Practice Guidelines

Fertility (update): summary of NICE guidance

BMJ 2013; 346 doi: http://dx.doi.org/10.1136/bmj.f650 (Published 20 February 2013) Cite this as: BMJ 2013;346:f650
  1. Ella Fields, research fellow1,
  2. Jiri Chard, senior research fellow1,
  3. David James, clinical co-director1,
  4. Tom Treasure, professor of cardiothoracic surgery2
  5. on behalf of the Guideline Development Group
  1. 1National Collaborating Centre for Women’s and Children’s Health, London W1T 2QA, UK
  2. 2University College London, London WC1H 0BT, UK
  1. Correspondence to: J Chard jchard{at}ncc-wch.org.uk

Infertility affects about one in seven couples in the United Kingdom1 and can have a severe psychological impact.2 Since publication in 2004 of the original fertility guideline by the then National Institute for Clinical Excellence (NICE),3 more people are now having fertility treatment, which is increasingly successful.4 5 It is mandatory that this care is appropriate. This article summarises the recommendations relevant to general clinicians from the recent update of NICE’s fertility guideline.6

Recommendations

NICE recommendations are based on systematic reviews of the best available evidence and explicit consideration of cost effectiveness. When minimal evidence is available, recommendations are based on the Guideline Development Group’s experience and opinion of what constitutes good practice. Evidence levels for the recommendations are given in italic in square brackets.

Information on conception

  • Inform people who are concerned about their fertility that:

    • -Over 80% of couples in the general population will conceive within one year if the woman is aged under 40 years and they have regular sexual intercourse without contraception

    • -Of those who do not conceive in the first year, about half will do so in the second year (cumulative pregnancy rate over 90%)

    • -Vaginal sexual intercourse every two to three days optimises the chance of pregnancy.

    • [Based on low quality evidence from observational studies and on the experience and opinion of the Guideline Development Group (GDG)]

  • For people who are unable to, or would find it very difficult to, have vaginal intercourse, offer an initial consultation to discuss other options for attempting conception (such as in vitro fertilisation (see definitions box)). (New recommendation.) [Based on the experience and opinion of the GDG]

  • Female fertility declines with age. Use a woman’s age as an initial predictor of her overall chance of success through natural conception or with in vitro fertilisation. (New recommendation.) [Based on low quality evidence from observational studies and the experience and opinion of the GDG]

  • Take a lifestyle and sexual history to identify people who are less likely to conceive:

    • -Inform men that the following factors may reduce the likelihood of conception: excessive alcohol intake, smoking, raised scrotal temperature. (However, whether wearing loose fitting underwear improves fertility is uncertain)

    • -Inform women that the following factors may reduce the likelihood of conception: smoking and passive smoking, body mass index of ≥30 in women who are not ovulating, and body mass index of <19 in women who have irregular menstruation or who are not menstruating.

    • [Based on the experience and opinion of the GDG]

  • Couples who have problems in conceiving should be seen as a couple because both partners are affected by decisions about investigation and treatment. [Based on the experience and opinion of the GDG]

  • Inform both partners 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, in turn contributing to fertility problems. [Based on low and very low quality evidence from observational studies and on the experience and opinion of the GDG]

  • Inform people who experience fertility problems

    • -That they may find it helpful to contact a fertility support group, and

    • -Offer counselling as fertility problems can cause psychological stress.

    • [Based on low quality evidence from observational studies and on the experience and opinion of the GDG]

Definitions box

  • Expectant management—When a health professional supportively offers an individual or couple information and advice about the regularity and timing of intercourse and any lifestyle changes that might improve their chances of conceiving. It does not involve active clinical or therapeutic interventions

  • Artificial insemination—A medical alternative to sexual intercourse; the introduction of semen into a woman’s vagina, cervix, or uterus. It includes intrauterine insemination

  • Intrauterine insemination—Artificial insemination involving delivery of sperm via the vagina into the uterine cavity

  • In vitro fertilisation (IVF)—A technique whereby eggs are collected from a woman and fertilised with a man’s sperm outside the body. A single embryo is usually transferred (sometimes two) with the aim of starting a pregnancy

  • Full cycle—A full IVF treatment, which should include one episode of ovarian stimulation and the transfer of any resultant fresh and frozen embryo(s)

