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## Complete Summary

#### GUIDELINE TITLE

Fertility: assessment and treatment for people with fertility problems.

#### BIBLIOGRAPHIC SOURCE(S)

National Collaborating Centre for Women\'s and Children\'s Health.
Fertility: assessment and treatment for people with fertility problems.
London: RCOG Press; 2004 Feb. 216 p. \[1151 references\]

#### GUIDELINE STATUS

This is the current release of the guideline. This guideline updates the
following guidelines previously released by the Royal College of
Obstetricians and Gynaecologists:

-   Royal College of Obstetricians and Gynaecologists. The initial
    investigation and management of the infertile couple. London: RCOG
    Press; 1998 Feb. 82 p. (Evidence-based clinical guidelines; no. 2).

-   Royal College of Obstetricians and Gynaecologists. The management of
    infertility in secondary care. London: RCOG Press; 1998 Feb. 148 p.
    (Evidence-based clinical guidelines; no. 3). \[677 references\]

-   Royal College of Obstetricians and Gynaecologists. The management of
    infertility in tertiary care. London: RCOG Press; 2000 Jan. 121 p.
    (Evidence-based clinical guidelines; no. 6).

### COMPLETE SUMMARY CONTENT

 SCOPE\
 METHODOLOGY - including Rating Scheme and Cost Analysis\
 RECOMMENDATIONS\
 EVIDENCE SUPPORTING THE RECOMMENDATIONS\
 BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS\
 QUALIFYING STATEMENTS\
 IMPLEMENTATION OF THE GUIDELINE\
 INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT
CATEGORIES\
 IDENTIFYING INFORMATION AND AVAILABILITY\
 DISCLAIMER

### SCOPE

#### DISEASE/CONDITION(S)

-   Infertility

-   Fertility problems

#### GUIDELINE CATEGORY

Counseling\
Diagnosis\
Evaluation\
Management\
Treatment

#### CLINICAL SPECIALTY

Family Practice\
Internal Medicine\
Obstetrics and Gynecology

#### INTENDED USERS

Advanced Practice Nurses\
Health Care Providers\
Nurses\
Patients\
Physicians

#### GUIDELINE OBJECTIVE(S)

To offer best practice advice on the care of people in the reproductive
age group who perceive that they may have problems in conceiving

#### TARGET POPULATION

Couples in the reproductive age group with fertility problems

**Note**: This guideline does not include the management of people who
are outside this definition, such as the initial management of those
with sexual dysfunction, couples who are using contraception (for
example, where one partner has been sterilised), non-heterosexual
couples, or couples outside the reproductive age range.

#### INTERVENTIONS AND PRACTICES CONSIDERED

**[Diagnostic Investigations]{.underline}**

1.  Semen analysis, including volume, liquefaction time, pH, sperm
    concentration, total sperm number, motility, vitality, white blood
    cells, and morphology

2.  Assessment of ovulation, including serum progesterone and serum
    gonadotrophins (follicle-stimulating hormone and luteinising
    hormone)

3.  Screening for *Chlamydia trachomatis*

4.  Assessment of tubal damage including hysterosalpingography (HSG),
    hysterosalpingo-contrast-ultrasonography, and laparoscopy and dye

5.  Assessment of uterine abnormalities

6.  Post-coital testing of cervical mucosa

**[Treatment/Management]{.underline}**

**General Management Principles**

1.  Providing initial advice to people concerned about delays to
    conception

2.  Providing information through couple-centred management

3.  Describing psychological effects of fertility problems

4.  Providing specialist and generalist care

**Medical Treatment**

1.  Gonadotrophin drugs, including human menopausal gonadotrophin,
    urinary follicle-stimulating hormone, and recombinant
    follicle-stimulating hormone

2.  Gonadotrophin-releasing hormone agonists

3.  Gonadotrophin-releasing hormone antagonists (not recommended)

4.  Anti-oestrogens, including clomiphene citrate and tamoxifen

5.  Androgens (not recommended)

6.  Kinin-enhancing drugs (not recommended)

7.  Systemic corticosteroids (not recommended)

8.  Antibiotic treatment

9.  Metformin

10. Growth hormone (not recommended)

11. Dopamine agonists, including bromocriptine

**Surgical Treatment**

1.  Surgical correction of epididymal blockage

2.  Surgical sperm recovery

3.  Laparoscopic ovarian drilling

4.  Tubal microsurgery

5.  Laparoscopic tubal surgery

6.  Tubal catheterisation or cannulation

7.  Uterine surgery

8.  Surgical ablation or resection of endometriosis plus laparoscopic
    adhesiolysis

9.  Laparoscopic cystectomy

**Assisted Reproduction**

1.  Intrauterine insemination

2.  In vitro fertilisation treatment

3.  Gamete intrafallopian transfer

4.  Zygote intrafallopian transfer

5.  Intracytoplasmic sperm injection

6.  Donor insemination

7.  Oocyte donation

8.  Cryopreservation in cancer treatment

#### MAJOR OUTCOMES CONSIDERED

**Primary Outcomes**:

-   Live birth

-   Patient satisfaction

-   Anxiety/depression

-   Multiple births

-   Fetal abnormalities

-   Ectopic pregnancy

-   Ovarian hyperstimulation syndrome (OHSS)

**Secondary Outcomes**:

-   Clinical pregnancy (confirmed by presence of fetal heart rate)

-   Miscarriage

-   Cycle cancellation

-   Low birth rate

-   Perinatal mortality

**Surrogate Outcomes**:

-   Tubal patency

-   Ovulation

-   Fertilisation

-   Implantation (number of gestational sacs identified by ultrasound)

-   Number of embryos transferred

-   Embryo quality

-   Improved semen parameters

-   Improved sexual function

**Other Outcomes**:

-   Cost measures including cost effectiveness and quality-adjusted life
    years (QALY)

### METHODOLOGY

#### METHODS USED TO COLLECT/SELECT EVIDENCE

Hand-searches of Published Literature (Primary Sources)\
Hand-searches of Published Literature (Secondary Sources)\
Searches of Electronic Databases

#### DESCRIPTION OF METHODS USED TO COLLECT/SELECT THE EVIDENCE

**Literature Search Strategy**

The aim of the literature review was to identify and synthesise relevant
evidence within the published literature, in order to answer specific
clinical questions. Searches were performed using generic and specially
developed filters, relevant medical subject heading terms, and free-text
terms. Details of all literature searches are available on application
to the National Collaborating Centre for Women´s and Children\'s Health
(NCC-WCH).

The National Guideline Clearinghouse database, the Turning Research into
Practice database, and the Organising Medical Networked Information
service on the Internet were searched for guidelines produced by other
development groups. The reference lists in these guidelines were checked
against the Guideline Development Group´s searches to identify any
missing evidence.

Searches were carried out for each topic of interest. The Cochrane
Library (up to Issue 3, 2003) was searched to identify systematic
reviews (with or without meta-analyses) of randomized controlled
(clinical) trials (RCTs) and individual RCTs. The electronic databases
MEDLINE (Ovid version for the period January 1966 to October 2003),
EMBASE (Ovid version for the period between 1988 to October 2003), the
Cumulative Index to Nursing and Allied Health Literature, the British
Nursing Index and PsychInfo were also searched, as was the Database of
Abstracts and Reviews of Effectiveness.

There was no systematic attempt to search the \"grey literature\"
(conferences, abstracts, theses, and unpublished trials). A preliminary
scrutiny of titles and abstracts was undertaken and full papers were
obtained if the research question addressed the Guideline Development
Group\'s question relevant to the topic. Following a further review of
the full version of the study, articles that did not address the
Group\'s question were excluded. Studies that did not report relevant
outcomes were also excluded. Submitted evidence from stakeholders was
included where the evidence was relevant to the Group\'s clinical
question and was of equivalent or better quality than the research
identified in the literature searches.

The economic evidence presented in this guideline is not a systematic
review of all the economic evidence around fertility treatment, but a
review of evidence relating to specific aspects of treatment (see
below). In addition to the databases listed above, the Health Economic
Evaluations Database and the National Health Service (NHS) Economic
Evaluations Database were searched for relevant economic studies.

The search strategies were designed to find any economic study related
to infertility. Abstracts and database reviews of papers found were
reviewed by the health economists and were discarded if they appeared
not to contain any cost data relevant to the UK setting or did not
relate to the precise topic or question being considered in the
algorithm. Relevant references in the bibliographies of reviewed papers
were also identified and assessed against standard criteria.

The topic had to focus on the appropriate alternatives (the appropriate
clinical question) and preferably be able to be generalised to the
England and Wales setting. The review of the evidence included
cost-effectiveness studies, cost-consequence studies (cost of present
and future costs only) and high quality systematic reviews of the
evidence (see below).

