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Response to National Institute for Health and Clinical Excellence Consultation on Draft Update of Clinical Guideline Fertility: Assessment and Treatment for People with Fertility Problems

3 July 2012
This policy document is a response submitted by the Progress Educational Trust (PET) to the National Institute for Health and Clinical Excellence (NICE)'s Consultation on its Draft Update (.pdf 772KB) of its clinical guideline Fertility: Assessment and Treatment for People with Fertility Problems.
PET is grateful to John Parsons for his contribution to this document.

Introduction The reference to 'pelvic conditions' in the introduction to the Guideline seems redundant, because this category is encompassed by that of 'uterine or endometrial factors' already mentioned.

Introduction The introduction to the Guideline refers to 'assisted reproduction techniques'. This terminology is used inconsistently throughout the Guideline, with references to 'assisted reproduction', 'assisted reproduction techniques', 'assisted reproduction procedures', 'assisted reproduction technology' singular and 'assisted reproduction technologies' plural. Furthermore, 'assisted conception' is a more useful and appropriate term than 'assisted reproduction'. It is a more familiar category in the UK, where hospitals often have 'assisted conception units'. It also refers to all assisted conception regardless of whether or not it results in live birth, which is appropriate to the scope of this Guideline.

1.2.1.2. The reference to 'people who are having artificial insemination to conceive and who are concerned about their fertility' is, insofar as we can tell, a reference to women in same-sex relationships. Presumably the provisions of the Equality Act 2010, and the fact that some people have become pregnant following gender transition and/or sex reassignment therapy, make it difficult or impossible to say as much. The Guideline would, however, be much easier to understand if something could be done to clarify or interpret sections such as this, or at least provide relevant examples.

1.2.1.3. This could be misconstrued as an endorsement of using fresh sperm provided without a license. The ambiguity could be resolved by replacing the words 'inform people who are having artificial insemination to conceive and who are concerned about their fertility' with 'inform those being artificially inseminated with their partner's sperm', to make it clear that this is the relevant scenario.

1.2.1.5. There is a reference above Table 2 to 'assisted reproduction technology'. This terminology is used inconsistently throughout the Guideline, with references to 'assisted reproduction', 'assisted reproduction techniques', 'assisted reproduction procedures', 'assisted reproduction technology' singular and 'assisted reproduction technologies' plural. Furthermore, 'assisted conception' is a more useful and appropriate term than 'assisted reproduction'. It is a more familiar category in the UK, where hospitals often have 'assisted conception units'. It also refers to all assisted conception regardless of whether or not it results in live birth, which is appropriate to the scope of this Guideline.

1.2.1.5. The column in Table 2 headed 'ICI using fresh semen' uses figures from van Noord-Zaadstra's 1991 paper 'Delaying childbearing: effect of age on fecundity and outcome of pregnancy'. This was a study of women married to azoospermic husbands who were inseminated with donor sperm. These figures therefore represent the cumulative probability of conceiving a clinical pregnancy among women whose male partners have a known and severe fertility problem, and not (as this table implies) the cumulative probability of conceiving a clinical pregnancy among women per se. These figures are almost certainly too high to represent the latter.

1.2.1.5. The column in Table 2 headed 'IUI using thawed semen' uses figures from the HFEA's website, which are in turn substantiated by a document on that website entitled 'Fertility Facts and Figures 2008'. It is difficult to deduce how the figures in Table 2 were derived from the latter document. Furthermore, it is not clear whether or not the figures in the HFEA's document – which appear to us to be unusually high – represent cumulative probability, and therefore take account of success rates diminishing with numbers of cycles. If these figures do not represent cumulative probability, then they are problematic in three different ways – they are intrinsically misleading, they make for a false juxtaposition with the other figures in Table 2, and they preclude Table 2 being entitled 'Cumulative probability of conceiving a clinical pregnancy'. In short, the derivation of these figures and the type of probability they represent needs to be made clearer. If these figures appear in NICE's Guideline, patients will use them to make decisions about their treatment and commissioners will use them to decide whether and how to fund treatment. It is therefore imperative that the figures and their provenance are made transparent.