  • Intracytoplasmic sperm injection—An IVF procedure in which a single sperm is injected directly into an egg

  • Ovulation induction—Stimulation of ovulation by medication to reverse anovulation or oligoovulation, usually by ovarian stimulation but can also mean triggering oocyte release from mature ovarian follicles

  • Ovarian stimulation—Stimulation of the development of ovarian follicles to produce oocytes

Classification of ovulatory disorders

The World Health Organization classifies ovulation disorders into three groups:

  • Group I: hypothalamic pituitary failure (hypothalamic amenorrhoea or hypogonadotrophic hypogonadism)

  • Group II: hypothalamic-pituitary-ovarian dysfunction (predominately polycystic ovary syndrome)

  • Group III: ovarian failure

Semen analysis

The WHO reference values for semen analysis:

  • Semen volume: ≥1.5 mL

  • Semen pH: ≥7.2

  • Sperm concentration: ≥15 million spermatozoa per mL

  • Total sperm number: ≥39 million spermatozoa per ejaculate

  • Total motility (percentage of progressive motility (sperm that move forward) and non-progressive motility (sperm that move but do not progress forward)): ≥40% motile or ≥32% with progressive motility

  • Vitality: ≥58% live spermatozoa

  • Sperm morphology (percentage of normal forms): 4%

Defining infertility and referral for specialist assessment and/or treatment

  • Define infertility as the period of time people have been trying to conceive without success after which formal investigation is justified and possible treatment implemented. (New recommendation.) [Based on low and very low quality evidence from observational studies and the experience and opinion of the GDG]

  • If a woman has not conceived after a year, offer further clinical assessment and investigation, along with her partner. (New recommendation.) [Based on the experience and opinion of the GDG]

  • If a woman who is using artificial insemination (see definitions box) has not conceived after six cycles of treatment, offer further clinical assessment and investigation. When artificial insemination is using partner sperm, the referral should include her partner. (New recommendation.) [Based on low and very low quality evidence from observational studies and the experience and opinion of the GDG]

  • Offer an earlier referral for specialist consultation when (new recommendation):

    • -The woman is aged ≥36 years

    • -There is a known cause of infertility or a history of predisposing factors for infertility

    • -Investigations show there is apparently no chance of pregnancy with expectant management (see definitions box) and IVF is the only effective treatment.

    • [Based on low and very low quality evidence from observational studies and the experience and opinion of the GDG]

Assessment options

  • Offer men semen analysis, comparing results with the World Health Organization values (see definitions box). If the result is abnormal, a repeat test should be offered and undertaken within three months. (Updated recommendation.) [Based on low and very low quality evidence from observational studies and the experience and opinion of the GDG]

  • Offer women:

    • -A blood test to measure serum progesterone in the mid-luteal phase of the cycle (day 21 of a 28 day cycle) to confirm ovulation. [Based on moderate to very low quality evidence from randomised controlled trials and observational studies and the experience and opinion of the GDG]

    • -A blood test to measure serum gonadotrophins (follicle stimulating hormone and luteinising hormone) if menstrual cycles are irregular [Based on moderate to very low quality evidence from randomised controlled trials and observational studies and the experience and opinion of the GDG]

    • -Hysterosalpingography or hysterosalpingo-contrast ultrasonography to women who are not known to have comorbidities (such as pelvic inflammatory disease, previous ectopic pregnancy, or endometriosis). Offer laparoscopy and dye in women who are thought to have comorbidities. [Based on high to low quality evidence from randomised controlled trials and observational studies and the experience and opinion of the GDG]

  • Do not routinely offer women other tests

  • Do not use basal body temperature charts to predict ovulation [Based on moderate to very low quality evidence from randomised controlled trials and observational studies and the experience and opinion of the GDG]

Treatment options

  • Inform couples that the effectiveness of complementary therapies for fertility problems has not been properly evaluated and that further research is needed. [Based on moderate quality evidence from randomised controlled trials and the experience and opinion of the GDG]

  • For women with unexplained infertility (new recommendation):

    • -Do not routinely offer intrauterine insemination (see definitions box)

    • -Do not offer oral ovarian stimulation agents (such as clomifene citrate, anastrozole, or letrozole)

    • -Offer IVF treatment to women who have not conceived after two years of regular unprotected sexual intercourse (this can include up to one year before their fertility investigations).