#### NUMBER OF SOURCE DOCUMENTS

Not stated

#### METHODS USED TO ASSESS THE QUALITY AND STRENGTH OF THE EVIDENCE

Weighting According to a Rating Scheme (Scheme Given)

#### RATING SCHEME FOR THE STRENGTH OF THE EVIDENCE

**Evidence Categories**

**1a**: Evidence obtained from systematic review and meta-analysis of
randomised controlled trials.

**1b**: Evidence obtained from at least one randomised controlled trial.

**2a**: Evidence obtained from at least one well-designed controlled
study without randomisation.

**2b**: Evidence obtained from at least one other type of well-designed
quasi-experimental study.

**3**: Evidence obtained from well-designed nonexperimental descriptive
studies, such as comparative studies, correlation studies, or case
studies.

**4**: Evidence obtained from expert committee reports or opinions
and/or clinical experience of respected authorities.

#### METHODS USED TO ANALYZE THE EVIDENCE

Meta-Analysis\
Review of Published Meta-Analyses\
Systematic Review with Evidence Tables

#### DESCRIPTION OF THE METHODS USED TO ANALYZE THE EVIDENCE

**Outcome Measures**

For this guideline, the management of fertility problems has been
assessed against a variety of reproductive and pregnancy outcomes. The
justification for using these outcomes is based on their relevance to
women and consensus among members of the Guideline Development Group
(GDG). These outcomes were also informed by the Cochrane Menstruation
Disorders and Subfertility Group. The outcomes were grouped to reflect
their importance to women, healthcare professionals, and the health
service. Outcomes include those that were felt to be desirable (for
example, a live birth) and those unwanted effects of treatment that it
would be important to reduce to a minimum (for example, ectopic
pregnancy or fetal abnormality). When assessing the effectiveness of a
particular treatment, information about the effect of that treatment on
one or more primary outcomes was sought. Where such information was not
available secondary outcomes were used. If neither primary nor secondary
outcomes were available, surrogate outcomes (indirect measures of
effectiveness) were considered.

**Clinical Effectiveness**

For all subject areas, evidence from the study designs least subject to
bias was included. Where possible, the highest levels of evidence were
used, but all papers were reviewed using established guides. Published
systematic reviews or meta-analyses were used where available. For
subject areas where neither was available, other appropriate
experimental or observational studies were sought.

Identified articles were assessed methodologically and the best
available evidence was used to form and support the recommendations. The
highest level of evidence was selected for each clinical question. The
retrieved evidence was graded according to the evidence-level structure
shown in Table 1.1 of the original guideline document and defined above
in the \"Rating Scheme for the Strength of the Evidence\" field.

Each clinical question dictated the highest level of evidence that could
be sought. For issues of therapy or treatment the highest possible level
of evidence was a meta-analysis of randomised controlled trials (RCTs)
or an individual RCT.

For issues of prognosis, a cohort study was the best possible level of
evidence. This equates to a grade B recommendation (defined below in the
\"Rating Scheme for the Strength of the Recommendations\" field).
However, this should not be interpreted as an inferior grade of
recommendation because it represents the highest level of evidence
attainable for that type of clinical question.

For diagnostic tests, test evaluation studies examining the performance
of the test were used if the efficacy of the test was required, but
where an evaluation of the effectiveness of the test in the management
and outcome was required, evidence from RCTs or cohort studies was
sought.

All retrieved articles were appraised methodologically using established
guides. Where appropriate, if a systematic review, meta-analysis, or RCT
existed in relation to a topic, studies of a weaker design were
excluded.

The evidence was synthesised using qualitative methods. These involved
summarising the content of identified papers in the form of evidence
tables and agreeing brief statements that accurately reflected the
relevant evidence. Quantitative synthesis (meta-analysis) was performed
where appropriate. Meta-analyses based on dichotomous outcomes are
presented as relative risks with 95% confidence intervals.

For the purposes of this guideline, data are presented as absolute
risks, relative risks, or odds ratios where relevant (i.e., in RCTs and
cohort studies). Where the data are statistically significant they are
also presented as numbers needed to treat (for beneficial outcomes) or
numbers need to harm (for adverse effects of treatment) if relevant.

#### METHODS USED TO FORMULATE THE RECOMMENDATIONS

Expert Consensus (Nominal Group Technique)\
Informal Consensus

#### DESCRIPTION OF METHODS USED TO FORMULATE THE RECOMMENDATIONS

The guideline was developed by a multiprofessional and lay working group
(the Guideline Development Group) convened by the National Collaborating
Centre for Women\'s and Children\'s Health (NCC-WCH). Membership
included:

-   two consumer representatives

-   two gynaecologists

-   an obstetrician

-   an embryologist

-   an andrologist

-   a counsellor

-   a nurse

-   a General Practitioner (GP)

-   a public health clinician

Staff from the NCC-WCH provided methodological support for the guideline
development process, undertook systematic searches, retrieval, and
appraisal of the evidence, and wrote successive drafts of the document.

**Forming and Grading Recommendations**

The Guideline Development Group (GDG) was presented with summaries (text
and evidence tables) of the best available research evidence to answer
its questions. Recommendations were based on, and explicitly linked to,
the evidence that supported them. Where possible, the Group worked on an
informal consensus basis. Formal consensus methods (the nominal group
technique) were employed when required (e.g., grading recommendations
and agreeing audit criteria).

#### RATING SCHEME FOR THE STRENGTH OF THE RECOMMENDATIONS

**Grading of Recommendations**

**A**: Directly based on level 1 evidence

**B**: Directly based on level 2 evidence, or extrapolated
recommendation from level 1 evidence

**C**: Directly based on level 3 evidence, or extrapolated
recommendation from either level 1 or 2 evidence

**D**: Directly based on level 4 evidence, or extrapolated
recommendation from either level 1, 2, or 3 evidence

**Good practice point (GPP)**: The view of the Guideline Development
Group

#### COST ANALYSIS

**Aim of the Economic Analysis**

The inclusion of economic evidence in guidelines is a fairly recent
phenomenon. The purpose of including economic evidence in a clinical
guideline is to allow recommendations to be made not just on the
clinical effectiveness of different forms of care, but also on their
cost effectiveness. The aim is to produce guidance that uses scarce
health service resources efficiently, that is providing the best
possible care within resource constraints.

**Cost Effectiveness of Assisted Reproduction**

The approach to presenting the economic evidence on assisted
reproduction was to model the cost effectiveness of assisted
reproduction under different assumptions and conditions. There were
several reasons for adopting this approach. First, decision analysis is
an important step towards understanding the cost effectiveness of
different treatment pathways that a couple may be offered. Second, the
approach allows for the synthesis of clinical effectiveness evidence,
alongside the estimated costs of diagnosis and treatment and the
consequences of treatment that relate to the United Kingdom (UK)
setting. Third, it clearly shows where gaps exist in the published
literature and research evidence.

The models developed in this guideline were based on clinical and cost
effectiveness data for assisted reproduction techniques. Since robust
trial data on the effectiveness of different options for assisted
reproduction were not available, the models used probabilities derived
from a combination of sources (see Appendix B of the original guideline
document).

Key topics for the economic analysis in the guideline were determined by
the Guideline Development Group (GDG) as the process of developing the
guideline and reviewing the evidence evolved. The key economic questions
to be considered in the guideline were:

-   the cost effectiveness of in vitro fertilisation (IVF) and other
    forms of assisted reproduction

-   the cost effectiveness of urinary versus recombinant gonadotrophins
    in IVF treatment

-   the cost effectiveness of stimulated and unstimulated intrauterine
    insemination (IUI)

-   a review of the current literature on the cost impact of reducing
    the number of embryos transferred during IVF treatment.

**Valuing the Cost of Assisted Reproduction**

Alongside the review of the research evidence, data were gathered from
other UK sources to obtain estimates of the costs for specific cost
elements in each model. Historically, many of the services offered as
part of an infertility diagnosis and treatment package have not been
provided by the National Health Service (NHS) but rather by private
clinics. However, the market prices of these services were assumed to be
likely to be close to \"opportunity costs\" for the services. The
sources of data are discussed in Appendix B of the original guideline
document.

Although the value of the resources used in assisted reproduction is an
important question, the overall cost effectiveness of assisted
reproduction will also be determined by important differences in
clinical effectiveness of assisted reproduction techniques. The clinical
and cost data that were available were not appropriate for making
detailed forecasts of future expenditure on assisted reproduction. This
would require a detailed costing exercise based on current and future
levels of demand for the service, current capacity and future resources
available. However, the data did indicate the magnitudes of costs that
would be likely to be needed if specific policies were adopted. This
analysis also indicates whether specific parameters (such as, the live
birth rate, the number of cycles offered and the rate at which couples
choose to discontinue treatment) are more important than others, and
where future research effort should be directed.

