." their Problemssperm DNA. can be that only detected using the sperm comet test. Things like stress, smoking, recreationalalcohol, drugs, obesity otherand avoidable lifestyle canfactors affect sperm quality. Even healthy sperm some have damage, DNA but it’s the ofamount matters. damage that the What are reasons the test? for having Aswell long a as way going to diagnose Unexplained Infertility, SpermDamage hasDNA nowto also been recurrentlinked Having miscarriage. detailedanalysisa of the sperm damageDNA means thatare weequipped better treat to you andadvice provideto which dramatic make can difference."a "Quad Therapy"Quad a is combination offour different types ofwhich drugs, help addressto 29 ID "Natural "Natural Fertilisation allows fertilisation of the eggs sperm inand optimalmaternalan Quad Quad therapy AneVivoTM Embryogen Embryogen (Gentle/LightIVF) Modified cycle IVF natural Dummy/mockembryo transfer Page 25 of 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from Page 26 of 32

http://www.createhealth.org/ http://www.ivfhammersmith.com/ http://www.createhealth.org/ ID 41ID ID 45ID ID 29ID ID 33ID BMJ Open http://bmjopen.bmj.com/ on October 4, 2021 by guest. Protected copyright. For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml For peer review only "Preimplantationgeneticdiagnosis specialiseda is treatment for couples whoan carry inherited genetic coulddefect that serious cause risks health children,for such their as cystic fibrosis, diseasesickle cell or Huntington’sAssisted disease. The worksConception closely withthe Genetics Department offerto thisthelargestareWe service. mostand "we "we mayhysteroscopy suggest a (passing flexible telescopein a the to womb under general anaesthetic) ifscar tissue we suspect formation theor of presence fibroida or polyp inside the womb whichtoneeds There be removed. isthat this some evidence procedure itself, performingor endometrialan scratch, can increase implantation rates." IVF as firsta the largest option patients. toare We provider CycleofIVF in the Natural UK pioneered have and the practice IVF. of Natural Our Medical Director, Professor Geeta isNargund, one of the world's foremostIVF.Natural expertsCycle on areWe able totreatment tailor with lowno or amounts of stimulation drugs, giving thereby you the best to baby withhave chance a haveyour own successfully We eggs. treated hundreds of women low ovarianwithcritically reserve/low AMH/high haveFSH. alsoWe had some of the oldest IVF mothers in the whoworldhad babies have with owntheir eggs. doWe not any have selection criteria will and woman try toallow any using IVF their own eggs if want stillthey andto ovulating (upare the to age of 50).By avoiding stimulating drugs, the womb is pregnancy.to receptive more also There evidenceis that babies born with Cycle IVF Natural are tolikely bornmore be full with and at term a healthier birth weight." issues clotting and with the immune inyour system bodymay preventingthat be you pregnantbecoming the or pregnancy progressing. Low dose low doseaspirin, Prednisolone, forma of heparin progesteroneworkand together to suppress an immuneoveractive response to pregnancy toa and regulate the inclotting body, your so your embryo canthat grow...notimplant and patients all benefit from it due theto varying ofcauses implantation miscarriage."andfailure By minimisingBy stimulation and putting back embryos in separate cycle,natural thea environment of favourable the uterusmore for is implantation. embryosTransferring intodrug-free healthy a womb a after cycle Natural thatmeans you giving are them the bestof possible chance implantation. hasResearch babiesshownbornthat after transfer cycle in Naturala have statisticallya significant higher birth weight than babies conceived from embryos transferred withinconventional cycle. Ababy’sstimulated a birthweight has long-terma impact on future development."health and "Insegmentation of cycle, the IVF mild embryos putareseparate back in a Natural cycle. "CREATE "CREATE Fertility is the first group of IVF toclinics offer successful safe and Natural Cycle diagnosisPGD Preimplantationgenetic Segmented Segmented IVF wombusing camera) a hysteroscopy(screening of Natural cycle IVF 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from

http://www.gcrmbelfast.com/ ID 39ID BMJ Open http://bmjopen.bmj.com/ on October 4, 2021 by guest. Protected copyright. For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml For peer review only "newer approaches [to arraycomprising PGS] CGH of are significant benefit, the and latest evidence from several clinics been very has encouraging. therehas only So far, been trialone PGS using this sort ofconducted intechnology, the United States. In that study, the chance of embryo transferredan to baby the wombwas making a found be to increased more50%by than cycles in where IVF embryos were chosen for transfer based upon analysis"the results of PGS successfulunit have in for the hadUK We 600PGD. over babies resultborn a of as this treatment."

subtype of PGS hybridisation CGH)(array array comparative genomic Page 27 of 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from

Page 28 of 32

25,39,62,71 25,39,62,71 71 39 25 25 24,25,46,51,62,71 claim claim reference in relation to the the to relation in reference 1 or more external external more or 1 IDs of fertility centres citing citing centres fertility ofIDs

4 1 1 1 8 cited * * cited No. references No.references

1 1 1 1 6

reference reference citing a a citing websites websites No.

1 1

1 1 2 4 4 1 6 4 1 7 9 13 2 12 fied fied quanti claims claims No. 4

BMJ Open

http://bmjopen.bmj.com/

9,58 4 25 2 2 3 3 3,43,57 14,26,40 15,50,51 40,41,74 3,40 3,16 15,26 5,6,22,29,42,65 6,15,40,61,69 15,27,32,33 7,16,22,28,32,36,38,64 7,16,22,28,32,36,38,64 2,3,6,9,15,28,59,62,71 2,29,39,40,41,45,50,62,69 3,6,27,36,38,39,40,42,57 4,6,7,10,13,14,24,25,26,28,30,39,41,51 14,24,25,30,33,38,40,41,42,45,46,51,53 3,6,14,19,25,27,30,33,36,42,45,47,59 3,4,6, 14,26,32,38,39,42,45,50,57,62,74 14,26,32,38,39,42,45,50,57,62,74 3,4,6, 4,6,10,14,22,24,25,28,29,30,39,44,45,46,51,57,59,62,69,71 2,4,7,9,13,14,26,29,30,36,41,42,50,53,54,60,62,64,67 19,23,24,25,26,27,28,32,33,34,36,44,45,48,49,58,59 2,3,4,7,9,10,14,15,22,23,25,26,28,29,30,31,38,39,40,45,46,48,49,53,65 2,4,6,9,10,15,25,27,30,31,33,34,36,38,39,42,43,45,46,48,52,54,64,74 – Project ID) ID) Project – IDs of fertility centres making claims of benefit statement (see webtable 1 webtable (see statement benefit of claims making centres fertility of IDs

2 1 1 1 1 1 1 3 3 3 3 2 2 2 6 5 4 8 9 9 9 14 13 13 14 20 19 17 25 24 centres centres fertility fertility No. 2 14,45 22 10,14,17,23,25,29,31,33,37,39,40,45,49,50,51,57,58,59,62,67,69,71 10 3 6 1 5 4 29,31,33,38 11 4,10,19,22,29,32,36,38,51,58,65

on October 4, 2021 by guest. Protected copyright.

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml injection (IMSI) injection

For peer review only

testing (Th1, Th2) (Th1, testing

reserve test/AMH & antral follicle count follicle antral & test/AMH reserve

PICSI Immunology Reproductive Freezing tissue Ovarian screen (thrombophilia) Clotting testing Immune Cytokine the receptor HCG to Autoimmunity test) (ROS semen in levels stress Oxidative Ovarian Ovarian (ERA) Array Receptivitiy Endometrial infusion Intralipid PGD diagnosis genetic Preimplantation &hysteroscopy HyCoSy Hysterosalpingogram, antibodies Thyroid Test/ SpermComet DNA Sperm SpermSlow™ Nutrition Nutrition (Eeva™) Assessment Viability Embryo Early freezing Sperm IVF) cycle natural IVF(Gentle/Light Modified Intracytoplasmic morphologically selected sperm sperm selected morphologically Intracytoplasmic (FER) Replacement Embryo Frozen (FET); Transfer Embryo Frozen TESE PESE TESA Micro MESA retrieval sperm Surgical monitoring cycle & induction Ovulation Assisted hatching Assisted technique eggs embryos/EVES and human of vitrification Embryoscope vision) primo (including imaging embryo lapse Time screening screening EmbryoGlue ® EmbryoGlue (IUI) insemination Intrauterine freezing Egg/embryo genetic CGH/preimplantation screening/array Chromosome Blastocyst culture Blastocyst ICSI Scratching Endometrial Intervention Intervention Web Table 3. Number of fertility centres making a claim of benefit on their website on benefit claim centres of fertility making a 3. Number Table of Web 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from

BMJ Open http://bmjopen.bmj.com/

33 33 30 31 29 26

1 282 1 1 1 1 1 1 15 on October 4, 2021 by guest. Protected copyright. For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml For peer review only

therapy (more than one website may have cited thereference) may cited same have website one than (more Segmented IVF Segmented Totals * (white IVFtreatments to standard on add as 26 techniques or interventions and (purple) 2 miscellaneous (yellow), NICErecomendations 6 part standard tests 42 8 claims: All (blue), of background) Embryogen Embryogen TM AneVivo Quad IVF cycle Natural Dummy/mock embryo transfer transfer embryo Dummy/mock (AOA) Activation Oocyte Artificial

Page 29 of 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from evidence evidence Page 30 of 32

1a 1c 1a 1a Highest level of level Highest theclaim* for cited

Systematic review Systematic Systematic review Systematic Prospective Prospective observational study, observational non-randomised group parallel study, intervention meta-analysis RCT, Study types cited types Study Systematic review review Systematic 1a RA,

Fenning N,Ferriani Fenning -

analysis. Reprod Biomed Online. 2012 Dec;25(6):561-71 Dec;25(6):561-71 2012 Online. Biomed Reprod analysis. Potdar N, Gelbaya T, Nardo LG. Endometrial injury to overcome overcome to injury Endometrial LG. Nardo T, Gelbaya N, Potdar meta- and review systematic a failure: implantation embryo recurrent Nastri CO, Lensen SF, Gibreel A, Raine A, Gibreel SF, Lensen CO, Nastri undergoing women injury in Endometrial WP. Martins S, Bhattacharya Systematic of Database Cochrane techniques. reproductive assisted DOI: No.: CD009517. Art. 3. Issue 2015, Reviews 10.1002/14651858.CD009517.pub3. Reference(s) we identified we Reference(s) Karimzadh MA et al. Endometrial local injury improves the pregnancy pregnancy the improves injury local Endometrial al. et MA Karimzadh vitro in undergoing patients failure implantation recurrent among rate trial. clinical randomised injection:a sperm cytoplasmic fertilisation/intra R, Wang R, Li L, Zhou Dec;49(6):677-80; 2009 Gynaecol. Obstet NZ J Aust controlled in endometrium the to injury K.Local ZhongHX, Huang Fertil rates. implantation cyclesimproves stimulation hyper ovarian I, Segal S, Fieldust N, Dekel A, Barash May;89(5):1166-76; 2008 Steril. Nastri CO, Lensen SF, Gibreel A, Raine-Fenning N, Ferriani RA, N,Ferriani Raine-Fenning A, Gibreel SF, Lensen CO, Nastri undergoing women injury in Endometrial WP. Martins S, Bhattacharya Systematic of Database Cochrane techniques. reproductive assisted DOI: No.: CD009517. Art. 3. Issue 2015, Reviews 10.1002/14651858.CD009517.pub3. Bartoov B, Berkovitz A, Eltes F, Kogosowski A, Menezo Y, Barak Y.Real- Y,Barak Menezo A, Kogosowski F, Eltes A, Berkovitz B, Bartoov with associated cellsis human sperm motile of morphology fine Time 23:1-8 2002; Androly outcome..J IVFICSI Y Y,Barak Menezo A, Kogosowski F, Eltes A, Berkovitz B, Bartoov morphologically intracytoplasmic with higher are rates Pregnancy intracytoplasmic conventional with than injection sperm selected G, E,Dani Licata M, Antinori Dec;80(6):1413-9. 2003 Steril injection.Fertil Intracytoplasmic S. D,Antinori d’Angelo C, Versaci F, Cerusico randomized prospective a injection: sperm selected morphologically No835-841 6: 16 Vol 2008; online. Biomedicine Reproductive trial. Cássia D,de Braga Ferreira Almeida de RC,Paes Ferreira A, Setti Souza sperm Intracytoplasmic Jr. E Borges Jr, A Iaconelli R, Figueira Sávio selected morphologically versus intracytoplasmic outcome injection 2010 Online. Biomed Reprod meta-analysis. a outcome: injection sperm 19. Jun 2010 Epub 10.1016/j.rbmo.2010.05.017. doi: Oct;21(4):450-5. - BMJ Open http://bmjopen.bmj.com/

