confidential: for review only · confidential: for review only the independent regulator that...

Confidential: For Review O

nly

Analysis of the evidence made for ‘add on’ treatments in UK

fertility centres.

Journal: BMJ

Manuscript ID BMJ.2016.036242

Article Type: Analysis

BMJ Journal: BMJ

Date Submitted by the Author: 25-Oct-2016

Complete List of Authors: Heneghan, Carl; Oxford University, Primary Health Care Spencer, Elizabeth; University of Oxford, Primary Care Health Sciences Bobrovitz, Niklas ; University of Oxford, Primary Care Health Sciences Collins, Dylan; University of Oxford, Nuffield Department of Primary Care Health Sciences

Gbinigie, Oghenekome; University of Oxford, Primary Care Health Sciences Nunan, David; University of Oxford, Primary Care Health Sciences Onakpoya, Igho; University of Oxford, Primary Care Health Sciences O'Sullivan, Jack; University of Oxford, Centre for Evidence-based medicine, Nuffield Department of Primary Care Health Sciences Pluddemann, Annette ; University of Oxford , Nuffield Dept. of Primary Care Health Sciences, Rollinson, Alice ; University of Oxford, Primary Care Health Sciences Tompson, Alice ; University of Oxford, Primary Care Health Sciences Goldacre, Ben; University of Oxford, Primary Care Health Sciences Mahtani, Kamal; University of Oxford, Nuffield Department of Primary Care Health Sciences

Keywords: fertilty, evidence-based, IVF

https://mc.manuscriptcentral.com/bmj

BMJ


nlyAnalysis of the evidence made for ‘add on’ treatments in UK fertility centres.

Heneghan C, Spencer EA, Bobrovitz N, Collins DRJ, Nunan D, Gbinigie OA, Plüddemann A,

Onakpoya I, O’Sullivan J, Rollinson A, Tompson A, Goldacre B, Mahtani KR

Corresponding author

[email protected]

Centre for Evidence-Based Medicine,

Nuffield Department Primary Care Health Sciences,

University of Oxford

Word count 2900

References 18 (plus 1 to BMJ Open submission)

Tables 1

Box 1

Analysis

Infertility is a significant problem, affecting about one in seven couples, many of whom seek

medical help in order to have a child. 1 Assisted reproduction treatments, as all medical

interventions, should be informed by reliable evidence. Many new fertility interventions and

products have been developed over the last decade; however, there are concerns that the use of

some new treatments additional to standard in vitro fertilisation (IVF) might not be evidence-

based, and some clinics may be offering additional services, which carry extra costs, that are not

based on the most up to date relevant research. 2

IVF is expensive: a single cycle can cost £5,000, thus placing considerable financial burden on

patients. Those who do not meet criteria for NHS funding can use private clinics; therefore the

majority of IVF (59%) is through private practice.3 In addition to standard IVF treatments, a range

of additional investigations and treatments may be offered at UK fertility treatment centres. [ref

bmjopen-2016-013940.R1] Additional costs can range from as little as £50 for a single screening

blood test to as much as £8,000 for egg freezing packages (see Box 1).

Page 1 of 27


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


nlyThe independent regulator that oversees fertility treatment and research in the UK is the Human

Fertilisation and Embryology Authority 4 (HFEA) Over 200 clinics offering NHS or private services

are registered with the HFEA. The HFEA recommend that women/couples discuss the evidence

with their clinician, and consider their own “research” before making a final decision. We regard

this as difficult, if not impossible, for non-specialists to do, and that even many clinicians might

not be fully aware of the current evidence.

Given concerns over the evidence base for fertility treatments, the implications for patients

undergoing these treatments, and the resources needed to fund them, we set out to look at the

evidence by answering the HFEA “research questions you may want to ask,” taken from their

guidance for couples thinking about having fertility treatments. These questions are: 1) Is this

treatment recommended by the National Institute for Health and Care Excellence (NICE)? If not,

why? 2) Has this treatment been subjected to ‘randomised controlled clinical trials’ which show

that it is effective and is there a ‘Cochrane review’ available? 3) Are there any adverse effects or

risks (known or potential) of the treatment? 2

What did we do?

We obtained from HFEA a list of all UK centres providing fertility treatments and examined their

websites. From these sites we compiled a list of interventions offered in addition to standard IVF

that are claimed to improve fertility outcomes. [ref bmjopen-2016-013940.R1] We excluded

interventions aimed at patients with a pre-existing disease such as diabetes, diagnosed conditions

such as polycystic ovarian syndrome, or neurological conditions such as spinal cord injury; we

Box 1 Example of costs.

Individual screening blood tests – start at £50

Embryoglue – up to £160

Intralipid infusions – up to £250

Endometrial scratch – up to £325

Assisted hatching – up to £450

Blastocyst culture – up to £800

Time lapse imaging – up to £850 for the Eeva time-lapse incubator, up to

£800 for the Embryoscope

Intracytoplasmic morphological sperm injection (IMSI) – up to £1,855

Percutaneous epididymal sperm aspiration/testicular sperm extraction:

(PESE/ TESE) – up to £1,600

Page 2 of 27


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


nlyexcluded interventions related to donation of sperm or eggs; and we excluded complementary

therapies such as homeopathy and nutrition. This gave a list of 38 fertility interventions additional

to standard IVF, offered by UK fertility clinics.

For these 38 additional fertility interventions, we searched for evidence as HFEA suggests, and

focused on the key outcome of whether they improve live birth rates. (Table 1) We checked each

intervention with the current NICE guideline CG156 (Question 1). Nine researchers (NB, DC, OG,

KM, DN, IO, AP, ES, JOS) independently searched MEDLINE (via PubMed) and the Cochrane library

for systematic reviews and randomised controlled trials (RCTs) (Question 2). When we could not

find any review of RCT evidence, we looked for the next highest level of available evidence (e.g.

observational study) and categorised the evidence found using the Oxford CEBM levels of

evidence. 5 We also searched the Cochrane reviews and NICE guidance CG156 for information on

harms. (Question 3)

What did we find?

1) Is this treatment recommended by the National Institute for Health and Care

Excellence (NICE)? If not, why?

Of the 38 interventions investigated, NICE provides clear recommendations for 13 (34%). Of these,

11 are recommended in specific populations and 2 interventions are not (hysteroscopy, assisted

hatching). There was no clear guidance for 19 interventions, and 6 interventions were

recommended for research. (see Figure 1 and Table 1)

NICE guidance is generally clear about the populations to which the 13 recommendations apply.

For example, sperm cryopreservation should be offered to men and adolescent boys who are

preparing for medical treatment for cancer that is likely to make them infertile. Similarly, oocyte or

embryo cryopreservation should be offered to those women preparing for medical treatment for

cancer that is likely to make them infertile, and the routine measurement of thyroid function

should not be offered to the general population but should be confined to women with

symptoms of thyroid disease. NICE guidance also clearly states recommendations on

interventions that should not be offered: assisted hatching and hysteroscopy are not

recommended because they have not been shown to improve pregnancy rates.

Page 3 of 27


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


nlyHowever, for half of the interventions that are additional to standard IVF treatments, and currently

offered at UK fertility clinics, there is no mention in CG156 as to whether they can be

recommended or not.

2) Has this treatment been subjected to ‘randomised controlled clinical trials’ which

show that it is effective and is there a ‘Cochrane review’ available?

For 26 of the 38 fertility interventions (67%) we found a relevant systematic review: 17 of these

were Cochrane reviews and 9 were non-Cochrane. (Figure 1) We also found one Cochrane

overview, published in 2015, including 59 systematic reviews examining the effectiveness of

assisted reproductive technologies.6 These reviews reported that five of these interventions (5/38,

13.2%) improved live birth outcomes; for 13 interventions, the evidence was insufficient to make a

summary estimate; for 6, there was evidence that the intervention did not improve live birth rates.

For one intervention, preimplantation genetic screening (PGS), older methods of PGS worsened

outcomes, whereas there was some evidence of benefit for PGS using more recently developed

techniques.

Table 1 shows the five interventions for which we found evidence of improvements in live birth

rates: blastocyst culture, endometrial scratching, adherence compounds, oral antioxidants and

intrauterine insemination (IUI) in a natural cycle. However, for all of these interventions, the

supporting studies had methodological problems that raise uncertainty about whether these

improvements in live birth rates are actually true results.

A Cochrane systematic review 7 of blastocyst culture including 13 RCTs (n=1,630 participants)

concluded that live birth rates were higher in the blastocyst group compared with culture to day

2 or 3 group: OR 1.48 (95% CI 1.20 to 1.82). Due to high dropout rates and poor randomisation

method descriptions for many trials the evidence was judged low quality. Removal of the low

quality studies meant differences in live birth rates were no longer statistically significant, OR 1.38

(95% CI 0.96 to 1.99). Variable embryo transfer policies between groups, and reductions in the

number of embryos transferred, and available for freezing, further limited the robustness of the

conclusions.