**Representation of the Consequences of Assisted Reproduction:
Quality-Adjusted life years (QALY)**

Ethical and moral arguments relating to the value of live births
resulting from assisted reproduction are not addressed in the economic
analysis because they go beyond the issues that can be addressed in a
clinical guideline. The primary outcome considered in the economic
models is a live birth and not a measure of life years. There is an
important debate about whether the outputs of assisted reproduction can
be incorporated into a measure than can be compared with other uses of
the same resources. It is not logical to try to derive a QALY measure
from live births arising from IVF. It has been argued that:

\"QALYs are intended to capture improvements in health among patients.
They are not appropriate for placing a value on additional lives.
Additional lives are not improvements in health; preventing someone´s
death is not the same as creating their life and it is not possible to
improve the quality of life of someone who has not been conceived by
conceiving them.\"

Another review stated that:

\"Cost-utility analysis has little relevance to the management of
infertility where lives are produced and not saved.\"

This is a valid argument, so QALYs cannot be reported in the context of
assisted reproduction unless they are related only to the couple seeking
treatment.

#### METHOD OF GUIDELINE VALIDATION

External Peer Review\
Internal Peer Review

#### DESCRIPTION OF METHOD OF GUIDELINE VALIDATION

The guideline has been developed in accordance with the National
Institute for Clinical Excellence (NICE) guideline development process.
This has included the opportunity for registered stakeholders to comment
on the scope of the guideline, the first draft of the full and summary
guidelines, and the second draft of all versions of the guideline. In
addition the drafts were reviewed by an independent Guideline Review
Panel established by NICE and by the NICE Executive and the Patient
Involvement Unit for NICE.

The comments made by the stakeholders, peer reviewers, and the Guideline
Review Panel were collated and presented anonymously for consideration
by the Guideline Development Group. All comments were considered
systematically by the Guideline Development Group, and the resulting
actions and responses were recorded.

### RECOMMENDATIONS

#### MAJOR RECOMMENDATIONS

Evidence categories (1a-4) and recommendation grades (A-D) are defined
at the end of the \"Major Recommendations\" field.

In addition to evidence-based recommendations, the guideline development
group (GDG) also identifies good practice points (GPP).

**Initial Advice to People Concerned about Delays in Conception**

***Natural conception***

**D** - People who are concerned about their fertility should be
informed that about 84% of couples in the general population will
conceive within 1 year if they do not use contraception and have regular
sexual intercourse. Of those who do not conceive in the first year,
about half will do so in the second year (cumulative pregnancy rate
92%).

**C** - People who are concerned about their fertility should be
informed that female fertility declines with age, but that the effect of
age on male fertility is less clear. With regular unprotected sexual
intercourse, 94% of fertile women aged 35 years, and 77% of those aged
38 years, will conceive after 3 years of trying.

***Frequency and timing of sexual intercourse***

**C** - People who are concerned about their fertility should be
informed that sexual intercourse every 2 to 3 days optimises the chance
of pregnancy. Timing intercourse to coincide with ovulation causes
stress and is not recommended.

***Alcohol***

**D** - Women who are trying to become pregnant should be informed that
drinking no more than one or two units of alcohol once or twice per week
and avoiding episodes of intoxication reduces the risk of harming a
developing fetus.

**GPP** - Men should be informed that alcohol consumption within the
Department of Health\'s recommendations of three to four units per day
for men is unlikely to affect their fertility.

**B** - Men should be informed that excessive alcohol intake is
detrimental to semen quality.

***Smoking***

**B** - Women who smoke should be informed that this is likely to reduce
their fertility.

**A** - Women who smoke should be offered referral to a smoking
cessation programme to support their efforts in stopping smoking.

**B** - Women should be informed that passive smoking is likely to
affect their chance of conceiving.

**GPP** - Men who smoke should be informed that there is an association
between smoking and reduced semen quality (although the impact of this
on male fertility is uncertain), and that stopping smoking will improve
their general health.

***Caffeinated beverages***

**B** - People who are concerned about their fertility should be
informed that there is no consistent evidence of an association between
consumption of caffeinated beverages (tea, coffee and colas) and
fertility problems.

***Body weight***

**B** - Women who have a body mass index of more than 29 should be
informed that they are likely to take longer to conceive.

**B** - Women who have a body mass index of more than 29 and who are not
ovulating should be informed that losing weight is likely to increase
their chance of conception.

**A** - Women should be informed that participating in a group programme
involving exercise and dietary advice leads to more pregnancies than
weight loss advice alone.

**C** - Men who have a body mass index of more than 29 should be
informed that they are likely to have reduced fertility.

**B** - Women who have a body mass index of less than 19 and who have
irregular menstruation or are not menstruating should be advised that
increasing body weight is likely to improve their chance of conception.

***Tight underwear for men***

**B** - Men should be informed that there is an association between
elevated scrotal temperature and reduced semen quality, but that it is
uncertain whether wearing loose-fitting underwear improves fertility.

***Occupation***

**B** - Some occupations involve exposure to hazards that can reduce
male or female fertility, and therefore a specific enquiry about
occupation should be made to people who are concerned about their
fertility and appropriate advice should be offered.

***Prescribed, over-the-counter and recreational drug use***

**B** - A number of prescription, over-the-counter and recreational
drugs interfere with male and female fertility, and therefore a specific
enquiry about these should be made to people who are concerned about
their fertility and appropriate advice should be offered.

***Complementary therapy***

**GPP** - People who are concerned about their fertility should be
informed that the effectiveness of complementary therapies for fertility
problems has not been properly evaluated and that further research is
needed before such interventions can be recommended.

***Folic acid supplementation***

**A** - Women intending to become pregnant should be informed that
dietary supplementation with folic acid before conception and up to 12
weeks\' gestation reduces the risk of having a baby with neural tube
defects. The recommended dose is 0.4 mg per day. For women who have
previously had an infant with a neural tube defect or who are receiving
antiepileptic medication, a higher dose of 5 mg per day is recommended.

***Susceptibility to rubella***

**D** - Women who are concerned about their fertility should be offered
rubella susceptibility screening so that those who are susceptible to
rubella can be offered rubella vaccination. Women who are susceptible to
rubella should be offered rubella vaccination and advised not to become
pregnant for at least 1 month following vaccination.

***Cervical cancer screening***

**GPP** - To avoid delay in fertility treatment a specific enquiry about
the timing and result of the most recent cervical smear test should be
made to women who are concerned about their fertility. Cervical
screening should be offered in accordance with the national cervical
screening programme guidance.

**Defining Infertility, Assessment and Referral**

***Defining infertility***

**D** - Infertility should be defined as failure to conceive after
regular unprotected sexual intercourse for 2 years in the absence of
known reproductive pathology.

***Assessment and referral***

**GPP** - People who are concerned about delays in conception should be
offered an initial assessment. A specific enquiry about lifestyle and
sexual history should be taken to identify people who are less likely to
conceive.

**GPP** - The environment in which investigation of fertility problems
takes place should enable people to discuss sensitive issues such as
sexual abuse.

**GPP** - People who have not conceived after 1 year of regular
unprotected sexual intercourse should be offered further clinical
investigation including semen analysis and/or assessment of ovulation.

**GPP** - Where there is a history of predisposing factors (such as
amenorrhoea, oligomenorrhoea, pelvic inflammatory disease, or
undescended testes), or where a woman is aged 35 years or over, earlier
investigation should be offered.

**GPP** - Where there is a known reason for infertility (such as prior
treatment for cancer), early specialist referral should be offered.

**GPP** - People who are concerned about their fertility and who are
known to have chronic viral infections such as hepatitis B, hepatitis C,
or human immunodeficiency virus (HIV) should be referred to centres that
have appropriate expertise and facilities to provide safe risk-reduction
investigation and treatment.

**Principles of Care**

***Information giving and couple-centred management***

**C** - Couples who experience problems in conceiving should be seen
together because both partners are affected by decisions surrounding
investigation and treatment.

**C** - People should have the opportunity to make informed decisions
regarding their care and treatment via access to evidence-based
information. These choices should be recognised as an integral part of
the decision-making process. Verbal information should be supplemented
with written information or audio-visual media.

**GPP** - Information regarding care and treatment options should be
provided in a form that is accessible to people who have additional
needs, such as people with physical, cognitive, or sensory disabilities,
and people who do not speak or read English.

***Psychological effects of fertility problems***

**C** - Couples should be informed that stress in the male and/or female
partner can affect the couple\'s relationship and is likely to reduce
libido and frequency of intercourse, which can contribute to fertility
problems.

**GPP** - People who experience fertility problems should be informed
that they may find it helpful to contact a fertility support group.

**C** - People who experience fertility problems should be offered
counselling because fertility problems themselves and the investigation
and treatment of fertility problems can cause psychological stress.

**GPP** - Counselling should be offered before, during, and after
investigation and treatment, irrespective of the outcome of these
procedures.

**GPP** - Counselling should be provided by someone who is not directly
involved in the management of the couple\'s fertility problems.

***Specialist and generalist care***

**D** - People who experience fertility problems should be treated by a
specialist team because this is likely to improve the effectiveness and
efficiency of treatment and is known to improve patient satisfaction.

