- This guideline covers diagnosing and treating fertility problems. It aims to reduce variation in practice and improve the way fertility problems are investigated and managed.
- This guideline replaces CG11.
- This guideline is the basis of QS73 and QS55.
Principles of care
- Couples who experience problems in conceiving should be seen together because both partners are affected by decisions surrounding investigation and treatment
- 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
- 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
- When couples have fertility problems, both partners 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 the fertility problems
- People who experience fertility problems should be informed that they may find it helpful to contact a fertility support group
- 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
- Counselling should be offered before, during and after investigation and treatment, irrespective of the outcome of these procedures
- Counselling should be provided by someone who is not directly involved in the management of the individual’s and/or couple’s fertility problems.
Generalist and specialist care
- 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 people’s satisfaction with treatment.
Initial advice to people concerned about delays in conception
Chance of conception
- People who are concerned about their fertility should be informed that over 80% of couples in the general population will conceive within 1 year if:
- the woman is aged under 40 years and
- 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 over 90%).
- Inform people who are using artificial insemination to conceive and who are concerned about their fertility that:
- over 50% of women aged under 40 years will conceive within 6 cycles of intrauterine insemination (IUI)
- of those who do not conceive within 6 cycles of intrauterine insemination, about half will do so with a further 6 cycles (cumulative pregnancy rate over 75%)
- Inform people who are using artificial insemination to conceive and who are concerned about their fertility that using fresh sperm is associated with higher conception rates than frozen–thawed sperm. However, intrauterine insemination, even using frozen–thawed sperm, is associated with higher conception rates than intracervical insemination
- Inform people who are concerned about their fertility that female fertility (and to a lesser extent) male fertility decline with age
- Discuss chances of conception with people concerned about their fertility who are:
Table 1 Cumulative probability of conceiving a clinical pregnancy by the number of menstrual cycles
Cumulative probability of conceiving a clinical pregnancy by the number of menstrual cycles attempting to conceive in different age categories (assuming vaginal intercourse occurs twice per week).
|Age category (years)||Pregnant after 1 year (12 cycles) (%)||Pregnant after 2 years (24 cycles) (%)|
Reproduced with permission: Dunson DB, Baird DD, Colombo B . Increased infertility with age in men and women. Obstetrics and Gynecology 103: 51–6
Table 2 Cumulative probability of conceiving a clinical pregnancy by the number of cycles of insemination
Cumulative probability of conceiving a clinical pregnancy by the number of cycles of insemination in different age categories and according to the method and sperm status where assisted reproduction technology is used (see the full guideline for references).
|Woman’s age (years)||ICI using thawed semen (Schwartz et al. 1982)||Woman’s age (years)||ICI using fresh semen (van Noord-Zaadstra, 1991)||Woman’s age (years)||IUI using thawed semen – HFEA data and personal communication|
|6 cycles||12 cycles||6 cycles||12 cycles||6 cycles||12 cycles|
Abbreviations: ICI=intracervical insemination; IUI=intrauterine insemination
Frequency and timing of sexual intercourse or artificial insemination
- People who are concerned about their fertility should be informed that vaginal sexual intercourse every 2 to 3 days optimises the chance of pregnancy
- People who are using artificial insemination to conceive should have their insemination timed around ovulation.
- Women who are trying to become pregnant should be informed that drinking no more than 1 or 2 units of alcohol once or twice per week and avoiding episodes of intoxication reduces the risk of harming a developing fetus
- Men should be informed that alcohol consumption within the Department of Health’s recommendations of 3 to 4 units per day for men is unlikely to affect their semen quality
- Men should be informed that excessive alcohol intake is detrimental to semen quality.
- Women who smoke should be informed that this is likely to reduce their fertility
- Women who smoke should be offered referral to a smoking cessation programme to support their efforts in stopping smoking
- Women should be informed that passive smoking is likely to affect their chance of conceiving
- 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.
- 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[A].
- Women who have a body mass index (BMI) of 30 or over should be informed that they are likely to take longer to conceive
- Women who have a BMI of 30 or over and who are not ovulating should be informed that losing weight is likely to increase their chance of conception
- Women should be informed that participating in a group programme involving exercise and dietary advice leads to more pregnancies than weight loss advice alone
- Men who have a BMI of 30 or over should be informed that they are likely to have reduced fertility.
Low body weight
- Women who have a BMI 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.
- 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.