1.2.1.5. There is a hyperlink to the HFEA website contained in the top row of Table 2 whose continued functioning is not assured. When the HFEA relaunched its website in 2009, URLs from the previous iteration of the organisation's website were not preserved and could no longer be used to access information as desired, thereby breaking the majority of 'deep links' to the website that were in use elsewhere. The breaking of links is made more likely in light of the Public Bodies Act 2011 and the Government's consultation on the prospective transfer of the HFEA's functions, which mean that the HFEA may be abolished before NICE next considers updating this Guideline.

1.2.13.4. It is unclear whether the fact that a person is single or is in a same-sex relationship qualifies as a 'known cause of infertility', or whether NICE proceeds from an assumption that medical and social causes of infertility can be distinguished. In our view, the distinction is not clear-cut.

1.2.13.5. This part of the Guideline specifies what should be offered to 'a woman of reproductive age who is in a heterosexual or a same-sex relationship and is having artificial insemination to conceive (using either partner or donor sperm)', but makes no mention of women who are not in relationships of any kind. This discriminates against single women.

1.3.3.3. We very much welcome the acknowledgement that the tests listed have no useful role in clinical practice.

1.3.4.2. The phrase 'in the mid-luteal phase of their cycle (day 21 of a 28-day cycle) to confirm ovulation' seems overly convoluted. A clearer wording would be '7 days prior to menstruation', and this would have the added benefit of properly contextualising the serum progesterone measurement.

1.8.1.1. We very much welcome the recommendation that oral ovarian stimulation agents not be offered to women with unexplained infertility.

1.11.1.2. There is no definition of 'absolute infertility' in the Guideline, beyond there being 'no chance of pregnancy with expectant management'. Providing a more concrete definition is essential, because in the absence of one, commissioners will define the concept in whichever way best suits their interests. It is unclear whether the fact that a person is single or is in a same-sex relationship qualifies as 'absolute infertility'. It is also unclear whether and how the category encompasses male factor infertility. Even men who have a sperm count of zero can occasionally ejaculate sperm, as a consequence of variable sperm production and reabsorption within the testes.

1.11.1.5. We very much welcome the setting of an age limit, while also welcoming the fact that this limit has been raised to 43.

1.11.1.6. While we welcome the recommendation that the outcome of previous IVF treatment be taken into account when considering IVF treatment, we believe it should be emphasised that what is being referred to here is the outcome of previous treatment and not the fact of previous treatment. We do not believe patients should be penalised for the mere fact of having previously received treatment, and would therefore like the distinction between fact and outcome to be made more explicit.

1.12.3.5. The recommendation that ovulation should not be triggered with the intention of fresh embryo transfer in women who have a level of estradiol exceeding 15,000 pm/l is not evidence-based. There have been no published randomised studies assessing risk in relation to estradiol levels, and therefore an upper limit has not been defined.

1.12.6.5. The statement 'when performing single embryo transfer in IVF treatment, transfer a single blastocyst if possible' could be misconstrued as tautological. It could be worded more clearly – for example, 'when performing single embryo transfer in IVF treatment, the embryo should be transferred at blastocyst stage if possible'.

1.12.6.9. The recommendation that two top-quality blastocysts not be used when performing double embryo transfer is impracticable. The quality of blastocysts is not a measure that can somehow be recalibrated in order to compensate for risks posed by the number of embryos transferred. Rather, the quality of blastocysts is contingent upon many factors over which clinicians have only limited control. Even when standard methods of grading are employed, assessing the quality of blastocysts involves a significant degree of subjective judgment. Knowingly transferring sub-optimal blastocysts is a perverse and counterintuitive exercise that runs counter to established clinical practice.

