- Email: [email protected]
National Institute for Health and Clinical Excellence guidelines on the management of infertility
ARTICLE IN PRESS Current Obstetrics & Gynaecology (2005) 15, 324–333
www.elsevier.com/locate/curobgyn
National Institute for Health and Clinical Excellence guidelines on the management of infertility Anthony J. Rutherford The General Infirmary at Leeds, Belmont Grove, Leeds LS2 9NS, UK
KEYWORDS NICE guideline; Infertility; IVF
Summary In 2001, the National Institute for Health and Clinical Excellence commissioned the National Collaborating Centre for Women and Children’s Health to produce clinical guidelines for clinically effective, cost-effective and appropriate infertility treatment. These guidelines were to build on the existing Royal College of Obstetricians and Gynaecologists’ guidelines on the management of infertility, incorporating any new published scientific evidence available, in order to produce a seamless guide to the management of the infertile couple. In addition, the guideline needed to address the clinical criteria that had to be met to qualify for National Health Service (NHS) treatment, as well as the cost implications of implementing the guideline for the NHS. Three versions of the guideline were published in March 2004. This article describes the process of developing the guideline, the major recommendations included in the report and their implications for the health service. & 2005 Elsevier Ltd. All rights reserved.
Introduction The provision of infertility investigation, and more importantly treatment, on a National Health Service (NHS) basis is widely variable throughout England and Wales. This has resulted in politically sensitive situations whereby patients living on one side of the street may have access to treatment, whereas their neighbours across the road may be denied access because of variations in policy between differing purchasing authorities, euphemistically described as ‘post-code prescribing’. This inequality was one of the factors that Tel.: +44 113 3926908; fax: +44 113 3922971.
E-mail address: [email protected].
prompted the UK government to ask for a review of infertility services. The aim was to produce a guideline that could be used by all professional groups involved in providing fertility services, including policy-makers and commissioners of NHS care, as well as couples seeking advice and possible treatment for infertility. Potentially, this document could act as a landmark in the NHS approach to a comprehensive infertility service.
The NICE process In November 2000, the UK government announced its intention to review the provision of infertility treatment in England and Wales. The Department
0957-5847/$ - see front matter & 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.curobgyn.2005.06.003
ARTICLE IN PRESS National institute of clinical excellence guidelines on the management of infertility of Health and the National Assembly for Wales asked the National Institute for Health and Clinical Excellence (NICE) to review available evidence and produce clinical guidelines outlining cost-effective infertility treatment. NICE commissioned the National Collaborating Centre for Women’s and Children’s Health (NCC WCH) to develop this guideline. Once the topic of infertility had been published on the NICE website, stakeholder organisations, which include those representing healthcare professionals, patients and relevant industry, were invited to register their interest. Seventyseven organisations registered as stakeholders. The first process for the NCC WCH was to develop the boundaries of the guideline, a document known as the ‘Scope’. Other organisations that had an input into developing the Scope include NICE, the registered stakeholders and an independent Guideline Review Panel. The Scope, which is based on the referral document from the Department of Health, outlined what was to be considered and excluded. Essentially, three areas were to be covered: population, the health-care setting and clinical management. The guideline was to offer best-practice advice on the care of people in the reproductive age group who perceived problems with conceiving and the optimal upper and lower age range for their treatment. It also included the management of those with a known condition or reason for fertility problems, for example cancer, human immunodeficiency virus or a genetic condition. However, those outside the reproductive age group and those couples not having regular unprotected sexual intercourse were excluded. The guideline was to take into account the delivery of care from primary through to tertiary health-care professionals, and included diagnosis and medical and surgical management within these health-care settings. It would not consider laboratory practice or standards. The guideline would address the definition of infertility, when to start investigations, the intermediate interventions in primary and secondary care, including the provision of treatments, and the issue of multiple pregnancies arising from treatment. Where advanced therapeutic interventions were considered appropriate, the guideline had to include the clinical eligibility criteria to be met to qualify for NHS treatment, the number of cycles of in vitro fertilisation (IVF) treatment that should be offered, and the number of embryos to be transferred. Guidance on the use of donor gametes was included. The need for counselling and support during and following treatment had to be considered. Where pharmaceutical preparations were
325
employed, they had to be used within their licensed indications, unless exceptionally, where there was clear benefit of a pharmacological intervention beyond their licensed indications. The guideline would not address primary prevention of infertility, or the management of pregnancies after fertility treatment and disorders discovered during the investigation of infertility, unless treatment improved pregnancy outcome or prognosis. Preimplantation genetic diagnosis was also excluded. Perhaps one of the more important exclusions from the Scope, which is likely to have a major impact on implementation, was the assessment of social criteria required to access NHSfunded fertility treatment. Assessing social value criteria is outside the remit of NICE. The NCC WCH established the Guideline Development Group (GDG), consisting of health-care professionals representing different medical and paramedical groups, lay representatives, experts in technical areas such as health economics, and staff from the NCC WCH who provided methodological support. These included experts in informatics, research assistants and fellows who performed the systematic searches, retrieved and processed the evidence, and scripted successive drafts of the guideline. The NCC WCH asked the major professional stakeholder organisations to nominate a member who was selected to represent their views, although each individual chosen acted on the group as an independent expert in his or her field. A list of members and their expertise is listed in Table 1. The first task of the GDG was to consider the Scope and develop specific clinical questions to address the issues covered by the scope. Outcome measures were chosen by the GDG, which were felt to be important to both women and the health service, with a particular emphasis on patient safety. They were grouped into primary, secondary and surrogate outcomes. For each question posed, the best outcome level was sought, as outlined in Table 2. A literature review was performed by the staff at the NCC WCH for each topic identified in a structured manner using conventional techniques. Other published guidelines, the Cochrane Library, and medical and relevant paramedical electronic databases were searched to find titles and abstracts that addressed the question. Full versions of the papers that specifically addressed the issue were retrieved and analysed. Those which did not report relevant outcomes were excluded. Information submitted from stakeholder organisations was also considered where appropriate. The economic studies included had to contain data relevant to the UK setting that addressed specific aspects of
ARTICLE IN PRESS 326 Table 1
A.J. Rutherford The guideline development group. Position
David Barlow Pauline Brimblecombe Clare Brown Kirsten Duckett Jenny Dunlop Geraldine Hartshorne Anthony Hirsh Anthony Rutherford Lorraine Simpson Elfed Williams Sarah Wilson Jane Thomas Moira Mugglestone Irene Kwan Alex McNeil Jennifer Gray Anna Bancsi Hannah-Rose Douglas Dimitra Lambrelli Gillian Roberts
Gynaecologist and Group Leader General Practitioner Patient Representative Obstetrician Counsellor Embryologist Andrologist Gynaecologist Nurse Consumer Representative Public Health Clinician Director, NCC WCH Deputy Director, NCC WCH Research Fellow NCC WCH Research Assistant, NCC WCH Informatics Specialist, NCC WCH Work Programme Coordinator, NCC WCH Health Economist, London School of Hygiene and Tropical Medicine London School of Hygiene and Tropical Medicine Publications Writer/Editor, Royal College of Obstetricians and Gynaecologists
NCC WCH, National Collaborating Centre for Women and Children’s Health.
Table 2
Table 3
Hierarchy of evidence.
Primary Live birth Patient satisfaction Anxiety/depression Multiple births Fetal abnormalities Ectopic pregnancy Ovarian hyperstimulation syndrome
Level
Evidence
1a
Secondary Clinical pregnancy Miscarriage Cycle cancellation Low birth rate Perinatal mortality
3
Systematic review and meta-analysis of randomised controlled trials At least one randomised controlled trial At least one well-designed controlled study without randomisation At least one other type of well-designed quasi-experimental study Well-designed, non-experimental descriptive studies, such as comparative studies, correlation studies or case studies Expert committee reports or opinions and/or clinical experience of respected authorities
Outcome measures.