- 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
- 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.
- 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
- 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 anti-epileptic medication or who have diabetes (see diabetes in pregnancy [NICE guideline NG3]), a higher dose of 5 mg per day is recommended.
- 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
- Offer an initial consultation to discuss the options for attempting conception to people who are unable to, or would find it very difficult to, have vaginal intercourse
- The environment in which investigation of fertility problems takes place should enable people to discuss sensitive issues such as sexual abuse
- Healthcare professionals should define infertility in practice as the period of time people have been trying to conceive without success after which formal investigation is justified and possible treatment implemented
- A woman of reproductive age who has not conceived after 1 year of unprotected vaginal sexual intercourse, in the absence of any known cause of infertility, should be offered further clinical assessment and investigation along with her partner
- A woman of reproductive age who is using artificial insemination to conceive (with either partner or donor sperm) should be offered further clinical assessment and investigation if she has not conceived after 6 cycles of treatment, in the absence of any known cause of infertility. Where this is using partner sperm, the referral for clinical assessment and investigation should include her partner
- Offer an earlier referral for specialist consultation to discuss the options for attempting conception, further assessment and appropriate treatment where:
- the woman is aged 36 years or over
- there is a known clinical cause of infertility or a history of predisposing factors for infertility
- Where treatment is planned that may result in infertility (such as treatment for cancer), early fertility specialist referral should be offered
- People who are concerned about their fertility and who are known to have chronic viral infections such as hepatitis B, hepatitis C or HIV should be referred to centres that have appropriate expertise and facilities to provide safe risk-reduction investigation and treatment.
Investigation of fertility problems and management strategies
- The results of semen analysis conducted as part of an initial assessment should be compared with the following World Health Organization reference values[B]:
- semen volume: 1.5 ml or more
- pH: 7.2 or more
- sperm concentration: 15 million spermatozoa per ml or more
- total sperm number: 39 million spermatozoa per ejaculate or more
- total motility (percentage of progressive motility and non-progressive motility): 40% or more motile or 32% or more with progressive motility
- vitality: 58% or more live spermatozoa
- sperm morphology (percentage of normal forms): 4% or more
- Screening for antisperm antibodies should not be offered because there is no evidence of effective treatment to improve fertility
- If the result of the first semen analysis is abnormal, a repeat confirmatory test should be offered
- 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.
Post-coital testing of cervical mucus
- The routine use of post-coital testing of cervical mucus in the investigation of fertility problems is not recommended because it has no predictive value on pregnancy rate.
Ovarian reserve testing
- Use a woman’s age as an initial predictor of her overall chance of success through natural conception or with in vitro fertilisation (IVF) (see full guideline for Figures 1 and 2, respectively)
- Use one of the following measures to predict the likely ovarian response to gonadotrophin stimulation in IVF:
- total antral follicle count of less than or equal to 4 for a low response[C] and greater than 16 for a high response[D]
- anti-Müllerian hormone of less than or equal to 5.4 pmol/l for a low response[E] and greater than or equal to 25.0 pmol/l for a high response[F]
- follicle-stimulating hormone greater than 8.9 IU/l for a low response and less than 4 IU/l for a high response[G]
- Do not use any of the following tests individually to predict any outcome of fertility treatment:
- ovarian volume
- ovarian blood flow
- inhibin B
- oestradiol (E2).
Regularity of menstrual cycles
- 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
- Women who are undergoing investigations for infertility should be offered a blood test to measure serum progesterone in the mid-luteal phase of their cycle (day 21 of a 28‑day cycle) to confirm ovulation even if they have regular menstrual cycles
- Women with prolonged irregular menstrual cycles should be offered a blood test to measure serum progesterone. Depending upon 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
- The use of basal body temperature charts to confirm ovulation does not reliably predict ovulation and is not recommended
- Women with irregular menstrual cycles should be offered a blood test to measure serum gonadotrophins (follicle-stimulating hormone and luteinising hormone).
- 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.
Thyroid function tests
- 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.
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.
Investigation of suspected tubal and uterine abnormalities
- 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
- 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
- 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
- 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.
Testing for viral status
- People undergoing IVF treatment should be offered testing for HIV, hepatitis B and hepatitis C (for donor insemination (see recommendation 126.96.36.199)
- People found to test positive for one or more of HIV, hepatitis B, or hepatitis C should be offered specialist advice and counselling and appropriate clinical management.