For endometrial injury (incorporating endometrial scratching) a Cochrane review 8 reported a

significant increase in live birth rates compared with no injury, RR 1.42 (95% CI 1.08 to 1.85; 9

RCTs, n =1,496 participants), for injury between day 7 of cycle prior to embryo transfer and day 7

of the cycle of embryo transfer (there was evidence that endometrial injury on the day of embryo

Page 4 of 27


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


nlytransfer was harmful). Due to low participant numbers, and limitations in the methods (in 5

studies both groups possibly received some degree of unintentional endometrial injury, and 3

studies were not published in full) the quality of the evidence was moderate. Removal of the low

quality studies, however, made no difference to the effect estimate. The review authors

highlighted the lack of information on harms: at present it is not known whether the intervention

affects the risk of miscarriage, multiple pregnancies, or vaginal bleeding, or other outcomes that

may be important to women undergoing the procedure, although it was reported that as

expected the procedure does cause some pain. We identified one ongoing UK multicentre

randomised trial (ISRCTN23800982): starting in July 2016 the trial aims to recruit 1,044 women

aged under 37 undergoing IVF for the first time; the protocol includes collection of data on harms

including miscarriage and ectopic pregnancy rates. 9

A Cochrane systematic review of adherence compounds including hyaluronic acid (marketed as

Embryoglue) reported an effect on live birth rates, OR 1.41 (95% CI, 1.17 to 1.69; 6 RCTs, n =

1,950 participants). 10 However, the comparison was between high and no hyaluronic acid or low

hyaluronic acid; in the three studies (n=324 participants) that only assessed high versus no

hyaluronic acid there was no significant effect, OR 1.35 (95% 0.86 to 2.12). Moreover, in some of

the studies, multiple pregnancy rates were increased due to the practice of transferring more

embryos per woman in the intervention groups.

A Cochrane review of antioxidants including 4 small trials with few events (only 44 live births in

total) reported a significant effect on live birth rates (OR 4.21, 95% CI 2.08 to 8.51, n= 277 men).

11 However, one study had inadequate methods (the numbers of participants initially randomised

to each group were not available) and a high unexplained dropout rate (26%) occurred; in

another, the principal investigator had a commercial agreement with the manufacturer, a practice

which has been shown systematically to lead to the publication of more favourable results than

with sponsorship from other sources. 12

Finally, a Cochrane review of 14 trials (n=1,867 women) of intrauterine insemination (IUI) reported

an increase in live birth rate in the one trial (n = 396) that compared IUI in a natural cycle versus

timed intercourse or expectant management in a stimulated cycle, OR 1.95 (95% CI 1.10 to 3.44).

13 The introduction of another intervention component (natural vs. stimulated) meant this effect

was confounded and for three other comparisons of IUI in the same review there was no

significant effect on live birth rates observed (see table 1).

Page 5 of 27


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


nlyA 2006 Cochrane review of preimplantation genetic screening (PGS) included 9 trials, and

concluded PGS significantly lowered live birth rate.14 PGS is a technique for screening embryos for

chromosomal numerical abnormalities and initially it used cleavage stage biopsy and fluorescence

in situ hybridization (FISH). This older version of PGS is now often referred to as version 1. PGS

version 2 uses newer techniques such as array comparative genomic hybridisation (CGH). We

therefore searched for more recent evidence to assess what is known on PGS version 2 (PGS-V2).

Firstly, a 2009 non-Cochrane review of seven trials showed PGS V1 led to lower rates of live

births, RR=0.76 (95% CI 0.64 to 0.91); an absolute decrease in the number of live births of 147 per

1000 women. 15 A 2015 non-Cochrane systematic review 16 of 4 RCTs of PGS V2 targeted

generally at younger women reported that in one trial delivery rates per cycle were higher in the

intervention group compared to the control group; however, in the pooled analysis including

identified cohort studies, there was no significant effect. NHS England’s 2013 Clinical

Commissioning Policy reports that in the “absence of evidence of its clinical and cost

effectiveness, there is no intention to support the introduction of PGS into NHS clinical practice.”

17

For twelve interventions we were unable to find systematic review evidence. For intralipid infusion

and sperm freezing we found one RCT each, and these did not report improvements in live birth

rates. For ovarian tissue freezing; endometrial receptivity array; early embryo viability assessment;

AneVivo; modified natural cycle IVF; PGD; autoimmunity to the HCG receptor we found only one

observational study per intervention. For three interventions (segmented IVF, dummy embryo

transfer and quad therapy) we were unable to find any evidence beyond expert opinion or

mechanism of action.

3) Are there any adverse effects or risks (known or potential) of the treatment?

NICE guidance CG156 was not helpful: for only two interventions (intracytoplasmic sperm injection

(ICSI) and ovulation induction & cycle monitoring) was there any comment on harms. For ICSI,

NICE guidance states that women should be informed that the absolute risks of long-term

adverse outcomes are low, but that a small increased risk of ovarian tumours cannot be excluded

(Web table 2. Harms reporting). For ovulation induction and cycle monitoring the guidance states

the lowest effective dose and duration of use of ovulation induction or ovarian stimulation agents

should be used - an indirect comment on harms.

The Cochrane reviews gave limited information on harms. In many of the reviews the included

trials either provided no information, inadequate information or inconsistently reported

Page 6 of 27


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


nlyinformation on adverse events and only a few reported any meaningful information. For example,

the review on assisted hatching reported that miscarriage rates were similar in both groups and

multiple pregnancy rates were significantly increased in the assisted hatching group; however,

there was insufficient data on ectopic pregnancy, congenital or chromosomal abnormalities,

blastocyst formation or embryo damage. 18 Harms that are important to patients, such as

miscarriage rates, should be central to all trials and reviews of fertility interventions; yet they were

often so poorly reported in the original trials that meaningful conclusions cannot be drawn. For

example, in a review of aspirin, miscarriage rates were reported in only five of 13 trials; multiple

pregnancy rates in four and ectopic pregnancy rates in only three trials. [Web table 2. Harms

reporting]

What could be done differently

People seeking fertility treatment need good quality evidence to make informed choices. The

current approach by HFEA leaves patients and clinicians to seek evidence either for themselves, or

from staff in private clinics selling fertility services to them. We do not believe this approach is

realistic, nor does it reflect the resources available to patients. Patients may be desperate, and

therefore vulnerable. They are unlikely to have specialist skills in seeking and critically appraising

clinical evidence.

Our related publication reports how fertility interventions are offered without supporting evidence

to back up claims of effect [ref bmjopen-2016-013940.R1]. We previously recommended that

fertility centres should keep up to date with the evidence and reflect this in the information on

their websites. [ref bmjopen-2016-013940.R1]

NICE provides some recommendations in specific populations, but it does not cover the range of

interventions currently on offer. NICE together with HFEA should provide guidance on what is

offered, and provide recommendations for or against each of the available interventions. They

should consider adopting the GRADE system for making recommendations, which also allows for

strong (offer to everyone) or weak (offer to some individuals) recommendations, with or without

certain conditions. 19 Furthermore, the key patient-relevant outcome for assisted reproductive

health should be live birth; however, guidance often refers to pregnancy rates to form

recommendations. Guidance also needs continually updating if it is to be relevant and

meaningful, particularly because of the growing number of available tests, techniques and

treatments.

Page 7 of 27


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


nlyCochrane systematic review evidence covers less than half of the available treatments. To find

information we had to look at non-Cochrane reviews or lower quality evidence, some of which is

not freely available to the public. The reporting of harms was very poor and therefore for many

treatments it is impossible to be informed about adverse effects. Furthermore, there are no

maintained relevant information resources appropriate for use by non-clinicians. Initiatives such as

PubMed Health and Cochrane's Plain Language Summaries are welcome but they can only be

fully useful if they cover the range of treatments being offered, are based on reviews that are

updated regularly, and go beyond published papers to overcome the reporting bias that affects

much of the published research in the fertility field.

What can we conclude?

The evidence for these additional interventions is both poor, and poorly accessible to potential

patients. Of the 38 interventions we reviewed, there are 11 for which NICE guidance recommends

use in targeted populations. Our appraisal of the evidence shows only one intervention,

endometrial scratching, for which the review evidence robustly supports an increase in live birth

rate, yet even this evidence is only moderate quality, and the observed benefit is only in women

with more than two previous embryo transfers. A UK multicentre trial is investigating the use of

endometrial injury in women undergoing IVF for the first time, which should provide relevant

information for a broader patient population. 9

It is possible that we did not find some higher quality evidence, but our current analysis reflects

what we could find, and whilst the Cochrane reviews are accessible, some of the evidence we

found is not freely available. Asking patients to do their own research, as the HFEA does, is

inappropriate and for many interventions not possible. For complex issues such as PGS we

consider it is also unreasonable for the HFEA, as it does, to advise that “you should talk to your

GP to go through the options available”, as there is likely to be insufficient knowledge available to

correctly reflect the potential benefits and harms of such interventions. 2

There is an urgent need for randomized controlled trials for many interventions that are currently

being offered. We recommend that treatments with uncertain effects (benefits and harms) are

only licensed for use in the context of meaningful research. There is also a lack of evidence on

the use of multiple interventions: undergoing two or more additional fertility interventions may

result in less benefit than is expected whilst adding in additional risks of harm and higher costs.

