Infertility is the inability to conceive. A couple is regarded as infertile if, after regular sexual intercourse, they have not conceived in 2 years.
It is estimated that one in seven UK couples has difficulty conceiving (approximately 3.5 million people).
Infertility is more common with increasing age.
About 85% of couples in the general population will conceive naturally within 1 year if they have regular unprotected sexual intercourse. Of 100 couples trying to conceive naturally:
20 will conceive within 1 month.
70 will conceive within 6 months.
85 will conceive within 1 year.
90 will conceive within 18 months.
95 will conceive within 2 years.
The most common identifiable causes of infertility include ovulatory disorders, tubal damage, and a low sperm count or low sperm quality. Less common causes include certain drugs, occupational and environmental factors, and stress.
Couples who are having trouble conceiving should be advised regarding risk factors such as smoking, weight control, occupational risks, alcohol consumption, and drug use.
National sources of up-to-date information include the Human Fertilisation and Embryology Authority (www.hfea.gov.uk), Infertility Network UK (www.infertilitynetworkuk.com) and British Infertility Counselling Association (www.bica.net).
Investigations for infertility are not usually recommended until the couple has been unable to conceive after 1 year of regular unprotected intercourse.
Initial investigations in women include: mid-luteal phase progesterone to confirm ovulation, serum gonadotrophins (in women with irregular menstrual cycles), thyroid function tests (in women with symptoms of thyroid disease), prolactin (in women with an ovulatory disorder, galactorrhoea, or a suspected pituitary tumour), and screening for chlamydia.
Initial investigations in men include semen analysis and screening for chlamydia.
Referral criteria may vary among health authorities.
For women younger than 35 years with normal history, examination, and investigations in both partners, referral should usually be considered if the couple has not conceived after 18 months.
Earlier referral may be considered in women older than 35 years, or if the history, examination, and investigations of either partner suggest an underlying cause.
This CKS topic is based on the National Institute for Health and Clinical Excellence (NICE) guideline Fertility: assessment and treatment for people with fertility problems (February 2004).
This CKS topic covers the primary care management of infertility.
This CKS topic does not cover secondary and tertiary care management of infertility but outlines the treatment that is offered. It gives only brief information on ovulation induction agents, in vitro fertilization, and other forms of assisted conception. It does not cover the treatment of impotence. It does not cover surrogacy, or issues around sperm and egg banking.
The target audience for this CKS topic is healthcare professionals working within the NHS in England, and providing first contact or primary health care.
February 2012 — minor update. Broken table link fixed in When to refer. Issued in March 2012.
March 2011 — topic structure revised to ensure consistency across CKS topics — no changes to clinical recommendations have been made.
June 2009 — minor typographical error corrected. Issued in June 2009.
May 2009 — minor update. The Human Fertilisation and Embryology Association is now correctly referred to as the Human Fertilisation and Embryology Authority. Issued in June 2009.
June to October 2007 — converted from CKS guidance to CKS topic structure. The evidence-base has been reviewed in detail, and recommendations are more clearly justified and transparently linked to the supporting evidence.
There are no major changes to the recommendations.
October 2005 — minor technical update. Issued in November 2005.
March 2004 — reviewed. Validated in May 2004 and issued in July 2004.
October 2003 — updated to incorporate Department of Health advice that seronegative women should be vaccinated using MMR (measles, mumps, and rubella).
November 2001 — reviewed. Validated in March 2002 and issued in April 2002.
January 1999 — written replacing the previous guidance on female infertility. Validated in March 1999 and issued in May 1999.
Guidelines published since the last revision of this topic:
HTAs (Health Technology Assessments)
No new HTAs since 1 June 2007.
No new economic appraisals relevant to England since 1 June 2007.