**Investigation of Fertility Problems and Management Strategies**

***Semen analysis***

**GPP** - The results of semen analysis conducted as part of an initial
assessment should be compared to the following World Health Organization
reference values:

-   Volume: 2.0 ml or more

-   Liquefaction time: within 60 minutes

-   pH: 7.2 or more

-   Sperm concentration: 20 million spermatozoa per mL or more

-   Total sperm number: 40 million spermatozoa per ejaculate or more

-   Motility: 50% or more motile (grades a\* and b\*\*) or 25% or more
    with progressive motility (grade a) within 60 minutes of ejaculation

> \* [Grade a]{.underline}: rapid progressive motility (sperm moving
> swiftly, usually in a straight line).
>
> \*\* [Grade b]{.underline}: slow or sluggish progressive motility
> (sperm may be less linear in their progression).

-   Vitality: 75% or more live

-   White blood cells: fewer than 1 million per mL

-   Morphology: 15% or 30%\*\*\*

> \*\*\* Currently being reassessed by the World Health Organization. In
> the interim, the proportion of normal forms accepted by laboratories
> in the United Kingdom (UK) is either the earlier World Health
> Organization lower limit of 30% or 15% based on strict morphological
> criteria.

**GPP** - Screening for antisperm antibodies should not be offered
because there is no evidence of effective treatment to improve
fertility.

**B** - If the result of the first semen analysis is abnormal, a repeat
confirmatory test should be offered.

**GPP** - Repeat confirmatory tests should ideally be undertaken 3
months after the initial analysis to allow time for the cycle of
spermatozoa formation to be completed. However, if a gross spermatozoa
deficiency (azoospermia or severe oligozoospermia) has been detected,
the repeat test should be undertaken as soon as possible.

***Assessing ovulation***

**B** - Women who are concerned about their fertility should be asked
about the frequency and regularity of their menstrual cycles. Women with
regular monthly menstrual cycles should be informed that they are likely
to be ovulating.

**B** - Women with regular menstrual cycles and more than 1 year\'s
infertility can be offered a blood test to measure serum progesterone in
the midluteal phase of their cycle (day 21 of a 28-day cycle) to confirm
ovulation.

**GPP** - Women with prolonged irregular menstrual cycles should be
offered a blood test to measure serum progesterone. Depending on the
timing of menstrual periods, this test may need to be conducted later in
the cycle (for example day 28 of a 35-day cycle) and repeated weekly
thereafter until the next menstrual cycle starts.

**B** - The use of basal body temperature charts to confirm ovulation
does not reliably predict ovulation and is not recommended.

**GPP** - Women with irregular menstrual cycles should be offered a
blood test to measure serum gonadotrophins (follicle-stimulating hormone
and luteinising hormone).

**C** - Women who are concerned about their fertility should not be
offered a blood test to measure prolactin. This test should only be
offered to women who have an ovulatory disorder, galactorrhoea, or a
pituitary tumour.

**C** - Tests of ovarian reserve currently have limited sensitivity and
specificity in predicting fertility. However, women who have high levels
of gonadotrophins should be informed that they are likely to have
reduced fertility.

**C** - Women should be informed that the value of assessing ovarian
reserve using Inhibin B is uncertain and is therefore not recommended.

**C** - Women with possible fertility problems are no more likely than
the general population to have thyroid disease and the routine
measurement of thyroid function should not be offered. Estimation of
thyroid function should be confined to women with symptoms of thyroid
disease.

**B** - Women should not be offered an endometrial biopsy to evaluate
the luteal phase as part of the investigation of fertility problems
because there is no evidence that medical treatment of luteal phase
defect improves pregnancy rates.

***Screening for Chlamydia trachomatis***

**B** - Before undergoing uterine instrumentation, women should be
offered screening for *Chlamydia trachomatis* using an appropriately
sensitive technique.

**C** - If the result of a test for *Chlamydia trachomatis* is positive,
women and their sexual partners should be referred for appropriate
management with treatment and contact tracing.

**GPP** - Prophylactic antibiotics should be considered before uterine
instrumentation if screening has not been carried out.

***Assessing tubal damage***

**B** - Women who are not known to have comorbidities (such as pelvic
inflammatory disease, previous ectopic pregnancy, or endometriosis)
should be offered hysterosalpingography (HSG) to screen for tubal
occlusion because this is a reliable test for ruling out tubal
occlusion, and it is less invasive and makes more efficient use of
resources than laparoscopy.

**A** - Where appropriate expertise is available, screening for tubal
occlusion using hysterosalpingo-contrast-ultrasonography should be
considered because it is an effective alternative to
hysterosalpingography for women who are not known to have comorbidities.

**B** - Women who are thought to have comorbidities should be offered
laparoscopy and dye so that tubal and other pelvic pathology can be
assessed at the same time.

***Assessing uterine abnormalities***

**B** - Women should not be offered hysteroscopy on its own as part of
the initial investigation unless clinically indicated because the
effectiveness of surgical treatment of uterine abnormalities on
improving pregnancy rates has not been established.

***Postcoital testing of cervical mucus***

**A** - The routine use of postcoital testing of cervical mucus in the
investigation of fertility problems is not recommended because it has no
predictive value on pregnancy rate.

**Medical and Surgical Management of Male Factor Fertility Problems**

***Medical management***

**B** - Men with hypogonadotropic hypogonadism should be offered
gonadotrophin drugs, because these are effective in improving fertility.

**A** - Men with idiopathic semen abnormalities should not be offered
antioestrogens, gonadotrophins, androgens, bromocriptine, or
kinin-enhancing drugs, because they have not been shown to be effective.

**A** - Men should be informed that the significance of antisperm
antibodies is unclear and the effectiveness of systemic corticosteroids
is uncertain.

**A** - Men with leukocytes in their semen should not be offered
antibiotic treatment unless there is an identified infection, because
there is no evidence that this improves pregnancy rates.

***Surgical management***

**C** - Where appropriate expertise is available, men with obstructive
azoospermia should be offered surgical correction of epididymal blockage
because it is likely to restore patency of the duct and improve
fertility. Surgical correction should be considered as an alternative to
surgical sperm recovery and in vitro fertilisation.

**A** - Men should not be offered surgery for varicoceles as a form of
fertility treatment because it does not improve pregnancy rates.

***Management of ejaculatory failure***

**C** - Treatment of ejaculatory failure can restore fertility without
the need for invasive methods of sperm retrieval or the use of assisted
reproduction procedures. However, further evaluation of different
treatment options is needed.

**Ovulation Induction**

***Antioestrogens***

**A** - Women with World Health Organization Group II ovulation
disorders (hypothalamic pituitary dysfunction) such as polycystic ovary
syndrome should be offered treatment with clomiphene citrate (or
tamoxifen) as the first line of treatment for up to 12 months because it
is likely to induce ovulation.

**B** - Women should be informed of the risk of multiple pregnancies
associated with both clomiphene citrate and tamoxifen.

**A** -- Women with unexplained fertility problems should be informed
that clomiphene citrate treatment increases the chance of pregnancy, but
that this needs to be balanced by the possible risks of treatment,
especially multiple pregnancy.

**GPP** - Women undergoing treatment with clomiphene citrate should be
offered ultrasound monitoring during at least the first cycle of
treatment to ensure that they receive a dose that minimises the risk of
multiple pregnancy.

***Metformin***

**A** - Anovulatory women with polycystic ovary syndrome who have not
responded to clomiphene citrate and who have a body mass index of more
than 25 should be offered metformin combined with clomiphene citrate
because this increases ovulation and pregnancy rates.

**GPP** - Women prescribed metformin should be informed of the side
effects associated with its use (such as nausea, vomiting, and other
gastrointestinal disturbances).

\***Note**: Metformin is not currently licensed for the treatment of
ovulatory disorders in the United Kingdom.

***Ovarian drilling***

**A** - Women with polycystic ovary syndrome who have not responded to
clomiphene citrate should be offered laparoscopic ovarian drilling
because it is as effective as gonadotrophin treatment and is not
associated with an increased risk of multiple pregnancy.

***Gonadotrophin use in ovulation induction therapy for ovulatory
disorders***

**A** - Women with World Health Organization Group II ovulation
disorders such as polycystic ovary syndrome who do not ovulate with
clomiphene citrate (or tamoxifen) can be offered treatment with
gonadotrophins. Human menopausal gonadotrophin, urinary
follicle-stimulating hormone, and recombinant follicle-stimulating
hormone are equally effective in achieving pregnancy and consideration
should be given to minimising cost when prescribing.

**A** - Women with World Health Organization Group II ovulation
disorders such as polycystic ovary syndrome who ovulate with clomiphene
citrate but have not become pregnant after 6 months of treatment should
be offered clomiphene citrate-stimulated intrauterine insemination.

***Gonadotrophin use during in vitro fertilisation treatment***

**A** - Human menopausal gonadotrophin, urinary follicle-stimulating
hormone, and recombinant follicle-stimulating hormone are equally
effective in achieving a live birth when used following pituitary
down-regulation as part of in vitro fertilisation treatment.
Consideration should be given to minimising cost when prescribing.