Fertility care requires treatments based on the best available evidence. The evidence that does

exist is not necessarily being best used and made available to facilitate decision making. We

Page 8 of 27


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


nlyconsider that the HFEA and NICE should provide a systematic and periodically updated overview

of the evidence to better inform those seeking advice on the benefits and harms of fertility

treatments.

Funding

This project received no specific funding.

Competing interests

All authors have completed the ICMJE uniform disclosure form at

http://www.icmje.org/coi_disclosure.pdf and declare: CH has received grant funding from the

WHO, the National Institute for Health Research (NIHR) and the NIHR School of Primary Care and

on occasion he receives expenses for teaching EBM and CEBM jointly runs the EvidenceLive

Conference with the BMJ. BG has received research funding from the Laura and John Arnold

Foundation, the Wellcome Trust, the NIHR, the Health Foundation, and the WHO; he also receives

personal income from speaking and writing for lay audiences on the misuse of science. KM has

received funding from the NIHR and the RCGP for independent research projects. AT, NB, DN, DC,

ES, OG, IO and AP have nothing to declare. All authors declare that they have no financial

relationships with any organisations that might have an interest in the submitted work in the

previous three years [or describe if any], no other relationships or activities that could appear to

have influenced the submitted work [or describe if any].

Disclaimer

The views expressed here are those of the authors and not necessarily those of any of the

affiliated institutions mentioned in the manuscript such as the NDPCHS, the NHS, the NIHR, or the

Department of Health.

Contribution statement:

CH devised the study and all authors reviewed the methods. KM and AR managed the data

extraction. AT, NB, DN, DC, ES, OG, IO and AP contributed to the searches for evidence and the

data extraction. CH, ES, BG and KM discussed and analysed the issues arising and all authors

commented on and approved the final draft,

Licence for Publication

The Corresponding Author has the right to grant on behalf of all authors and does grant on

behalf of all authors, an exclusive licence (or non exclusive for government employees) on a

worldwide basis to the BMJ Publishing Group Ltd to permit this article (if accepted) to be

published in BMJ and any other BMJPGL products and sublicences such use and exploit all

Page 9 of 27


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


nlysubsidiary rights, as set out in our licence (http://group.bmj.com/products/journals/instructions-

for-authors/licence-forms).

References

1Fertility problems: assessment and treatment. NICE Clinical guideline [CG156] https://www.nice.org.uk/Guidance/CG156 (Accessed 26th Oct 2016)

2 Getting Started: your guide to fertility treatment. http://www.hfea.gov.uk/docs/GSG_amended_September_2016_full_version.pdf (Accessed 26th Oct 2016)

3 Fertility treatment 2014: trends and figures (page 12). http://www.hfea.gov.uk/docs/HFEA_Fertility_treatment_Trends_and_figures_2014.pdf (Accessed 1/10/2016)

4 http://www.hfea.gov.uk/ 5 Howick J, Chalmers I, Glasziou P, Greenhalgh T, et al; OCEBM Levels of Evidence Working Group. The Oxford 2011 Levels of Evidence 2011 30th May 2012. http://www.cebm.net/index.aspx?o=5653

6 Farquhar C, Rishworth JR, Brown J, Nelen WL, Marjoribanks J. Assisted reproductive technology: an overview of Cochrane Reviews. Cochrane Database Syst Rev. 2015 Jul 15;(7):CD010537. doi: 10.1002/14651858.CD010537.pub4.

7 Cleavage stage versus blastocyst stage embryo transfer in assisted reproductive technology. Glujovsky D et al. Cochrane Database Syst Rev. 2012 Jul 11;7:CD002118. doi: 10.1002/14651858.CD002118.pub4.

8 Nastri CO, Lensen SF, Gibreel A, Raine-Fenning N, Ferriani RA, Bhattacharya S, Martins WP. Endometrial injury in women undergoing assisted reproductive techniques. Cochrane Database of Systematic Reviews 2015, Issue 3. Art. No.: CD009517. DOI: 10.1002/14651858.CD009517.pub3.

9 Endometrial scratch trial: http://www.isrctn.com/ISRCTN23800982?q=&filters=conditionCategory:Pregnancy%20and%20Childbirth&sort=&offset=8&totalResults=656&page=1&pageSize=10&searchType=basic-search

10 Heineman MJ, et al. Adherence compounds in embryo transfer media for assisted reproductive

technologies. Cochrane Database of Systematic Reviews 2014. CD DOI: 10.1002/ 14651858.CD007421.pub3.

11 Showell MG et al. Antioxidants for male subfertility. Cochrane Database of Systematic Reviews

2014. CD007411. DOI:10.1002/14651858.CD007411.pub3.

12 Lundh A, Sismondo S, Lexchin J, Busuioc OA, Bero L.Industry sponsorship and research outcome.

Cochrane Database Syst Rev. 2012 Dec 12;12:MR000033. doi: 10.1002/14651858.MR000033.pub2. Review.

13 van Rumste MM, Evers JL, Farquhar CM.Intra-cytoplasmic sperm injection versus conventional

techniques for oocyte insemination during in vitro fertilisation in patients with non-male subfertility. Cochrane Database Syst Rev. 2003;(2):CD001301. Review.

Page 10 of 27


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


nly 14 Twisk M et al. Preimplantation genetic screening for abnormal number of chromosomes

(aneuploidies) in in vitro fertilisation or intracytoplasmic sperm injection. Cochrane Database Syst Rev. 2006 Jan 25;(1):CD005291. Review.

15 Checa MA, Alonso-Coello P, Solà I, Robles A, Carreras R, Balasch J. IVF/ICSI with or without

preimplantation genetic screening for aneuploidy in couples without genetic disorders: a systematic review and meta-analysis. J Assist Reprod Genet. 2009 May;26(5):273-83. doi: 10.1007/s10815-009-9328-4. Epub 2009 Jul 24. Review.

16 Chen M, Wei S, Hu J, Quan S. Can Comprehensive Chromosome Screening Technology Improve

IVF/ICSI Outcomes? A Meta-Analysis. PLoS One. 2015 Oct 15;10(10):e0140779. doi: 10.1371/journal.pone.0140779. eCollection 2015.

17 https://www.england.nhs.uk/wp-content/uploads/2013/04/e01-p-a.pdf

18 Carney SK, Das S, Blake D, Farquhar C, Seif MM, Nelson L. Assisted hatching on assisted

conception (in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI). Cochrane Database Syst Rev. 2012 Dec 12;12:CD001894. doi: 10.1002/14651858.CD001894.pub5. Review.

19 Guyatt Gordon H, Oxman Andrew D, Vist Gunn E, Kunz Regina, Falck-Ytter Yngve, Alonso-Coello

Pablo et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations BMJ 2008; 336 :924

Page 11 of 27


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


nly

ummary of IVF interventions (N=38) evidence and NICE guidance in relation to live births

Comparator Summary effect for live

birth rate

NNT Number

of RCTs

Number

of

patients

in trials

Quality of

evidence 1

Level of

evidence

*cochrane

review

NICE comment in CG156 (and recommendation number)

Ovarian reserve test/AMH and - No result - - - Low 1

1.3 Investigation of fertility problems and management

strategies

1.3.3 Ovarian reserve testing

1.3.3.1. Use a woman's age as an initial predictor of her overall chance

of success through natural conception (see figure 1) or with in vitro

fertilisation (IVF) (see figure 2). [new 2013]

1.3.3.2. Use one of the following measures to predict the likely ovarian

response to gonadotrophin stimulation in IVF:

- total antral follicle count of less than or equal to 4 for a low

response[3] and greater than 16 for a high response

- anti-Müllerian hormone of less than or equal to 5.4 pmol/l

for a low response and greater than or

for a high response

- follicle-stimulating hormone greater than 8.9 IU/l for a low

response and less than 4 IU/l for a high response. [new 2013]

No intervention No result - - - Very Low 1*

1.3.8.4. Women should not be offered hysteroscopy on its own as part

of the initial investigation unless clinically indicated because the

effectiveness of surgical treatment of uterine abnormalities on

improving pregnancy rates has not been established. [2004]

No result - - - Low 4 1

1.3.6.1. Women with possible fertility problems are no more likely than

the general population to have thyroid disease and the routine

measurement of thyroid function should not be offered. Estimation of

thyroid function should be confined to women with symptoms of

thyroid disease. [2004]

Intrauterine insemination (IUI) timed intercourse (TI) or

expectant management in

natural cycle

OR 1.60 (0.92 to 2.78) - 1 334 Moderate 1* 1.9 Intrauterine insemination 1.9.1.1. Consider unstimulated intrauterine insemination as a treatment

option in the following groups as an alternative to vaginal sexual

Quality of evidence from the systematic reviews is based on the GRADE working group unless otherwise stated.