Systematic reviews and meta-analyses
Systematic reviews published since the last revision of this topic:
Eley, A. and Pacey, A.A. (2010) The value of testing semen for Chlamydia trachomatis in men of infertile couples. International Journal of Andrology34(5 Pt 1), 391-401. [Abstract]
Ried, K. And Stuart, K. (2011) Efficacy of traditional Chinese herbal medicine in the management of female infertility: a systematic review. Complementary Therapies in Medicine19(6), 319-331. [Abstract]
Showell, M.G, Brown, J., Yazdani, A., et al. (2011) Antioxidants for male subfertility(Cochrane Review). The Cochrane Library. Issue 1. John Wiley & Sons, Ltd. www.thecochranelibrary.com [Free Full-text]
Tan, L., Tong, Y., Sze, S.C., et al. (2012) Chinese herbal medicine for infertility with anovulation: a systematic review. Journal of Alternative and Complementary Medicine18(12), 1087-1100. [Abstract]
Randomized controlled trials published since the last revision of this topic:
Bhattacharya, S., Harrild, K., Mollison, J., et al. (2008) Clomifene citrate or unstimulated intrauterine insemination compared with expectant management for unexplained infertility: pragmatic randomised controlled trial. BMJ337, a716. [Abstract] [Free Full-text]
Wilkes, S., Murdoch, A., Steen, N., et al. (2009) Open Access Tubal aSsessment for the initial management of infertility in general practice (the OATS trial): a pragmatic cluster randomised controlled trial. British Journal of General Practice59(562), 329-335. [Abstract] [Free Full-text]
Observational studies published since the last revision of this topic:
Calderon-Margalit, R., Friedlander, Y., Yanetz, R., et al. (2008) Cancer risk after exposure to treatments for ovulation induction. American Journal of Epidemiology169(3), 365-375. [Abstract] [Free Full-text]
van der Steeg, J.W., Steures, P., Eijkemans, M.J., et al. (2008) Obesity affects spontaneous pregnancy chances in subfertile, ovulatory women. Human Reproduction23(2), 324-428. [Abstract] [Free Full-text]
Wilke, S., Chinn, D.J., Murdoch, A., Rubin, G. (2009) Epidemiology and management of infertility: a population-based study in UK primary care. Family Practice 26(4), 269-274. [Abstract] [Free Full-text]
No new national policies or guidelines since 1 June 2007.
No new safety alerts since 1 June 2007.
No changes in product availability since 1 June 2007.
To guide initial management of the infertile couple and suggest appropriate referral and investigation criteria
Infertility is the inability to conceive. A couple is regarded as infertile if, after regular sexual intercourse, they have not conceived in 2 years [National Collaborating Centre for Women's and Children's Health, 2004; NICE, 2004].
Infertility is classed as primary in couples who have never conceived and secondary in couples who have previously conceived [National Collaborating Centre for Women's and Children's Health, 2004].
Subfertility generally describes any form of reduced fertility that results in a prolonged duration of unwanted lack of conception [Gnoth et al, 2005].
It is estimated that one in seven UK couples has difficulty conceiving (approximately 3.5 million people) [HFEA, 2006a]:
A typical primary care trust, health board, or strategic health authority may expect to see around 230 new consultant referrals (couples) per 250,000 population per year [National Collaborating Centre for Women's and Children's Health, 2004].
Infertility is more common with increasing age:
Female fertility declines with age; the effect of age on male fertility is less clear.
With regular sexual intercourse, 6% of women aged 35 years and 23% of those aged 38 years will not conceive after 3 years [National Collaborating Centre for Women's and Children's Health, 2004].
The number of couples seeking help has increased, although it is not thought that the prevalence of infertility has increased greatly. Such theories as a decline in sperm count due to environmental factors are controversial. Behavioural factors, such as a tendency to delay childbearing, may play a role [Himmel et al, 1997; Templeton, 2000; National Collaborating Centre for Women's and Children's Health, 2004].
Of 100 couples trying to conceive naturally [HFEA, 2006a]:
20 will conceive within 1 month.