on October 4, 2021 by guest. Protected copyright. For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml For peer review only Endometrial injury to overcome recurrent embryo implantation failure: a failure: implantation embryo recurrent overcome to injury Endometrial LG. Nardo T, Gelbaya N, Potdar meta-analysis. and review systematic Dec;25(6):561-71 2012 Online. Biomed Reprod a Cochrane review (CD009517) (CD009517) review Cochrane a 10.1002/14651858.CD009517.pub3. 10.1002/14651858.CD009517.pub3. Reviews 2015, Issue 3. Art. No.: CD009517. DOI: DOI: CD009517. No.: Art. 3. Issue 2015, Reviews assisted reproductive techniques. Cochrane Database of Systematic Systematic of Database Cochrane techniques. reproductive assisted Bhattacharya S, Martins WP. Endometrial injury in women undergoing undergoing women injury in WP. Endometrial S, Martins Bhattacharya web link to Nastri CO, Lensen SF, Gibreel A, Raine-Fenning N, Ferriani RA, RA, N,Ferriani Raine-Fenning A, SF,Gibreel CO, Nastri Lensen to link web 3. Bartoov B, Berkovitz A, Eltes F, Kogosowski A, Menezo Y, Barak Y.Real Y,Barak Menezo A, Kogosowski F, Eltes A, Berkovitz B, Bartoov 3. of morphology fine Time Androly outcome..J IVFICSI with cellsis associated sperm human motile 23:1-8 2002; Y Y,Barak Menezo A, F, Eltes Kogosowski A, Berkovitz B, Bartoov 4. with higher are rates Pregnancy with than injection sperm selected morphologically intracytoplasmic intracytoplasmic conventional G, E,Dani M,Licata Dec;80(6):1413-9.Antinori 2003 Steril injection.Fertil Versaci F, Cerusico selected morphologically Intracytoplasmic S. Antinori D, C,d’Angelo a injection: sperm Vol 2008; online. Biomedicine Reproductive trial. randomized prospective 835-841 6: No 16 versus outcome injection sperm Intracytoplasmic al. et Setti 6. morphologically intracytoplasmic Reproductive meta-analysis. a outcome: injection sperm selected 21,Issue Volume Online, BioMedicine 450-455 pp. 4; Citation(s) as found on the website the on as found Citation(s) among recurrent implantation failure patients undergoing in vitro vitro in undergoing patients failure implantation recurrent among trial. clinical randomised injection:a sperm cytoplasmic fertilisation/intra al.Local L et Zhou Dec;49(6):677-80; 2009 Gynaecol. Obstet Z J N Aust cycles stimulation hyper ovarian controlled in endometrium the to injury Barash May;89(5):1166-76; 2008 Steril. Fertil rates. implantation improves of incidence the doubles endometrium the to injury Local et Al. A

ID 71 71 ID rate pregnancy the improves injury local Endometrial . al et MA Karimzadh ID 62 ID ID 39 ID ID 71 ID Website Website ID 25 25 ID

Endometrial Endometrial scratching IMSI Intervention Webtable 4. Citations found on fertility centre websites, and the corresponding references identified, with the level of evidence. evidence. of the level with identified, references corresponding the and websites, centre fertility on found Citations 4. Webtable 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from

2b 1a 1a 1a 1a 2b 1a 1a 2b 2b

atic review atic Case series Case System Systematic review Systematic Systematic review Systematic Systematic review Systematic Retrospective Retrospective Systematic review Systematic study cohort Systematic review Systematic Retrospective Retrospective study cohort

07421 07421 to the endometrium doubles the the doubles endometrium the to

RC, Huang JY, Tan SL, Lucena E, Saa A, Rojas A, Ruvalcaba Castellón Castellón Ruvalcaba RojasA, SaaA, E, Lucena SL, Tan JY, Huang RC,

Chian Das S, Blake D, Farquhar C, Seif MM. Assisted hatching on assisted assisted on hatching Assisted MM. Seif C, D,Farquhar Blake DasS, perinatal and Obstetric JE. Sarmiento Montoya MI, Amador García LA, Biomed oocytes.Reprod vitrified from conceived infants 200 in outcome May;16(5):608-10. 2008 Online. Bontekoe S, Blake D, Heineman MJ, Williams EC, Johnson N. Adherence Adherence N. EC, Johnson Williams MJ, Heineman D, Blake S, Bontekoe Apr 2009 Rev. Syst Database Cochrane ICSI). and (IVF conception Review. 10.1002/14651858.CD001894.pub4. doi: 15;(2):CD001894. 2012;12:CD001894. Rev. Syst Database Cochrane in: Update Bontekoe S, Blake D, Heineman MJ, Williams EC, Johnson N. Adherence Adherence N. EC, Johnson Williams MJ, Heineman D, Blake S, Bontekoe reproductive assisted for media transfer embryo in compounds 2010;7:CD007421 Rev. Syst Database Cochrane technologies. Bontekoe S, Blake D, Heineman MJ, Williams EC, Johnson N. Adherence Adherence N. EC, Johnson Williams MJ, Heineman D, Blake S, Bontekoe reproductive assisted for media transfer embryo in compounds 2010;7:CD007421 Rev. Syst Database Cochrane technologies. compounds in embryo transfer media for assisted reproductive reproductive assisted for media transfer embryo in compounds HX, Sun 2010;7:CD007421; Rev. Syst Database Cochrane technologies. of effects on study clinical retrospective A B. Wang NY, YL, Zhang Hu and pregnancy implantation, on medium transfer hyaluronan-containing at available abstract, poster (conference 2010 IFFS delivery. al.2004 et Balaban 66/147) page http://www.kup.at/kup/pdf/9085.pdf, 2004). for available not ESHRE for archive (online found not Bontekoe S, Blake D, Heineman MJ, Williams EC, Johnson N. Adherence Adherence N. EC, Johnson Williams MJ, Heineman D, Blake S, Bontekoe 2010;7:CD0 Rev. Syst Database Cochrane technologies. studyon clinical retrospective A NY,B. Wang Zhang YL, Hu HX, Sun implantation, on medium transfer hyaluronan-containing of effects available abstract, poster (conference 2010 IFFS delivery. and pregnancy 66/147) page http://www.kup.at/kup/pdf/9085.pdf, at Bontekoe S, Blake D, Heineman MJ, Williams EC, Johnson N. Adherence Adherence N. EC, Johnson Williams MJ, Heineman D, Blake S, Bontekoe reproductive assisted for media transfer embryo in compounds Schechtman E, Granot I. Local injury Local I. Granot E, Schechtman reproductive assisted for media transfer embryo in compounds 2010;7:CD007421 Rev. Syst Database Cochrane technologies. incidence of successful pregnancies in patients undergoing in vitro vitro in undergoing patients in pregnancies successful of incidence Local al. et Y Gnainsky Jun;79(6):1317-22; 2003 Steril. Fertil fertilization. response that inflammatory an induces endometrium the of injury 2010 Nov;94(6):2030-6 Steril Fertil implantation. successful promotes Meseguer M1, Rubio I, Cruz M, Basile N, Marcos J, Requena A. Embryo Embryo A. Requena J, N,Marcos Basile M, I,Cruz M1,Rubio Meseguer improves system monitoring time-lapse a in selection and incubation retrospective incubator:a standard a with compared outcome pregnancy doi: Dec;98(6):1481-9.e10. 2012 Steril. Fertil study. cohort 10. Sep 2012 Epub 10.1016/j.fertnstert.2012.08.016.

BMJ Open http://bmjopen.bmj.com/ analysis from the independent independent the from analysis - meta on October 4, 2021 by guest. Protected copyright. ents undergoing in vitro fertilization. .Fertil .Fertil fertilization. in vitro undergoing ents For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

For peer review only 0282(12)02068-7/pdf 0282(12)02068-7/pdf A recent review of obstetric and perinatal outcomes in 200 infants infants 200 in outcomes perinatal and obstetric of review recent A conceived following egg vitrification cycles Chian et al. 2008 Reprod. Med Med Reprod. 2008 al. et cyclesChian vitrification egg following conceived 16:608-610. Online International Review of the effectiveness of Assisted hatching (conducted (conducted hatching Assisted of theeffectiveness of Review International 2009). in Bontekoe S, Blake D, Heineman MJ, Williams EC, Johnson N. Adherence N.Adherence EC, Johnson Williams MJ, D, Heineman S, Blake Bontekoe reproductive assisted for media transfer embryo in compounds 2010;7:CD007421 Rev. Syst Database Cochrane technologies. A literature study by the independent research institute “Cochrane “Cochrane institute research independent studybythe literature A increased of effects the on results published covering all Collaboration” transfer embryo during hyaluronan The Cochrane Collaboration, an independent research institute, published published institute, research independent an Collaboration, Cochrane The transfer... embryo during hyaluronan increased of effects the on results a with EmbryoGlue® comparing study2004-2008 Retrospective 2010al.IFFS et Sun Ref: ~1300 patients. for medium transfer conventional a with EmbryoGlue® comparing study2004-2008 Retrospective 2010 al.IFFS et Sun Ref: ~1300 patients. for medium transfer conventional Unit, Rep Ass Am Hosp. Balaban B Ref: chart] secondbar also [shows and 2004 ESHRE Turkey Istanbul, Sun et al 2010 al et Sun according to a newly published published newly a to according Collaboration Cochrane network research successful pregnancies in pati in pregnancies successful Cochrane institute research independent studybythe literature A increased of effects the resultson published all covering Collaboration transfer embryo during hyaluronan Steril. 2003 Jun;79(6):1317-22 Gnainsky Y et al. Local injury of the the of injury al.Local et YGnainsky Jun;79(6):1317-22 2003 Steril. successful promotes that response inflammatory an induces endometrium Nov;94(6):2030-6 2010 Steril Fertil implantation.