    • [Based on moderate to very low quality evidence from randomised controlled trials and observational studies and the experience and opinion of the GDG]

  • For people with mild endometriosis or “mild male factor infertility” who are having regular unprotected sexual intercourse (new recommendation):

    • -Do not routinely offer intrauterine insemination (see definitions box)

    • -Advise them to try to conceive for a total of two years (this can include up to one year before their fertility investigations) before IVF will be considered.

    • [Based on low and very low quality evidence from observational studies and the experience and opinion of the GDG]

  • For women with WHO Group I ovulation disorders (see definitions box), offer pulsatile administration of gonadotrophin releasing hormone or gonadotrophins with luteinising hormone activity to induce ovulation. [Based on moderate and low quality evidence from observational studies and the experience and opinion of the GDG]

  • For women with WHO Group II anovulatory infertility (including polycystic ovary syndrome), offer one of the following treatments (new recommendation):

    • -Clomifene citrate (for ovulation induction and ovarian stimulation (see definitions box))

    • -Metformin

    • -A combination of the above.

    • [Based on high to very low quality evidence from randomised controlled trials and observational studies and the experience and opinion of the GDG]

  • Inform women who are offered ovulation induction that (new recommendation):

    • -No direct association has been found between these treatments and invasive cancer

    • -No association has been found in the short to medium term between these treatments and adverse outcomes (including cancer) in children born from ovulation induction

    • -Information about long term health outcomes in women and children is still awaited.

    • [Based on very low quality evidence from observational studies and the experience and opinion of the GDG]

  • Inform couples who are considering IVF treatment (new recommendation):

    • -The chance of a live birth after IVF treatment falls with rising female age

    • -IVF treatment is more effective in women who have previously been pregnant or had a live birth

    • -Of the risks and benefits of IVF treatment and subsequent pregnancy in accordance with the current Human Fertilisation and Embryology Authority code of practice7

    • -Although the absolute risks of long term adverse outcomes from IVF treatment, with or without intracytoplasmic sperm injection (see definitions box), are low, a small increased maternal risk of borderline ovarian tumours cannot be excluded

    • -The absolute risks of long term adverse outcomes in children born as a result of IVF are low.

    • [Based on low to high quality evidence from observational studies and the experience and opinion of the GDG]

  • When IVF is used (new recommendation):

    • -Offer three full cycles to women aged under 40 years. If a woman reaches the age of 40 during treatment, do not offer further full cycles

    • -Offer one full cycle to women aged 40–42 years, provided these three criteria are fulfilled:

      • They have never previously had IVF treatment

      • There is no evidence of low ovarian reserve

      • There has been a discussion of the additional implications of IVF and pregnancy at this age.

    • [Based on high to very low quality evidence from randomised controlled studies and observational studies and the experience and opinion of the majority of the GDG]

  • When IVF is used and a top quality blastocyst is available, use single embryo transfer. (New recommendation.) [Based on moderate to very low quality evidence from randomised controlled trials and observational studies and the experience and opinion of the GDG]

Overcoming barriers

To maximise the chance of pregnancy while minimising medical intervention, the guideline recommends against routinely using intrauterine insemination for people with unexplained infertility, mild endometriosis, or mild male factor infertility. This will change practice in the UK.

NHS funding for IVF in the UK varies widely. The updated guideline aims to remedy this by clarifying when IVF should be offered, to whom, and what appropriate management comprises.

Currently double embryo transfer in IVF is the most commonly used strategy in the UK. However, to maximise the chance of pregnancy while minimising the risk of a multiple pregnancy, the guideline recommends using a single fresh embryo and subsequently any frozen and thawed embryos.

Further information on the guidance

The existing NICE clinical guideline on fertility published in 2004 provided a comprehensive coverage of the subject. However, its implementation has been variable. NHS funding for investigation of infertility is generally available but there is wide variation and often limited access to NHS funded treatment, particularly assisted reproduction techniques.