70 will conceive within 6 months.
85 will conceive within 1 year.
90 will conceive within 18 months.
95 will conceive within 2 years.
For couples who have been trying to conceive for more than 3 years, the chance of a spontaneous pregnancy in the next year is 25% or less [Hargreave and Mills, 1998].
A cause of infertility is not identified in 30% of couples.
Identifiable causes of infertility include:
Ovulatory disorders in 27% of couples.
Tubal damage in 14% of couples.
A low sperm count or low sperm quality in 19% of couples.
The presence of disorders in both the man and the woman has been reported in about 39% of couples.
The most common causes of infertility in women are ovulation failure (amenorrhoea or oligomenorrhoea) and tubal damage secondary to infection [Cahill and Wardel, 2002].
Premature ovarian failure.
Polycystic ovary syndrome: often associated with hirsutism, obesity, acne, and menstrual irregularity. See the CKS topic on Polycystic ovary syndrome for further information.
Anterior pituitary macro- or microadenoma may alter prolactin secretion and lead to amenorrhoea and anovulation. Although stress may cause a transient rise in the prolactin level, values higher than 1500 mIU/L suggest an adenoma.
Hypothalamic causes. The most common causes are excessive exercising or being underweight, or both. People with anorexia nervosa are usually amenorrhoeic.
Sheehan's syndrome (panhypopituitarism most often following massive postpartum haemorrhage or trauma) is now very rare.
Kallmann's syndrome (due to congenital lack of hypothalamic production of gonadotrophin-releasing hormone) is rare and presents with amenorrhoea and anosmia.
Thyroid: hyperthyroidism and hypothyroidism may lead to menstrual disorders and ovulatory dysfunction.
Adrenal: Cushing's syndrome and congenital adrenal hyperplasia may cause anovulation.
Chronic debilitating disease (e.g. uncontrolled diabetes, cancer, AIDS, end-stage kidney disease, and malabsorption) may lead to anovulation and amenorrhoea [American Society for Reproductive Medicine, 2004].
Many women who present with primary or secondary infertility have amenorrhoea. For further information on primary and secondary amenorrhoea, see the CKS topic on Amenorrhoea.
Previous pelvic surgery causing tubal damage or adhesions.
Previous cervical surgery causing scarring or shortening of the cervix and, rarely, cervical stenosis.
Submucosal fibroids may distort the uterine cavity and impair implantation [Campbell and Monga, 2000].
Cervical mucus defect or dysfunction.
Endometriosis: tubal distortion and limitation of fimbrial motility due to pelvic adhesions.
Examples of drugs that can impair fertility in women are:
Nonsteroidal anti-inflammatory drugs (NSAIDs): the Committee on Safety of Medicines (CSM) advise that for women who have difficulty conceiving or who are undergoing investigation of infertility, withdrawal of NSAID therapy should be considered [CSM, 2006]. The effect on fertility is reversed upon withdrawal of NSAID therapy [Aronson, 2006c].
Cyclo-oxygenase inhibitors can have a negative local effect on ovulation [Aronson, 2006c].
Spironolactone can cause infertility and menstrual irregularities. Normal menstruation resumes within 2 months of therapy withdrawal [Aronson, 2006d].
Chemotherapy with cytotoxic drugs can induce ovarian failure, which may be permanent [Janssen and Genta, 2000].
Neuroleptic drugs may cause amenorrhoea and infertility [Aronson, 2006c].
Recreational drugs, such as marijuana and cocaine, have been associated with impaired ovulatory and tubal function [National Collaborating Centre for Women's and Children's Health, 2004].
Occupational and environmental factors which may affect fertility include exposure to pesticides, metals (lead, cadmium, manganese), solvents, and formaldehyde. Three cohort studies have reported an association between work-related stress and a lower probability of conception in women [National Collaborating Centre for Women's and Children's Health, 2004].