ID 25 ID ID 39 ID ID 71 ID ID 62 ID ID 51 ID ID 46 ID ID 25 ID ID 24 ID

Embryoscope Embryoscope 25 ID http://www.fertstert.org/article/S0015- paper published of pdf linksto Vitrification of of Vitrification and eggs human embryos/EVES technique Assisted hatching Assisted

Embryoglue Page 31 of 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from Page 32 of BMJ Open http://bmjopen.bmj.com/ on October 4, 2021 by guest. Protected copyright. For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml For peer review only

All or All none§or

b b RCT (with Individual narrow Confidence Interval”¡) 1c * CEBM levels of evidence for therapeutic interventions (http://www.cebm.net/oxford-centre-evidence-based-medicine-levels-evidence-march-2009/) (http://www.cebm.net/oxford-centre-evidence-based-medicine-levels-evidence-march-2009/) interventions therapeutic for evidence of levels CEBM * a 1 (with SR of homogeneity*) RCTs 2a (with SR of homogeneity*) cohortstudies 2b cohort Individual study (including low e.g.,RCT; quality <80%follow-up) 2c “Outcomes” Research; studiesEcological 3a (with SR of homogeneity*) case-control studies 3b Case-Control Individual Study 4 5 Case-series (and cohortpoor quality case-controland studies§§) opinion Expert without appraisal, explicit orcritical based onbench physiology, research “firstor principles” 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from

Claims for fertility interventions: a systematic assessment of statements on UK fertility centre websites.

ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2016-013940.R1

Article Type: Research

Date Submitted by the Author: 23-Sep-2016

Complete List of Authors: Spencer, Elizabeth; University of Oxford, Primary Care Health Sciences Mahtani, Kamal; University of Oxford, Department of Primary Health Care Sciences Goldacre, Ben; University of Oxford, Primary Health Care Heneghan, Carl; Oxford University, Primary Health Care

Primary Subject Communication Heading:

Secondary Subject Heading: Reproductive medicine

fertility, evidence-based medicine, patient information, Reproductive Keywords: medicine < GYNAECOLOGY

http://bmjopen.bmj.com/

on October 4, 2021 by guest. Protected copyright.

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 1 of 33 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from

35 http://bmjopen.bmj.com/ 36 37 38 39 40 41 42

43 on October 4, 2021 by guest. Protected copyright. 44 45 46 47

48 49 50 Word count, excluding title page, abstract, references, figures and tables = 2,805 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 33 BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from

1 2 3 ABSTRACT 4 5 6 7 Objectives 8 Fertility services in the UK are offered by over 200 HFEA-registered NHS and private clinics. Whilst IVF 9 10 and ICSI form part of NICE guidance many further interventions are offered. We aimed to record claims 11 12 of benefit for interventions offered by fertility centres via information on the centres’ websites, and 13 14 record what evidence was cited for these claims. 15 For peer review only 16 17 Methods 18 19 20 We obtained from HFEA a list of all UK centres providing fertility treatments and examined their 21 22 websites. We listed fertility interventions offered in addition to standard IVF and ICSI, and recorded 23 24 statements about interventions that claimed or implied improvements in fertility in healthy women. We 25 recorded which claims were quantified, and the evidence cited in support of the claims. Two reviewers 26 27 extracted data from websites. We accessed websites from 21 December 2015 to 31 March 2016. 28 29 30 31 Results 32 33 34 We found 233 websites for HFEA-registered fertility treatment centres, of which 152 (65%) were

35 http://bmjopen.bmj.com/ 36 excluded as duplicates or satellite centres, two were andrology clinics and five were unavailable or 37 under construction websites. In total, 74 fertility centre websites, incorporating 1,401 web-pages, were 38 39 examined for claims. We found 276 claims of benefit relating to 41 different fertility interventions made 40 41 by 60 of the 74 centres, (median 3 per website; range 0 to 10). Quantification was given for 79 (29%) of 42 the claims. 16 published references were cited 21 times on 13 of the 74 websites. 43 on October 4, 2021 by guest. Protected copyright. 44 45 46 Conclusions 47 48 49 Many fertility centres in the UK offer a range of treatments in addition to standard IVF procedures, and 50 51 for many of these interventions claims of benefit are made. In most cases the claims are not quantified 52 53 and evidence is not cited to support the claims. There is a need for more information on interventions to 54 be made available by fertility centres, to support well informed treatment decisions. 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 33 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from

35 http://bmjopen.bmj.com/ 36 37 38 39 40 41 42

43 on October 4, 2021 by guest. Protected copyright. 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4 of 33 BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from

43 offered at UK fertility treatment centres. All centres, whether they provide private, NHS or both types of on October 4, 2021 by guest. Protected copyright. 44 45 services, are registered with the Human Fertilisation and Embryology Authority (HFEA), the independent 46 regulator that oversees fertility treatment and research in the UK. [4] However, despite this regulation it 47 48 has been suggested that some of these interventions - offered beyond routine IVF - may not best serve 49 50 patients, as they are not based on evidence of effectiveness, are costly, and some clinics might be using 51 52 IVF techniques that have not been stringently tested. [5] Furthermore, the HFEA recommends that some 53 treatments, such as reproductive immunology, are only used in the context of clinical trials.[6] 54 55 Given the concerns over the evidence base underpinning fertility treatments as well as the implications 56 57 for couples undergoing these treatments, and the resources needed to fund them, we set out to 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 5 of 33 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from

43 centres. on October 4, 2021 by guest. Protected copyright. 44 45 46 We excluded claims of effectiveness for: 47 48 ● IVF itself and its associated standard treatment ICSI 49 50 ● Freezing of sperm or eggs 51 ● Donation of sperm or eggs 52 53 ● Nutrition, acupuncture or hypnotherapy 54 55 ● Interventions in women with pre-existing disease such as diabetes or diagnosed conditions such 56 57 as polycystic ovarian syndrome, or neurological conditions such as spinal cord injury 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 6 of 33 BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from

43 referred directly to one of the cohort of included websites). Of the 81 sites we reviewed four (4.9%) on October 4, 2021 by guest. Protected copyright. 44 45 were unavailable; two (2.5 %) were andrology clinics and one website (1.2%) was under construction. 46 Therefore we included a total cohort of 74 (30%) separate websites of centres providing IVF services in 47 48 the UK (See Fig 1 and Web Table 1). 49 50 51 Across these 74 sites we searched 1,401 webpages (median 16 per website; range 1 to 60) that related 52 53 to treatment interventions meeting our inclusion criteria. We found 276 claims of benefit relating to 54 55 fertility interventions made by 60 of the 74 centres (median 3 per website; range 0 to 10). 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 7 of 33 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from

1 2 3 Examples of claims statements are shown in Web Table 2. Some of the claims were moderately direct, 4 5 stating that the intervention increased the likelihood, optimised or increased the chance, of conception 6 7 or pregnancy. For example: "A pre-treatment scan gives the clinician the information they need to decide 8 9 on the most appropriate treatment pathway for you. This allows the team to optimise your chances of 10 achieving a pregnancy." and "Special tests may identify couples who are at risk of these problems. 11 12 Treatment which stimulates the proper immune response (immuno-modulation) in the mother may then 13 14 improve the chances of a successful pregnancy." Rarely, a claim stated that there was a benefit relating 15 to live birth, for example:For "Intralipid peer infusion therapyreview can help to stabilise only your immune system and 16 17 increase your chances of having a baby....It is safe, non-invasive and may help to increase your chance of 18 19 success." Many of the claims were more indirect, suggesting a generalised benefit or improvement, for 20 21 example: "Hyaluranon may also help to isolate mature sperm for use in ICSI (intracytoplasmic sperm 22 injection) cycles helping to increase fertilisation rates". 23 24 25 26 The interventions additional to standard IVF offered on the websites are shown in Web Table 3. 27 Quantification was given for 79 (29%) of the 276 claims. As an example, “chance of an embryo 28 29 transferred to the womb making a baby was found to be increased by more than 50%.” In conjunction 30 31 with the 276 claims, a total of 16 unique references were cited 21 times on 13 of the 74 websites. Web 32 33 Table 4 shows the citations found on the websites and the corresponding references identified, by 34 intervention offered, and shows the category for the highest level of evidence cited. References 35 http://bmjopen.bmj.com/ 36 supported six interventions: IMSI (4 unique publications); endometrial scratching (6 unique publications 37 38 cited in 7 instances by 4 websites); Embryoglue (3 unique references cited in 8 instances by 6 websites); 39 assisted hatching (1 reference cited once on one website); vitrification of human eggs and 40 41 embryos/EVES technique (1 reference cited once on one website) and Embryoscope (1 reference cited 42

43 once on one website). on October 4, 2021 by guest. Protected copyright. 44 45 46 Of the 16 cited references, four were systematic reviews [7, 8, 9, 10]. One was a meta-analysis [11], two 47 48 were randomised trials [12, 13]. Four were reports of prospective observational studies [14-17] and one 49 50 was a report of a non-randomised parallel group intervention study [18]. Two were reports of 51 retrospective cohort studies [19, 20] and two were conference abstracts, of which we were only able to 52 53 locate one [21]. 61 (82%) of the 74 websites provided no references. On the 13 websites that did, the 54 55 number of references cited ranged from one (five sites) to nine references (one site: 56 57 http://cheshirewomenshealth-fertility.co.uk/). 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 8 of 33 BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from

1 2 3 The 276 claims made related to 41 different interventions (Figure 2): eight of these were tests (shown in 4 5 the table on a blue background), six were interventions considered part of NICE recommendations 6 7 (shown on a yellow background), one was miscellaneous (natural cycle IVF, shown on a purple 8 9 background) and 26 interventions or techniques were classified as additional to standard IVF 10 treatments. Figure 2 shows that the five most commonly made claims were for blastocyst culture, ICSI, 11 12 endometrial scratching, Embryoglue and IUI, accounting for 110 (39%) of the overall claims. 13 14 The eight tests for which claims were made included an ovarian reserve test/AMH and antral follicle 15 count, thyroid antibodies,For hysterosalpingogram, peer review semen analysis and chromosomeonly tests. For all these 16 17 tests except immunology testing, NICE gives guidance, [2] which was not referred to by any of the 18 19 websites. 20 21 22 Six interventions for which claims were made are also referred to in current NICE recommendations [22] 23 24 and not referred to by the website in relation to claims: intrauterine insemination (IUI) [NICE 25 26 recommendation 1.2.1.2]; intracytoplasmic injection (ICSI) [NICE recommendation 1.11.1.2, cycle 27 28 monitoring, ovulation induction and cycle monitoring [NICE recommendation 1.5.5.3, 1.5.4.2, 1.12.3.4 29 and 1.12.4] and egg freezing and sperm freezing [NICE recommendation 1.16.1 Cryopreservation of 30 31 semen, oocytes and embryos]. NICE guidance on cryopreservation relates to patients preparing to 32 33 undergo chemotherapy or radiotherapy when it is likely to affect their fertility [NICE recommendation 34 1.16.1.1] and is therefore in most cases not relevant to cryopreservation in non-cancer patients seeking 35 http://bmjopen.bmj.com/ 36 help with fertility. 37 38 39 40 DISCUSSION 41 42

43 Summary of findings on October 4, 2021 by guest. Protected copyright. 44 45 Our findings demonstrate that whilst many claims were made on the benefits of fertility treatments, 46 there was a lack of supporting evidence cited, with the majority of the websites providing no sources for 47 48 claims made. From 74 websites and reviewing 1,401 web pages from UK based centres providing IVF 49 50 treatments, we found a substantial number of claims of effectiveness for interventions additional to 51 52 standard IVF treatment. Despite 276 claims made across these 74 websites, we identified only 13 53 websites where any references were included, which referred to just 16 unique published references. Of 54 55 these 16 references cited, only five were high level systematic review evidence; the remaining 12 were 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 9 of 33 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from