Systematic reviews of diagnostic accuracy show that ovarian reserve tests have only “modest-to-poor predictive properties and are therefore far from suitable for relevant clinical use.”

In women with suspected major uterine cavity abnormalities. Judged to be very low quality due to high risk of selective outcome reporting and unclear whether there is other bias caused by imbalance in the baseline characteristics.

Systematic review of 12 cohorts studies (6 prospective, 6 retrospective).

Page 12 of 27


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


nlyTI or expectant management in

stimulated cycle OR 1.95 (95% CI 1.10 to 3.44)

5 11 1 342 Moderate

intercourse:

- people who are unable to, or would find it very difficult to,

have vaginal intercourse because of a clin

physical disability or psychosexual problem who are using

partner or donor sperm

- people with conditions that require specific consideration in

relation to methods of conception (for example, after sperm

washing where the man is HIV positive)

- people in same-sex relationships. [new 2013]

1.9.1.2. For people in recommendation 1.9.1.1 who have not conceived

after 6 cycles of donor or partner insemination, despite evidence of

normal ovulation, tubal patency and semenalysis, offer a further 6 cyc

of unstimulated intrauterine insemination before IVF is considered.

[new 2013]

1.9.1.3. For people with unexplained infertility, mild endometriosis or

'mild male factor infertility', who are having regular unprotected sexual

intercourse:

- do not routinely offer intrauterine insemination, either with

or without ovarian stimulation (exceptional circumstances

include, for example, when people have social, cultural or

religious objections to IVF)

Intrauterine insemination (IUI)

TI or expectant management in

stimulated cycle OR 1.59 (95% CI 0.88 to 2.88) - 2 208 Moderate

TI or expectant management in

a natural cycle OR 0.82 (95% CI 0.45 to 1.49) - 1 253 Moderate

Frozen embryo transfer (FET) fresh transfer No result - 3 633 cycles Low 1

1.11 Access criteria for IVF

1.11.1.2. Inform people that normally a full cycle of IVF treatment, with

or without intracytoplasmic sperm injection (ICSI), should comprise 1

episode of ovarian stimulation and the transfer of any resultant fresh

and frozen embryo(s). [new 2013]

Use of ejaculated sperm No result - - - Low 6 1* 1.12 Procedures used during IVF treatment

1.12.5.4. Surgical sperm recovery before ICSI may be performed using

several different techniques depending on the pathology and wishes of

the man. In all cases, facilities for cryopreservation of spermatozoa

should be available. [2004]

Physiologic intracytoplasmic

sperm injection (PICSI) RR 1.16 (95% CI 0.65 to 2.05) - 1 99 Low 1*

No assisted hatching OR 1.03 (95% CI 0.85 to 1.26) - 9 1,921 Moderate 1* 1.12.5.5. Assisted hatching is not recommended because it has not

been shown to improve pregnancy rates. [2004]

Culture to days 2 to 3 OR 1.48 (95% CI 1.20 to 1.82)7 12 13 1,630 Low 1*

1.12.6. Where a top-quality blastocyst is available use single embryo

transfer.

1.12.6.4 Evaluate embryo quality, at both cleavage and blastocyst

stages, according to the Association of Clinical Embryologists (ACE) and

UK National External Quality Assessment Service (UK NEQAS) for

Reproductive Science Embryo and Blastocyst Grading sch

figure 3). [new 2013]

fresh cycles No result - 0 0 - 1

1.12.6.10. Offer cryopreservation to store any remaining good

embryos after embryo transfer. [new 2013] 1.16.1.10. Offer oocyte or

embryo cryopreservation as appropriate to women of reproductive age

(including adolescent girls) who are preparing for medical treatment for

cancer that is likely to make them infertile if:

- they are well enough to undergo ovarian stimulation and egg

Small sample size and wide confidence interval; none of the studies reported blinding and overall meta-analysis from 14 RCTs showed no conclusive evidence of a difference in live birth rates.

Only two trials involving 98 men were included in the Cochrane review.

Removal of the low quality studies meant differences in live birth rates were no longer significant.

Page 13 of 27


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


nly

collection and

- this will not worsen their condition and

- enough time is available before the start of their cancer

treatment. [new 2013]

Intracytoplasmic sperm injection Standard exposure of egg with

sperm in vitro No result - 0 0 Low 1*

1.13 Intracytoplasmic sperm injection

1.13.1. The recognised indications for treatment by ICSI include:

● Severe deficits in semen quality

● Obstructive azoospermia

● Non-obstructive azoospermia.

● In addition, treatment by ICSI should be considered for

couples in whom a previous IVF treatment cycle has resulted

in failed or very poor fertilisation.

Recommendations for research

5 Long-term effects of IVF with or without intracytoplasmic

injection in children:

What are the long-term (over 20 years) effects of IVF with or without

ICSI in children in the UK?

No result - - - Low 8 1

1.13.2.3. Where a specific genetic defect associated with male infertility

is known or suspected couples should be offered appropriate genetic

counselling and testing. [2004]

1.13.2.4. Where the indication for ICSI is a severe deficit of semen

quality or nonobstructive azoospermia, the man's karyotype should be

established. [2004]

1.13.2.6. Testing for Y chromosome microdeletions should not be

regarded as a routine investigation before ICSI. However, it is likely that

a significant proportion of male infertility results from abnormalities of

genes on the Y chromosome involved in the regul

spermatogenesis, and couples should be informed of this. [2004]

Standard slow freezing

technique No result - - - Low 1*

1.16 People with cancer who wish to preserve fertility

1.16.1.11. In cryopreservation of oocytes and embryos, use vitrification

instead of controlled-rate freezing if the necessary equipment and

expertise is available. [new 2013]

Fresh Sperm No Result - - - - 2

1.16.1.7. When using cryopreservation to preserve fertility in people

diagnosed with cancer, use sperm, embryos or oocytes. [new 2013]

1.16.1.8. Offer sperm cryopreservation to men and adolescent boys who

are preparing for medical treatment for cancer that is likely to make

them infertile. [new 2013]

1.16.1.9. Use freezing in liquid nitrogen vapour as the preferred

cryopreservation technique for sperm. [new 2013]

Ovulation induction & cycle Control - - - - Low 1*

1.17 Long-term safety of assisted reproductive

women with infertility and their children

1.17.1.1. Give people who are considering ovulation induction or

ovarian stimulation up-to-date information about the long

outcomes of these treatments. [new 2013]

1.17.1.2. Inform women who are offered ovulation induction or ovarian

stimulation that:

- no direct association has been found between these

treatments and invasive cancer and

We found a systematic review of 16 cohort studies but no RCTs were included.

Page 14 of 27


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


nly

- no association has been found in the short

between these treatments and adverse out

cancer) in children born from ovulation induction and

- information about long-term health outcomes in women and

children is still awaited.[new 2013]

1.17.1.3. Limit the use of ovulation induction or ovarian stimulation

agents to the lowest effective dose and duration of use. [new 2013]

- No result - - - - 4

- not mentioned directly although there is a comment:

- 1.17.1.3. Limit the use of ovulation induction or ovarian

stimulation agents to the lowest effective dose and duration

of use. [new 2013]

Conventional embryo incubation OR 1.10 (95% CI 0.45 to 2.73) - 1 76 Moderate 1* Not mentioned

morphologically

selected sperm injection (IMSI)

Regular intracytoplasmic sperm

injection (ICSI) RR 1.14 (95% CI 0.79 to 1.64) - 1 168 Low 1* Not mentioned

No endometrial scratch RR 1.42 (95% CI 1.08 to 1.85) 12 9 1,496 Moderate 10

1* Not mentioned

No, or low, adherence

compound in embryo transfer

medium

RR 1.41 (95% CI 1.17 to 1.69) 13 6 1,950 Moderate 1* Not mentioned

Endometrial Receptivity Array - No result - - - - 4 Not mentioned

Traditional morphology

assessment No result - - - - 4 Not mentioned

No result - - - - 4 Not mentioned

Artificial Oocyte Activation (AOA) No result Low 1 Not mentioned



Oral antioxidants vs placebo OR 4.21 (95% CI 2.08 to 8.51)12

8 4 277 Low 1* Not mentioned

Dummy/mock embryo transfer No result - - - - 5 Not mentioned

IVF/ICSI without PGS. RR=0.76 ( 95% CI 0.64 to 0.91) 14

NNH=7 1 139 Low 1* Not mentioned

(PGS IVF/ICSI without array CGH No Result 16

17

- - - Low 18

1 Not mentioned

We did find a Cochrane review on natural IVF (Allersma et al) but not modified natural cycle IVF.