***Gonadotrophin-releasing hormone analogues in ovulation induction
therapy***

**A** - Women with polycystic ovary syndrome who are being treated with
gonadotrophins should not be offered treatment with
gonadotrophin-releasing hormone agonist concomitantly because it does
not improve pregnancy rates, and it is associated with an increased risk
of ovarian hyperstimulation.

***Gonadotrophin-releasing hormone analogues during in vitro
fertilisation treatment***

**A** - For pituitary down-regulation as part of in vitro fertilisation
treatment, using gonadotrophin-releasing hormone agonist in addition to
gonadotrophin stimulation facilitates cycle control and results in
higher pregnancy rates than the use of gonadotrophins alone. The routine
use of gonadotrophin-releasing hormone agonist in long protocols during
in vitro fertilisation is therefore recommended.

**A** - The use of gonadotrophin-releasing hormone antagonists is
associated with reduced pregnancy rates and is therefore not recommended
outside a research context.

***Growth hormone as an adjunct to ovulation induction therapy***

**A** -- The use of adjuvant growth hormone treatment with
gonadotrophin-releasing hormone agonist and/or human menopausal
gonadotrophin during ovulation induction in women with polycystic ovary
syndrome who do not respond to clomiphene citrate is not recommended
because it does not improve pregnancy rates.

***Pulsatile gonadotrophin-releasing hormone***

**B** -- Women with World Health Organization Group I ovulation
disorders (hypothalamic pituitary failure, characterized by hypothalamic
amenorrhoea or hypogonadotropic hypogonadism) should be offered
pulsatile administration of gonadotrophin-releasing hormone or
gonadotrophins with luteinising hormone activity because these are
effective in inducing ovulation.

**A** -- The effectiveness of pulsatile gonadotrophin-releasing hormone
in women with clomiphene citrate-resistant polycystic ovary syndrome is
uncertain and is therefore not recommended outside a research context.

***Dopamine agonists***

**A** -- Women with ovulatory disorders due to hyperprolactinaemia
should be offered treatment with dopamine agonists such as
bromocriptine. Consideration should be given to safety for use in
pregnancy and minimising cost when prescribing.

***Monitoring ovulation induction during gonadotrophin therapy***

**C** -- Women who are offered ovulation induction with gonadotrophins
should be informed about the risk of multiple pregnancy and ovarian
hyperstimulation before starting treatment.

**C** -- Ovarian ultrasound monitoring to measure follicular size and
number should be an integral part of patient management during
gonadotrophin therapy to reduce the risk of multiple pregnancy and
ovarian hyperstimulation.

***Other risks and side effects associated with ovulation induction
agents***

**C** -- Women who are offered ovulation induction should be informed
that a possible association between ovulation induction therapy and
ovarian cancer remains uncertain. Practitioners should confine the use
of ovulation induction agents to the lowest effective dose and duration
of use.

**Tubal and Uterine Surgery**

***Tubal microsurgery and laparoscopic tubal surgery***

**D** -- For women with mild tubal disease tubal surgery may be more
effective than no treatment. In centres where appropriate expertise is
available, it may be considered as a treatment option.

***Tubal catheterisation or cannulation***

**B** -- For women with proximal tubal obstruction, selective
salpingography plus tubal catheterisation, or hysteroscopic tubal
cannulation, may be treatment options because these treatments improve
the chance of pregnancy.

***Uterine surgery***

**C** -- Women with amenorrhoea who are found to have intrauterine
adhesions should be offered hysteroscopic adhesiolysis because this is
likely to restore menstruation and improve the chance of pregnancy.

**Medical and Surgical Management of Endometriosis**

***Medical management (ovarian suppression)***

**A** -- Medical treatment of minimal and mild endometriosis does not
enhance fertility in subfertile women and should not be offered.

***Surgical ablation***

**A** -- Women with minimal or mild endometriosis who undergo
laparoscopy should be offered surgical ablation or resection of
endometriosis plus laparoscopic adhesiolysis because this improves the
chance of pregnancy.

**A** -- Women with ovarian endometriomas should be offered laparoscopic
cystectomy because this improves the chance of pregnancy.

**B** -- Women with moderate or severe endometriosis should be offered
surgical treatment because it improves the chance of pregnancy.

**A** -- Postoperative medical treatment does not improve pregnancy
rates in women with moderate to severe endometriosis and is not
recommended.

**Intrauterine Insemination**

**A** -- Couples with mild male factor fertility problems, unexplained
fertility problems, or minimal to mild endometriosis should be offered
up to six cycles of intrauterine insemination because this increases the
chance of pregnancy.

**A** -- Where intrauterine insemination is used to manage male factor
fertility problems, ovarian stimulation should not be offered because it
is no more clinically effective than unstimulated intrauterine
insemination and it carries a risk of multiple pregnancy.

**A** -- Where intrauterine insemination is used to manage unexplained
fertility problems, both stimulated and unstimulated intrauterine
insemination are more effective than no treatment. However, ovarian
stimulation should not be offered, even though it is associated with
higher pregnancy rates than unstimulated intrauterine insemination,
because it carries a risk of multiple pregnancy.

**A** -- Where intrauterine insemination is used to manage minimal or
mild endometriosis, couples should be informed that ovarian stimulation
increases pregnancy rates compared with no treatment, but that the
effectiveness of unstimulated intrauterine insemination is uncertain.

**A** -- Where intrauterine insemination is undertaken, single rather
than double insemination should be offered.

**A** -- Where intrauterine insemination is used to manage unexplained
fertility problems, fallopian sperm perfusion for insemination (a
large-volume solution, 4 mL) should be offered because it improves
pregnancy rates compared with standard insemination techniques.

**Factors Affecting the Outcome of In Vitro Fertilisation Treatment**

***Surgery for hydrosalpinges before in vitro fertilisation treatment***

**A** -- Women with hydrosalpinges should be offered salpingectomy,
preferably by laparoscopy, before in vitro fertilisation treatment
because this improves the chance of a live birth.

***Female age***

**C** -- Women should be informed that the chance of a live birth
following in vitro fertilisation treatment varies with female age and
that the optimal female age range for in vitro fertilisation treatment
is 23--39 years. Chances of a live birth per treatment cycle are:

-   greater than 20% for women aged 23--35 years

-   15% for women aged 36--38 years

-   10% for women aged 39 years

-   6% for women aged 40 years or older.

The effectiveness of in vitro fertilisation treatment in women younger
than 23 years is uncertain because very few women in this age range have
in vitro fertilisation treatment.

***Number of embryos to be transferred and multiple pregnancy***

**C** -- Couples should be informed that the chance of multiple
pregnancy following in vitro fertilisation treatment depends on the
number of embryos transferred per cycle of treatment. To balance the
chance of a live birth and the risk of multiple pregnancy and its
consequences, no more than two embryos should be transferred during any
one cycle of in vitro fertilisation treatment.

***Number of previous treatment cycles***

**C** -- Couples should be informed that the chance of a live birth
following in vitro fertilisation treatment is consistent for the first
three cycles of treatment, but that the effectiveness after three cycles
is less certain.

***Pregnancy history***

**C** -- Women should be informed that in vitro fertilization treatment
is more effective in women who have previously been pregnant and/or had
a live birth.

***Alcohol, smoking and caffeine consumption***

**C** -- Couples should be informed that the consumption of more than
one unit of alcohol per day reduces the effectiveness of assisted
reproduction procedures, including in vitro fertilisation treatment.

**C** -- Couples should be informed that maternal and paternal smoking
can adversely affect the success rates of assisted reproduction
procedures, including in vitro fertilization treatment.

**C** -- Couples should be informed that caffeine consumption has
adverse effects on the success rates of assisted reproduction
procedures, including in vitro fertilisation treatment.

***Body weight***

**B** -- Women should be informed that female body mass index should
ideally be in the range 19--30 before commencing assisted reproduction,
and that a female body mass index outside this range is likely to reduce
the success of assisted reproduction procedures.

***Clinical effectiveness and referral for in vitro fertilisation
treatment***

**GPP** - Couples in which the woman is aged 23--39 years at the time of
treatment and who have an identified cause for their fertility problems
(such as azoospermia or bilateral tubal occlusion) or who have
infertility of at least 3 years´ duration should be offered up to three
stimulated cycles of in vitro fertilisation treatment.

**GPP** - Embryos not transferred during a stimulated in vitro
fertilisation treatment cycle may be suitable for freezing. If two or
more embryos are frozen, then they should be transferred before the next
stimulated treatment cycle because this will minimise ovulation
induction and egg collection, both of which carry risks for the woman
and use more resources.

***Gamete intrafallopian transfer and zygote intrafallopian transfer***

**A** -- There is insufficient evidence to recommend the use of gamete
intrafallopian transfer or zygote intrafallopian transfer in preference
to in vitro fertilisation in couples with unexplained fertility problems
or male factor fertility problems.