1 2 3 either small prospective or retrospective studies, including two conference abstract reports which 4 5 include only limited information. 6 7 8 Strengths and Weaknesses 9 10 We attempted to execute replicable methods but there are some limitations worth noting. Whilst our 11 12 list of websites was provided by the UK regulator, web pages do change, and a different set of reviewers 13 14 might locate further intervention claims that we missed, not least because on some sites it is not 15 straightforward toFor locate all treatmentspeer offered. review Different reviewers onlymay disagree in categorising some 16 17 statements as claims, and it is possible that a repeat of our analysis would record a different number of 18 19 claims, but it is unlikely that the pattern of findings would change substantially. In this study we 20 examined only the evidence cited by these websites, we did not examine all available evidence on the 21 22 safety and effectiveness of the interventions for which claims were made. We have therefore followed 23 24 this work with further research to examine the published evidence relating to fertility interventions 25 26 identified in this study as being currently offered by regulated clinics, and to investigate whether the 27 claims of benefit can be substantiated. 28 29 30 31 We did not use the Health on the Net Foundation HONcode 32 33 [www.healthonnet.org/HONcode/Conduct.html] to assess websites, as it was outside the scope of this 34 investigation, which may be a limitation of our study. The Health on the Net Foundation promotes the 35 http://bmjopen.bmj.com/ 36 provision of high quality health information. Adherence to the HONcode requires websites to include 37 38 statements on attribution (HON Code principle 4): “Cite the source(s) of published information, date 39 medical and health pages.” In addition, websites should also adhere to the principle of justifiability: “any 40 41 claims relating to the benefits/performance of a specific treatment, commercial product or service will 42

43 be supported by appropriate, balanced evidence in the manner outlined in Principle 4.” Our current on October 4, 2021 by guest. Protected copyright. 44 45 results suggest that none of the websites we reviewed would meet the HONcode requirements. 46 47 48 Context of previous findings 49 50 Previous studies have shown that couples undergoing reproductive treatment are not well informed, 51 particularly when it comes to the risks of treatment. [23] A Dutch questionnaire survey of 1,499 couples 52 53 concluded that information provision for infertile couples is currently poor and in need of improvement: 54 55 on average only half were aware of national fertility guideline based recommendations, [24] and 56 57 strategies to improve uptake of guidelines had so far proved to be ineffective. [25] Surveys have also 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 10 of 33 BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from

1 2 3 shown that the success rates of reproductive treatments are often overestimated, and that IVF couples 4 5 often want to decide independently whether or not the particular risks and burden of interventions are 6 7 acceptable. [25, 26] Qualitative studies have also shown that many women start IVF treatment with 8 9 unrealistic expectations of the effectiveness of treatments. [27] 10 11 12 A survey of women undergoing fertility treatments in university hospitals and private fertility clinics in 13 14 Canada reported that most women “wanted to share knowledge equally with their doctors about 15 possible fertility treatments.”For peerAbout half the womanreview wanted to make only decisions mostly by themselves, 16 17 [28] which emphasizes the importance of high quality online information and access to relevant 18 19 evidence. Previous work has found there is insufficient information on the web for couples to 20 adequately inform themselves about available treatment options; but also that the overwhelming 21 22 majority of infertile couples use the internet to look for information relevant to their situation; and 23 24 those that do want a better understanding of fertility problems. [29] This survey of 163 couples with 25 26 fertility problems in Holland reported that many couples felt the internet improved their knowledge 27 about fertility treatments and facilitated decision-making [30] However, similar to our findings, an 28 29 analysis of the Society for Assisted Reproductive Technology websites in the US reported that the 30 31 majority did not meet the American Medical Association (AMA) Internet health information guidelines. 32 33 [30] Furthermore, that analysis of 263 sites found that the “quality of the hospital centers' websites was 34 better than that of private clinics”. 35 http://bmjopen.bmj.com/ 36 37 38 Implications 39 Current NICE guidance on fertility treatments, under “Principles of Care: Providing Information”, states 40 41 that: “people should have the opportunity to make informed decisions regarding their care and 42

43 treatment via access to evidence-based information.” [22] The best current evidence shows that the on October 4, 2021 by guest. Protected copyright. 44 45 information provided to potential patients on fertility centre websites is likely to be a primary 46 information source for most individuals seeking medical help with fertility. This information should 47 48 therefore ideally be of high quality, provide evidence for claims, and state its limitations. This is currently 49 50 not the case. Whereas in the UK it is mandatory for fertility clinics to publish their success rates, there is 51 no requirement to cite national guidance or relevant evidence. There may be a need for regulatory 52 53 oversight of the evidence on fertility interventions provided to couples by clinics through the web to 54 55 ensure accuracy and relevance of the information. Ideally, regulatory bodies should require that 56 57 information provided on these websites is accurate, reflects the highest level of available evidence, and 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 11 of 33 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from

1 2 3 links to national guidance where appropriate. The situation in countries without such regulatory 4 5 authorities as the HFEA may be worse, and it may be worthwhile replicating this research in other 6 7 settings. 8 9 10 Conclusions 11 12 Many fertility centres in the UK offer a range of treatments in addition to standard IVF procedures, and 13 14 for many of these interventions claims are made, implying or stating a benefit. In most cases these 15 claims are made withoutFor referring peer to any evidence review to support them. Fertilityonly treatment centres should 16 17 provide information based on the best available evidence, citing sources including NICE guidance where 18 19 appropriate, and should state the limitations of what is known about interventions offered. The fertility 20 regulator takes an active role on ensuring data for success rates is correct and correctly reported; they 21 22 could, and in our view should, do the same for evidence given by clinics to patients about the benefits 23 24 and risks of interventions. 25 26 27 ACKNOWLEDGMENTS 28 29 We thank Deborah Cohen and Joseph McAuley of the BBC for their helpful discussion in formulating the 30 protocol and the manuscripts. 31 32 33 34 COMPETING INTERESTS 35 ES has no competing interests. Carl Heneghan has received expenses from the WHO and holds grant http://bmjopen.bmj.com/ 36 37 funding from the NIHR, the NIHR School of Primary Care Research and the WHO. BG has received 38 39 research funding from the Wellcome Trust, the NIHR School of Primary Care Research, the Laura and 40 41 John Arnold Foundation, NHS England, and the Health Foundation; he receives personal income from 42 speaking and writing for lay audiences on problems in science.

43 on October 4, 2021 by guest. Protected copyright. 44 45 46 FUNDING 47 This project received no specific funding. Carl Heneghan receives funding from the National Institute of 48 49 Health Research (NIHR) School of Primary Care Research; BG has received research funding from the 50 51 Wellcome Trust, the NIHR School of Primary Care Research, the Laura and John Arnold Foundation, NHS 52 53 England, and the Health Foundation; and Kamal Mahtani is funded by a NIHR clinical lectureship. 54 55 56 CONTRIBUTIONS 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 12 of 33 BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from

1 2 3 CH and ES conceived the study design, extracted and analysed the data. BG, KM, CH and ES all 4 5 contributed to the methods, and the writing of the manuscript. All authors approved the final draft 6 7 8 9 DATA SHARING AGREEMENT 10 A copy of the full web table of data extraction of each website is available upon request from the 11 12 corresponding author 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34

35 http://bmjopen.bmj.com/ 36 37 38 39 40 41 42

43 on October 4, 2021 by guest. Protected copyright. 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 13 of 33 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from

43 failure: a systematic review and meta-analysis. Reprod Biomed Online. 2012 Dec;25(6):561-71 on October 4, 2021 by guest. Protected copyright. 44 45 [9] Bontekoe S, Blake D, Heineman MJ, Williams EC, Johnson N. Adherence compounds in embryo 46 transfer media for assisted reproductive technologies. Cochrane Database Syst Rev. 2010;7:CD007421 47 48 [10] Carney SK, Das S, Blake D, Farquhar C, Seif MM, Nelson L. Assisted hatching on assisted conception 49 50 (in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI)). Cochrane Database of Systematic 51 52 Reviews 2012, Issue 12. Art. No.: CD001894. DOI: 10.1002/14651858.CD001894.pub5. 53 [11] Souza Setti A, Ferreira RC, Paes de Almeida Ferreira Braga D, de Cássia Sávio Figueira R, Iaconelli A 54 55 Jr, Borges E Jr. Intracytoplasmic sperm injection outcome versus intracytoplasmic morphologically 56 57 selected sperm injection outcome: a meta-analysis. Reprod Biomed Online. 2010 21(4):450-5. 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 14 of 33 BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from

43 time-lapse monitoring system improves pregnancy outcome compared with a standard incubator:a on October 4, 2021 by guest. Protected copyright. 44 45 retrospective cohort study. Fertil Steril. 2012 Dec;98(6):1481-9.e10. doi: 46 10.1016/j.fertnstert.2012.08.016 47 48 [21] Sun HX, Hu YL, Zhang NY, Wang B. A retrospective clinical study on effects of hyaluronan-containing 49 50 transfer medium on implantation, pregnancy and delivery. IFFS 2010 (conference poster abstract, 51 52 available at http://www.kup.at/kup/pdf/9085.pdf, page 66/147. Accessed August 2016) 53 [22] https://www.nice.org.uk/guidance/cg156?unlid=373307668201622815432 Accessed 18 August 54 55 2016. NICE guidelines [CG156] Fertility problems: assessment and treatment. Published February 2013, 56 57 last updated August 2016. 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 15 of 33 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from

35 http://bmjopen.bmj.com/ 36 37 38 39 40 41 42

43 on October 4, 2021 by guest. Protected copyright. 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 16 of 33 BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 Figure 1. Flowchart of websites included in the analysis 33 34 254x190mm (200 x 200 DPI)

35 http://bmjopen.bmj.com/ 36 37 38 39 40 41 42

43 on October 4, 2021 by guest. Protected copyright. 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 17 of 33 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 Figure 2. Nos. of claim statement found

26 155x80mm (300 x 300 DPI) 27 28 29 30 31 32 33 34

35 http://bmjopen.bmj.com/ 36 37 38 39 40 41 42

43 on October 4, 2021 by guest. Protected copyright. 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from

BMJ Open Page 18 of 33

1 2 3 Web Table: list of included UK HFEA fertility centres 4 5 6 Name of fertility centre Web address project ID Date website accessed

7 Aberdeen Fertility Centre http://www.aberdeenfertility.org.uk/ ID1 21/12/2015 (website unavailable) 8 Agora Gynaecology and Fertility Centre http://www.agoraclinic.co.uk/fertility-screening/ ID 2 21/12/2016 9

10 The Lister Fertility Clinic http://www.ivf.org.uk/ ID 3 21/12/2016 11 Albert House For peerhttp://www.carefertility.com/ review only ID 4 21/12/2016 12 13 Andrology Solutions http://www.andrologysolutions.co.uk/ ID 5 21/12/2016

14 Hewitt Fertility Centre http://www.thehewittfertilitycentre.org.uk/ ID 6 21/12/2016 15 Assisted Reproduction and Gynaecology Centre http://www.argc.co.uk/ ID 7 21/12/2016 16

17 Assisted Reproduction Univt, University Hospital of Hartlepool http://www.nth.nhs.uk/services/assisted-reproduction-unit/ ID 8 21/12/2016

18 http://www.healthcentre.org.uk/fertility-treatment/find-clinic- http://bmjopen.bmj.com/ 19 Ayrshire Fertility Unit crosshouse-hospital.html ID 9 22/12/2016

20 Bath Fertility Centre http://www.bathfertility.com/ ID 10 22/12/2016 21

Heart of England Fertility Services http://www.heartofengland.nhs.uk/fertility-services/ ID 11 22/12/2016 22

23 Birmingham Women's Hospital http://www.bhamivf.org.uk/ ID 12 22/12/2016 24 BMI Chelsfield Park Assisted Conception Unit http://www.bmihealthcare.co.uk/fertility ID 13 23/12/2016 25

Boston Place http://www.bostonplaceclinic.co.uk/ ID 14 29/12/2015

26 on October 4, 2021 by guest. Protected copyright.