Ongoing pregnancy, defined as a clinical pregnancy of >12 weeks gestation, was used as surrogate for live birth in cases where studies did not report live birth but reported ongoing pregnancy.

Egg collection and embryo transfer occur in two separate cycles

Only 4 small RCTs were included, there were few events (only 44 live births in total), and in one study there was inadequate methods (the numbers of participants initially randomised to each group were not available,) and large (26%)

unexplained dropouts occurred (Suleiman 1996) and in one study the PI has a commercial agreement with the manufacturer, which is not clear in the review (Tremellan 2007)

nce in situ hybridization (FISH) analysis: HFEA: “It is now widely accepted that PGS by FISH does not improve pregnancy outcomes and that it’s premature introduction was a mistake.”

uk/docs/SCAAC_Preimplantation_genetic_screening_-_ACTIVE.pdf

In a 2009 review of 10 RCTS (1,512 women, moderate quality evidence) meta-analyses of seven trials showed PGS led to lower rates of live births, RR=0.76 ( 95% CI 0.64 to 0.91) and its use does not appear to be justified.

A newer approaches to PGS comprising array CGH - Four methods are currently in use: comparative genomic hybridisation (aCGH), single nucleotide polymorphism array (SNP-array), quantitative polymerase chain reaction (qPCR), and

generation sequencing (NGS).

Criteria for the 3 included RCTs were not targeted to women with high rates of embryonic aneuploidy.

delivery rates per cycle were higher in the CCS group (61/72 (85%) treatment cycles led to delivery compared to 56/83 (67.5%). But in pooled analysis with the included cohort studies there was no significant effect.

Single centres, small sample size and one study was a pilot

Page 15 of 27


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


nlyPreimplantation genetic diagnosis

No result - - - Low 3 Not mentioned

Preimplantation genetic diagnosis

for aneuploidy screening (PGD-A) Selection without PGD-A No result 21

- - - Low 1 Not mentioned

Cytokine testing (Th1, Th2) and Glucocorticoid vs placebo/no

intervention OR 1.21 (95% CI 0.67 to 2.19) - 3 424 Moderate 1* Recommendations for research

22

Control (not specified) No result - - - - 3 Recommendations for research 22

Intravenous immunoglobulin23

No result - - - - 2 Recommendations for research 22

No result - - - Median 24

1 Recommendations for research 22

No result - - - - 5 Recommendations for research 22

Low dose aspirin vs placebo/no

intervention RR 0.91 (95% CI 0.72 to 1.15) - 3 1,053 Moderate 1* Recommendations for research

22

Testing for a specific genetic condition (e.g., cystic fibrosis).

men with advancing age have increased rates of chromosomally abnormal eggs - aneuploidy.

A is PGS screening for aneuploidy used particularly in women of advanced maternal age, recurrent miscarriage and implantation failure: Three RCTs report benefit in young and good prognosis patients for clinical pregnancy. However,

there are no RCTs in women of advanced maternal age, recurrent miscarriage and implantation failure.

Recommendations for research 3 Adjuvant luteal phase support treatments in IVF Further research is needed to assess the efficacy of adjuvant luteal phase support treatments such as low-dose aspirin, heparin, prednisolone,

immunoglobulins and/or fat emulsions

The review is in recurrent miscarriage patients, not undergoing IVF. We also found a case control studies in IVF patients, which shows no effect.

Quality evaluated using the Quality of Reporting of Meta-analyses (QUOROM) and the nine-item Newcastle-Ottawa Quality Scale.

Low dose Prednisolone, a form of heparin and progesterone. If the treatment results in pregnancy then aspirin too.

Page 16 of 27


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

Confidential: For Review Only

●

●

●

●

●●

Page 17 of 27


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


nly

1

References for summary of IVF interventions (n =39) evidence and NICE guidance in relation to live births.

Adherence Compounds:

• Heineman MJ, et al. Adherence compounds in embryo transfer media for assisted reproductive technologies. Cochrane

Database of Systematic Reviews 2014. CD DOI: 10.1002/ 14651858.CD007421.pub3.

Anevivo:

• See application to HFEA for a novel device (Anecova AneVivo), in which published paper is cited.

www.hfea.gov.uk/docs/SCAAC_NPA.pdf refers to Blockeel, C., Mock, P., Verheyen, G., Bouche, N., Le Goff, P., Heyman,

Y., Simón, C. (2009). An in vivo culture system for human embryos using an encapsulation technology: A pilot study.

Human Reproduction, 24(4), 790–796. doi:10.1093/humrep/dep005 www.hfea.gov.uk/docs/SCAAC_NPA.pdf

Artificial Oocyte activation:

• Sfontouris et al.. Artificial oocyte activation to improve reproductive outcomes in women with previous fertilization

failure: a systematic review and meta-analysis of RCTs. Hum Reprod. 2015 Aug;30(8):1831-41. doi:

10.1093/humrep/dev136

Aspirin:

• Siristatidis CS, et al. Aspirin for in vitro fertilisation Cochrane Database of Systematic Reviews 2011. DOI:

10.1002/14651858.CD004832.pub3

Assisted Hatching:

• Carney SK, Das S, Blake D, Farquhar C, Seif MM, Nelson L. Assisted hatching on assisted conception (in vitro fertilisation

(IVF) and intracytoplasmic sperm injection (ICSI). Cochrane Database Syst Rev. 2012 Dec 12;12:CD001894. doi:

10.1002/14651858.CD001894.pub5. Review.

Autoimmunity to the HCG receptor:

• Zou SH, Yang ZZ, Zhang P, Song DP, Li B, Wu RY, Cong X. Autoimmune disorders affect the in vitro fertilization outcome in

infertile women. Zhonghua Nan Ke Xue. 2008 Apr;14(4):343-6. Wang L, Huang P, Huang X. Analysis on the treatment of

1,020 patients with immunologic infertility.

Blastocyst Culture:

• Glujovsky D et al. Cleavage stage versus blastocyst stage embryo transfer in assisted reproductive technology. Cochrane

Database Syst Rev. 2012. CD002118. doi: 10.1002/14651858.CD002118.pub4.

Cytokine testing (Th1, Th2) and treatment:

● Thum MY, et al. The relationship of systemic TNF-alpha and IFN-gamma with IVF treatment outcome and peripheral

blood NK cells. Am J Reprod Immunol. 2007 Mar;57(3):210-7.

● Kuon RJ, et al. Immune profiling in patients with recurrent miscarriage. J Reprod Immunol. 2015 Apr;108:136-41.

● Salmassi A et al. Circulating level of macrophage colony-stimulating factor can be predictive for human in vitro

fertilization outcome. Fertil Steril. 2010 Jan;93(1):116-23.

● Boomsma CM et al. Peri-implantation glucocorticoid administration for assisted reproductive technology cycles. Cochrane

Database Syst Rev. 2012. :CD005996. doi: 10.1002/14651858.CD005996.pub3. (review not directly answering the

question of cytokine testing, but the effect of glucocorticoid treatment (which is proposed to improve the intrauterine

environment by normalising the cytokine expression profile)

Dummy/mock embryo transfer: Expert opinion and mechanism

Early Embryo Viability Assessment (Eeva™):

Page 18 of 27


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


nly

2

• VerMilyea MD et al. Computer-automated time-lapse analysis results correlate with embryo implantation and clinical

pregnancy: a blinded, multi-centre study. Reprod Biomed Online. 2014 Dec;29(6):729-36. doi:

10.1016/j.rbmo.2014.09.005. Epub 2014 Sep 21.

Egg/embryo Freezing:

• Wennerholm UB et al. Children born after cryopreservation of embryos or oocytes: a systematic review of outcome data.

Hum Reprod. 2009 Sep;24(9):2158-72. doi: 10.1093/humrep/dep125. Epub 2009 May 20

Embryogen:

• Siristatidis C et al. Granulocyte macrophage colony stimulating factor supplementation in culture media for subfertile

women undergoing assisted reproduction technologies: a systematic review. Int J Endocrinol. 2013;2013:704967. doi:

10.1155/2013/704967. Epub 2013 Feb 21

Endometrial Receptivity Array (ERA):

• Ruiz-Alonso M et al. The endometrial receptivity array for diagnosis and personalized embryo transfer as a treatment for

patients with repeated implantation failure. Fertil Steril. 2013 Sep;100(3):818-24. doi: 10.1016/j.fertnstert.2013.05.004.

Epub 2013 Jun 4.