Stress in either the man or the woman may affect the couple's relationship and is likely to reduce libido and the frequency of intercourse, which may contribute to infertility [National Collaborating Centre for Women's and Children's Health, 2004].
The most common cause of male infertility is testicular deficiency (not caused by hypothalamic-patriotism disease or obstruction of the male genital tract). In this situation, physical findings and endocrine investigations (usually done in secondary care) are normal. Semen analysis shows either [Jungwirth et al, 2012]:
Non-obstructive aoospermia, OR
Severe oligospermia, asthenozoospermia, and teratozoospermia which usually occur together and are described as the oligo-astheno-teratozoospermia (OAT) [Jungwirth et al, 2012].
A decreased number of spermatozoa (oligozoospermia).
Decreased sperm motility (asthenozoospermia).
Many abnormal sperm on morphological examination (teratozoospermia).
Absence of testes.
Congenital factors (e.g. testicular dysgenesis).
Acquired factors (e.g. testicular trauma, testicular torsion, tumour, surgery).
Post-inflammatory factors (e.g. orchitis).
Chromosome abnormalities (e.g. Klinefelter's syndrome — karyotype 47, XXY; small testes; and sterility).
Germ cell aplasia (Sertoli-cell-only syndrome). Most causes are idiopathic [Kim and Mobley, 2007].
Exogenous factors (e.g. drugs, toxins, irradiation, heat).
Systemic disease (e.g. liver cirrhosis, renal disease).
Varicoceles (found in 11.7% of men with normal semen and 25.4% of men with abnormal semen). The mechanism by which varicoceles might impair fertility and spermatogenesis is not clear [National Collaborating Centre for Women's and Children's Health, 2004].
Obstructive azoospermia is the absence of both spermatozoa and spermatogenic cells in semen and post-ejaculate urine due to bilateral obstruction of the seminal ducts. Causes include [Dohle et al, 2007]:
Congenital: idiopathic epididymal obstruction.
Acquired: after infection (e.g. epididymitis) or surgery (e.g. epididymal cysts).
Vas deferens obstruction:
Congenital: absence of the vas deferens.
Acquired: after vasectomy or surgery (e.g. hernia, scrotal surgery).
Ejaculatory duct obstruction:
Congenital: prostatic cysts (Mϋllerian cysts).
Acquired: after infection or surgery (e.g. bladder neck surgery).
Hypogonadism is defined as deficient androgen secretion. Causes of hypogonadism of hypothalamic or pituitary origin include [Dohle et al, 2007]:
Idiopathic hypogonadotropic hypogonadism (e.g. Kallmann's syndrome).
Hyperprolactinaemia from a pituitary adenoma.
Delay of puberty.
Use of drugs or anabolic steroids.
Examples of drugs that can induce infertility in men are:
Sulfasalazine can cause infertility and oligospermia. Oral and rectal treatments have the same effects, which are reversible on withdrawal of therapy or by switching to mesalazine [Aronson, 2006a].
Androgens and anabolic steroids can lead to reduction in the volume of the testes and azoospermia or oligospermia because of suppression of gonadotropins [Aronson, 2006a].
Chemotherapy with cytotoxic drugs can induce permanent azoospermia [Janssen and Genta, 2000].
Recreational drugs, such as cocaine, can adversely affect the quality of semen [National Collaborating Centre for Women's and Children's Health, 2004].
Herbal remedies may cause oligospermia and azoospermia and reduction in testicular size (e.g. root extracts of Tripterygium wilfordii and gossypol extracted from certain species of Gossypium) [Aronson, 2006b; Aronson, 2006c].
Stress, although its association with infertility in men is not clear. A higher incidence of male sexual disturbance has been observed in couples undergoing fertility investigations and treatment [Saleh et al, 2003; National Collaborating Centre for Women's and Children's Health, 2004].
Antibodies against spermatozoa. Sperm function may be impaired by antisperm antibodies. The significance of antisperm antibodies is unclear [National Collaborating Centre for Women's and Children's Health, 2004].