27 Bourn Hall http://www.bourn-hall-clinic.co.uk/ ID 15 29/12/2015 28

Jessop Fertility http://www.jessopfertility.org.uk/ ID 16 29/12/2015 29

30 Genesis IVF http://www.genesisivf.co.uk/ ID 17 30/12/2015 31 Brentwood Fertility Centre http://www.nuffieldhealth.com/hospitals/brentwood/fertility ID 18 30/12/2015 32 33 Bridge Centre http://www.thebridgecentre.co.uk/ ID 19 30/12/2015

34 Brighton Fertility Associates http://www.brightonfertility.co.uk/ ID 20 30/12/2015 35 Bristol Centre for Reproductive Medicine https://www.nbt.nhs.uk/bcrm ID 21 30/12/2015 36

37 Burton Fertility http://burtonfertility.co.uk/ ID 22 03/01/2016 38 Herts and Essex Fertility http://www.hertsandessexfertility.com/ ID 23 03/01/2016 39 40 Cambridge IVF http://www.cambridge-ivf.org.uk/ ID 24 01/04/2016 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from

Page 19 of 33 BMJ Open

1 2 3 4 Centre for Reproduction & Gynaecology Wales http://crgw.co.uk/ ID 25 01/11/2016

5 Centre for Reproductive and Genetic Health http://www.crgh.co.uk/ ID 26 01/11/2016 6 Centre for Reproductive Medicine, Coventry http://www.uhcw.nhs.uk/ivf ID 27 01/12/2016 7 http://www.chelwest.nhs.uk/services/womens-health- 8 Chelsea & Westminster Hospital Assisted Conception Unit services/assisted-conception-unit-acu ID 28 02/01/2016 9

10 Manchester Fertility https://www.manchesterfertility.com/ ID 29 02/01/2016

11 City Fertility For peerhttp://www.city review-fertility.com/ only ID 30 02/03/2016 12 13 Complete Fertility http://www.completefertility.co.uk/ ID 31 02/03/2016

14 Concept Fertility http://www.conceptfertility.co.uk/ ID 32 02/04/2016 15 Create Health http://www.createhealth.org/ ID 33 02/05/2016 16 http://www.nhslothian.scot.nhs.uk/Services/A- 17 Edinburgh Assisted Conception Unit Z/EdinburghAssistedConceptionProgramme/Pages/default.aspx ID 34 02/06/2016

18 http://bmjopen.bmj.com/ 19 Epsom and St Helier Assisted Conception Unit https://www.epsom-sthelier.nhs.uk/assisted-conception-unit ID 35 02/08/2016

20 Fertility & Gynaecology Academy http://www.fertility-academy.co.uk/ ID 36 02/08/2016 21 Fertility Exeter http://www.fertilityexeter.co.uk/ ID 37 02/08/2016 22

23 London Women's Clinic http://www.londonwomensclinic.com/ ID 38 02/09/2016 24 GCRM Belfast http://www.gcrmbelfast.com/ ID 39 02/09/2016 25

Glasgow Centre for Reproductive Medicine http://www.gcrm.co.uk/ ID 40 02/10/2016

26 on October 4, 2021 by guest. Protected copyright. 27 http://www.guysandstthomasprivatehealthcare.co.uk/units/assi 28 Gusy and St Thomas Assisted Conception Unit sted-conception/ ID 41 15/02/2016

29 Harley Street Fertility Clinic http://hsfc.org.uk/ ID 42 15/02/2016 30 http://www.homerton.nhs.uk/our-services/services-a-

31 Homerton Fertility Centre z/f/fertility-centre/ ID 43 15/02/2016 32 Hull IVF http://www.hullivf.org.uk/ ID 44 15/02/2016 33 34 IVF Hammersmith http://www.ivfhammersmith.com/ ID 45 15/02/2016

35 James Cook University Hospital Reproductive Medicine Centre http://southtees.nhs.uk/services/reproductive-medicine/ ID 46 15/02/2016 36 King's Hewitt Fertility Centre https://www.kch.nhs.uk/service/a-z/acu ID 47 15/02/2016 37

38 Kingston Hospital Associated Conception Unit http://www.kingstonacu.org.uk/ ID 48 16/02/2016 39 Leicester Fertility Centre http://www.leicesterfertilitycentre.org.uk/ ID 49 16/02/2016 40 41 London Fertility Centre http://www.lfc.org.uk/ ID 50 18/02/2016 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from

BMJ Open Page 20 of 33

1 2 3 4 Midland Fertility Services http://www.midlandfertility.com/ ID 51 18/02/2016 5 http://www.newcastle-hospitals.org.uk/services/fertility- 6 Newcastle Fertility Centre centre.aspx ID 52 23/02/2016

7 NewLife Fertility Centre http://www.newlifeclinic.org.uk/ ID 53 19/02/2016 8 Ninewells Hospital Assisted Conception Unit http://www.acudundee.org/ ID 54 23/02/2016 9

10 North Middlesex University Hospital Reproductive Medicines Unit http://www.northmid.nhs.uk/Our-Services/Fertility ID 55 23/02/2016

11 Nuffield Health Woking Hospital For peerhttp://www.surreyivf.co.uk/ review only ID 56 24/02/2016 12 13 Nurture Fertility http://www.nurturefertility.co.uk/ ID 57 24/02/2016

14 Origin Fertility Care http://www.originfertilitycare.com/ ID 58 29/02/2016 15 Oxford Fertility Unit http://www.oxfordfertilityunit.com/ ID 59 29/02/2016 16

17 Queens Medical Centre Fertility Unit http://www.nuh.nhs.uk/our-services/services/fertility/ ID 60 03/02/2016 http://bmjopen.bmj.com/

18 Regional Fertility Centre, Belfast http://www.rfc.hscni.net/ ID 61 03/02/2016 19 20 Reproductive Health Group http://www.reproductivehealthgroup.co.uk/ ID 62 03/02/2016

21 Salisbury Fertility Centre http://www.fertility.salisbury.nhs.uk/Pages/testHome.aspx ID 63 03/03/2016 22 Shropshire & Mid-Wales Fertility Centre http://www.shropshireivf.nhs.uk/ ID 64 03/08/2016 23 24 Simply Fertility http://www.simply-fertility.com/ ID 65 03/09/2016 25 http://www.plymouthhospitals.nhs.uk/ourservices/clinicaldepar

South West Centre for Reproductive Medicine tments/ivf/Pages/Home.aspx ID 66 16/03/2016

26 on October 4, 2021 by guest. Protected copyright.

27 Fertility Bristol http://www.fertilitybristol.com/ ID 67 16/03/2016 28 St Jude's Women's Hospital http://www.stjudeclinic.com/ ID 68 16/03/2016 29

30 Wessex Fertility http://www.wessexfertility.com/ ID 69 16/03/2016 31 http://www.cht.nhs.uk/services/clinical-services/fertility-

32 Calderdale Assisted Conception Unit service-and-assisted-conception-unit/ ID 70 09/06/2016

33 Cheshire Women's Health http://cheshirewomenshealth-fertility.co.uk/ ID 71 09/06/2016 34 Fertility in Community http://www.fertilityincommunity.org.uk/ ID 72 14/06/2016 35

36 Amanda Tozer http://www.amandatozer.com/ ID 73 14/06/2016 (unable to access)

37 Zita West http://www.zitawest.com/ ID 74 14/06/2016 38 39 40 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from

Page 21 of 33 BMJ Open

1 2 3 Table 2. Examples of claims statements recorded from fertility centre websites accessed December 2015 to March 2016 4 Intervention Website claim Project ID for Website and link 5 the fertility 6 7 centre (see 8 Web Table 1) 9 Ovarian reserve test/AMH "A pre-treatment scan gives the clinician the information they need to decide on the ID 57 http://www.nurturefertility.co.uk/ 10 and antral follicle count most appropriate treatment pathway for you. This allows the team to optimise your 11 chances of achieving a pregnancy." For peer review only

12 Clotting (thrombophilia) "this is a test that determines whether you are at an increased risk of developing blood ID 2 http://www.agoraclinic.co.uk/ 13 screen clots that could be a potential cause of miscarriage and implantation failure (where the 14 embryo doesn’t attach to the womb and develop). If this test is positive, the problem 15 can be easily treated by taking aspirin and/or an anticoagulant (medication that thins 16 the blood) throughout your treatment cycle and early pregnancy"

17 Immune testing "Immune testing – there has been a lot of research to try to discover possible ID 2 http://www.agoraclinic.co.uk/ 18 immunological reasons why an embryo fails to attach to the womb and develop, causing http://bmjopen.bmj.com/ 19 repeated miscarriages. It has been suggested that this can be caused by higher than 20 normal levels of ‘natural killer’ cells (a type of white blood cell that is part of a healthy 21 immune system) and auto-antibodies (antibodies that attack specific organs) and 22 positive results have been reported from women treated for these. The treatment for a 23 positive test result involves taking various medications that gently suppress the natural 24 killer cell activity in the immune system." (ID2) 25

Intrauterine insemination "In general intrauterine insemination is a good assisted conception treatment if it is ID 4 http://www.carefertility.com/

26 on October 4, 2021 by guest. Protected copyright. 27 (IUI) performed to overcome a problem of lack of sperm ie using donor sperm for severe 28 male subfertility, and for single women or lesbian couples. It is also successful if 29 intercourse is not occurring normally such as in cases of ejaculation dysfunction (ED). 30 Intrauterine insemination is moderately successful when used for cervical mucus 31 hostility when sperm are killed within the cervix. Intrauterine insemination tends to be 32 less useful if the indication is male factor subfertility ie low numbers or movement of 33 sperm or in unexplained infertility."

34 Intracytoplasmic "Research has shown that IMSI may have a positive impact in the following cases: ID 15 http://www.bourn-hall-clinic.co.uk/ 35 morphologically selected Men who have elevated levels of DNA fragmentation 36 sperm injection (IMSI) When there have been recurrent miscarriages 37 Where implantation hasn’t worked on several occasions following ICSI treatment 38 Where previous embryos have developed poorly 39 When there’s a high number of abnormal sperm." 40 Frozen Embryo Transfer "...we have a good success rate for frozen embryo transfer procedures, because a great ID 29 https://www.manchesterfertility.com/ 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from

BMJ Open Page 22 of 33

1 2 3 (FET); also known as Frozen deal of our research effort goes into ways of identifying the very best embryos." 4 Embryo Replacement (FER) 5

Blastocyst culture "Leaving the embryos to develop onto Day Five enables the embryologists to select the ID 7 http://www.argc.co.uk/ 6 7 most advanced embryos for transfer, thereby increasing the chance of transferring the 8 embryos most likely to implant." 9 Chromosome screening / "Chromosomal abnormalities are often the explanation for unsuccessful pregnancies, so ID 32 http://www.conceptfertility.co.uk 10 preimplantation genetic selecting the correct embryos can improve the chances of a successful implantation and 11 screening PGS birth." For peer review only 12 Cytokine testing (Th1, Th2) "Th1 and Th2 cells are immune cells whose balance is vital for maintaining pregnancy. If ID 3 http://www.ivf.org.uk/ 13 you are producing too many Th1-type immune cells this may also reduce the chances of 14 successful implantation and we may again recommend immunosuppression treatment."