Surrogate Tubal patency Ovulation Fertilisation Implantation Number of embryos transferred Embryo quality Improved semen parameters Improved sexual function
treatment, predetermined by the GDG. A hierarchy of evidence was employed, as outlined in Table 3, and the highest level of evidence available was
1b 2a 2b
4
used to address each clinical question. Study designs with the least bias were sought for each specific topic; for example, a meta-analysis of randomised controlled trials was used to compare treatments, whereas cohort studies were used to address prognosis. The evidence was summarised by the NCC WCH staff and presented to the GDG in the form of evidence tables. An example of an evidence table is provided in Fig. 1. The GDG considered the information provided on each question and drafted recommendations based
Study Koet et al 200389
Koet et al 200390
Population 30 semen samples from men with mean BMI (SEM) of 26.9 (+0.62)
52 semen samples from men with mean BMI (±SEM) of 27.5 (±0.49)
Comments
Outcomes
Results
DNA fragmentation Index (DFI)
Significant correlation between BMI and DFI
Number of normal motile sperm
Study type
EL
3 OB (abstract)
An increase in BMI beyond 25 is associated with a increase in the DFI of sperm Significant inverse relationship between BMI and number of normal motile sperm
3
Comments
Study type
EL
Randomisation method not clear Small sample
RCT
1b
Normal BMI: normal motile sperm 18.6 x 106 cells Overweight: normal motile sperm 3.6 x 106 cells 6
Obese: normal motile sperm 0.7 x 10 cells
3.6.1 Weight reduction and female fertility Results
Study
Population
Interventions
Outcomes
Guzick et al. 199485
12 obese anovulatory women: Programme (n = 6) Waiting list (n = 6)
A 12-week weight loss programme versus on waiting list
Weight loss Significant weight loss: Detection of ovulation by On programme: 16kg serum progesterone On waiting list: no change
No significance difference Between the 2 groups at Baseline
Clark et al 200086
‘Obese’: 130 – 200% of ideal body weight 171 obese women with infertility history > 1 year group programme: (n = 87) standard programme: (n = 84) 2 groups similar age and length of infertility
Group programme (weekly meeting with 2 hours for support exercise, advice on diet) versus standard programme (usual clinical approach) for 6 months
Weight loss Pregnancy at 18 months
Ovulation: On programme: 4/6 (67%) On waiting list: 1/6 (17%)
Other outcomes include
Significant weight loss Group programme: 4.7kg Standard programme: 1.3kg
Randomisation method not clear
RCT 1b (abstract)
Ovulation status not clear Significant increase in pregnancy Other outcomes included rates group programme: 53/87 (61%) standard programme: 18/84 (21.4%)
‘obese’; BMI > 29kg/m2 <45 kg/m2
327
Figure 1 An example of an evidence tables as supplied to the GDG by NCC-WCH. Published in NICE Guideline, Fertility assessment and Treatment for people with fertility problems. RCOG 2004.
ARTICLE IN PRESS
OB (abstract)
National institute of clinical excellence guidelines on the management of infertility
3.6.1 Obesity and male fertility
ARTICLE IN PRESS 328 on this evidence. The recommendations were reached generally on a consensus basis and graded according to the strength of evidence available (Table 4). A first draft of the full and summary guidelines was circulated in June 2003 to all registered stakeholders, nine peer reviewers appointed by the NCC WCH, an independent Guideline Review Panel established by NICE, the NICE Executive and the Patient Involvement Unit for NICE for comment. A total of 1139 comments were received, collated anonymously and presented to the GDG for consideration. A second draft was published in September 2003, with a further 699 comments received and processed in a similar manner. The final documents—a full guideline, a summary guideline and a version for the public—were published in February 2004 after final editing by the NCC WCH. The whole process had taken just over 2 years to complete.
The guideline document The full guideline document is over 200 pages long and includes 1151 references. It contains 167 recommendations, 29% of which are based on grade A evidence, the bulk (44%) on grade B and C evidence, and only 27% relying on low-level evidence (grade 4) or the views of the GDG. This is a substantial improvement on the Royal College of Obstetricians and Gynaecologists guidelines published in 2000. The document is broken down into chapters that cover the principles of care, the initial advice given to couples experiencing a delay in conception, the investigation and management strategies, followed by chapters on the various treatment options available. Chapters also address the need to follow up children born after assisted conception, topics suitable for audit and where further research is required. There is a full reference list and two appendices, one containing the text of the guideline prepared for public use and the other the economic models employed.
Principles of care Infertility concerns both partners, and there is general agreement that they should be seen together—‘couple-centered’ management. Decisions taken about their investigations and treatments affect both partners, and they need to be provided with appropriate evidence-based information, verbal as well as written, in a format that they can understand. The stress that infertility causes is well recognised. This may manifest as problems within the
A.J. Rutherford couple’s relationship, including decreased libido, which can in itself compromise fertility. There is strong evidence that psychological interventions, such as cognitive-behavioural therapy and group support, improve outcome in those with a relatively short history of infertility. Surveys of patients have established the need for access to support groups and counselling. However, access to independent counselling has until now been mandatory only for those treatments licensed through the Human Fertilization and Embryology Authority. NICE guidelines recommend widening access to counselling to all those seeking help with fertility, throughout their investigation and treatment. Expanding access to counselling to primary and secondary care will of course have significant implications in terms of the cost and training of appropriate individuals. Although the earlier Royal College of Obstetricians and Gynaecologists guidelines document carefully dissected the management of infertility into primary secondary and tertiary care, this guideline emphasises the importance of couples being managed by specialist teams, irrespective of where they are based. Evidence suggests that specialists are more likely to be knowledgeable about their subject and are quicker to implement new and more effective treatments than generalists.
Investigation of fertility problems Men The assessment of semen quality should use standardised techniques, performed to an auditable, verifiable standard. The World Health Organization criteria are almost universally accepted as the best reference range available. The test is based on the analysis of semen from a population of fertile men. Applying these standards, a single semen analysis will identify almost 90% of men who have a true semen abnormality. If an abnormality is identified, a second confirmatory test will significantly improve the specificity. There is, however, little point in repeating a normal test as this provides little additional information. The second test should be delayed for 3 months to allow a full spermatogenic cycle to take place, although the test can be performed in a shorter time scale if azoospermia or severe oligospermia is identified. If both tests confirm an abnormality, further sperm function tests are commonly performed. There appears to be little uniformity of approach in terms of which specific test is used. In these circumstances, the test that is used in the local tertiary centre should be employed. The detection
ARTICLE IN PRESS National institute of clinical excellence guidelines on the management of infertility
these cannot be justified in clinical practice as they make little impact on treatment. Karyotyping is, however, thought to be beneficial, as up to 5% of men with severe oligoazoospermia will have a chromosomal abnormality, the knowledge of which may alter management.
History Physical examination Chlamydia antibody titre
Negative
Positive
HSG
Laparoscopy & dye
Negative
Wait
Positive
329
Negative
Positive
Wait
Treat
Figure 2 Assessment of tubal pathology (based on a presentation by Professor Johannes L. H. Evers at the launch meeting for the National Institute of Clinical Excellence Fertility Guideline, 3 March 2004). HSG, Hysterosalpingography.
of anti-sperm antibodies is part of the normal World Health Organization assessment. As, however, there are no treatments that have been shown to be universally effective in improving outcome, NICE decided not to recommend routine testing. A male factor, either alone or in combination with other female factors, is one of the most common causes of infertility in the UK population. The reason for the semen abnormality may not found in up to 50% of cases, but where a semen abnormality is detected, physical examination of the man is valuable. A varicocele is found more commonly in men with abnormal semen, although the true significance of this to fertility is not understood. Serum to measure the follicle-stimulating hormone (FSH), luteinising hormone and testosterone will help to distinguish between the causes of azoospermia. Hypothalamic-pituitary dysfunction is a rare cause of male infertility associated with low levels of FSH and luteinising hormone. Obstructive azoospermia, characterised by testes of normal volume and a normal FSH level, may have an iatrogenic (vasectomy), an infective (epididymitis) or a congenital (congenital bilateral absence of the vas deferens) origin. The latter is associated with the mutations that cause cystic fibrosis; if found, screening for these mutations is required. If the man screens positive, his partner also needs to be screened. The most common cause of oligozoospermia and non-obstructive azoospermia, characterised by a raised FSH and small volume testes, is primary testicular failure. Although tests are available to detect the few microdeletions on the Y chromosome already identified that may be responsible,
Women Ovulation. The majority of women with a history of regular menstrual cycles (26–35 days) will be ovulating. In patients who have not conceived within 2 years, a mid-luteal progesterone estimation can be offered to confirm ovulation. Those patients with more irregular cycles could have their serum progesterone measured on a weekly basis until they have their next period, although these patients almost certainly will benefit from ovulation induction therapy. In patients with irregular cycles, their FSH and luteinising hormone should be assessed. Routine prolactin measurement in regular cycling women cannot be justified, and the test should be reserved for those with evidence of anovulation and or galactorrhoea. Basal body temperature charts are or poor prognostic value and should be avoided. In patients with oligoamenorrhoea, where polycystic ovarian syndrome is suspected, further investigations are warranted, although these were not included in the guideline document (see information on Scope). Thyroid function tests are commonly performed as part of the infertility assessment. Although thyroid dysfunction can lead to menstrual and ovulatory disorders, the incidence of subclinical thyroid disease in women with ovulatory disorders is no more prevalent than the incidence of asymptomatic thyroid disease in the general population. As such, the guideline recommends that thyroid function tests are not required for asymptomatic women. Assessing ovarian reserve, by measuring early follicular phase gonadotrophin levels in regularly cycling women, can be useful in predicting outcome in patients undergoing complex ovulation induction and assisted conception treatments. However, their role in the initial assessment of infertility is not established. Chlamydia screening. There is evidence that screening for, and treating, those at risk of Chlamydia infection can reduce the risk of pelvic inflammatory disease. Although the infertile population has a relatively low (1.9%) incidence of chlamydia, clinical pelvic infection affects up to 4% of women having a hysterosalpingogram and 10% of those with tubal pathology. If screening has not been performed, antibiotic prophylaxis should be used if tubal patency tests are performed.