What’s new in the 2013 guideline

New recommendations were formulated on the following topics:

  • Information for patients about the chances of conception, particularly with respect to maternal age

  • The criteria for investigation of people with fertility problems

  • Which tests/methods to use (or not use) to predict the outcome of fertility treatment

  • Advice for couples on how to conceive safely where the man is positive for HIV infection or hepatitis C

  • Advice for couples where one partner is positive for hepatitis B

  • Advice for women with WHO Group I ovulation disorders

  • Advice and treatment for women with WHO Group II ovulation disorders, including those who are resistant to clomifene citrate

  • Advice for and treatment of women with unexplained infertility

  • The indications for intrauterine insemination

  • Which factors predict the success of in vitro fertilisation (IVF) treatment

  • Which criteria should be used to offer IVF treatment to couples and what information should be given

  • Procedures used during and after IVF treatment, including pre-treatment, down regulation, controlled ovarian stimulation, triggering ovulation, embryo transfer strategies, and luteal phase support

  • What advice and options to offer to people with cancer who wish to preserve their fertility

  • What advice to offer people regarding the long term safety of assisted reproductive technologies for women and their children

  • When formulating recommendations, the following groups were specifically considered to ensure equality:

    • -People in same sex relationships who have unexplained infertility after donor insemination

    • -People who are unable to, or would find it very difficult to, or have been advised not to have heterosexual intercourse

    • -People with conditions or disabilities that require specific consideration in relation to methods of conception

    • -People who are preparing for cancer treatment who may wish to preserve their fertility.

Methods

This guidance was developed by the National Collaborating Centre for Women’s and Children’s Health in accordance with NICE guideline development methods (www.nice.org.uk/guidelinesmanual). A Guideline Development Group (GDG) was established by the National Collaborating Centre for Women’s and Children’s Health, which incorporated healthcare professionals (consultant obstetricians, subspecialists in reproductive medicine, a professor in reproductive medicine, an embryologist, a nurse, and a general practitioner), a healthcare services commissioner, people with experience of fertility treatment, and experts in guideline methodology. The GDG identified relevant clinical questions, collected and appraised clinical evidence, and evaluated the cost effectiveness of proposed interventions where possible. The draft guideline underwent a public consultation in which stakeholder organisations were invited to comment; the GDG then took all comments into consideration when producing the final version of the guideline.

Four different versions of this guideline have been produced: a full version containing all the evidence, the process undertaken to develop the recommendations, and all the recommendations; a care pathway; a version containing a list of all the recommendations, known as the “NICE guideline”; and a version for patients and the public. All of these versions are available from the NICE website (www.nice.org.uk/CG156).

Future research

The GDG identified the following priority areas for future research:

  • What is the optimum period of expectant management for women of different age groups before invasive treatment such as IVF is considered?

  • Is there an association between ovulation induction or ovarian stimulation and adverse long term (>20 years) effects in women?

  • What are the long term (>20 years) effects of IVF with or without intracytoplasmic sperm injection in children?

  • What criteria for embryo selection should be used to facilitate single embryo transfers?

  • What is the efficacy of adjuvant luteal phase support treatments (such as low dose aspirin, heparin, prednisolone, immunoglobulins, and fat emulsions)?

Notes

Cite this as: BMJ 2013;346:f650

Footnotes

  • This is one of a series of BMJ summaries of new guidelines based on the best available evidence; they highlight important recommendations for clinical practice, especially where uncertainty or controversy exists.

  • The members of the Guideline Development Group were (elected members): Susan Bewley, Siladitya Bhattacharya, Kate Brian, Tim Child, Melanie Davies, Stephen Harbottle, Helen Kendrew, Clare Lewis-Jones, Clare Searle, Peter Taylor, and Tom Treasure (chair); and (technical team of the National Collaborating Centre for Women’s and Children’s Health): Maria Bastos (until May 2011), David Bevan (from May 2011), Liz Bickerdike (from October 2010 until May 2011), Jiri Chard, Ella Fields, Zipporah Iheozor-Ejiofor, Paul Jacklin, David James, Rosalind Lai, Hugh McGuire, and Cristina Visintin (until October 2010).

  • Contributors: All authors contributed to the initial draft, as well as making revisions and approving the final version for publication. DJ is the guarantor.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: EF, JC, and DJ have support from the National Institute for Health and Clinical Excellence for the submitted work. None of the authors has financial relationships with any organisation that might have an interest in the submitted work. None of the authors has other relationships or activities that could appear to have influenced the submitted work.

  • Provenance and peer review: Commissioned; not externally peer reviewed.

References