15 Autoimmunity to the human "hCG is a hormone produced in the early pregnancy and there is evidence that it causes ID 3 http://www.ivf.org.uk/ 16 chorionic gonatrophin (hCG) natural suppression of the immune system in order to assist in the implantation of the 17 receptor embryo in the womb. A receptor is a part of a cell that attaches to the hormone to have 18 an effect. A theory exists that the presence of maternal antibodies against hCG or its http://bmjopen.bmj.com/ 19 receptor may affect implantation, leading to failure to achieve a pregnancy or to 20 miscarriage." 21 Thyroid antibodies "A hormonal imbalance is quite often the cause of infertility in both men and women. It ID 16 http://www.jessopfertility.org.uk/ 22 is probably the leading cause of infertility in women. The pituitary gland, the 23 hypothalamus and to some extent the thyroid gland affect hormonal control of the 24 reproductive organs and any defect in any of these may result in fertility problems. The 25 following conditions can affect the hormonal control, PCOS (polycystic ovary syndrome),

26 on October 4, 2021 by guest. Protected copyright. 27 hypothyroidism, luteal phase defect. Often once the irregularity is corrected and the 28 hormones regulated, it is likely that couples will be able to conceive." 29 Surgical sperm retrieval "In men with obstructive azoospermia there is a very high chance of ID 27 http://www.uhcw.nhs.uk/ivf 30 MESA TESA PESE Micro TESE recovering sperm by this method (>90%). In men with non-obstructive 31 azoospermia the chances of recovering sperm is approximately 40%. If we 32 are successful at retrieving sperm the pregnancy rate for this treatment 33 is very similar to that of ICSI with ejaculated sperm."

34 Embryoscope "Embryoscope – recording information by time-lapse photography allows us to assess ID 14 http://www.bostonplaceclinic.co.uk/ 35 more subtle changes seen during embryo development and identify the best embryos 36 for transfer. A new time-lapse technology called the Embryoscope™ involves culturing 37 embryos in an incubator equipped with a special microscope, camera and computer. 38 Available since 2011 it has already led to the birth of thousands of healthy babies. Each 39 individual embryo is imaged separately and monitored every 15 minutes allowing subtle 40 changes in development to be detected. This allows selection of embryos with the 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from

Page 23 of 33 BMJ Open

1 2 3 highest pregnancy potential - so-called morphokinetics." 4 hysterosalpingogram (womb "The chance of a pregnancy after either a hysterosalpingogram or laparoscopy may be ID 3 http://www.ivf.org.uk/ 5 x ray) slightly higher in the 2 or 3 cycles after the fertility test." 6 7 assisted hatching "Microsurgical assisted hatching involves making a small tear in the zona pellucida ID 24 http://www.cambridge-ivf.org.uk/ 8 (shell) around the embryo with a laser. This creates a weak spot which makes it easier 9 for the embryo inside to 'hatch' and implant in your womb. If the embryo cannot escape 10 from the zona it will never be able to implant no matter how good it is. The procedure 11 can either be done on day three or day five of your treatment."For peer review only

12 Egg Freezing with the EVES "CARE Fertility has been freezing embryos using the vitrification technique (EVES) for a ID 4 http://www.carefertility.com/ 13 technique number years. This has been associated with a remarkable increase in pregnancy rates. "

14 Reproductive Immunology "Special tests may identify couples who are at risk of these problems. Treatment which ID 4 http://www.carefertility.com/ 15 stimulates the proper immune response (immuno-modulation) in the mother may then 16 improve the chances of a successful pregnancy." 17 EmbryoGlue ® "EmbryoGlue ® is a culture medium that is used to transfer your embryos back to the ID 22 http://burtonfertility.co.uk/ 18 uterus. It is unique as it contains a high concentration of hyaluronan, a substance which http://bmjopen.bmj.com/ 19 is naturally occurring in the uterus & known to be involved in implantation. Through our 20 own research at our partnership clinic Nurture, we have shown that a small sub-group of 21 patients may benefit from using EmbryoGlue ®. They saw a dramatic rise in pregnancy 22 rates in womenover the age of 34 who had previously had multiple unsuccessful IVF 23 cycles. Our 2012 results show a clinical pregnancy rate of 55% in day 5 transfers in this 24 25 group; this is an increase of 19% compared to the previous year."

Time Lapse Embryo Imaging "Studies so far suggest that embryos selected with the help of time-lapse imaging have a ID 38 http://www.londonwomensclinic.com/

26 on October 4, 2021 by guest. Protected copyright. 27 (see primo high chance of forming a healthy pregnancy, so the technology will be especially 28 vision)/embryoscope welcome for patients with a poor reproductive record - that is, women who have 29 already been unsuccessful in IVF and/or those of an older reproductive age."

30 Oxidative stress levels in "Increased levels of ROS may be reduced with a change in lifestyle and a diet rich in anti- ID 57 http://www.andrologysolutions.co.uk/ 31 semen (ROS test) oxidants, designed to protect against oxidative stress. Randomised placebo controlled 32 studies have shown that anti-oxidant supplements can reduce ROS levels and sperm 33 DNA damage, and improve pregnancy rates. Treatment of infections can also reduce 34 ROS levels. A large randomised study compared men with Chlamydia or Ureaplasma 35 infection with and without antibiotics for 3 months. Those treated showed a significant 36 fall in ROS levels, improved sperm motility and a significant increase in pregnancy rates" 37 Early Embryo Viability "EEVA is designed to safely identify which embryos are most likely to develop to ID 40 http://www.gcrm.co.uk/ 38 Assessment (Eeva™), a blastocyst stage – a critical stage in embryo development that typically happens on ‘day’ 39 subtype of time lapse 5 or 6. With access to this unique information, your IVF team can more accurately select 40 embryo imaging the best embryo(s) for transfer, and this could improve your chances for a successful 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from

BMJ Open Page 24 of 33

1 2 3 pregnancy." 4 Ovulation Induction & Cycle "Ovulation induction is recommended for women who haven’t yet reached menopause ID 32 http://www.conceptfertility.co.uk 5 Monitoring but aren’t ovulating. Depending on your age, this treatment is 10-20% successful. For 6 7 women whose only fertility issue is anovulation, up to 80% of patients ovulate once 8 induced and 50% of those conceive. We begin by using ultrasound to see whether there 9 is a follicle maturing.... We would then use the information from your ultrasound to 10 recommend either natural ovulation, tablets or a series of injections to encourage your 11 body to produce a mature egg. For peerThis treatment is often successful reviewand is used as the first only 12 option when treating infertility due to polycystic ovarian syndrome or other conditions 13 which inhibit ovulation." 14 vitrification of human eggs "Research indicates may improve pregnancy rates by increasing the survival rates of the ID 46 http://southtees.nhs.uk/services/reproduc

15 and embryos eggs after thawing from 65% to 95%." tive-medicine/

16 PICSI "A recently completed trial of PICSI has delivered a pregnancy rate of 66 % of those ID 58 http://www.originfertilitycare.com/ 17 patients participating."

18 Metabolomics "The metabolomics procedure is a simple one, and can be done within a few minutes, ID 9 http://bmjopen.bmj.com/ http://www.healthcentre.org.uk/fertility- 19 and the embryo itself isn’t tested, but the materials around it. It effectively provides a treatment/find-clinic-crosshouse- 20 metabolomics profile for embryos to determine their quality, what does that mean? This hospital.html 21 profile is a measure of the performance of the embryo in a sense, and is composed of 22 the end results of all the pathways and reactions that keep an embryo alive and 23 developing. The better the metabolomics profile of the embryo, the better it is 24 functioning and so the better its chances of leading to a full term pregnancy." 25

Egg/ embryo Freezing "It is important to be aware that not all embryos survive the freezing/thawing process ID 59 http://www.oxfordfertilityunit.com/

26 on October 4, 2021 by guest. Protected copyright. 27 outcomes but it is typically around 80% that do. Having a frozen embryo transferred in a 28 subsequent cycle can be done either with or without medication. A recent study in 29 Oxford has confirmed that success rates for both treatments are similar. Once an 30 embryo has implanted, the chance of a successful outcome does not appear to be 31 different from that of any other IVF pregnancy."

32 Endometrial Scratching "For an IVF/ICSI cycle to be successful, in addition to good quality embryos it is also ID 17 http://www.genesisivf.co.uk/ 33 important that the lining of the womb (endometrium) where the embryo is going to 34 implant is favourable. 35 Recent studies have suggested that a simple procedure called “endometrial scratch” can 36 boost the chances of successful implantation."

37 Ovulation induction (see "Drug treatment of ovulation failure has a high success rate. Patients should, however, ID 64 http://www.shropshireivf.nhs.uk/ 38 above cell ovulation bear in mind that it may take several months to achieve a pregnancy and there is no 39 induction and cycle guarantee of success." 40 monitoring) 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from

Page 25 of 33 BMJ Open

1 2 3 endometrial Receptivitiy "A small amount of tissue from the womb lining (endometrium) can be sampled and ID 40 http://www.gcrm.co.uk/ 4 Array (ERA) analysed for the presence of over 200 genes known to be associated with implantation. 5 Studies have shown that for some women this “window of implantation” is shifted 6 either earlier or later in the menstrual cycle, or it is very narrow. Furthermore, by 7 moving the planned embryo transfer to the appropriate time, chances of successful 8 9 implantation are improved." 10 Ovarian tissue Freezing "Several small strips from the outside of one of the ovaries are removed by laparoscopy ID 14 http://www.bostonplaceclinic.co.uk/ 11 (key-hole surgery). This tissue containing immature eggs is then frozen until a suitable For peer review only 12 time after which it may be transplanted back (grafted) on to the ovary. This is an 13 experimental procedure with a few reported livebirths."

14 SpermSlow™ "Hyaluranon may also help to isolate mature sperm for use in ICSI (intracytoplasmic ID 45 http://www.ivfhammersmith.com/ 15 sperm injection) cycles helping to increase fertilisation rates"

16 Sperm freezing "The sample will be frozen by our embryologists using vitrification technology, an ID 33 http://www.createhealth.org/ 17 advanced fast-freezing which allows for almost indefinite storage. Once frozen, the

18 sperm can be thawed at your disposal, with very high survival rates from thawing." http://bmjopen.bmj.com/ 19 Artificial Oocyte Activation "In order for fertilisation to be successful, the sperm must release a specific functioning ID 15 http://www.bourn-hall-clinic.co.uk/ 20 (AOA) enzyme called Phospholipase C zeta (PLCζ) when it enters the egg. This induces waves of 21 calcium oscillations across the egg to “activate it” allowing fertilisation to take place. A 22 deficient or abnormal PLCζ may be the cause of failed or very low fertilisation. This can 23 be overcome in some situations using a calcium ionophore solution to artificially 24 activate the egg." 25

intralipid infusion "Intralipid infusion therapy can help to stabilise your immune system and increase your ID 50 http://www.lfc.org.uk/

26 on October 4, 2021 by guest. Protected copyright. 27 chances of having a baby....It is safe, non-invasive and may help to increase your chance 28 of success." 29 Sperm DNA Test/ "The SpermComet test is a second-generation investigation that can measure the actual ID 15 http://www.bourn-hall-clinic.co.uk/ 30 SpermComet damage in individual sperm. It can help us to diagnose and treat couples previously 31 faced with ‘Unexplained Infertility’. 1 in 6 couples have trouble conceiving and as many 32 as 25% of these continue to have trouble even when undergoing fertility treatment. In 33 some clinics men are only offered a traditional semen analysis and, should this show 34 normal results, then the couple will be diagnosed with ‘Unexplained Infertility’. Recent 35 tests have shown that up to 80% of men with unexplained infertility have problems in 36 their sperm DNA. Problems that can only be detected using the sperm comet test. 37 Things like stress, smoking, alcohol, recreational drugs, obesity and other avoidable 38 lifestyle factors can affect sperm quality. Even healthy sperm have some DNA damage, 39 but it’s the amount of damage that matters. What are the reasons for having the test? 40 As well as going a long way to diagnose Unexplained Infertility, Sperm DNA Damage has 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from

BMJ Open Page 26 of 33

1 2 3 now also been linked to recurrent miscarriage. Having a detailed analysis of the sperm 4 DNA damage means that we are better equipped to treat you and to provide advice 5 which can make a dramatic difference." 6 7 Dummy/mock embryo "The dummy embryo transfer is a trial run for the process of embryo transfer. This is ID 26 http://www.crgh.co.uk/ 8 transfer necessary to establish whether the actual transfer is likely to encounter difficulties. It 9 also allows us to take measurements and/or note any deviations of the uterus. 10 When the time comes for the actual embryo transfer this information allows us to 11 proceed with the least amount of trauma to the fragile embryosFor peer review. Should we encounter only 12 resistance to the passage of the catheter we may recommend ways to dilate the cervix. 13 The use of dilapan/cervical dilatation facilitates the embryo transfer procedure and this 14 helps to improve the pregnancy rate."