ARTICLE IN PRESS 330 Tubal pathology. Tubal pathology is one of the most common female causes of infertility, accounting for 14% of all cases. Disease can be proximal (25%) or distal (75%). All tests of tubal patency are invasive, and it is important to complete other infertility investigations first. The two most commonly employed techniques are hysterosalpingography (HSG) and laparoscopy, although some advocate the use of hystero-contrast-sonography. In trained hands, hystero-contrast-sonography seems to be comparable with both HSG and laparoscopy with dye. HSG is a good test of tubal patency but not a reliable predictor of tubal occlusion. There is evidence that tubal pathology detected by laparoscopy is more likely to affect outcome than that detected after HSG. Chlamydial antibody titre has also been shown to comparable at detecting tubal pathology to HSG. In both cases, a confirmatory laparoscopy is required to assess the extent of the damage. In light of these findings, a simple model for investigating tubal fertility has been proposed (Fig. 2). Newer techniques such as fertiloscopy and falloposcopy still require further research before they can be considered as useful in clinical practice. Uterine and pelvic abnormalities. Abnormalities such as polyps, fibroids, intrauterine adhesions and structural abnormalities are found in 15% of patients presenting with infertility. Whether these have a direct impact on fertility is poorly understood. Hysteroscopy is undoubtedly better than HSG at detecting these abnormalities, but in the absence of hard data showing any benefit from surgery, a hysteroscopy should not be performed as an isolated procedure as part of an infertility work-up. Similarly, pelvic ultrasound is much more accurate than pelvic examination in picking up abnormalities in the pelvis. If pelvic pathology is suspected, for example in a patient with oligoamenorrhoea, a scan should be employed. In an asymptomatic patient with a normal pelvic examination, there is, however, no current evidence that a pelvic scan will alter or improve outcome. Finally, the post-coital test does not appear to offer any improvement in outcome but does result in more intervention, and as such it is now considered unnecessary.
Treatment Male Medical therapies are rarely of value in male infertility, with a few notable exceptions. For
A.J. Rutherford example, hypogonadotrophic hypogonadism, an uncommon cause of male infertility, can be treated effectively, with human chorionic gonadotrophin and human menopausal gonadotrophin, achieving normal sperm counts and fertility. An equally effective alternative would be to use pulsatile gonadotrophin-releasing hormone. The use of corticosteroids in immunological male infertility, which is associated with a significant side-effect profile, has been evaluated in five randomised controlled trials with indifferent results, three showing no and two showing only a small benefit. As such, the use of corticosteroids cannot be recommended. Likewise, the routine use of antibiotics for men with leukospermia, without a recognised infection, has not shown to be of proven benefit in improving pregnancy rates. The use of antioxidants has shown some promise, but further research is required to prove a beneficial effect. The surgical treatment of obstructive azoospermia of infective origin would appear to be of benefit if appropriate expertise is available and offers an alternative to sperm retrieval and IVF. If surgery is performed, sperm retrieval should be attempted at the same time to avoid the need for a second operative procedure should the original surgery prove unsuccessful. A meta-analysis of the surgical treatment of a varicocele, whether clinical or subclinical, demonstrated no improvement in pregnancy rate, and this should therefore not be offered as a form of fertility treatment. Ejaculatory failure can be treated by a variety of methods without resorting to invasive methods of sperm retrieval or assisted conception. Over 50% of men with anejaculation can be successfully treated with parasympathomimetics, whereas retrograde ejaculation may respond to drugs aiming to increase the sympathetic tone of the bladder or reduce parasympathetic activity. If medical treatment fails, electrovibratory or electro-ejaculation using a transrectal probe is usually successful. In retrograde ejaculation, the sperm is recovered from the bladder, often after alkalisation of the urine to prevent sperm damage. Psychogenic disorders resulting in erectile dysfunction can be successfully treated with sildenafil. Should simple methods fail, surgical sperm retrieval followed by IVF and intracytoplasmic sperm injection is a successful alternative. Donor insemination remains an effective treatment that can be used to treat men with both obstructive and non-obstructive azoospermia, infectious diseases such as human immunodeficiency virus in the male partner, severe rhesus isoimmunisation, where there is a high risk of passing on a genetic risk to the offspring, and severe defects in
ARTICLE IN PRESS National institute of clinical excellence guidelines on the management of infertility semen quality when the couple do not want to undergo more complex assisted conception. It is essential that those contemplating donor insemination be offered independent counselling on all the psychological implications of treatment for themselves and their potential children, in particular on how to advise the child of its genetic origins. Women with evidence of regular ovulation in whom there is no history suggestive of tubal pathology can have up to three cycles of treatment before checking their tubal patency. Intrauterine insemination (IUI) is preferred, timed to the detection of the luteinising hormone surge using urine prediction kits. Up to six cycles of treatment should be offered before contemplating more complex alternatives. Intracytoplasmic sperm injection has revolutionised the treatment of male infertility where there are insufficient sperm to achieve fertilisation using conventional insemination. Such situations include men with obstructive and non-obstructive azoospermia, and severe defects in semen quality, and those couples in whom where an IVF cycle has resulted in failed fertilisation. It is important that couples are aware of the potential increased genetic risks associated with intracytoplasmic sperm injection and are investigated and counselled accordingly. Female Ovulation induction. The majority of patients with anovulatory infertility (85%) will have World Health Organization type II ovulation disorders, and most of these will have polycystic ovaries. The firstline treatment in these women are the antioestrogens, clomifene and tamoxifen, which appear to be equally effective and restore ovulation in up to 70% of women. Multiple pregnancy is a considered risk with clomifene, and as a good practice point the GDG recommended monitoring at least during the first cycle to try to determine the minimal effective dose. Failure to respond to clomifene is often associated with an increased body mass index. There is good evidence that natural ovulation and the response to clomifene can be improved by participating in a weight-loss programme. Those patients who fail to respond to clomifene and who have a body mass index greater than 25 benefit from the addition of metformin. Once a satisfactory ovulatory response has been achieved, treatment can be continued for up to 12 cycles, although the addition of IUI may be considered after six. Those who do not respond to simple weight loss and oral medication can be treated by gonadotrophins or surgery (ovarian drilling), which appear to be equally effective.