**Procedures Used during In Vitro Fertilisation Treatment**

***Medical assessment and screening***

**B** - People undergoing in vitro fertilisation treatment should be
offered screening for HIV, hepatitis B virus, and hepatitis C virus;
people found to test positive should be managed and counselled
appropriately.

***Management of couples with viral infections***

**D** - In considering the decision to provide fertility treatment for
couples with HIV, hepatitis B, or hepatitis C infections, the
implications of these infections for potential children should be taken
into account.

***Ovulation induction during in vitro fertilisation treatment***

**A** - Natural cycle in vitro fertilisation has lower pregnancy rates
per cycle of treatment than clomiphene citrate-stimulated and
gonadotrophin-stimulated in vitro fertilisation and is therefore not
recommended, except in the rare circumstances where gonadotrophin use is
contraindicated.

**B** - For women who have regular ovulatory cycles, the likelihood of a
live birth after replacement of frozen-thawed embryos is similar whether
the embryos are replaced during natural or stimulated cycles.

**A** - The use of adjuvant growth hormone with gonadotrophins during in
vitro fertilisation cycles does not improve pregnancy rates and is
therefore not recommended.

***Oocyte maturation -- human chorionic gonadotrophin***

**A** - Couples should be informed that, in effecting oocyte maturation,
recombinant human chorionic gonadotrophin achieves similar results to
urinary human chorionic gonadotrophin in terms of pregnancy rates and
incidence of ovarian hyperstimulation syndrome. Consideration should be
given to minimising cost when prescribing.

***Monitoring of stimulated cycles***

**C** - Ultrasound monitoring of ovarian response should form an
integral part of the in vitro fertilisation treatment cycle.

**A** - Monitoring oestrogen levels during ovulation induction as part
of in vitro fertilisation treatment is not recommended as a means of
improving in vitro fertilisation treatment success rates because it does
not give additional information with regard to live birth rates or
pregnancy rates compared with ultrasound monitoring.

***Ovarian hyperstimulation syndrome***

**GPP** - Clinics providing ovarian stimulation with gonadotrophins
should have protocols in place for preventing, diagnosing, and managing
ovarian hyperstimulation syndrome.

**A** - Women who have a significant risk of developing ovarian
hyperstimulation syndrome should not be offered oocyte maturation (or
luteal support) using human chorionic gonadotrophin.

***Oocyte retrieval***

**A** - Women undergoing transvaginal retrieval of oocytes should be
offered conscious sedation because it is a safe and acceptable method of
providing analgesia.

**D** - The safe practice of administering sedative drugs published by
the Academy of Medical Royal Colleges should be followed.

**A** - Women who have developed at least three follicles before oocyte
retrieval should not be offered follicle flushing because this procedure
does not increase the numbers of oocytes retrieved or pregnancy rates,
and it increases the duration of oocyte retrieval and associated pain.

***Assisted hatching***

**A** - Assisted hatching is not recommended because it has not been
shown to improve pregnancy rates.

***Embryo transfer techniques***

**A** - Women undergoing in vitro fertilisation treatment should be
offered ultrasound-guided embryo transfer because this improves
pregnancy rates.

**B** - Embryo transfers on day 2 or 3 and day 5 or 6 appear to be
equally effective in terms of increased pregnancy and live birth rates
per cycle started.

**B** - Replacement of embryos into a uterine cavity with an endometrium
of less than 5 mm thickness is unlikely to result in a pregnancy and is
therefore not recommended.

**A** - Women should be informed that bed rest of more than 20 minutes´
duration following embryo transfer does not improve the outcome of in
vitro fertilisation treatment.

***Luteal support***

**A** - Women who are undergoing in vitro fertilization treatment using
gonadotrophin-releasing hormone agonists for pituitary down-regulation
should be informed that luteal support using human chorionic
gonadotrophin or progesterone improves pregnancy rates.

**A** - The routine use of human chorionic gonadotrophin for luteal
support is not recommended because of the increased likelihood of
ovarian hyperstimulation syndrome.

**Intracytoplasmic Sperm Injection**

***Indications for intracytoplasmic sperm injection***

**B** - The recognised indications for treatment by intracytoplasmic
sperm injection include:

-   Severe deficits in semen quality

-   Obstructive azoospermia

-   Non-obstructive azoospermia.

In addition, treatment by intracytoplasmic sperm injection should be
considered for couples in whom a previous in vitro fertilisation
treatment cycle has resulted in failed or very poor fertilisation.

***Genetic issues and counselling***

**C** - Before considering treatment by intracytoplasmic sperm
injection, couples should undergo appropriate investigations, both to
establish a diagnosis and to enable informed discussion about the
implications of treatment.

**B** - Before treatment by intracytoplasmic sperm injection,
consideration should be given to relevant genetic issues.

**B** - Where a specific genetic defect associated with male infertility
is known or suspected, couples should be offered appropriate genetic
counselling and testing.

**B** - Where the indication for intracytoplasmic sperm injection is a
severe deficit of semen quality or non-obstructive azoospermia, the
man\'s karyotype should be established.

**GPP** - Men who are undergoing karyotype testing should be offered
genetic counselling regarding the genetic abnormalities that may be
detected.

**C** - Testing for Y chromosome microdeletions should not be regarded
as a routine investigation before intracytoplasmic sperm injection.
However, it is likely that a significant proportion of male infertility
results from abnormalities of genes on the Y chromosome involved in the
regulation of spermatogenesis, and couples should be informed of this.

***Intracytoplasmic sperm injection versus in vitro fertilisation***

**A** - Couples should be informed that intracytoplasmic sperm injection
improves fertilisation rates compared to in vitro fertilisation alone,
but once fertilisation is achieved the pregnancy rate is no better than
with in vitro fertilisation.

***Sperm recovery***

**C** - Surgical sperm recovery before intracytoplasmic sperm injection
may be performed using several different techniques depending on the
pathology and wishes of the patient. In all cases, facilities for
cryopreservation of spermatozoa should be available.

**Donor Insemination**

***Indications for donor insemination***

**B** - The use of donor insemination is considered effective in
managing fertility problems associated with the following conditions:

-   Obstructive azoospermia

-   Non-obstructive azoospermia

-   Infectious disease in the male partner (such as HIV)

-   Severe rhesus isoimmunisation

-   Severe deficits in semen quality in couples who do not wish to
    undergo intracytoplasmic sperm injection

Donor insemination should also be considered in certain cases where
there is a high risk of transmitting a genetic disorder to the
offspring.

***Information and counselling***

**C** - Couples should be offered information about the relative merits
of intracytoplasmic sperm injection and donor insemination in a context
that allows equal access to both treatment options.

**C** - Couples considering donor insemination should be offered
counselling from someone who is independent of the treatment unit
regarding all the physical and psychological implications of treatment
for themselves and potential children.

***Screening of sperm donors***

**C** - Units undertaking semen donor recruitment and the
cryopreservation of donor spermatozoa for treatment purposes should
follow the current guidelines issued by the British Andrology Society
describing the selection and screening of donors.

**GPP** - All potential semen donors should be offered counseling from
someone who is independent of the treatment unit regarding the
implications for themselves and their genetic children, including any
potential children resulting from donated semen.

***Assessment of female partner***

**C** - Before starting treatment by donor insemination it is important
to confirm that the woman is ovulating. Women with a history that is
suggestive of tubal damage should be offered tubal assessment before
treatment.

**GPP** - Women with no risk factors in their history should be offered
tubal assessment after three cycles if treatment has been unsuccessful.

***Intrauterine insemination versus intracervical insemination***

**A** - Couples using donor sperm should be offered intrauterine
insemination in preference to intracervical insemination because it
improves pregnancy rates.

***Unstimulated versus stimulated donor insemination***

**GPP** - Women who are ovulating regularly should be offered a minimum
of six cycles of donor insemination without ovarian stimulation to
reduce the risk of multiple pregnancy and its consequences.

***Timing of donor insemination***

**C** - Couples should be informed that timing of insemination using
either urinary luteinising hormone or basal body temperature changes is
equally effective in donor cycles. However, using urinary luteinising
hormone detection reduces the number of clinic visits per cycle.

***Maximum number of cycles***

**GPP** - Couples should be offered other treatment options after six
unsuccessful cycles of donor insemination.

**Oocyte Donation**

***Indications for oocyte donation***

**C** - The use of donor oocytes is considered effective in managing
fertility problems associated with the following conditions:

-   Premature ovarian failure

-   Gonadal dysgenesis including Turner syndrome

-   Bilateral oophorectomy

-   Ovarian failure following chemotherapy or radiotherapy

-   Certain cases of in vitro fertilisation treatment failure.

Oocyte donation should also be considered in certain cases where there
is a high risk of transmitting a genetic disorder to the offspring.