15 Modified natural cycle IVF "IVF Lite: A low-dose, single embryo transfer, which avoids the risk of twins and counts ID 38 http://www.londonwomensclinic.com/ 16 (Gentle/Light IVF) on the delivery of a healthy single baby."

17 Embryogen "It is a culture medium which represents a new assistance for patients who have 30 http://www.city-fertility.com/

18 suffered miscarriages. The medium contains the growth factor cytokine (a signaling http://bmjopen.bmj.com/ 19 protein that essentially participates in the immunological response of the organism), 20 which has a verifiably positive influence on a group of patients with recurrent 21 spontaneous abortions.... The cytokine (GM-CSF), which is included in the EmbryoGen 22 medium, verifiably improves the development of the embryo and the placenta and it is 23 not a threat to the cultivation of human embryos. This broad-acting cytokine creates an 24 environment for the in vitro cultivated embryos that rather resembles the in vivo 25 environment (under natural conditions) and thus increases the ability of the embryos to

26 on October 4, 2021 by guest. Protected copyright. implant (sink into the endometrium) and remain implanted (survive and continue to 27 28 grow in the endometrium)." 29 AneVivo TM "Natural Fertilisation allows fertilisation of the eggs and sperm in an optimal maternal ID 31 http://www.completefertility.co.uk/ 30 environment thanks to AneVivo, a permeable medical device, that allow fluid exchanges 31 between the maternal environment and the embryo. Restoring this stage to the womb 32 may result in an increase in the number of high quality embryos, both on a 33 morphological and genetic level and improve the success rate....The preliminary results 34 are encouraging. "

35 Quad therapy "Quad Therapy is a combination of four different types of drugs, which help to address ID 29 https://www.manchesterfertility.com/ 36 issues with the immune and clotting system in your body that may be preventing you 37 becoming pregnant or the pregnancy progressing. Low dose aspirin, low dose 38 Prednisolone, a form of heparin and progesterone work together to suppress an 39 overactive immune response to a pregnancy and to regulate the clotting in your body, 40 so that your embryo can implant and grow...not all patients benefit from it due to the 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from

Page 27 of 33 BMJ Open

1 2 3 varying causes of implantation failure and miscarriage." 4 Natural cycle IVF "CREATE Fertility is the first group of IVF clinics to offer successful and safe Natural Cycle ID 29 http://www.createhealth.org/ 5 IVF as a first option to patients. We are the largest provider of Natural Cycle IVF in the 6 7 UK and have pioneered the practice of Natural IVF. Our Medical Director, Professor 8 Geeta Nargund, is one of the world's foremost experts on Natural Cycle IVF. We are able 9 to tailor treatment with no or low amounts of stimulation drugs, thereby giving you the 10 best chance to have a baby with your own eggs. We have successfully treated hundreds 11 of women with critically low ovarian reserve/low AMH/high FSH. We have also had For peer review only 12 some of the oldest IVF mothers in the world who have had babies with their own eggs. 13 We do not have any selection criteria and will allow any woman to try IVF using their 14 own eggs if they want to and are still ovulating (up to the age of 50).By avoiding 15 stimulating drugs, the womb is more receptive to pregnancy. There is also evidence that 16 babies born with Natural Cycle IVF are more likely to be born at full term and with a 17 healthier birth weight." http://bmjopen.bmj.com/ 18 hysteroscopy (screening of "we may suggest a hysteroscopy (passing a flexible telescope in to the womb under ID 45 http://www.ivfhammersmith.com/ 19 womb using a camera) general anaesthetic) if we suspect scar tissue formation or the presence of a fibroid or 20 polyp inside the womb which needs to be removed. There is some evidence that this 21 procedure itself, or performing an endometrial scratch, can increase implantation 22 rates." 23 Segmented IVF "In segmentation of mild IVF cycle, the embryos are put back in a separate Natural cycle. ID 33 http://www.createhealth.org/ 24 By minimising stimulation and putting embryos back in a separate natural cycle, the 25 environment of the uterus is more favourable for implantation. Transferring embryos

26 on October 4, 2021 by guest. Protected copyright. into a healthy drug-free womb after a Natural cycle means that you are giving them the 27 28 best possible chance of implantation. Research has shown that babies born after 29 transfer in a Natural cycle have a statistically significant higher birth weight than babies 30 conceived from embryos transferred within a conventional stimulated cycle. A baby’s 31 birth weight has a long-term impact on future health and development." 32 Preimplantation genetic "Preimplantation genetic diagnosis is a specialised treatment for couples who carry an ID 41 33 diagnosis PGD inherited genetic defect that could cause serious health risks for their children, such as 34 cystic fibrosis, sickle cell disease or Huntington’s disease. The Assisted Conception works 35 closely with the Genetics Department to offer this service. We are the largest and most 36 successful unit in the UK for PGD. We have had over 600 babies born as a result of this 37 treatment."

38 array comparative genomic "newer approaches [to PGS] comprising array CGH are of significant benefit, and the ID 39 http://www.gcrmbelfast.com/ 39 hybridisation (array CGH) latest evidence from several clinics has been very encouraging. So far, there has only 40 subtype of PGS been one PGS trial using this sort of technology, conducted in the United States. In that 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from

BMJ Open Page 28 of 33

1 2 3 study, the chance of an embryo transferred to the womb making a baby was found to be 4 increased by more than 50% in IVF cycles where embryos were chosen for transfer 5 based upon the results of PGS analysis" 6 7 8 9 10 11 For peer review only 12 13 14 15 16 17

18 http://bmjopen.bmj.com/ 19 20 21 22 23 24 25

26 on October 4, 2021 by guest. Protected copyright. 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from

Page 29 of 33 BMJ Open Web Table 3. Number of fertility centres making a claim of benefit on their website for different 41 interventions

1 Intervention No. IDs of fertility centres making claims of benefit statement (see webtable 1 No. No. No. References IDs of fertility centres citing 2 Fertility – Project ID) claims Websites cited * 1 or more external centres quanti citing a reference in relation to the 3 fied reference claim 4 Blastocyst culture 25 2,3,4,7,9,10,14,15,22,23,25,26,28,29,30,31,38,39,40,45,46,48,49,53,65 2 5 6 ICSI 24 2,4,6,9,10,15,25,27,30,31,33,34,36,38,39,42,43,45,46,48,52,54,64,74 12

7 Endometrial Scratching 22 10,14,17,23,25,29,31,33,37,39,40,45,49,50,51,57,58,59,62,67,69,71 10 3 6 25,39,62,71 8 EmbryoGlue ® 20 4,6,10,14,22,24,25,28,29,30,39,44,45,46,51,57,59,62,69,71 7 6 8 24,25,46,51,62,71 9 Intrauterine insemination (IUI) 19 2,4,7,9,13,14,26,29,30,36,41,42,50,53,54,60,62,64,67 9

10 Egg/ embryo freezing 17 19,23,24,25,26,27,28,32,33,34,36,44,45,48,49,58,59 13 11 For peer review only Chromosome screening/array CGH/preimplantation genetic 12 screening 14 3,4,6, 14,26,32,38,39,42,45,50,57,62,74 1

13 Assisted hatching 14 4,6,7,10,13,14,24,25,26,28,30,39,41,51 1 1 1 39 14 15 vitrification of human eggs and embryos/EVES technique 13 14,24,25,30,33,38,40,41,42,45,46,51,53 6 1 1 25 16 Embryoscope 13 3,6,14,19,25,27,30,33,36,42,45,47,59 4 1 1 25 17 Time lapse embryo imaging (including primo vision) 11 4,10,19,22,29,32,36,38,51,58,65 4

18 Intracytoplasmic morphologically selected sperm injection (IMSI) 9 2,3,6,9,15,28,59,62,71 2http://bmjopen.bmj.com/ 1 4 71 19 Frozen Embryo Transfer (FET); Frozen Embryo Replacement (FER) 9 2,29,39,40,41,45,50,62,69 4

20 Surgical sperm retrieval MESA TESA PESE Micro TESE 9 3,6,27,36,38,39,40,42,57 4 21 Ovulation induction & cycle monitoring 8 7,16,22,28,32,36,38,64 1 22 23 Early Embryo Viability Assessment (Eeva™) 5 6,15,40,61,69

24 Sperm freezing 4 15,27,32,33 1

25 Modified natural cycle IVF (Gentle/Light IVF) 4 29,31,33,38

26 Ovarian reserve test/AMH & antral follicle count 3 3,43,57 on October 4, 2021 by guest. Protected copyright.

27 Endometrial Receptivitiy Array (ERA) 3 14,26,40 28 Intralipid infusion 3 15,50,51 29 30 Preimplantation genetic diagnosis PGD 3 40,41,74

31 Hysterosalpingogram, HyCoSy & hysteroscopy 2 3,40

32 Thyroid antibodies 2 3,16

33 Sperm DNA Test/ SpermComet 2 15,26

34 SpermSlow™ 2 14,45 35 PICSI 2 9,58 1 36 Reproductive Immunology 1 4 37 38 Ovarian tissue Freezing 1 25 1

39 Clotting (thrombophilia) screen 1 2

40 Immune testing 1 2

41 Cytokine testing (Th1, Th2) 1 3

42 Autoimmunity to the HCG receptor 1 3 43 Oxidative stress levels in semen (ROS test) 1 5 44 45 Dummy/mock embryo transfer For peer review1 only26 - http://bmjopen.bmj.com/site/about/guidelines.xhtml

46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from

BMJ Open Page 30 of 33 Artificial Oocyte Activation (AOA) 1 15

Embryogen 1 30

1 AneVivo TM 1 31 2 Quad therapy 1 29 3 4 Natural cycle IVF 1 33

5 Segmented IVF 1 33

6 Totals 276 83 13 21 7 8 *(more than one website may have cited the same reference) 9 10 11 For peer review only All 41 claims: 8 tests (blue), 6 part of standard NICE recomendations (yellow), 1 miscellaneous (purple) and 26 interventions or techniques as add on to standard IVF treatments (white 12 background) 13 14 15 16 17