331
Interestingly, all forms of commercially available gonadotrophins seem to be equally effective, and consideration should be given to cost when prescribing. Oocyte donation may be considered with a diagnosis of premature ovarian failure, gonadal dysgenesis, where there is a high risk of passing on genetic disease, iatrogenic ovarian damage (surgery, chemotherapy or radiotherapy) and rarely in cases of repeated failure of IVF. Both donor and recipient should be offered independent counselling about the potential impact of oocyte donation on them and their potential children. Donors should be made aware of the very real risks of undergoing ovarian stimulation and the oocyte recovery procedure, and the possible impact on their future fertility. Tubal and uterine surgery. Tubal disease is an important cause of infertility. Although goodquality studies have addressed the benefits of the methodologies used in tubal surgery, there are few objective data to confirm the true benefit of surgery compared with not operating or with alternative approaches such as IVF. Irrespective of the method used to confirm tubal blockage, there are patients who will conceive spontaneously. If a proximal block is suspected, selective salpingography should be attempted, as this is a better diagnostic test than laparoscopy and dye. Furthermore, tubal catheterisation under X-ray control or hysteroscopic tubal recanulation may improve the chance of a pregnancy. When such treatment is unsuccessful, tubocornual anastomosis would appear to be effective in trained hands, with term pregnancy rates of up to 50% reported. Such expertise is, however, in short supply, and the majority of these patients will be treated with IVF. The vast majority of patients with tubal pathology have distal disease, which may range from mild peritubal adhesions to grossly distended hydrosalpinges. The prospect for spontaneous pregnancy and the outcome of surgery depend on the degree of damage, with pregnancy more likely in mild disease. The chance of success declines with the severity of disease, such that those with the worst pathology are unlikely to benefit at all from surgery. Unfortunately, only about a quarter of all patients have mild disease suitable for surgery, and the remainder will require IVF. Pregnancy normally occurs within the first 12–14 months after surgery, so those patients who have not conceived within 12 months of surgery will also need IVF. Uterine abnormalities. The incidence of leiomyoma in women with unexplained infertility is around 2%. There are no randomised controlled trials comparing myomectomy with expectant
ARTICLE IN PRESS 332 management. There is limited evidence suggesting that the removal of submucous fibroids improves pregnancy rates, and retrospective data indicate that women with leiomyoma have a reduced chance of conception following IVF. Further research is, however, required to establish the true benefits of the surgical treatment of leiomyoma. A septate uterus is no more likely to be found in an infertile woman than other women, although it is more commonly associated with those who suffer recurrent miscarriage. Surgery has not been shown to be of benefit. Intrauterine adhesions, associated with previous surgical procedures on the uterus, can be divided hysteroscopically to improve pregnancy outcome. Endometriosis. There is solid evidence indicating that there is no benefit to be gained from treating minimal and mild endometriosis with any form of medical treatment to improve fertility. In contrast, there are two studies indicating that laparoscopic ablation or the resection of similar grades of disease plus adhesiolysis improves fertility outcome. In asymptomatic patients, the benefits of surgery, which are relatively small in absolute terms, have to be balanced against the risks of general anaesthesia, surgical complications and of course cost. In more significant grades of endometriosis, the benefits of surgery are more evident. There is, for example, a large improvement in cumulative pregnancy rate after laparoscopic ovarian cystectomy compared with simple drainage or the coagulation of large endometrioma (66.7% versus 23.5%; odds ratio 2.83, 95% confidence interval 1.01–7.50). Again, however, there would seem to be no benefit from adjunctive medical therapy after surgery. In those for whom surgery is not possible, or those who have not conceived within 12 months, IVF is indicated. Assisted conception techniques. The recommendation to extend the use of IUI is one of the most controversial aspects of these guidelines. This treatment is currently one of the few that involves the manipulation and handling of gametes that is not directly regulated by the Human Fertilisation and Embryology Authority. IUI is used in the treatment of unexplained infertility, mild male factor infertility and lesser forms of endometriosis. IUI in combination with ovarian stimulation is more successful than simple IUI alone when there is unexplained infertility or endometriosis, but not seemingly with mild male factor infertility. However, at a time where measures have been put in place to reduce the overall incidence of multiple pregnancy in licensed treatment, it seemed illogical to advocate stimulated IUI, which has the potential to increase the number of high-order
A.J. Rutherford multiple pregnancies. The GDG took a pragmatic decision on the grounds of safety to recommend up to six cycles of IUI without stimulation for the large group with unexplained infertility, and for those with male factor in whom stimulation had not shown to be beneficial. As there were no data on the effectiveness of IUI without stimulation for patients suffering from endometriosis, the recommendation was to include stimulation with this group. The argument put forward by advocates of IUI in the UK is that the lack of stimulation will significantly reduce the success rate, and as most UK practitioners use a more cautious stimulation strategy, the rate of multiple pregnancy is lower than those reported in the published studies (29%). IVF is used for a range of fertility disorders that have failed to respond to conventional therapy, as outlined in Table X. Various factors determine an individual’s chance of success. Age is perhaps the most important factor, with success declining with age. Although there are few data available on the effectiveness of IVF in women under 23 years of age, the validated Human Fertilisation and Embryology Authority database of over 110,000 cycles clearly shows that the live birth rate remains fairly constant between the ages of 23 and 32 years, but above the age of 33 the success rate declines, falling by 50% by the age of 40 years and down to as low as 1% by the time women reach 45 years old. The database also shows that the success rate is maintained at a similar level over the first three attempts, but after three cycles effectiveness is less certain. This information fashioned GDG thinking on the lower (23 years old) and upper (39 years old) age range for treatment, and on the number of treatments offered: up to three fresh IVF cycles plus the transfer of any surplus embryos generated during these treatments. Factors that adversely affect a successful treatment outcome include a long history of infertility, and certain pathologies, such as endometriosis and, in cases of tubal disease, the presence of a hydrosalpinx. The surgical removal of hydrosalpinges is associated with an increased live birth rate (odds ratio 2.13, 95% confidence interval 1.24–3.65). Lifestyle issues also play a role, with excess alcohol, smoking and caffeine all implicated as causing a reduced chance of a live birth. Both low and high body mass index are associated with a poor outcome, and women should be advised to try to maintain their body mass index within the range 19–30. Conversely, a history of a previous pregnancy, particularly after IVF, increases the likelihood of conception. The main thrust of the recommendations dealing with the IVF process is effectiveness and safety.
ARTICLE IN PRESS National institute of clinical excellence guidelines on the management of infertility Prior to patients undergoing advanced fertility treatment, their human immunodeficiency virus, hepatitis B and hepatitis C status should be established as this has implications for the management of their treatment cycle, and potentially for the welfare of the child. All currently available gonadotrophin preparations are equally efficacious, and the choice of compound should be determined by cost. In contrast, gonadotrophin releasing hormone agonists are preferred to antagonists on the basis of a higher chance of a live birth. During treatment, the response to stimulation must be monitored closely, with ultrasound alone the preferred option. Clinics need to be aware of the risk of ovarian hyperstimulation syndrome and have protocols in place to deal with this eventuality. Although various methods have been used to reduce the risk of establishing ovarian hyperstimulation syndrome, the only reliable way to ensure that it does not develop is to withhold the human chorionic gonadotrophin trigger. Oocyte collection should be performed under conscious sedation following the guidelines developed by the Academy of Medical Royal Colleges. Embryo transfer can be arranged at the early cleavage stage (days 2–3) or at the blastocyst stage (days 5–6). In order to limit the risk of multiple pregnancy, it should be performed under ultrasound control with no more than two embryos transferred. Luteal support is required, preferably using progesterone, as human chorionic gonadotrophin potentially increases the risk of ovarian hyperstimulation syndrome. The evidence to date on the health of children born following assisted conception is broadly reassuring. It is, however, important that couples contemplating using assisted conception are given up-to-date information as it becomes available, and that further long-term follow-up studies should be organised on a national basis.
333
Summary The NICE guideline document was heralded as an essential prerequisite to establishing a fair national policy for the investigation and treatment of infertility. It is built on the solid foundation of the three Royal College of Obstetricians and Gynaecologists guidelines, updated with the latest evidence so that almost 50% of the recommendations were based on class A and class B evidence. For clinicians and patients, the most eagerly received changes were the proposals to increase the number of IVF cycles available and the age range of women to whom IVF could be offered. Unfortunately for many, access to appropriate fertility treatment remains elusive as ‘social’ factors, which underpin most purchaser contracts, were not included as part of the original Scope document and therefore remain unchanged. Furthermore, despite protestations that the guidelines would be implemented, no new money was allocated to fund the proposals, leaving purchasing authorities the unenviable task of potentially having to cull other services to fund infertility treatment.
Acknowledgements This document and the recommendations included within it are based closely on the NICE Clinical Guideline, Fertility Assessment and Treatment for People with Fertility Problems, published in February 2004.