Scenario : Initial assessment: covers the initial assessment of couple who seek information regarding infertility.
Scenario: Management: covers the initial management of infertility in primary care including advice to couples, initial investigations and when to refer. This scenario also provides information regarding what the couple might expect following a referral, and problems that may subsequently arise in primary care.
Offer all couples who are concerned about their fertility an initial assessment (history and examination) in primary care.
Assess couples who are concerned about infertility to identify those:
Who need early investigation or referral.
Who have modifiable factors (e.g. overweight, heavy smoking).
This advice is based on recommendations issued by the National Institute for Health and Clinical Excellence [National Collaborating Centre for Women's and Children's Health, 2004; NICE, 2004].
Take a full medical, sexual, and social history, including:
The woman's age (fertility decreases with age).
Children born to the woman, and previous pregnancies and miscarriages (with the same or a different partner). It is important to consider a new partner's fertility history.
Length of time trying to conceive.
Frequency of sexual intercourse (including any difficulties with intercourse), as the chances of conception improve with regular sexual intercourse.
Length of time since stopping contraception and type of contraception. Check that there are no problems that may explain the inability to conceive, such as a 'lost' intrauterine contraceptive device.
History and symptoms that may indicate ovulatory problems:
Menstrual cycle details, including length of cycle and menorrhagia. Oligomenorrhoea or amenorrhoea may indicate lack of or infrequent ovulation. Ask about symptoms and signs of ovulation (e.g. ovulatory discomfort, dysmenorrhoea).
Galactorrhoea or hirsutism.
Systemic disease, including thyroid dysfunction, diabetes, and inflammatory bowel disease.
Excessive exercise, weight loss, or psychological distress.
History and symptoms that may indicate tubal, uterine, or cervical factors:
Symptoms of pelvic inflammatory disease or endometriosis, such as dyspareunia and dysmenorrhoea.
History of sexually transmitted diseases or pelvic inflammatory disease.
Cervical smear history (including any investigations or treatment for an abnormal smear) and previous pelvic surgery, such as appendicitis, ovarian cyst.
Intermenstrual or postcoital bleeding.
Details of occupation for possible exposure to hazards that can reduce fertility, such as pesticides, nitrous oxide, formaldehyde, and solvents.
Lifestyle factors that may affect fertility (e.g. smoking, weight gain).
Perform physical examination to identify problems that may contribute to infertility:
Pelvic examination may identify such factors as vaginal infection or tenderness indicating endometriosis or pelvic inflammatory disease. Bimanual examination may reveal fibroids or an ovarian cyst.
Look for obesity (associated with lower fertility), hirsutism and acne (associated with polycystic ovary syndrome), and galactorrhoea (suggestive of hyperprolactinaemia).
These recommendations are based on expert opinion from standard textbooks [Chambers, 1999; Symonds and Symonds, 2004], review articles [Hargreave and Mills, 1998; Cahill and Wardel, 2002], national guidance [National Collaborating Centre for Women's and Children's Health, 2004; NICE, 2004].
Natural female fertility declines with age: this is seen after 30 years of age but is more marked after 35 years. Reliable data on fertility rates in different age groups are limited, and these figures should be interpreted with caution, as they are based on women receiving artificial donor insemination. Conception rates are likely to be higher in fertile women having sexual intercourse than in fertile women receiving donor insemination [National Collaborating Centre for Women's and Children's Health, 2004].
Evidence from well-designed non-experimental descriptive studies suggests that coitus every 2–3 days is likely to maximize the overall chance of natural conception [National Collaborating Centre for Women's and Children's Health, 2004].
A multi-centre case control study that compared women with bilateral tubal occlusion (n = 74), women with other causes of infertility (n = 155), and fertile women (n = 466) found that women with a past history of chlamydia or gonococcal infection were significantly more likely to have bilateral tubal occlusion [World Health Organization Task Force on the Prevention and Management of Infertility, 1995].