- For couples where the man is HIV positive, any decision about fertility management should be the result of discussions between the couple, a fertility specialist and an HIV specialist
- Advise couples where the man is HIV positive that the risk of HIV transmission to the female partner is negligible through unprotected sexual intercourse when all of the following criteria are met:
- the man is compliant with highly active antiretroviral therapy (HAART)
- the man has had a plasma viral load of less than 50 copies/ml for more than 6 months
- there are no other infections present
- unprotected intercourse is limited to the time of ovulation
- Advise couples that if all the criteria in recommendation 188.8.131.52 are met, sperm washing may not further reduce the risk of infection and may reduce the likelihood of pregnancy
- For couples where the man is HIV positive and either he is not compliant with HAART or his plasma viral load is 50 copies/ml or greater, offer sperm washing
- Inform couples that sperm washing reduces, but does not eliminate, the risk of HIV transmission
- If couples who meet all the criteria in recommendation 184.108.40.206 still perceive an unacceptable risk of HIV transmission after discussion with their HIV specialist, consider sperm washing
- Inform couples that there is insufficient evidence to recommend that HIV negative women use pre-exposure prophylaxis, when all the criteria in recommendation 220.127.116.11 are met
- For partners of people with hepatitis B, offer vaccination before starting fertility treatment
- Do not offer sperm washing as part of fertility treatment for men with hepatitis B
- For couples where the man has hepatitis C, any decision about fertility management should be the result of discussions between the couple, a fertility specialist and a hepatitis specialist
- Advise couples who want to conceive and where the man has hepatitis C that the risk of transmission through unprotected sexual intercourse is thought to be low
- Men with hepatitis C should discuss treatment options to eradicate the hepatitis C with their appropriate specialist before conception is considered.
Susceptibility to rubella
- Women who are concerned about their fertility should be offered testing for their rubella status so that those who are susceptible to rubella can be offered vaccination. Women who are susceptible to rubella should be offered vaccination and advised not to become pregnant for at least 1 month following vaccination.
Cervical cancer screening
- 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.
Screening for Chlamydia trachomatis
- Before undergoing uterine instrumentation women should be offered screening for Chlamydia trachomatis using an appropriately sensitive technique
- 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
- Prophylactic antibiotics should be considered before uterine instrumentation if screening has not been carried out.
Classification of ovulatory disorders
The World Health Organization (WHO) classifies ovulation disorders into 3 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.
WHO Group I ovulation disorders
- Advise women with WHO Group I anovulatory infertility that they can improve their chance of regular ovulation, conception and an uncomplicated pregnancy by:
- increasing their body weight if they have a BMI of less than 19 and/or
- moderating their exercise levels if they undertake high levels of exercise
- Offer women with WHO Group I ovulation disorders pulsatile administration of gonadotrophin-releasing hormone or gonadotrophins with luteinising hormone activity to induce ovulation.
WHO Group II ovulation disorders
In women with WHO Group II ovulation disorders receiving first-line treatment for ovarian stimulation:
- Advise women with WHO Group II anovulatory infertility who have a BMI of 30 or over to lose weight (see recommendation 18.104.22.168). Inform them that this alone may restore ovulation, improve their response to ovulation induction agents, and have a positive impact on pregnancy outcomes
- Offer women with WHO Group II anovulatory infertility one of the following treatments, taking into account potential adverse effects, ease and mode of use, the woman’s BMI, and monitoring needed:
- clomifene citrate or
- metformin[H] or
- a combination of the above
- For women who are taking clomifene citrate, offer ultrasound monitoring during at least the first cycle of treatment to ensure that they are taking a dose that minimises the risk of multiple pregnancy
- For women who are taking clomifene citrate, do not continue treatment for longer than 6 months
- Women prescribed metformin[H] should be informed of the side effects associated with its use (such as nausea, vomiting and other gastrointestinal disturbances).
In women with WHO Group II ovulation disorders who are known to be resistant to clomifene citrate:
- For women with WHO Group II ovulation disorders who are known to be resistant to clomifene citrate, consider one of the following second-line treatments, depending on clinical circumstances and the woman’s preference:
- laparoscopic ovarian drilling or
- combined treatment with clomifene citrate and metformin[H] if not already offered as first-line treatment or
- 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
- 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 clomifene citrate is not recommended because it does not improve pregnancy rates
- The effectiveness of pulsatile gonadotrophin-releasing hormone in women with clomifene citrate-resistant polycystic ovary syndrome is uncertain and is therefore not recommended outside a research context.