Further reading 1. Fertility assessment and treatment for people with fertility problems, www.nice.org.uk.
www.elsevier.com/locate/curobgyn
National Institute for Health and Clinical Excellence guidelines on the management of infertility Anthony J. Rutherford The General Infirmary at Leeds, Belmont Grove, Leeds LS2 9NS, UK
KEYWORDS NICE guideline; Infertility; IVF
Summary In 2001, the National Institute for Health and Clinical Excellence commissioned the National Collaborating Centre for Women and Children’s Health to produce clinical guidelines for clinically effective, cost-effective and appropriate infertility treatment. These guidelines were to build on the existing Royal College of Obstetricians and Gynaecologists’ guidelines on the management of infertility, incorporating any new published scientific evidence available, in order to produce a seamless guide to the management of the infertile couple. In addition, the guideline needed to address the clinical criteria that had to be met to qualify for National Health Service (NHS) treatment, as well as the cost implications of implementing the guideline for the NHS. Three versions of the guideline were published in March 2004. This article describes the process of developing the guideline, the major recommendations included in the report and their implications for the health service. & 2005 Elsevier Ltd. All rights reserved.
Introduction The provision of infertility investigation, and more importantly treatment, on a National Health Service (NHS) basis is widely variable throughout England and Wales. This has resulted in politically sensitive situations whereby patients living on one side of the street may have access to treatment, whereas their neighbours across the road may be denied access because of variations in policy between differing purchasing authorities, euphemistically described as ‘post-code prescribing’. This inequality was one of the factors that Tel.: +44 113 3926908; fax: +44 113 3922971.
E-mail address: [email protected].
prompted the UK government to ask for a review of infertility services. The aim was to produce a guideline that could be used by all professional groups involved in providing fertility services, including policy-makers and commissioners of NHS care, as well as couples seeking advice and possible treatment for infertility. Potentially, this document could act as a landmark in the NHS approach to a comprehensive infertility service.
The NICE process In November 2000, the UK government announced its intention to review the provision of infertility treatment in England and Wales. The Department
0957-5847/$ - see front matter & 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.curobgyn.2005.06.003
ARTICLE IN PRESS National institute of clinical excellence guidelines on the management of infertility of Health and the National Assembly for Wales asked the National Institute for Health and Clinical Excellence (NICE) to review available evidence and produce clinical guidelines outlining cost-effective infertility treatment. NICE commissioned the National Collaborating Centre for Women’s and Children’s Health (NCC WCH) to develop this guideline. Once the topic of infertility had been published on the NICE website, stakeholder organisations, which include those representing healthcare professionals, patients and relevant industry, were invited to register their interest. Seventyseven organisations registered as stakeholders. The first process for the NCC WCH was to develop the boundaries of the guideline, a document known as the ‘Scope’. Other organisations that had an input into developing the Scope include NICE, the registered stakeholders and an independent Guideline Review Panel. The Scope, which is based on the referral document from the Department of Health, outlined what was to be considered and excluded. Essentially, three areas were to be covered: population, the health-care setting and clinical management. The guideline was to offer best-practice advice on the care of people in the reproductive age group who perceived problems with conceiving and the optimal upper and lower age range for their treatment. It also included the management of those with a known condition or reason for fertility problems, for example cancer, human immunodeficiency virus or a genetic condition. However, those outside the reproductive age group and those couples not having regular unprotected sexual intercourse were excluded. The guideline was to take into account the delivery of care from primary through to tertiary health-care professionals, and included diagnosis and medical and surgical management within these health-care settings. It would not consider laboratory practice or standards. The guideline would address the definition of infertility, when to start investigations, the intermediate interventions in primary and secondary care, including the provision of treatments, and the issue of multiple pregnancies arising from treatment. Where advanced therapeutic interventions were considered appropriate, the guideline had to include the clinical eligibility criteria to be met to qualify for NHS treatment, the number of cycles of in vitro fertilisation (IVF) treatment that should be offered, and the number of embryos to be transferred. Guidance on the use of donor gametes was included. The need for counselling and support during and following treatment had to be considered. Where pharmaceutical preparations were
325
employed, they had to be used within their licensed indications, unless exceptionally, where there was clear benefit of a pharmacological intervention beyond their licensed indications. The guideline would not address primary prevention of infertility, or the management of pregnancies after fertility treatment and disorders discovered during the investigation of infertility, unless treatment improved pregnancy outcome or prognosis. Preimplantation genetic diagnosis was also excluded. Perhaps one of the more important exclusions from the Scope, which is likely to have a major impact on implementation, was the assessment of social criteria required to access NHSfunded fertility treatment. Assessing social value criteria is outside the remit of NICE. The NCC WCH established the Guideline Development Group (GDG), consisting of health-care professionals representing different medical and paramedical groups, lay representatives, experts in technical areas such as health economics, and staff from the NCC WCH who provided methodological support. These included experts in informatics, research assistants and fellows who performed the systematic searches, retrieved and processed the evidence, and scripted successive drafts of the guideline. The NCC WCH asked the major professional stakeholder organisations to nominate a member who was selected to represent their views, although each individual chosen acted on the group as an independent expert in his or her field. A list of members and their expertise is listed in Table 1. The first task of the GDG was to consider the Scope and develop specific clinical questions to address the issues covered by the scope. Outcome measures were chosen by the GDG, which were felt to be important to both women and the health service, with a particular emphasis on patient safety. They were grouped into primary, secondary and surrogate outcomes. For each question posed, the best outcome level was sought, as outlined in Table 2. A literature review was performed by the staff at the NCC WCH for each topic identified in a structured manner using conventional techniques. Other published guidelines, the Cochrane Library, and medical and relevant paramedical electronic databases were searched to find titles and abstracts that addressed the question. Full versions of the papers that specifically addressed the issue were retrieved and analysed. Those which did not report relevant outcomes were excluded. Information submitted from stakeholder organisations was also considered where appropriate. The economic studies included had to contain data relevant to the UK setting that addressed specific aspects of
ARTICLE IN PRESS 326 Table 1
A.J. Rutherford The guideline development group. Position
David Barlow Pauline Brimblecombe Clare Brown Kirsten Duckett Jenny Dunlop Geraldine Hartshorne Anthony Hirsh Anthony Rutherford Lorraine Simpson Elfed Williams Sarah Wilson Jane Thomas Moira Mugglestone Irene Kwan Alex McNeil Jennifer Gray Anna Bancsi Hannah-Rose Douglas Dimitra Lambrelli Gillian Roberts
Gynaecologist and Group Leader General Practitioner Patient Representative Obstetrician Counsellor Embryologist Andrologist Gynaecologist Nurse Consumer Representative Public Health Clinician Director, NCC WCH Deputy Director, NCC WCH Research Fellow NCC WCH Research Assistant, NCC WCH Informatics Specialist, NCC WCH Work Programme Coordinator, NCC WCH Health Economist, London School of Hygiene and Tropical Medicine London School of Hygiene and Tropical Medicine Publications Writer/Editor, Royal College of Obstetricians and Gynaecologists
NCC WCH, National Collaborating Centre for Women and Children’s Health.
Table 2
Table 3
Hierarchy of evidence.
Primary Live birth Patient satisfaction Anxiety/depression Multiple births Fetal abnormalities Ectopic pregnancy Ovarian hyperstimulation syndrome
Level
Evidence
1a
Secondary Clinical pregnancy Miscarriage Cycle cancellation Low birth rate Perinatal mortality
3
Systematic review and meta-analysis of randomised controlled trials At least one randomised controlled trial At least one well-designed controlled study without randomisation At least one other type of well-designed quasi-experimental study Well-designed, non-experimental descriptive studies, such as comparative studies, correlation studies or case studies Expert committee reports or opinions and/or clinical experience of respected authorities
Outcome measures.