Endometrial Scratching:

• Nastri CO, et al. Endometrial injury in women undergoing assisted reproductive techniques. Cochrane Database of

Systematic Reviews 2015. CD009517. DOI: 10.1002/14651858.CD009517.pub3.

Frozen Embryo Transfer (FET):

• Roque M, Lattes K, Serra S, Solà I, Geber S, Carreras R, Checa MA. Fresh embryo transfer versus frozen embryo transfer in

in vitro fertilization cycles: a systematic review and meta-analysis.Fertil Steril. 2013 Jan;99(1):156-62. doi:

10.1016/j.fertnstert.2012.09.003. Epub 2012 Oct 3. Review.

Hysteroscopy:

● Bosteels J, Kasius J, Weyers S, Broekmans FJ, Mol BWJ, D'Hooghe TM. Hysteroscopy for treating subfertility associated

with suspected major uterine cavity abnormalities. Cochrane Database of Systematic Reviews 2015, Issue 2. Art. No.:

CD009461. DOI: 10.1002/14651858.CD009461.pub3.

● Di Spiezio Sardo A, Di Carlo C, Minozzi S, Spinelli M, Pistotti V, Alviggi C, De Placido G, Nappi C, Bifulco G.Efficacy of

hysteroscopy in improving reproductive outcomes of infertile couples: a systematic review and meta-analysis. Hum

Reprod Update. 2016 Jun;22(4):479-96. doi: 10.1093/humupd/dmw008. Epub 2016 Mar 23. Review.

ICSI:

● van Rumste MM, Evers JL, Farquhar CM.Intra-cytoplasmic sperm injection versus conventional techniques for oocyte

insemination during in vitro fertilisation in patients with non-male subfertility. Cochrane Database Syst Rev.

2003;(2):CD001301. Review.

● Johnson LN, Sasson IE, Sammel MD, Dokras A. Does intracytoplasmic sperm injection improve the fertilization rate and

decrease the total fertilization failure rate in couples with well-defined unexplained infertility? A systematic review and

meta-analysis. Fertil Steril. 2013 Sep;100(3):704-11. doi: 10.1016/j.fertnstert.2013.04.038. Epub 2013 Jun 15. Review.

● RCT cited but not included in the above review: IVF-patients with nonmale factor "to ICSI" or "not to ICSI" that is the

question? Poehl M, Holagschwandtner M, Bichler K, Krischker U, Jürgen S, Feichtinger W. J Assist Reprod Genet. 2001

Apr;18(4):205-8. (live birth dated not repported.

IMSI:

• Teixeira DM et al. Regular (ICSI) versus ultra-high magnification (IMSI) sperm selection for assisted reproduction.

Cochrane Database Syst Rev. 2013 Jul 25;7:CD010167. doi: 10.1002/14651858.CD010167.pub2.

Intralipid infusion:

● Zhonghua Fu Chan Ke Za Zhi. 1999 Apr;34(4):234-6.Meng L, et al. Effectiveness and potential mechanisms of intralipid in

treating unexplained recurrent spontaneous abortion. Arch Gynecol Obstet. 2015 Dec 15; (RCT)

Page 19 of 27


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


nly

3

● See also Check JH et al. Intravenous intralipid therapy is not beneficial in having a live delivery in women aged 40-42 years

with a previous history of miscarriage or failure to conceive despite embryo transfer undergoing in vitro fertilization-

embryo transfer. Clin Exp Obstet Gynecol. 2016;43(1):14-5. (matched control study)

IUI:

• Veltman-Verhulst SM et al.Intra-uterine insemination for unexplained subfertility Cochrane Database Syst Rev. 2016 Feb

19;2:CD001838. doi: 10.1002/14651858.CD001838.pub5.

Modified natural cycle IVF (Gentle/Light IVF) Expert opinion and mechanism

Ovarian reserve test/AMH & antral follicle count:

● Maheshwari A, Gibreel A, Bhattacharya S, Johnson NP. Dynamic tests of ovarian reserve: a systematic review of diagnostic

accuracy. Reprod Biomed Online. 2009 May;18(5):717-34. Review.

● Broekmans FJ, Kwee J, Hendriks DJ, Mol BW, Lambalk CB..A systematic review of tests predicting ovarian reserve and IVF

outcomes. Hum Reprod Update. 2006 Nov-Dec;12(6):685-718. Epub 2006 Aug 4. Review.

Ovarian tissue freezing:

• Donnez J et al. Ovarian tissue freezing: current status. Curr Opin Obstet Gynecol. 2015 Jun;27(3):222-30. doi:

10.1097/GCO.0000000000000171. Review.

Ovulation induction & cycle monitoring:

● Kwan I, Bhattacharya S, Kang A, Woolner A. Monitoring of stimulated cycles in assisted reproduction (IVF and ICSI).

Cochrane Database Syst Rev. 2014 Aug 24; 8:CD005289. Epub 2014 Aug 24.

● Martins WP, Vieira CV, Teixeira DM, Barbosa MA, Dassunção LA, Nastri CO. Ultrasound for monitoring controlled ovarian

stimulation: a systematic review and meta-analysis of randomized controlled trials. Ultrasound Obstet Gynecol. 2014 Jan;

43(1):25-33.

Oral antioxidant treatment: Showell MG et al. Antioxidants for male subfertility. Cochrane Database of Systematic Reviews 2014.

CD007411. DOI:10.1002/14651858.CD007411.pub3.

Preimplantation genetic diagnosis PGD:

● Verpoest W, et al. Cumulative reproductive outcome after preimplantation genetic diagnosis: a report on 1498 couples.

Hum Reprod. 2009 Nov;24(11):2951-9. doi: 10.1093/humrep/dep272. Epub 2009 Aug 3.

Preimplantation genetic diagnosis PGD-A:

● Lee E, Illingworth P, Wilton L, Chambers GM. The clinical effectiveness of preimplantation genetic diagnosis for

aneuploidy in all 24 chromosomes (PGD-A): systematic review. Hum Reprod. 2015 Feb;30(2):473-83. doi:

10.1093/humrep/deu303. Epub 2014 Nov 28. Review.

Preimplantation Genetic Screening (v1): (FISH)

● Twisk M et al. Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro

fertilisation or intracytoplasmic sperm injection. Cochrane Database Syst Rev. 2006 Jan 25;(1):CD005291. Review.

● Mastenbroek S, et al. In vitro fertilization with preimplantation genetic screening. N Engl J Med. 2007 Jul 5;357(1):9-17.

Epub 2007 Jul 4.

● Checa MA, Alonso-Coello P, Solà I, Robles A, Carreras R, Balasch J. IVF/ICSI with or without preimplantation genetic

screening for aneuploidy in couples without genetic disorders: a systematic review and meta-analysis. J Assist Reprod

Genet. 2009 May;26(5):273-83. doi: 10.1007/s10815-009-9328-4. Epub 2009 Jul 24. Review.

● S. Mastenbroek et al. Preimplantation genetic screening: a systematic review and meta-analysis of RCTs Hum. Reprod.

Update (2011) 17 (4): 454-466 first published online April 29, 2011 doi:10.1093/humupd/dmr003

In this RCT PGS was carried out using fluorescent in situ hybridization (FISH) for chromosomes 13, 18, 21, X and Y. Implantation

rates obtained in the PGS and control groups were 30 and 32% respectively and not significantly different (P>0.05).

Page 20 of 27


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


nly

4

Preimplantation Genetic Screening (v2): comprehensive chromosome screening

● Dahdouh, E.M., Balayla, J. & García Velasco, J.A., 2014. Impact of blastocyst biopsy and comprehensive chromosome

screening technology on preimplantation genetic screening: a systematic review of randomized controlled trials.

Reproductive BioMedicine Online, 30(3), pp.281–289.

● Chen M, Wei S, Hu J, Quan S. Can Comprehensive Chromosome Screening Technology Improve IVF/ICSI Outcomes? A

Meta-Analysis. PLoS One. 2015 Oct 15;10(10):e0140779. doi: 10.1371/journal.pone.0140779. eCollection 2015.

● Orvieto R. Preimplantation genetic screening- the required RCT that has not yet been carried out. Reprod Biol Endocrinol.

2016 Jun 24;14(1):35. doi: 10.1186/s12958-016-0171-z.

● Moayeri M, Saeidi H, Modarresi MH, Hashemi M. The Effect of Preimplantation Genetic Screening on Implantation Rate in

Women over 35 Years of Age. Cell J. 2016 Spring;18(1):13-20. Epub 2016 Apr 4.