Take a full medical, sexual, and social history, including:
Children born to the man (with the same or a different partner).
Length of time trying to conceive, and frequency and difficulties of sexual intercourse.
Symptoms or history that may suggest primary spermatogenic failure or obstructive azoospermia:
History of mumps, sexually transmitted diseases, or testicular trauma.
Previous urogenital abnormality and treatment (e.g. undescended testis or orchidopexy).
Systemic diseases (e.g. cardiac failure, chronic renal failure, neoplasia, uncontrolled diabetes, liver cirrhosis, thyrotoxicosis).
Previous surgery (e.g. hernia repair, orchidopexy).
Ejaculatory or erectile dysfunction.
Details of occupation for possible exposure to pesticides, X-rays, solvents, paints, or chemicals from smelting or welding.
Lifestyle factors that may affect fertility, such as smoking, alcohol intake, illicit drugs, excessive travelling that limits optimal coital timing, excessive exercise, stress, or social or occupational situations that may cause testicular hyperthermia.
Perform physical examination to identify factors that may contribute to infertility:
Scrotal examination may reveal lumps (cancer, varicocele, or hernia); small, soft testes (which may indicate hypogonadism); or undescended testes.
The penis should be examined, including a check of the position of the urethral meatus, for structural abnormalities.
Assess secondary sexual characteristics. In hypogonadism, there may be a decrease in beard and body hair growth and a decrease in muscle mass.
Look for gynaecomastia, which may indicate hypogonadism.
These recommendations are based on expert opinion from standard textbooks [Wu, 1996; Chambers, 1999; Symonds and Symonds, 2004], review articles [Cooke, 1996; Hargreave and Mills, 1998; Cahill and Wardel, 2002], and national guidance [National Collaborating Centre for Women's and Children's Health, 2004; NICE, 2004].
Involve both partners in all aspects of management. Discussion of wishes, plans, beliefs, and motives is important.
Offer information about normal patterns of conception. For many couples, this will provide reassurance that they have a good chance of conception and may be all that they need.
In general, do not advise investigations for infertility until the couple has been unable to conceive after 1 year of unprotected intercourse.
Advise regular sexual intercourse (two or three times weekly) throughout the woman's cycle; this should ensure that intercourse falls within the fertile period. Do not recommend the use of temperature charts or luteinizing hormone detection methods.
Inform couples that stress in either partner can affect their relationship and is likely to reduce libido and frequency of intercourse, which can contribute to fertility problems.
Provide up-to-date information. Information on infertility is often available locally. National sources of up-to-date information include the Human Fertilisation and Embryology Authority (www.hfea.gov.uk), Infertility Network UK (www.infertilitynetworkuk.com) and British Infertility Counselling Association (www.bica.net).
General health issues
Advise women on preparation for pregnancy (e.g. taking folic acid), check rubella status, and offer cervical screening in accordance with the national cervical screening programme.
For further information, see the CKS topic on Pre-conception - advice and management.
Advise women who smoke that smoking is likely to reduce their fertility.
Advise women that passive smoking is likely to reduce their chances of conceiving.
Advise men that smoking is associated with reduced semen quality and that stopping smoking will improve their general health.
Offer women and men referral to a smoking cessation programme. See the CKS topic on Smoking cessation for more information.
Advise women to aim for a body mass index (BMI) of 19–25 kg/m2:
In particular, encourage weight loss in women with a BMI greater than 29 kg/m2, as weight loss is likely to increase their chance of ovulation and therefore conception.
Advise women with a BMI less than 19 kg/m2 and either amenorrhoea or irregular menstruation that gaining weight is likely to increase their chance of conception.
Inform women that participating in a group programme involving exercise and dietary advice increases the chances of pregnancy.
Advise men with a body mass index greater than 29 kg/m2 that they are likely to have reduced fertility and that they should lose weight.