Surrogate Tubal patency Ovulation Fertilisation Implantation Number of embryos transferred Embryo quality Improved semen parameters Improved sexual function
treatment, predetermined by the GDG. A hierarchy of evidence was employed, as outlined in Table 3, and the highest level of evidence available was
1b 2a 2b
4
used to address each clinical question. Study designs with the least bias were sought for each specific topic; for example, a meta-analysis of randomised controlled trials was used to compare treatments, whereas cohort studies were used to address prognosis. The evidence was summarised by the NCC WCH staff and presented to the GDG in the form of evidence tables. An example of an evidence table is provided in Fig. 1. The GDG considered the information provided on each question and drafted recommendations based
Study Koet et al 200389
Koet et al 200390
Population 30 semen samples from men with mean BMI (SEM) of 26.9 (+0.62)
52 semen samples from men with mean BMI (±SEM) of 27.5 (±0.49)
Comments
Outcomes
Results
DNA fragmentation Index (DFI)
Significant correlation between BMI and DFI
Number of normal motile sperm
Study type
EL
3 OB (abstract)
An increase in BMI beyond 25 is associated with a increase in the DFI of sperm Significant inverse relationship between BMI and number of normal motile sperm
3
Comments
Study type
EL
Randomisation method not clear Small sample
RCT
1b
Normal BMI: normal motile sperm 18.6 x 106 cells Overweight: normal motile sperm 3.6 x 106 cells 6
Obese: normal motile sperm 0.7 x 10 cells
3.6.1 Weight reduction and female fertility Results
Study
Population
Interventions
Outcomes
Guzick et al. 199485
12 obese anovulatory women: Programme (n = 6) Waiting list (n = 6)
A 12-week weight loss programme versus on waiting list
Weight loss Significant weight loss: Detection of ovulation by On programme: 16kg serum progesterone On waiting list: no change
No significance difference Between the 2 groups at Baseline
Clark et al 200086
‘Obese’: 130 – 200% of ideal body weight 171 obese women with infertility history > 1 year group programme: (n = 87) standard programme: (n = 84) 2 groups similar age and length of infertility
Group programme (weekly meeting with 2 hours for support exercise, advice on diet) versus standard programme (usual clinical approach) for 6 months
Weight loss Pregnancy at 18 months
Ovulation: On programme: 4/6 (67%) On waiting list: 1/6 (17%)
Other outcomes include
Significant weight loss Group programme: 4.7kg Standard programme: 1.3kg
Randomisation method not clear
RCT 1b (abstract)
Ovulation status not clear Significant increase in pregnancy Other outcomes included rates group programme: 53/87 (61%) standard programme: 18/84 (21.4%)
‘obese’; BMI > 29kg/m2 <45 kg/m2
327
Figure 1 An example of an evidence tables as supplied to the GDG by NCC-WCH. Published in NICE Guideline, Fertility assessment and Treatment for people with fertility problems. RCOG 2004.
ARTICLE IN PRESS
OB (abstract)
National institute of clinical excellence guidelines on the management of infertility
3.6.1 Obesity and male fertility
ARTICLE IN PRESS 328 on this evidence. The recommendations were reached generally on a consensus basis and graded according to the strength of evidence available (Table 4). A first draft of the full and summary guidelines was circulated in June 2003 to all registered stakeholders, nine peer reviewers appointed by the NCC WCH, an independent Guideline Review Panel established by NICE, the NICE Executive and the Patient Involvement Unit for NICE for comment. A total of 1139 comments were received, collated anonymously and presented to the GDG for consideration. A second draft was published in September 2003, with a further 699 comments received and processed in a similar manner. The final documents—a full guideline, a summary guideline and a version for the public—were published in February 2004 after final editing by the NCC WCH. The whole process had taken just over 2 years to complete.
The guideline document The full guideline document is over 200 pages long and includes 1151 references. It contains 167 recommendations, 29% of which are based on grade A evidence, the bulk (44%) on grade B and C evidence, and only 27% relying on low-level evidence (grade 4) or the views of the GDG. This is a substantial improvement on the Royal College of Obstetricians and Gynaecologists guidelines published in 2000. The document is broken down into chapters that cover the principles of care, the initial advice given to couples experiencing a delay in conception, the investigation and management strategies, followed by chapters on the various treatment options available. Chapters also address the need to follow up children born after assisted conception, topics suitable for audit and where further research is required. There is a full reference list and two appendices, one containing the text of the guideline prepared for public use and the other the economic models employed.
Principles of care Infertility concerns both partners, and there is general agreement that they should be seen together—‘couple-centered’ management. Decisions taken about their investigations and treatments affect both partners, and they need to be provided with appropriate evidence-based information, verbal as well as written, in a format that they can understand. The stress that infertility causes is well recognised. This may manifest as problems within the
A.J. Rutherford couple’s relationship, including decreased libido, which can in itself compromise fertility. There is strong evidence that psychological interventions, such as cognitive-behavioural therapy and group support, improve outcome in those with a relatively short history of infertility. Surveys of patients have established the need for access to support groups and counselling. However, access to independent counselling has until now been mandatory only for those treatments licensed through the Human Fertilization and Embryology Authority. NICE guidelines recommend widening access to counselling to all those seeking help with fertility, throughout their investigation and treatment. Expanding access to counselling to primary and secondary care will of course have significant implications in terms of the cost and training of appropriate individuals. Although the earlier Royal College of Obstetricians and Gynaecologists guidelines document carefully dissected the management of infertility into primary secondary and tertiary care, this guideline emphasises the importance of couples being managed by specialist teams, irrespective of where they are based. Evidence suggests that specialists are more likely to be knowledgeable about their subject and are quicker to implement new and more effective treatments than generalists.
Investigation of fertility problems Men The assessment of semen quality should use standardised techniques, performed to an auditable, verifiable standard. The World Health Organization criteria are almost universally accepted as the best reference range available. The test is based on the analysis of semen from a population of fertile men. Applying these standards, a single semen analysis will identify almost 90% of men who have a true semen abnormality. If an abnormality is identified, a second confirmatory test will significantly improve the specificity. There is, however, little point in repeating a normal test as this provides little additional information. The second test should be delayed for 3 months to allow a full spermatogenic cycle to take place, although the test can be performed in a shorter time scale if azoospermia or severe oligospermia is identified. If both tests confirm an abnormality, further sperm function tests are commonly performed. There appears to be little uniformity of approach in terms of which specific test is used. In these circumstances, the test that is used in the local tertiary centre should be employed. The detection
ARTICLE IN PRESS National institute of clinical excellence guidelines on the management of infertility
these cannot be justified in clinical practice as they make little impact on treatment. Karyotyping is, however, thought to be beneficial, as up to 5% of men with severe oligoazoospermia will have a chromosomal abnormality, the knowledge of which may alter management.
History Physical examination Chlamydia antibody titre
Negative
Positive
HSG
Laparoscopy & dye
Negative
Wait
Positive
329
Negative
Positive
Wait
Treat
Figure 2 Assessment of tubal pathology (based on a presentation by Professor Johannes L. H. Evers at the launch meeting for the National Institute of Clinical Excellence Fertility Guideline, 3 March 2004). HSG, Hysterosalpingography.
of anti-sperm antibodies is part of the normal World Health Organization assessment. As, however, there are no treatments that have been shown to be universally effective in improving outcome, NICE decided not to recommend routine testing. A male factor, either alone or in combination with other female factors, is one of the most common causes of infertility in the UK population. The reason for the semen abnormality may not found in up to 50% of cases, but where a semen abnormality is detected, physical examination of the man is valuable. A varicocele is found more commonly in men with abnormal semen, although the true significance of this to fertility is not understood. Serum to measure the follicle-stimulating hormone (FSH), luteinising hormone and testosterone will help to distinguish between the causes of azoospermia. Hypothalamic-pituitary dysfunction is a rare cause of male infertility associated with low levels of FSH and luteinising hormone. Obstructive azoospermia, characterised by testes of normal volume and a normal FSH level, may have an iatrogenic (vasectomy), an infective (epididymitis) or a congenital (congenital bilateral absence of the vas deferens) origin. The latter is associated with the mutations that cause cystic fibrosis; if found, screening for these mutations is required. If the man screens positive, his partner also needs to be screened. The most common cause of oligozoospermia and non-obstructive azoospermia, characterised by a raised FSH and small volume testes, is primary testicular failure. Although tests are available to detect the few microdeletions on the Y chromosome already identified that may be responsible,
Women Ovulation. The majority of women with a history of regular menstrual cycles (26–35 days) will be ovulating. In patients who have not conceived within 2 years, a mid-luteal progesterone estimation can be offered to confirm ovulation. Those patients with more irregular cycles could have their serum progesterone measured on a weekly basis until they have their next period, although these patients almost certainly will benefit from ovulation induction therapy. In patients with irregular cycles, their FSH and luteinising hormone should be assessed. Routine prolactin measurement in regular cycling women cannot be justified, and the test should be reserved for those with evidence of anovulation and or galactorrhoea. Basal body temperature charts are or poor prognostic value and should be avoided. In patients with oligoamenorrhoea, where polycystic ovarian syndrome is suspected, further investigations are warranted, although these were not included in the guideline document (see information on Scope). Thyroid function tests are commonly performed as part of the infertility assessment. Although thyroid dysfunction can lead to menstrual and ovulatory disorders, the incidence of subclinical thyroid disease in women with ovulatory disorders is no more prevalent than the incidence of asymptomatic thyroid disease in the general population. As such, the guideline recommends that thyroid function tests are not required for asymptomatic women. Assessing ovarian reserve, by measuring early follicular phase gonadotrophin levels in regularly cycling women, can be useful in predicting outcome in patients undergoing complex ovulation induction and assisted conception treatments. However, their role in the initial assessment of infertility is not established. Chlamydia screening. There is evidence that screening for, and treating, those at risk of Chlamydia infection can reduce the risk of pelvic inflammatory disease. Although the infertile population has a relatively low (1.9%) incidence of chlamydia, clinical pelvic infection affects up to 4% of women having a hysterosalpingogram and 10% of those with tubal pathology. If screening has not been performed, antibiotic prophylaxis should be used if tubal patency tests are performed.