Quad therapy: Expert opinion and mechanism

Segmented IVF: Expert opinion and mechanism

Sperm DNA Test/ SpermComet: L. Robinson et al. Coomarasamy The effect of sperm DNA fragmentation on miscarriage rates: a

systematic review and meta-analysis. Hum Reprod, 27 (10) (2012), pp. 2908–2917

Sperm Freezing: Subak LL, Adamson GD, Boltz NL.Therapeutic donor insemination: a prospective randomized trial of fresh versus

frozen sperm. Am J Obstet Gynecol. 1992 Jun;166(6 Pt 1):1597-604; discussion 1604-6.

Surgical sperm retrieval:

● Van Peperstraten et al. Techniques for surgical retrieval of sperm prior to intracytoplasmic sperm injection (ICSI) for

azoospermia. Cochrane Database Syst Rev. 2008 Apr 16;(2):CD002807. Doi 10.1002/14651858.CD002807.pub3. Review.

● Abhyankar N, et al. Use of testicular versus ejaculated sperm for intracytoplasmic sperm injection among men with

cryptozoospermia: a meta-analysis. Fertil Steril. 2016 Feb 28. pii: S0015-0282(16)00097-2. doi:

10.1016/j.fertnstert.2016.02.013

SpermSlow™: (SpermSlow is a semi viscous medium containing Hyaluronan for slowing down the movement and used in the

selection of an individual sperm)

● McDowell S et al. Advanced sperm selection techniques for assisted reproduction. Cochrane Database of Systematic

Reviews 2014. CD010461. DOI: 10.1002/14651858.CD010461.pub2.

● See also: J Assist Reprod Genet. 2013 Nov;30(11):1471-5. doi: 10.1007/s10815-013-0108-9. Epub 2013 Oct 2.

● See also. Majumdar G et al. A prospective randomized study to evaluate the effect of hyaluronic acid sperm selection on

the intracytoplasmic sperm injection outcome of patients with unexplained infertility having normal semen parameters. J

Assist Reprod Genet. 2013 Nov;30(11):1471-5. doi: 10.1007/s10815-013-0108-9. Epub 2013 Oct 2.

Thyroid antibodies:

● Busnelli A, Paffoni A, Fedele L, Somigliana E. The impact of thyroid autoimmunity on IVF/ICSI outcome: a systematic

review and meta-analysis. Hum Reprod Update. 2016 Jun 20. Review.

● Toulis KA, Goulis DG, Venetis CA, Kolibianakis EM, Negro R, Tarlatzis BC, Papadimas I.Risk of spontaneous miscarriage in

euthyroid women with thyroid autoimmunity undergoing IVF: a meta-analysis. Eur J Endocrinol. 2010 Apr;162(4):643-52.

doi: 10.1530/EJE-09-0850. Epub 2009 Dec 2. Review.

● Chen L, Hu R. Thyroid autoimmunity and miscarriage: a meta-analysis. Clin Endocrinol (Oxf). 2011 Apr;74(4):513-9. doi:

10.1111/j.1365-2265.2010.03974.x.

Time lapse embryo imaging:

• Armstrong S et al. Time-lapse systems for embryo incubation and assessment in assisted reproduction. Cochrane

Database Syst Rev. 2015 Feb 27;2:CD011320. doi: 10.1002/14651858.CD011320.pub2.

Vitrification of human eggs and embryos:

Page 21 of 27


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


nly

5

• Glujovsky D, Riestra B, Sueldo C, Fiszbajn G, Repping S, Nodar F, Papier S, Ciapponi A. Vitrification versus slow freezing for

women undergoing oocyte cryopreservation. Cochrane Database Syst Rev. 2014 Sep 5;(9):CD010047. doi:

10.1002/14651858.CD010047.pub2

Page 22 of 27


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


Intervention Does NICE report harms?

If yes, what does NICE state about harms? Cochrane review (where available) Were harms examined in the Cochrane review?

From the Cochrane review, what was the evidence on harms? Adequacy of harms reporting in the trials

Ovarian reserve test/AMH and antral follicle count

no

Hysteroscopy no Bosteels J, Kasius J, Weyers S, Broekmans FJ, Mol BWJ, D'Hooghe TM.Hysteroscopy for treating subfertility associated with suspected major uterine cavity abnormalities. Cochrane Database of Systematic Reviews 2015, Issue 2. Art. No.: CD009461. DOI: 10.1002/14651858.CD009461.pub3.yes: miscarriage and hysteroscopy complications

Hysteroscopy complications: no data. Miscarriage: no data. No study reported data on adverse procedure-related events.

Inadequate. No evidence available from the trials.

Cytokine testing (Th1, Th2) and treatment

no Boomsma CM et al. Peri-implantation glucocorticoid administration for assisted reproductive technology cycles. Cochrane Database Syst Rev. 2012. :CD005996. doi: 10.1002/14651858.CD005996.pub3.yes: multiple pregnancy rate, miscarriage rate, incidence of ectopic pregnancies, incidence of side effects from steroids,infection rate following oocyte retrieval, ovarian hyperstimulation syndrome, incidence of fetal abnormalities.

There were no significant differences in adverse events (multiple pregnancy rate, miscarriage rate), but these were poorly and inconsistently reported: only three trials reported the incidence of side effects from glucocorticoids and no cases were documented

Inadequate and poor reporting in the trials.

Autoimmunity to the HCG receptor

no

Intralipid infusion no

Embryogen no

Quad therapy no

Thyroid antibodies no

Aspirin no Aspirin for in vitro fertilisation Cochrane Database of Systematic Reviews 2011. DOI: 10.1002/14651858.CD004832.pub3Harms and adverse events not categorically reported as such, but the following outcomes were reported: miscarriage rate, ectopic pregnancy rate, hypertensive complications, vaginal bleeding, intrauterine growth restriction in singletons and blood loss at delivery, ovarian hyperstimulation syndrome

Multiple pregnancy rate was presented in 4/13 studies; miscarriage rate was presented in 5/13 studies; ectopic pregnancy rate 3/13 studies; 1/13 studies hypertensive complications, vaginal bleeding, intrauterine growth restriction in singletons and blood loss at delivery; 1/13 studies ovarian hyperstimulation syndrome. No significant differences between aspirin and control groups found.

Inadequate reporting of adverse events. Few included studies (from 8 to 38% of the studies for different adverse events) reported adverse events.

Intrauterine insemination (IUI) in natural cycle

no Veltman-Verhulst SM et al.Intra-uterine insemination for unexplained subfertility Cochrane Database Syst Rev. 2016 Feb 19;2:CD001838. doi: 10.1002/14651858.CD001838.pub5.yes: multiple pregnancy rate, OHSS, miscarriage rate, ectopic pregnancy rate

Many trials reported AEs poorly, sometimes are totals rather than within intervention group. Multiple pregnancy rates: no evidence of difference between groups. No evidence on ovarian hyperstimulation syndrome. Very limited evidence (1 trial, n=100) that there was no difference in ectopic pregnancy rates.

Poor and inadequate reporting of harms in the included trials.

Page 23 of 27


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

https://www.ncbi.nlm.nih.gov/pubmed/25701429





Intrauterine insemination (IUI) in stimulated cycle

no Veltman-Verhulst SM et al.Intra-uterine insemination for unexplained subfertility Cochrane Database Syst Rev. 2016 Feb 19;2:CD001838. doi: 10.1002/14651858.CD001838.pub5.as above (same review) as above (same review)

Frozen Embryo Transfer (FET)

no

Surgical sperm retrieval no Van Peperstraten et al.Techniques for surgical retrieval of sperm prior to intracytoplasmic sperm injection (ICSI) for azoospermia. Cochrane Database Syst Rev. 2008 Apr 16;(2):CD002807. Doi 10.1002/14651858.CD002807.pub3yes, investigated adverse effects associated with sperm-retrieval technique (e.g.haematoma, infection, severe bruising, pain), also miscarriage rate, fetal abnormalities

Only 2 trials including 98 participants were included. In one trial no SAEs were reported. In the other trial no adverse effects needing medical intervention were reported, and a non-significant difference in rates of small haematoma was reported. The other adverse events (miscarriage rates, fetal abnormalities etc) were not reported by the studies.

Inadequate reporting of adverse events in the included trials.

SpermSlow™ no

Assisted hatching no Carney SK, Das S, Blake D, Farquhar C, Seif MM, Nelson L. Assisted hatching on assisted conception (in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI). Cochrane Database Syst Rev. 2012 Dec 12;12:CD001894. doi: 10.1002/14651858.CD001894.pub5yes: multiple pregnancy rate per woman, miscarriage, monozygotic twinning, ectopic pregnancy rates, congenital or chromosomal abnormalities, failure to transfer any embryos per woman, embryo damage.

Miscarriage rates per woman were similar in both groups (14 RCTs; OR 1.03, 95% CI 0.69 to 1.54, P = 0.90, moderate quality evidence). Multiple pregnancy rates per woman were significantly increased in women who were randomised to AH compared with women in the control groups (14 RCTs, 3447 women; OR 1.38, 95% CI 1.11 to 1.70, P = 0.004, low quality evidence). There was insufficient data on ectopic pregnancy, congenital or chromosomal abnormalities, blastocyst formation or embryo damage.