Advise anyone concerned about occupational risks to their health, including their fertility, to seek specialist advice. Advice may be obtained from:
Occupational health at their place of work for some people.
Other risk factors
Inform women that evidence is inconsistent on the effect of alcohol on fertility, but alcohol poses a definite risk to the fetus, and the Department of Health now recommends consumption of no alcohol at all whilst trying to conceive. Women who choose to drink should consume no more than 1–2 units of alcohol once or twice weekly and should not get intoxicated, to minimize risk to the baby.
Inform men that alcohol consumption within the Department of Health's recommendations of 3–4 units daily is unlikely to affect their fertility. Excessive alcohol consumption can be detrimental to semen quality.
Inform women and men that there is no consistent evidence of an association between consumption of caffeinated beverages and fertility problems.
Inform men that although an elevated scrotal temperature is associated with reduced semen quality, it is uncertain whether wearing loose-fitting underwear improves semen quality.
Advise people trying to conceive that the effectiveness of complementary therapies has not been properly evaluated, and these therapies are not recommended.
Advise women and men that the use of illicit drugs may affect fertility. Offer users of illicit drugs referral to a specialist drugs and alcohol service.
These recommendations are based on expert opinion from national guidance [National Collaborating Centre for Women's and Children's Health, 2004; NICE, 2004] and a review article [Himmel et al, 1997].
The National Institute for Health and Clinical Excellence (NICE) based their recommendations on the following sources [National Collaborating Centre for Women's and Children's Health, 2004]:
Two surveys reported that women are more satisfied if seen with their partners at their infertility consultation.
Evidence from well-designed non-experimental descriptive studies suggests that sexual intercourse every 2–3 days is likely to maximize the overall chance of natural conception, as spermatozoa survive in the female reproductive tract for up to 7 days after insemination.
Evidence from six cohort studies that evaluated the use of basal body temperature or urinary luteinizing hormone (LH) kits to time intercourse showed that use of these kits causes stress. Moreover, they have not been shown to improve conception rates. The use of these kits is therefore not recommended. However, NICE guidelines recommend that use of LH kits to predict ovulation can be useful for a minority of couples who find it difficult to have frequent sexual intercourse.
The chance of conception is 84% in the first year if they do not use contraception and have regular sexual intercourse [National Collaborating Centre for Women's and Children's Health, 2004].
General health issues:
The basis for recommendation is expert opinion from the National Institute for Health and Clinical Excellence [National Collaborating Centre for Women's and Children's Health, 2004; NICE, 2004].
The basis for these recommendations is expert opinion from national guidance, which advises that smoking is likely to impair fertility [National Collaborating Centre for Women's and Children's Health, 2004; NICE, 2004].
Evidence from a systematic review and a meta-analysis of observational studies shows that smoking and reduced fertility in women are significantly associated [Hughes and Brennan, 1996; Augood et al, 1998].
Evidence from a longitudinal study shows that passive smoking is detrimental to fertility in women [Hull et al, 2000]. In men, there is no clear evidence that smoking delays conception or affects fertility, but it may affect sperm quality and general health [BMA, 2004].
There is no proven association between male obesity and infertility, although observational studies have found that obesity is associated with poorer general health, a reduction in sperm motility, and increased DNA fragmentation [Kort et al, 2003a; Kort et al, 2003b; National Collaborating Centre for Women's and Children's Health, 2004].
Women with a body mass index (BMI) greater than 30 kg/m2 take longer to conceive than women with a lower BMI, even after adjustment for other factors, such as menstrual irregularity [National Collaborating Centre for Women's and Children's Health, 2004].
For infertile anovulatory women with a BMI greater than 29 kg/m2, there is evidence that a supervised weight loss programme or a group programme including exercise, dietary advice, and support helps to reduce weight, resume ovulation, and improve pregnancy rates [Clark et al, 1998; National Collaborating Centre for Women's and Children's Health, 2004].