18 http://bmjopen.bmj.com/ 19 20 21 22 23 24 25

Page 31 of 33 BMJ Open

1 2 3 Webtable 4. Citations found on fertility centre websites, and the corresponding references identified, with the level of evidence. 4 5 Intervention Website Citation(s) as found on the website Reference(s) we identified Study types cited Highest level of evidence 6 cited for the claim* 7 IMSI ID 71 3. Bartoov B, Berkovitz A, Eltes F, Kogosowski A, Menezo Y, Barak Y. Real- Prospective 1a 8 Time fine morphology of observational study, 9 motile human sperm cells is associated with IVFICSI outcome..J Androly non-randomised 10 2002; 23:1-8 parallel group 11 4. Bartoov B, Berkovitz A, EltesFor F, Kogosowski A, Menezo Y, Barak Y peer reviewBartoov B, Berkovitz A, Eltes F, Kogosowski A, Menezo Y, Barak Y. Real only - intervention study, Pregnancy rates are higher with Time fine morphology of motile human sperm cells is associated with RCT, meta-analysis 12 intracytoplasmic morphologically selected sperm injection than with IVFICSI outcome..J Androly 2002; 23:1-8 13 conventional intracytoplasmic Bartoov B, Berkovitz A, Eltes F, Kogosowski A, Menezo Y, Barak Y 14 injection.Fertil Steril 2003 Dec;80(6):1413-9.Antinori M, Licata E, Dani G, Pregnancy rates are higher with intracytoplasmic morphologically 15 Cerusico F, Versaci selected sperm injection than with conventional intracytoplasmic 16 C, d’Angelo D, Antinori S. Intracytoplasmic morphologically selected injection.Fertil Steril 2003 Dec;80(6):1413-9. Antinori M, Licata E, Dani G, sperm injection: a Cerusico F, Versaci C, d’Angelo D, Antinori S. Intracytoplasmic 17 prospective randomized trial. Reproductive Biomedicine online. 2008; Vol morphologically selected sperm injection: a prospective randomized 18 16 No 6: 835-841 trial. Reproductive Biomedicine online. 2008; Vol 16 No 6: 835http://bmjopen.bmj.com/ -841 19 6. Setti et al. Intracytoplasmic sperm injection outcome versus Souza Setti A, Ferreira RC, Paes de Almeida Ferreira Braga D, de Cássia 20 intracytoplasmic morphologically Sávio Figueira R, Iaconelli A Jr, Borges E Jr. Intracytoplasmic sperm 21 selected sperm injection outcome: a meta-analysis. Reproductive injection outcome versus intracytoplasmic morphologically selected 22 BioMedicine Online, Volume 21, Issue sperm injection outcome: a meta-analysis. Reprod Biomed Online. 2010 4; pp. 450-455 Oct;21(4):450-5. doi: 10.1016/j.rbmo.2010.05.017. Epub 2010 Jun 19. 23 24 Endometrial ID 25 web link to Nastri CO, Lensen SF, Gibreel A, Raine-Fenning N, Ferriani RA, Nastri CO, Lensen SF, Gibreel A, Raine-Fenning N, Ferriani RA, Systematic review 1a scratching Bhattacharya S, Martins WP. Endometrial injury in women undergoing Bhattacharya S, Martins WP. Endometrial injury in women undergoing 25 assisted reproductive techniques. Cochrane Database of Systematic assisted reproductive techniques. Cochrane Database of Systematic

26 Reviews 2015, Issue 3. Art. No.: CD009517. DOI: Reviews 2015, Issue 3. Art. No.: CD009517. DOI: on October 4, 2021 by guest. Protected copyright. 27 10.1002/14651858.CD009517.pub3. 10.1002/14651858.CD009517.pub3. 28 ID 39 a Cochrane review (CD009517) Nastri CO, Lensen SF, Gibreel A, Raine-Fenning N, Ferriani RA, Systematic review 1a 29 Bhattacharya S, Martins WP. Endometrial injury in women undergoing 30 assisted reproductive techniques. Cochrane Database of Systematic 31 Reviews 2015, Issue 3. Art. No.: CD009517. DOI: 10.1002/14651858.CD009517.pub3. 32 33 ID 62 Endometrial injury to overcome recurrent embryo implantation failure: a Potdar N, Gelbaya T, Nardo LG. Endometrial injury to overcome Systematic review 1a systematic review and meta-analysis. Potdar N, Gelbaya T, Nardo LG. recurrent embryo implantation failure: a systematic review and meta- 34 Reprod Biomed Online. 2012 Dec;25(6):561-71 analysis. Reprod Biomed Online. 2012 Dec;25(6):561-71 35 ID 71 Karimzadh MA et al . Endometrial local injury improves the pregnancy rate Karimzadh MA et al. Endometrial local injury improves the pregnancy 1c 36 among recurrent implantation failure patients undergoing in vitro rate among recurrent implantation failure patients undergoing in vitro 37 fertilisation/intra cytoplasmic sperm injection:a randomised clinical trial. fertilisation/intra cytoplasmic sperm injection:a randomised clinical trial. 38 Aust N Z J Obstet Gynaecol. 2009 Dec;49(6):677-80; Zhou L et al. Local Aust N Z J Obstet Gynaecol. 2009 Dec;49(6):677-80; Zhou L, Li R, Wang R, 39 injury to the endometrium in controlled ovarian hyper stimulation cycles Huang HX, Zhong K. Local injury to the endometrium in controlled 40 improves implantation rates. Fertil Steril. 2008 May;89(5):1166-76; Barash ovarian hyper stimulation cycles improves implantation rates. Fertil A et Al. Local injury to the endometrium doubles the incidence of Steril. 2008 May;89(5):1166-76; Barash A, Dekel N, Fieldust S, Segal I, 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from

BMJ Open Page 32 of 33

1 2 3 successful pregnancies in patients undergoing in vitro fertilization. .Fertil Schechtman E, Granot I. Local injury to the endometrium doubles the 4 Steril. 2003 Jun;79(6):1317-22 Gnainsky Y et al. Local injury of the incidence of successful pregnancies in patients undergoing in vitro 5 endometrium induces an inflammatory response that promotes successful fertilization. Fertil Steril. 2003 Jun;79(6):1317-22; Gnainsky Y et al. Local 6 implantation. Fertil Steril 2010 Nov;94(6):2030-6 injury of the endometrium induces an inflammatory response that 7 promotes successful implantation. Fertil Steril 2010 Nov;94(6):2030-6 8 Embryoglue ID 24 A literature study by the independent research institute Cochrane Bontekoe S, Blake D, Heineman MJ, Williams EC, Johnson N. Adherence Systematic review 1a 9 Collaboration covering all published results on the effects of increased compounds in embryo transfer media for assisted reproductive 10 hyaluronan during embryo transfer technologies. Cochrane Database Syst Rev. 2010;7:CD007421 11 ID 25 according to a newly published Formeta -peeranalysis from the independent reviewBontekoe S, Blake D, Heineman MJ, Williams EC, Johnson N. Adherence only Systematic review 1a 12 research network Cochrane Collaboration compounds in embryo transfer media for assisted reproductive technologies. Cochrane Database Syst Rev. 2010;7:CD007421 13 14 ID 46 Sun et al 2010 Sun HX, Hu YL, Zhang NY, Wang B. A retrospective clinical study on Retrospective 2b effects of hyaluronan-containing transfer medium on implantation, cohort study 15 pregnancy and delivery. IFFS 2010 (conference poster abstract, available 16 at http://www.kup.at/kup/pdf/9085.pdf, page 66/147) 17 ID 51 The Cochrane Collaboration, an independent research institute, published Bontekoe S, Blake D, Heineman MJ, Williams EC, Johnson N. Adherence Systematic review 1a

18 results on the effects of increased hyaluronan during embryo transfer... compounds in embryo transfer media for assisted reproductive http://bmjopen.bmj.com/ 19 Retrospective study 2004-2008 comparing EmbryoGlue® with a technologies. Cochrane Database Syst Rev. 2010;7:CD007421; Sun HX, 20 conventional transfer medium for ~1300 patients. Ref: Sun et al. IFFS 2010 Hu YL, Zhang NY, Wang B. A retrospective clinical study on effects of 21 Retrospective study 2004-2008 comparing EmbryoGlue® with a hyaluronan-containing transfer medium on implantation, pregnancy and conventional transfer medium for ~1300 patients. Ref: Sun et al. IFFS 2010 delivery. IFFS 2010 (conference poster abstract, available at 22 and also [shows second bar chart] Ref: B Balaban Am Hosp. Ass Rep Unit, http://www.kup.at/kup/pdf/9085.pdf, page 66/147) Balaban et al. 2004 23 Istanbul, Turkey ESHRE 2004 not found (online archive for ESHRE not available for 2004). 24 ID 62 A literature study by the independent research institute “Cochrane Bontekoe S, Blake D, Heineman MJ, Williams EC, Johnson N. Adherence Systematic review 1a 25 Collaboration” covering all published results on the effects of increased compounds in embryo transfer media for assisted reproductive hyaluronan during embryo transfer technologies. Cochrane Database Syst Rev. 2010;7:CD007421 26 on October 4, 2021 by guest. Protected copyright. 27 ID 71 Bontekoe S, Blake D, Heineman MJ, Williams EC, Johnson N. Adherence Bontekoe S, Blake D, Heineman MJ, Williams EC, Johnson N. Adherence Systematic review 1a 28 compounds in embryo transfer media for assisted reproductive compounds in embryo transfer media for assisted reproductive 29 technologies. Cochrane Database Syst Rev. 2010;7:CD007421 technologies. Cochrane Database Syst Rev. 2010;7:CD007421 30 Assisted hatching ID 39 International Review of the effectiveness of Assisted hatching (conducted Das S, Blake D, Farquhar C, Seif MM. Assisted hatching on assisted Systematic review 1a 31 in 2009). conception (IVF and ICSI). Cochrane Database Syst Rev. 2009 Apr 32 15;(2):CD001894. doi: 10.1002/14651858.CD001894.pub4. Review. Update in: Cochrane Database Syst Rev. 2012;12:CD001894. 33 34 Vitrification of ID 25 A recent review of obstetric and perinatal outcomes in 200 infants Chian RC, Huang JY, Tan SL, Lucena E, Saa A, Rojas A, Ruvalcaba Castellón Case series 2b human eggs and conceived following egg vitrification cycles Chian et al. 2008 Reprod. Med LA, García Amador MI, Montoya Sarmiento JE. Obstetric and perinatal 35 embryos/EVES Online 16:608-610. outcome in 200 infants conceived from vitrified oocytes. Reprod Biomed 36 technique Online. 2008 May;16(5):608-10. 37 Embryoscope ID 25 links to pdf of published paper http://www.fertstert.org/article/S0015- Meseguer M1, Rubio I, Cruz M, Basile N, Marcos J, Requena A. Embryo Retrospective 2b 38 0282(12)02068-7/pdf incubation and selection in a time-lapse monitoring system improves cohort study 39 pregnancy outcome compared with a standard incubator:a retrospective 40 cohort study. Fertil Steril. 2012 Dec;98(6):1481-9.e10. doi: 41 10.1016/j.fertnstert.2012.08.016. Epub 2012 Sep 10. 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2016-013940 on 27 November 2016. Downloaded from

Page 33 of 33 BMJ Open

1 2 3 * CEBM levels of evidence for therapeutic interventions (http://www.cebm.net/oxford-centre-evidence-based-medicine-levels-evidence-march-2009/) 4 5 a SR (with homogeneity*) of RCTs 6 7 1b Individual RCT (with narrow Confidence Interval”¡) 8 1c All or none§ 9 2a SR (with homogeneity*) of cohort studies 10 11 2b Individual cohort study (including low quality RCT; e.g., <80% followFor peer- up)review only 12 2c “Outcomes” Research; Ecological studies 13 3a SR (with homogeneity*) of case-control studies 14 15 3b Individual Case-Control Study 16 4 Case-series (and poor quality cohort and case-control studies§§) 17 5 Expert opinion without explicit critical appraisal, or based on physiology, bench research or “first principles”

18 http://bmjopen.bmj.com/ 19 20 21 22 23 24 25