Moderately adequate reporting of adverse events in the included trials.

Blastocyst culture no Glujovsky D et al. Cleavage stage versus blastocyst stage embryo transfer in assisted reproductive technology. Cochrane Database Syst Rev. 2012. CD002118. doi: 10.1002/14651858.CD002118.pub4.yes: multiple pregnancy rate, high order multiple pregnancy rate, miscarriage rate, failure to transfer embryos rate.

There was no evidence of a difference between the groups in rates of multiple pregnancy (OR 1.05, 95% CI 0.83 to 1.33; 19 RCTs,3019 women, I2= 30%, low quality evidence), or miscarriage (OR 1.15, 95% CI 0.88 to 1.50; 18 RCTs, 2917 women, I2= 0%, lowquality evidence). These data are incomplete as under 70% of studies reported these outcomes. Rates of failure to transfer any embryos were higher in the blasto-cyst transfer group (OR 2.50, 95% CI 1.76 to 3.55; 17 studies,2577 women, I2= 36%, moderate quality evidence).The evidence was of low quality for most outcomes.

Moderately adequate reporting of adverse events in the included trials.

Egg/embryo freezing no

Intracytoplasmic sperm injection (ICSI)

yes 1.17.2.2 Inform women that while the absolute risks of long-term adverse outcomes of IVF treatment, with or without ICSI, are low, a small increased risk of borderline ovarian tumours cannot be excluded. [new 2013] 1.17.2.3 Inform people who are considering IVF treatment that the absolute risks of long-term adverse outcomes in children born as result of IVF are low. [new 2013]

van Rumste MM, Evers JL, Farquhar CM.Intra-cytoplasmic sperm injection versus conventional techniques for oocyte insemination during in vitro fertilisation in patients with non-male subfertility. Cochrane Database Syst Rev. 2003;(2):CD001301. Review.Yes: adverse events, miscarriage rate ( but the included study (1 RCT) did not)

There were no data on miscarriage rates from the one identified randomised clinical trial, nor on other adverse events that may be of concern such as congenital malformations...Further research should report live birth rates and adverse events.

Inadequate reporting of adverse events in the included trial.

Preimplantation genetic screening (PGS V1)

no

array comparative genomichybridisation (array CGH)(PGS V2)

no

Page 24 of 27


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960







Preimplantation genetic diagnosis (PGD)

no

Preimplantation genetic diagnosis for aneuploidy screening (PGD-A)

no

Sperm DNA Test/ SpermComet

no

Vitrification of human eggs and embryos/EVES technique

no

Sperm freezing no

Ovulation induction & cycle monitoring

yes 1.17.1.2 Inform women who are offered ovulation induction or ovarian stimulation that:no direct association has been found between these treatments and invasive cancerandno association has been found in the short- to medium-term between these treatmentsand adverse outcomes (including cancer) in children born from ovulation induction andinformation about long-term health outcomes in women and children is still awaited.[new 2013]1.17.1.3 Limit the use of ovulation induction or ovarian stimulation agents to the lowesteffective dose and duration of use. [new 2013]

Kwan I, Bhattacharya S, Kang A, Woolner A. Monitoring of stimulated cycles in assisted reproduction (IVF and ICSI). Cochrane Database Syst Rev. 2014 Aug 24; 8:CD005289. Epub 2014 Aug 24.yes: adverse outcomes: rate of ovarian hyperstimulation syndrome (OHSS) per woman; number of cancelled cycles per woman

There was no evidence of a difference between the groups in the reported cases of OHSS (OR 1.03; 95% CI 0.48 to 2.20; six studies; N = 781; I² = 0%; low quality evidence). The cycle cancellation rate was similar in the two arms of two studies (0/34 versus 1/31, 1/25 versus 1/25; OR 0.57; 95% CI 0.07 to 4.39; N = 115; I² =0%; low quality evidence.

Moderately adequate reporting of adverse events in the included trials. The Cochrane review did not look at some adverse events that may be important.

Modified natural cycle IVF (Gentle/Light IVF)

no

Time lapse embryo imaging (including Primo vision and Embryoscope trade names)

no

Intracytoplasmic morphologically selected sperm injection (IMSI)

no Teixeira DM et al. Regular (ICSI) versus ultra-high magnification (IMSI) sperm selection for assisted reproduction. Cochrane Database Syst Rev. 2013 Jul 25;7:CD010167. doi: 10.1002/14651858.CD010167.pub2.yes: miscarriage per clinical pregnancy; congenital abnormalities per live birth

We found no significant difference in miscarriage rate between IMSI and ICSI (RR 0.82, 95% CI 0.59 to 1.14, 6RCTs, 552 clinical pregnancies, I2= 17%, very-low-quality evidence). None of the included studies reported congenital abnormalities.

Moderately adequate reporting of adverse events in the included trials. The Cochrane review did not look at some adverse events that may be important.

Page 25 of 27


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

http://www.ncbi.nlm.nih.gov/pubmed/25150465

https://www.ncbi.nlm.nih.gov/pubmed/?term=CD010167


Endometrial scratching no Nastri CO, et al. Endometrial injury in women undergoing assisted reproductive techniques. Cochrane Database of Systematic Reviews 2015. CD009517. DOI: 10.1002/14651858.CD009517.pub3yes: miscarriage rates per clinical pregnancy; multiple gestation per clinical pregnancy; Pain reported during the intervention and any mock intervention, as measured by any validated qualitative or quantitative scale; Abnormal bleeding during or after the intervention or the mock intervention.

There was no evidence of an effect on miscarriage, however the evidence is of low-quality: RR 0.99, 95% CI 0.63 to 1.53; P value 0.06; eight RCTs; 500 clinical pregnancies; I² = 10%; low-quality evidence. Endometrial injury was associated with increased pain, however the evidence was of very low quality. One study reported pain on a VA scale: MD 4.60, 95% CI 3.98 to 5.22; P value < 0.00001; one RCT; 158 women. Two studies reported the number of pain complaintsafter the procedure; one recorded no events in eith er group, and the other repor ted that endometrial injury increased pain complaints:OR 8.65, 95% CI 2.49 to 30.10; P value 0.0007; one RCT; 101 women.

Moderately adequate reporting of adverse events in the trials: From 21 to 71% of the trials reported on the AEs.

Adherence compounds (EmbryoGlue®)

no Heineman MJ, et al.Adherence compounds in embryo transfer media for assisted reproductive technologies. Cochrane Database of Systematic Reviews 2014. CD DOI: 10.1002/ 14651858.CD007421.pub3.yes: Adverse events such as ectopic pregnancy, miscarriage, fetal or congenital defects and pelvic inflammation or other adverse events per randomly assigned couple

The multiple pregnancy rate (O R1.86, 95% CI 1.49 to 2.31; five RCTs, N = 1951, I2= 0%, moderate-quality evidence) was significantly increased in the high HAgroup, but no significant differences in adverse event rates were found (OR 0.74, 95% CI 0.49 to 1.12; four RCTs, N = 1525, I2=0%, moderate-quality evidence

Inadequate reporting of adverse events by the trials: 6/17 (35%) of the studies reported adverse events.

Endometrial Receptivity Array (ERA)

no

Early Embryo Viability Assessment (Eeva™)

no

Ovarian tissue freezing no

Artificial Oocyte Activation (AOA)

no

AneVivoTM no

Segmented IVF no

Oxidative stress levels in semen (ROS test) and oral antioxidant treatment:

no Showell MG et al. Antioxidants for male subfertility. Cochrane Database of Systematic Reviews 2014. CD007411. DOI:10.1002/14651858.CD007411.pub3. yes: adverse events as reported by the trials

Adverse events were poorly reported and we could not make conclusions on any harmful effects. More high quality, larger placebo-controlled trials reporting on these outcomes and adverse events are needed to draw definite conclusions.

Inadequate and poor reporting of adverse events in the trials.

Dummy/mock embryo transfer

no

Page 26 of 27


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960





nlyBox 1 Example of costs.

Individual screening blood tests – start at £50

Embryoglue – up to £160

Intralipid infusions – up to £250

Endometrial scratch – up to £325

Assisted hatching – up to £450

Blastocyst culture – up to £800

Time lapse imaging – up to £850 for the Eeva time-lapse incubator, up to £800 for the Embryoscope

Intracytoplasmic morphological sperm injection (IMSI) – up to £1,855

Percutaneous epididymal sperm aspiration/testicular sperm extraction: (PESE/ TESE) – up to £1,600

Preimplantation genetic screening – £3,500

Egg freezing packages – up to £8,000

Page 27 of 27


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

confidential: for review only · confidential: for review only the independent regulator that...

Documents