***Screening of oocyte donors***

**D** - Before donation is undertaken, oocyte donors should be screened
for both infectious and genetic diseases in accordance with guidance
issued by the Human Fertilisation and Embryology Authority.

***Oocyte donation and egg sharing***

**C** - Oocyte donors should be offered information regarding the
potential risks of ovarian stimulation and oocyte collection. The
section above titled \"Other risks and side effects associated with
ovulation induction agents\" refers to risks and side effects associated
with ovarian stimulation.

**GPP** - Oocyte recipients and donors should be offered counselling
from someone who is independent of the treatment unit regarding the
physical and psychological implications of treatment for themselves and
their genetic children, including any potential children resulting from
donated oocytes.

**GPP** - All people considering participation in an egg-sharing scheme
should be counselled about its particular implications.

**Applications of Cryopreservation in Cancer Treatment**

**D** - Before commencing chemotherapy or radiotherapy likely to affect
fertility, or management of post-treatment fertility problems, the
procedures recommended by the Royal College of Physicians and the Royal
College of Radiologists should be followed.

**B** - Men and adolescent boys preparing for medical treatment that is
likely to make them infertile should be offered semen cryostorage
because the effectiveness of this procedure has been established.

**C** - Local protocols should exist to ensure that health professionals
are aware of the value of semen cryostorage in these circumstances, so
that they deal with the situation sensitively and effectively.

**C** - Women preparing for medical treatment that is likely to make
them infertile should be offered oocyte or embryo cryostorage as
appropriate if they are well enough to undergo ovarian stimulation and
egg collection, provided that this will not worsen their condition and
that sufficient time is available.

**D** - Women preparing for medical treatment that is likely to make
them infertile should be informed that oocyte cryostorage has very
limited success, and that cryopreservation of ovarian tissue is still in
an early stage of development.

**GPP** - People preparing for medical treatment that is likely to make
them infertile should be offered counselling from someone who is
independent of the treatment unit to help them cope with the stress and
the potential physical and psychological implications for themselves,
their partners, and any potential children resulting from cryostorage of
gametes and/or embryos.

**GPP** - Where cryostorage of gametes and/or embryos is to be
undertaken because of medical treatment that is likely to make people
infertile, this should occur before such treatment begins.

**Follow-up of Children Born as a Result of Assisted Reproduction**

**C** - Couples contemplating assisted reproduction should be given
up-to-date information about the health of children born as a result of
assisted reproduction. Current research is broadly reassuring about the
health and welfare of children born as a result of assisted
reproduction.

**[Definitions]{.underline}**

**Evidence Categories**

**1a**: Evidence obtained from systematic review and meta-analysis of
randomised controlled trials

**1b**: Evidence obtained from at least one randomised controlled trial

**2a**: Evidence obtained from at least one well-designed controlled
study without randomisation

**2b**: Evidence obtained from at least one other type of well-designed
quasi-experimental study.

**3**: Evidence obtained from well-designed nonexperimental descriptive
studies, such as comparative studies, correlation studies, or case
studies

**4**: Evidence obtained from expert committee reports or opinions
and/or clinical experience of respected authorities

**Grading of Recommendations**

**A**: Directly based on level 1 evidence

**B**: Directly based on level 2 evidence, or extrapolated
recommendation from level 1 evidence

**C**: Directly based on level 3 evidence, or extrapolated
recommendation from either level 1 or level 2 evidence

**D**: Directly based on level 4 evidence, or extrapolated
recommendation from either level 1, 2, or 3 evidence

**Good practice point (GPP)**: The view of the Guideline Development
Group

#### CLINICAL ALGORITHM(S)

Clinical algorithms are provided for the assessment and treatment for
people with fertility problems, clinical investigation of fertility
problems and management strategies, and management options associated
with in vitro fertilisation treatment and other forms of assisted
reproduction.

### EVIDENCE SUPPORTING THE RECOMMENDATIONS

#### TYPE OF EVIDENCE SUPPORTING THE RECOMMENDATIONS

The type of supporting evidence is identified and graded for each
recommendation (see \"Major Recommendations\").

### BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS

#### POTENTIAL BENEFITS

Appropriate assessment and treatment of fertility problems

#### POTENTIAL HARMS

-   Women who are offered ovulation induction should be informed that a
    possible association between ovulation induction therapy and ovarian
    cancer remains uncertain. Practitioners should confine the use of
    ovulation induction agents to the lowest effective dose and duration
    of use.

-   Women with polycystic ovary syndrome who are being treated with
    gonadotrophins should not be offered treatment with
    gonadotrophin-releasing hormone agonist concomitantly because it
    does not improve pregnancy rates, and it is associated with an
    increased risk of ovarian hyperstimulation.

-   There is a risk of multiple pregnancies associated with both
    clomiphene and tamoxifen. Multiple gestations are high-risk
    pregnancies associated with higher obstetric complications,
    perinatal, neonatal and infant mortality, as well as significant
    financial and psychological consequences. However, assisted
    reproduction multiple pregnancies do not appear to be at any more
    risk of poor obstetric and neonatal outcomes than those conceived
    spontaneously. Recent surveys have suggested that multiple
    pregnancies may not be viewed as an adverse outcome by women with
    fertility problems.

-   The theoretical risk of transmitting prion disease, however
    unlikely, must always be considered when medicinal products are
    derived from or contain materials of human or bovine origin. In the
    case of gonadotrophins, such theoretical risks could arise from the
    human source material used to manufacture urinary-derived products
    or from bovine reagents used in the manufacture of recombinant
    products. However, there is no evidence of transmission of prion
    disease by any gonadotrophin.

-   Gonadotrophins can cause symptoms of the menopause such as hot
    flushes.

-   Metformin has side effects, which can include nausea, vomiting and
    other digestive symptoms.

### QUALIFYING STATEMENTS

#### QUALIFYING STATEMENTS

-   The guideline does not address primary prevention of fertility or
    the management of pregnancies resulting from fertility treatment
    (for example, the management of multiple births). It is also beyond
    the scope of this guideline to address the effective management and
    treatment of conditions or comorbidities that are not directly
    related to the treatment of subfertility, such as endometriosis or
    sexual dysfunction.

-   Infertility is defined as failure to conceive after frequent
    unprotected sexual intercourse for one to two years in couples in
    the reproductive age group. This guideline does not include the
    management of people who are outside this definition, such as the
    initial management of sexual dysfunction, couples who are using
    contraception (for example, where one partner has been sterilised),
    non-heterosexual couples, or couples outside the reproductive age
    range. If the problem persists despite appropriate treatment then
    their management is within the remit of the guideline. Embryo
    donation and surrogacy are outside the remit.

-   The guideline does not include preimplantation genetic diagnosis.

-   The guideline does not address laboratory standards or service
    configuration that may impact on the quality of care. It also does
    not include assessment of social criteria that might be relevant to
    access for fertility services funded by the National Health Service
    for example whether there are any existing children in the family.

### IMPLEMENTATION OF THE GUIDELINE

#### DESCRIPTION OF IMPLEMENTATION STRATEGY

**[Implementation in the National Health Service]{.underline}**

**Resource implications**

Information on the cost impact of this guideline is available on the
National Institute for Clinical Excellence (NICE) website and includes a
template for local health communities to use
(<http://www.nice.org.uk/page.aspx?o=202212>). In light of this
information, local health communities should review their existing
practice for assessment and treatment for people with fertility problems
against this guideline as they develop their Local Delivery Plans. The
review should consider the resources required to implement the
recommendations, the people and processes involved, and the timeline
over which full implementation is envisaged. It is in the interests of
people with fertility problems and their partners that the
implementation timeline is as rapid as possible.

**In general**

Relevant local clinical guidelines, care pathways, and protocols should
be reviewed in the light of this guidance and revised accordingly. The
following guidance is referred to in the recommendations of the original
guideline document.

Academy of Medical Royal Colleges (2001) Implementing and ensuring safe
sedation for healthcare procedures in adults: report of an
Intercollegiate Working Party chaired by the Royal College of
Anaesthetists (see [www.aomrc.org.uk](http://www.aomrc.org.uk/)).

British Andrology Society (1999). British Andrology Society guidelines
for the screening of semen donors for donor insemination. *Human
Reproduction* 14, 1823--26 (see
[www.britishandrology.org.uk](http://www.britishandrology.org.uk/)).

Human Fertilisation and Embryology Authority (2004). Code of Practice,
6th edition (see [www.hfea.gov.uk](http://www.hfea.gov.uk/)).

Royal College of Physicians and Royal College of Radiologists (1998).
Management of gonadal toxicity resulting from the treatment of adult
cancer: report of a working party of the Joint Council for Clinical
Oncology. Joint Council for Clinical Oncology (see
[www.rcplondon.ac.uk](http://www.rcplondon.ac.uk/)).

**Audit**

Suggested audit criteria are listed in the original guideline document.
These can be used as the basis for local clinical audit, at the
discretion of those in practice.