ARTICLE IN PRESS 330 Tubal pathology. Tubal pathology is one of the most common female causes of infertility, accounting for 14% of all cases. Disease can be proximal (25%) or distal (75%). All tests of tubal patency are invasive, and it is important to complete other infertility investigations first. The two most commonly employed techniques are hysterosalpingography (HSG) and laparoscopy, although some advocate the use of hystero-contrast-sonography. In trained hands, hystero-contrast-sonography seems to be comparable with both HSG and laparoscopy with dye. HSG is a good test of tubal patency but not a reliable predictor of tubal occlusion. There is evidence that tubal pathology detected by laparoscopy is more likely to affect outcome than that detected after HSG. Chlamydial antibody titre has also been shown to comparable at detecting tubal pathology to HSG. In both cases, a confirmatory laparoscopy is required to assess the extent of the damage. In light of these findings, a simple model for investigating tubal fertility has been proposed (Fig. 2). Newer techniques such as fertiloscopy and falloposcopy still require further research before they can be considered as useful in clinical practice. Uterine and pelvic abnormalities. Abnormalities such as polyps, fibroids, intrauterine adhesions and structural abnormalities are found in 15% of patients presenting with infertility. Whether these have a direct impact on fertility is poorly understood. Hysteroscopy is undoubtedly better than HSG at detecting these abnormalities, but in the absence of hard data showing any benefit from surgery, a hysteroscopy should not be performed as an isolated procedure as part of an infertility work-up. Similarly, pelvic ultrasound is much more accurate than pelvic examination in picking up abnormalities in the pelvis. If pelvic pathology is suspected, for example in a patient with oligoamenorrhoea, a scan should be employed. In an asymptomatic patient with a normal pelvic examination, there is, however, no current evidence that a pelvic scan will alter or improve outcome. Finally, the post-coital test does not appear to offer any improvement in outcome but does result in more intervention, and as such it is now considered unnecessary.
Treatment Male Medical therapies are rarely of value in male infertility, with a few notable exceptions. For
A.J. Rutherford example, hypogonadotrophic hypogonadism, an uncommon cause of male infertility, can be treated effectively, with human chorionic gonadotrophin and human menopausal gonadotrophin, achieving normal sperm counts and fertility. An equally effective alternative would be to use pulsatile gonadotrophin-releasing hormone. The use of corticosteroids in immunological male infertility, which is associated with a significant side-effect profile, has been evaluated in five randomised controlled trials with indifferent results, three showing no and two showing only a small benefit. As such, the use of corticosteroids cannot be recommended. Likewise, the routine use of antibiotics for men with leukospermia, without a recognised infection, has not shown to be of proven benefit in improving pregnancy rates. The use of antioxidants has shown some promise, but further research is required to prove a beneficial effect. The surgical treatment of obstructive azoospermia of infective origin would appear to be of benefit if appropriate expertise is available and offers an alternative to sperm retrieval and IVF. If surgery is performed, sperm retrieval should be attempted at the same time to avoid the need for a second operative procedure should the original surgery prove unsuccessful. A meta-analysis of the surgical treatment of a varicocele, whether clinical or subclinical, demonstrated no improvement in pregnancy rate, and this should therefore not be offered as a form of fertility treatment. Ejaculatory failure can be treated by a variety of methods without resorting to invasive methods of sperm retrieval or assisted conception. Over 50% of men with anejaculation can be successfully treated with parasympathomimetics, whereas retrograde ejaculation may respond to drugs aiming to increase the sympathetic tone of the bladder or reduce parasympathetic activity. If medical treatment fails, electrovibratory or electro-ejaculation using a transrectal probe is usually successful. In retrograde ejaculation, the sperm is recovered from the bladder, often after alkalisation of the urine to prevent sperm damage. Psychogenic disorders resulting in erectile dysfunction can be successfully treated with sildenafil. Should simple methods fail, surgical sperm retrieval followed by IVF and intracytoplasmic sperm injection is a successful alternative. Donor insemination remains an effective treatment that can be used to treat men with both obstructive and non-obstructive azoospermia, infectious diseases such as human immunodeficiency virus in the male partner, severe rhesus isoimmunisation, where there is a high risk of passing on a genetic risk to the offspring, and severe defects in
ARTICLE IN PRESS National institute of clinical excellence guidelines on the management of infertility semen quality when the couple do not want to undergo more complex assisted conception. It is essential that those contemplating donor insemination be offered independent counselling on all the psychological implications of treatment for themselves and their potential children, in particular on how to advise the child of its genetic origins. Women with evidence of regular ovulation in whom there is no history suggestive of tubal pathology can have up to three cycles of treatment before checking their tubal patency. Intrauterine insemination (IUI) is preferred, timed to the detection of the luteinising hormone surge using urine prediction kits. Up to six cycles of treatment should be offered before contemplating more complex alternatives. Intracytoplasmic sperm injection has revolutionised the treatment of male infertility where there are insufficient sperm to achieve fertilisation using conventional insemination. Such situations include men with obstructive and non-obstructive azoospermia, and severe defects in semen quality, and those couples in whom where an IVF cycle has resulted in failed fertilisation. It is important that couples are aware of the potential increased genetic risks associated with intracytoplasmic sperm injection and are investigated and counselled accordingly. Female Ovulation induction. The majority of patients with anovulatory infertility (85%) will have World Health Organization type II ovulation disorders, and most of these will have polycystic ovaries. The firstline treatment in these women are the antioestrogens, clomifene and tamoxifen, which appear to be equally effective and restore ovulation in up to 70% of women. Multiple pregnancy is a considered risk with clomifene, and as a good practice point the GDG recommended monitoring at least during the first cycle to try to determine the minimal effective dose. Failure to respond to clomifene is often associated with an increased body mass index. There is good evidence that natural ovulation and the response to clomifene can be improved by participating in a weight-loss programme. Those patients who fail to respond to clomifene and who have a body mass index greater than 25 benefit from the addition of metformin. Once a satisfactory ovulatory response has been achieved, treatment can be continued for up to 12 cycles, although the addition of IUI may be considered after six. Those who do not respond to simple weight loss and oral medication can be treated by gonadotrophins or surgery (ovarian drilling), which appear to be equally effective.