Hyperprolactinaemic amenorrhoea – dopamine agonists
- 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.
Ovarian stimulation for unexplained infertility
- Do not offer oral ovarian stimulation agents (such as clomifene citrate, anastrozole or letrozole) to women with unexplained infertility
- Inform women with unexplained infertility that clomifene citrate as a stand-alone treatment does not increase the chances of a pregnancy or a live birth
- Advise women with unexplained infertility who are having regular unprotected sexual intercourse to try to conceive for a total of 2 years (this can include up to 1 year before their fertility investigations) before IVF will be considered
- Offer IVF treatment (see recommendations 22.214.171.124–4) to women with unexplained infertility who have not conceived after 2 years (this can include up to 1 year before their fertility investigations) of regular unprotected sexual intercourse.
Access criteria for IVF
Criteria for referral for IVF
- When considering IVF as a treatment option for people with fertility problems, discuss the risks and benefits of IVF in accordance with the current Human Fertilisation and Embryology Authority (HFEA) Code of Practice
- Inform people that normally a full cycle of IVF treatment, with or without intracytoplasmic sperm injection (ICSI), should comprise 1 episode of ovarian stimulation and the transfer of any resultant fresh and frozen embryo(s)
- In women aged under 40 years who have not conceived after 2 years of regular unprotected intercourse or 12 cycles of artificial insemination (where 6 or more are by intrauterine insemination), offer 3 full cycles of IVF, with or without ICSI. If the woman reaches the age of 40 during treatment, complete the current full cycle but do not offer further full cycles
- In women aged 40–42 years who have not conceived after 2 years of regular unprotected intercourse or 12 cycles of artificial insemination (where 6 or more are by intrauterine insemination), offer 1 full cycle of IVF, with or without ICSI, provided the following 3 criteria are fulfilled:
- they have never previously had IVF treatment
- there is no evidence of low ovarian reserve (see recommendation 126.96.36.199)
- there has been a discussion of the additional implications of IVF and pregnancy at this age
- Where investigations show there is no chance of pregnancy with expectant management and where IVF is the only effective treatment, refer the woman directly to a specialist team for IVF treatment
- In women aged under 40 years any previous full IVF cycle, whether self- or NHS-funded, should count towards the total of 3 full cycles that should be offered by the NHS
- Take into account the outcome of previous IVF treatment when assessing the likely effectiveness and safety of any further IVF treatment
- Healthcare providers should define a cancelled IVF cycle as one where an egg collection procedure is not undertaken. However, cancelled cycles due to low ovarian reserve should be taken into account when considering suitability for further IVF treatment.
Terms used in this guideline
A formal approach that encourages conception through unprotected vaginal intercourse. It involves supportively offering an individual or couple information and advice about the regularity and timing of intercourse and any lifestyle changes which might improve their chances of conceiving. It does not involve active clinical or therapeutic interventions.
This term is used to define a full IVF treatment, which should include 1 episode of ovarian stimulation and the transfer of any resultant fresh and frozen embryo(s).
[A] Also see recommendation 188.8.131.52 about caffeine intake and IVF treatment.
[B] Please note the reference ranges are only valid for the semen analysis tests outlined by the World Health Organization.
[C] Follicles of ≤5 mm measured by transvaginal ultrasound on day 3 of cycle: low response was <4 oocytes.
[D] Follicles of 2–10 mm measured by transvaginal ultrasound on day 3 of cycle: high response was ≥15 oocytes or ≥20 oocytes.
[E] Beckman Coulter assay: poor response defined as <4 oocytes or cancellation.
[F] Beckman Coulter or DSL assays: defined high response as ≥15 oocytes to >21 oocytes.
[G] Long protocol of down-regulation: low response defined as <4 oocytes or cancellation; high response defined as >20 oocytes.
[H] At the time of publication (February 2013), metformin did not have a UK marketing authorisation for this indication. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. The patient should provide Informed consent, which should be documented. See the General Medical Council’s Good practice in prescribing medicines – guidance for doctors for further information.
NICE guidance is prepared for the National Health Service in England. All NICE guidance is subject to regular review and may be updated or withdrawn. NICE accepts no responsibility for the use of its content in this product/publication.
Published date: 20
Last updated: 06