**[Key Priorities for Implementation]{.underline}**

The following recommendations have been identified as priorities for
implementation.

**Screening for *Chlamydia trachomatis***

-   Before undergoing uterine instrumentation women should be offered
    screening for *Chlamydia trachomatis* using an appropriately
    sensitive technique.

**Assessing tubal damage**

-   Women who are not known to have comorbidities (such as pelvic
    inflammatory disease, previous ectopic pregnancy, or endometriosis)
    should be offered hysterosalpingography (HSG) to screen for tubal
    occlusion because this is a reliable test for ruling out tubal
    occlusion, and it is less invasive and makes more efficient use of
    resources than laparoscopy.

**Intrauterine insemination**

-   Couples with mild male factor fertility problems, unexplained
    fertility problems, or minimal to mild endometriosis should be
    offered up to six cycles of intrauterine insemination because this
    increases the chance of pregnancy.

**In vitro fertilisation treatment**

-   Couples in which the woman is aged 23--39 years at the time of
    treatment and who have an identified cause for their fertility
    problems (such as azoospermia or bilateral tubal occlusion) or who
    have infertility of at least 3 years´ duration should be offered up
    to three stimulated cycles of in vitro fertilization treatment.

-   Human menopausal gonadotrophin, urinary follicle-stimulating
    hormone, and recombinant follicle-stimulating hormone are equally
    effective in achieving a live birth when used following pituitary
    down-regulation as part of in vitro fertilization treatment.
    Consideration should be given to minimizing cost when prescribing.

-   Couples should be informed that the chance of multiple pregnancy
    following in vitro fertilisation treatment depends on the number of
    embryos transferred per cycle of treatment. To balance the chance of
    a live birth and the risk of multiple pregnancy and its
    consequences, no more than two embryos should be transferred during
    any one cycle of in vitro fertilisation treatment.

-   Embryos not transferred during a stimulated in vitro fertilisation
    treatment cycle may be suitable for freezing. If two or more embryos
    are frozen then they should be transferred before the next
    stimulated treatment cycle because this will minimise ovulation
    induction and egg collection, both of which carry risks for the
    woman and use more resources.

#### IMPLEMENTATION TOOLS

Clinical Algorithm\
Patient Resources

For information about
[availability](#identifying-information-and-availability), see the
\"Availability of Companion Documents\" and \"Patient Resources\" fields
below.

### INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT CATEGORIES

#### IOM CARE NEED

Getting Better

#### IOM DOMAIN

Effectiveness\
Patient-centeredness

### IDENTIFYING INFORMATION AND AVAILABILITY

#### BIBLIOGRAPHIC SOURCE(S)

National Collaborating Centre for Women\'s and Children\'s Health.
Fertility: assessment and treatment for people with fertility problems.
London: RCOG Press; 2004 Feb. 216 p. \[1151 references\]

#### ADAPTATION

Not applicable: The guideline was not adapted from another source.

#### DATE RELEASED

2004 Feb

#### GUIDELINE DEVELOPER(S)

National Collaborating Centre for Women\'s and Children\'s Health -
National Government Agency \[Non-U.S.\]

#### SOURCE(S) OF FUNDING

National Institute for Clinical Excellence

#### GUIDELINE COMMITTEE

Not stated

#### COMPOSITION OF GROUP THAT AUTHORED THE GUIDELINE

*Guideline Development Group Members*: David Barlow, Gynaecologist and
Group Leader; Pauline Brimblecombe, General Practitioner; Clare Brown,
Consumer Representative; Kirsten Duckitt, Obstetrician; Jenny Dunlop,
Counsellor; Geraldine Hartshorne, Embryologist; Anthony Hirsh,
Andrologist; Anthony Rutherford, Gynaecologist; Lorraine Simpson, Nurse;
Elfed Williams, Consumer Representative; Sarah Wilson, Public Health
Clinician; Jane Thomas, Director, National Collaborating Centre for
Women\'s and Children\'s Health (NCC-WCH); Moira Mugglestone, Deputy
Director, NCC-WCH; Irene Kwan, Research Fellow, NCC-WCH; Alex McNeil,
Research Assistant, NCC-WCH; Jennifer Gray, Informatics Specialist,
NCC-WCH; Anna Bancsi, Work Programme Coordinator, NCC-WCH; Hannah-Rose
Douglas, Health Economist, London School of Hygiene and Tropical
Medicine (LSHTM); Dimitra Lambrelli, Health Economist, LSHTM; Gillian
Roberts, Publications Writer/Editor, Clinical Governance and Standards
Department, Royal College of Obstetricians and Gynaecologists

#### FINANCIAL DISCLOSURES/CONFLICTS OF INTEREST

All Guideline Development Group members\' interests were recorded in a
standard form that covered consultancies, fee-paid work, share-holdings,
fellowships, and healthcare industry in accordance with guidance from
the National Institute for Clinical Excellence (NICE).

#### GUIDELINE STATUS

This is the current release of the guideline. This guideline updates the
following guidelines previously released by the Royal College of
Obstetricians and Gynaecologists:

-   Royal College of Obstetricians and Gynaecologists. The initial
    investigation and management of the infertile couple. London: RCOG
    Press; 1998 Feb. 82 p. (Evidence-based clinical guidelines; no. 2).

-   Royal College of Obstetricians and Gynaecologists. The management of
    infertility in secondary care. London: RCOG Press; 1998 Feb. 148 p.
    (Evidence-based clinical guidelines; no. 3). \[677 references\]

-   Royal College of Obstetricians and Gynaecologists. The management of
    infertility in tertiary care. London: RCOG Press; 2000 Jan. 121 p.
    (Evidence-based clinical guidelines; no. 6).

#### GUIDELINE AVAILABILITY

Electronic copies: Available in Portable Document Format (PDF) from the
[Royal College of Obstetricians and Gynaecologists (RCOG) Web
site](http://www.rcog.org.uk/index.asp?PageID=696).

Print copies: Available from the National Collaborating Centre for
Women\'s and Children\'s Health (NCC-WCH), 27 Sussex Place, Regent\'s
Park, London NW1 4RG

#### AVAILABILITY OF COMPANION DOCUMENTS

The following are available:

-   National Collaborating Centre for Women\'s and Children\'s Health.
    Fertility: assessment and treatment for people with fertility
    problems. Evidence tables. 2004 Feb. 115 p. Available from the
    [Royal College of Obstetricians and Gynaecologists (RCOG) Web
    site](http://www.rcog.org.uk/resources/Public/pdf/Fertility_tables.pdf).

-   National Collaborating Centre for Women\'s and Children\'s Health.
    Fertility: assessment and treatment for people with fertility
    problems. Summary. 2004 Feb. 45 p. Available from the [Royal College
    of Obstetricians and Gynaecologists (RCOG) Web
    site](http://www.rcog.org.uk/resources/Public/pdf/Fertility_summary.pdf).

-   National Collaborating Centre for Women\'s and Children\'s Health.
    Fertility: assessment and treatment for people with fertility
    problems. Clinical practice algorithm. 2004 Feb. 3 p. Available from
    the [Royal College of Obstetricians and Gynaecologists (RCOG) Web
    site](http://www.rcog.org.uk/resources/Public/pdf/Fertility_algorithm.pdf).

Print copies: Available from the National Collaborating Centre for
Women\'s and Children\'s Health (NCC-WCH), 27 Sussex Place, Regent\'s
Park, London NW1 4RG

#### PATIENT RESOURCES

The following is available:

-   Assessment and treatment for people with fertility problems.
    Understanding NICE guidance -- information for people with fertility
    problems, their partners, and the public. 2004 Feb. 75 p. Available
    from the [Royal College of Obstetricians and Gynaecologists (RCOG)
    Web
    site](http://www.rcog.org.uk/resources/Public/pdf/Fertility_IFP.pdf).

Print copies: Available from the National Collaborating Centre for
Women\'s and Children\'s Health (NCC-WCH), 27 Sussex Place, Regent\'s
Park, London NW1 4RG

Please note: This patient information is intended to provide health
professionals with information to share with their patients to help them
better understand their health and their diagnosed disorders. By
providing access to this patient information, it is not the intention of
NGC to provide specific medical advice for particular patients. Rather
we urge patients and their representatives to review this material and
then to consult with a licensed health professional for evaluation of
treatment options suitable for them as well as for diagnosis and answers
to their personal medical questions. This patient information has been
derived and prepared from a guideline for health care professionals
included on NGC by the authors or publishers of that original guideline.
The patient information is not reviewed by NGC to establish whether or
not it accurately reflects the original guideline\'s content.

#### NGC STATUS

This NGC summary was completed by ECRI on August 27, 2004.

#### COPYRIGHT STATEMENT

This NGC summary is based on the original guideline, which is subject to
the guideline developer\'s copyright restrictions.

### DISCLAIMER

#### NGC DISCLAIMER

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<http://www.guideline.gov/about/inclusion.aspx> .

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Date Modified: 11/10/2008