1.12.7.3. It could potentially be inferred from the statement that 'the evidence does not support continuing any form of treatment for luteal phase support beyond 8 weeks' gestation' that evidence supports continuing treatment for luteal phase support up to 8 weeks' gestation. Evidence to date does not appear to support continuing luteal phase support beyond a positive pregnancy test.

1.16.1.7. Italy's first live birth following transplantation of ovarian tissue is due to be discussed at the 2012 Annual Meeting of the European Society of Human Reproduction and Embryology (ESHRE), and the relevant paper has been publicised with a press release headed 'Fertility preservation with the cryopreservation of ovarian tissue moves from the experimental to the mainstream'. We are sceptical about the latter claim, and we therefore agree with NICE's recommendation that only sperm, embryos or oocyctes should be cryopreserved in order to preserve fertility in people diagnosed with cancer. That said, we think it is important to allow for further developments in this area, which could conceivably catch up with the associated hyperbole in the near future.

1.16.1.11. We question whether the comparative merits and demerits of vitrification and controlled-rate freezing are sufficiently well established to make such an unambiguous recommendation in favour of vitrification.

1.17. This heading for the recommendations that follow refers to 'assisted reproduction technologies'. This terminology is used inconsistently throughout the Guideline, with references to 'assisted reproduction', 'assisted reproduction techniques', 'assisted reproduction procedures', 'assisted reproduction technology' singular and 'assisted reproduction technologies' plural. Furthermore, 'assisted conception' is a more useful and appropriate term than 'assisted reproduction'. It is a more familiar category in the UK, where hospitals often have 'assisted conception units'. It also refers to all assisted conception regardless of whether or not it results in live birth, which is appropriate to the scope of this Guideline.

4.1. There is a reference above table 2 to 'assisted reproduction technology'. This terminology is used inconsistently throughout the Guideline, with references to 'assisted reproduction', 'assisted reproduction techniques', 'assisted reproduction procedures', 'assisted reproduction technology' singular and 'assisted reproduction technologies' plural. Furthermore, 'assisted conception' is a more useful and appropriate term than 'assisted reproduction'. It is a more familiar category in the UK, where hospitals often have 'assisted conception units'. It also refers to all assisted conception regardless of whether or not it results in live birth, which is appropriate to the scope of this Guideline.

4.3. There is a reference above table 2 to 'assisted reproduction'. This terminology is used inconsistently throughout the Guideline, with references to 'assisted reproduction', 'assisted reproduction techniques', 'assisted reproduction procedures', 'assisted reproduction technology' singular and 'assisted reproduction technologies' plural. Furthermore, 'assisted conception' is a more useful and appropriate term than 'assisted reproduction'. It is a more familiar category in the UK, where hospitals often have 'assisted conception units'. It also refers to all assisted conception regardless of whether or not it results in live birth, which is appropriate to the scope of this Guideline.

There are three references in the replacement text on p70 to 'assisted reproduction procedures'. This terminology is used inconsistently throughout the Guideline, with references to 'assisted reproduction', 'assisted reproduction techniques', 'assisted reproduction procedures', 'assisted reproduction technology' singular and 'assisted reproduction technologies' plural. Furthermore, 'assisted conception' is a more useful and appropriate term than 'assisted reproduction'. It is a more familiar category in the UK, where hospitals often have 'assisted conception units'. It also refers to all assisted conception regardless of whether or not it results in live birth, which is appropriate to the scope of this Guideline.

The statement on p70 that 'the consumption of more than one unit of alcohol per day reduces the effectiveness of assisted reproduction procedures' is much easier to substantiate in relation to women (to whom this statement presumably applies) than it is in relation to men. We are guessing that NICE's reference to 'people' rather than 'women' may reflect the fact that some people have become pregnant following gender transition and/or sex reassignment therapy. Nonetheless, the suggestion that alcohol consumption reduces the effectiveness of assisted conception to the same extent in women and men is misleading, and greater clarity is therefore required.