331
Interestingly, all forms of commercially available gonadotrophins seem to be equally effective, and consideration should be given to cost when prescribing. Oocyte donation may be considered with a diagnosis of premature ovarian failure, gonadal dysgenesis, where there is a high risk of passing on genetic disease, iatrogenic ovarian damage (surgery, chemotherapy or radiotherapy) and rarely in cases of repeated failure of IVF. Both donor and recipient should be offered independent counselling about the potential impact of oocyte donation on them and their potential children. Donors should be made aware of the very real risks of undergoing ovarian stimulation and the oocyte recovery procedure, and the possible impact on their future fertility. Tubal and uterine surgery. Tubal disease is an important cause of infertility. Although goodquality studies have addressed the benefits of the methodologies used in tubal surgery, there are few objective data to confirm the true benefit of surgery compared with not operating or with alternative approaches such as IVF. Irrespective of the method used to confirm tubal blockage, there are patients who will conceive spontaneously. If a proximal block is suspected, selective salpingography should be attempted, as this is a better diagnostic test than laparoscopy and dye. Furthermore, tubal catheterisation under X-ray control or hysteroscopic tubal recanulation may improve the chance of a pregnancy. When such treatment is unsuccessful, tubocornual anastomosis would appear to be effective in trained hands, with term pregnancy rates of up to 50% reported. Such expertise is, however, in short supply, and the majority of these patients will be treated with IVF. The vast majority of patients with tubal pathology have distal disease, which may range from mild peritubal adhesions to grossly distended hydrosalpinges. The prospect for spontaneous pregnancy and the outcome of surgery depend on the degree of damage, with pregnancy more likely in mild disease. The chance of success declines with the severity of disease, such that those with the worst pathology are unlikely to benefit at all from surgery. Unfortunately, only about a quarter of all patients have mild disease suitable for surgery, and the remainder will require IVF. Pregnancy normally occurs within the first 12–14 months after surgery, so those patients who have not conceived within 12 months of surgery will also need IVF. Uterine abnormalities. The incidence of leiomyoma in women with unexplained infertility is around 2%. There are no randomised controlled trials comparing myomectomy with expectant
ARTICLE IN PRESS 332 management. There is limited evidence suggesting that the removal of submucous fibroids improves pregnancy rates, and retrospective data indicate that women with leiomyoma have a reduced chance of conception following IVF. Further research is, however, required to establish the true benefits of the surgical treatment of leiomyoma. A septate uterus is no more likely to be found in an infertile woman than other women, although it is more commonly associated with those who suffer recurrent miscarriage. Surgery has not been shown to be of benefit. Intrauterine adhesions, associated with previous surgical procedures on the uterus, can be divided hysteroscopically to improve pregnancy outcome. Endometriosis. There is solid evidence indicating that there is no benefit to be gained from treating minimal and mild endometriosis with any form of medical treatment to improve fertility. In contrast, there are two studies indicating that laparoscopic ablation or the resection of similar grades of disease plus adhesiolysis improves fertility outcome. In asymptomatic patients, the benefits of surgery, which are relatively small in absolute terms, have to be balanced against the risks of general anaesthesia, surgical complications and of course cost. In more significant grades of endometriosis, the benefits of surgery are more evident. There is, for example, a large improvement in cumulative pregnancy rate after laparoscopic ovarian cystectomy compared with simple drainage or the coagulation of large endometrioma (66.7% versus 23.5%; odds ratio 2.83, 95% confidence interval 1.01–7.50). Again, however, there would seem to be no benefit from adjunctive medical therapy after surgery. In those for whom surgery is not possible, or those who have not conceived within 12 months, IVF is indicated. Assisted conception techniques. The recommendation to extend the use of IUI is one of the most controversial aspects of these guidelines. This treatment is currently one of the few that involves the manipulation and handling of gametes that is not directly regulated by the Human Fertilisation and Embryology Authority. IUI is used in the treatment of unexplained infertility, mild male factor infertility and lesser forms of endometriosis. IUI in combination with ovarian stimulation is more successful than simple IUI alone when there is unexplained infertility or endometriosis, but not seemingly with mild male factor infertility. However, at a time where measures have been put in place to reduce the overall incidence of multiple pregnancy in licensed treatment, it seemed illogical to advocate stimulated IUI, which has the potential to increase the number of high-order
A.J. Rutherford multiple pregnancies. The GDG took a pragmatic decision on the grounds of safety to recommend up to six cycles of IUI without stimulation for the large group with unexplained infertility, and for those with male factor in whom stimulation had not shown to be beneficial. As there were no data on the effectiveness of IUI without stimulation for patients suffering from endometriosis, the recommendation was to include stimulation with this group. The argument put forward by advocates of IUI in the UK is that the lack of stimulation will significantly reduce the success rate, and as most UK practitioners use a more cautious stimulation strategy, the rate of multiple pregnancy is lower than those reported in the published studies (29%). IVF is used for a range of fertility disorders that have failed to respond to conventional therapy, as outlined in Table X. Various factors determine an individual’s chance of success. Age is perhaps the most important factor, with success declining with age. Although there are few data available on the effectiveness of IVF in women under 23 years of age, the validated Human Fertilisation and Embryology Authority database of over 110,000 cycles clearly shows that the live birth rate remains fairly constant between the ages of 23 and 32 years, but above the age of 33 the success rate declines, falling by 50% by the age of 40 years and down to as low as 1% by the time women reach 45 years old. The database also shows that the success rate is maintained at a similar level over the first three attempts, but after three cycles effectiveness is less certain. This information fashioned GDG thinking on the lower (23 years old) and upper (39 years old) age range for treatment, and on the number of treatments offered: up to three fresh IVF cycles plus the transfer of any surplus embryos generated during these treatments. Factors that adversely affect a successful treatment outcome include a long history of infertility, and certain pathologies, such as endometriosis and, in cases of tubal disease, the presence of a hydrosalpinx. The surgical removal of hydrosalpinges is associated with an increased live birth rate (odds ratio 2.13, 95% confidence interval 1.24–3.65). Lifestyle issues also play a role, with excess alcohol, smoking and caffeine all implicated as causing a reduced chance of a live birth. Both low and high body mass index are associated with a poor outcome, and women should be advised to try to maintain their body mass index within the range 19–30. Conversely, a history of a previous pregnancy, particularly after IVF, increases the likelihood of conception. The main thrust of the recommendations dealing with the IVF process is effectiveness and safety.
ARTICLE IN PRESS National institute of clinical excellence guidelines on the management of infertility Prior to patients undergoing advanced fertility treatment, their human immunodeficiency virus, hepatitis B and hepatitis C status should be established as this has implications for the management of their treatment cycle, and potentially for the welfare of the child. All currently available gonadotrophin preparations are equally efficacious, and the choice of compound should be determined by cost. In contrast, gonadotrophin releasing hormone agonists are preferred to antagonists on the basis of a higher chance of a live birth. During treatment, the response to stimulation must be monitored closely, with ultrasound alone the preferred option. Clinics need to be aware of the risk of ovarian hyperstimulation syndrome and have protocols in place to deal with this eventuality. Although various methods have been used to reduce the risk of establishing ovarian hyperstimulation syndrome, the only reliable way to ensure that it does not develop is to withhold the human chorionic gonadotrophin trigger. Oocyte collection should be performed under conscious sedation following the guidelines developed by the Academy of Medical Royal Colleges. Embryo transfer can be arranged at the early cleavage stage (days 2–3) or at the blastocyst stage (days 5–6). In order to limit the risk of multiple pregnancy, it should be performed under ultrasound control with no more than two embryos transferred. Luteal support is required, preferably using progesterone, as human chorionic gonadotrophin potentially increases the risk of ovarian hyperstimulation syndrome. The evidence to date on the health of children born following assisted conception is broadly reassuring. It is, however, important that couples contemplating using assisted conception are given up-to-date information as it becomes available, and that further long-term follow-up studies should be organised on a national basis.
333
Summary The NICE guideline document was heralded as an essential prerequisite to establishing a fair national policy for the investigation and treatment of infertility. It is built on the solid foundation of the three Royal College of Obstetricians and Gynaecologists guidelines, updated with the latest evidence so that almost 50% of the recommendations were based on class A and class B evidence. For clinicians and patients, the most eagerly received changes were the proposals to increase the number of IVF cycles available and the age range of women to whom IVF could be offered. Unfortunately for many, access to appropriate fertility treatment remains elusive as ‘social’ factors, which underpin most purchaser contracts, were not included as part of the original Scope document and therefore remain unchanged. Furthermore, despite protestations that the guidelines would be implemented, no new money was allocated to fund the proposals, leaving purchasing authorities the unenviable task of potentially having to cull other services to fund infertility treatment.
Acknowledgements This document and the recommendations included within it are based closely on the NICE Clinical Guideline, Fertility Assessment and Treatment for People with Fertility Problems, published in February 2004.
Further reading 1. Fertility assessment and treatment for people with fertility problems, www.nice.org.uk.