An observational study reported an inverse relationship between BMI and the total number of normal motile sperm. Men who were overweight (BMI 25–30 kg/m2) had a significantly reduced number of motile sperm compared to men with normal body weight (BMI 20–24 kg/m2) [National Collaborating Centre for Women's and Children's Health, 2004].
Some occupations involve exposure to hazards that can reduce male or female infertility. Heat, metals, pesticides, and X-rays have been found to be harmful, but information on the association of most chemical and physical agents with infertility is lacking, mainly because these agents were rapidly introduced into industry [National Collaborating Centre for Women's and Children's Health, 2004; NICE, 2004].
More than 104,000 chemical and physical agents have been identified in the workplace, but at least 95% of these have not been assessed for their effect on reproduction [National Collaborating Centre for Women's and Children's Health, 2004].
Other risk factors:
The recommendation on alcohol use by women is based on advice from the Department of Health, who now recommend no alcohol consumption when trying to conceive [DH, 2007a]:
The Department of Health states that this revision to their previous advice, which was to drink a maximum of 1–2 units once or twice weekly, is not based on new scientific evidence but is consistent with current thinking.
The new advice will be easier to understand and will provide consistent advice across the UK [DH, 2007b].
The revision was needed to help ensure that women did not underestimate the risks to their baby:
The National Institute for Health and Clinical Excellence (NICE) states that the evidence for a link between alcohol and female infertility is inconsistent [National Collaborating Centre for Women's and Children's Health, 2004].
Until more is known, women are advised not to drink during pregnancy [DH, 2007a].
Excessive alcohol consumption can be detrimental to semen quality, but the effect is reversible and there is no evidence for a causal relationship between moderate alcohol consumption and poor semen quality [National Collaborating Centre for Women's and Children's Health, 2004].
The association between caffeine and female infertility is inconsistent. NICE found no studies on the effect of caffeine on pregnancy rates or the effect of decaffeinated beverages on fertility. One observational study of caffeine intake and male fertility found no evidence of an association between caffeine intake and poor semen variables. However, the combination of coffee drinking with smoking diminished sperm motility and increased the proportion of dead sperm [National Collaborating Centre for Women's and Children's Health, 2004].
The recommendation on complementary therapies is issued by NICE and is based on expert opinion, which found the effectiveness of complementary therapies for fertility problems has not been probably evaluated. Further research is needed before such interventions can be recommended [National Collaborating Centre for Women's and Children's Health, 2004].
Marijuana and cocaine can adversely affect ovulatory and tubal function. NICE found no studies that assessed the effect of recreational drug use on pregnancy rates. Anabolic steroids and cocaine can adversely affect semen quality [National Collaborating Centre for Women's and Children's Health, 2004].
Well-designed non-experimental descriptive studies have shown that increased scrotal temperature is closely associated with reduced semen quality in healthy men and that a sedentary work position and occupational heat exposure are associated with abnormal semen quality [National Collaborating Centre for Women's and Children's Health, 2004].
Evidence on the effect of tight-fitting versus loose-fitting underwear on semen quality is limited and conflicting:
A cohort study of 97 men with subfertility showed that scrotal temperatures and semen variables did not differ between a group wearing boxer shorts and a group wearing briefs [Munkelwitz and Gilbert, 1998].
A very small (n = 20) prospective randomized crossover trial which only 9 men completed suggested that wearing tight-fitting underwear can impair semen quality, whereas wearing loose-fitting underwear had no effect on semen quality [Tiemessen et al, 1996]. The effect of impaired semen quality on pregnancy rates has not been established [National Collaborating Centre for Women's and Children's Health, 2004].
Start investigations in couples who have not conceived after 1 year of regular unprotected sexual intercourse.
Offer investigations earlier than 1 year to couples who have been identified as less likely to conceive.
Early investigations may be prompted by the same factors that prompt an early referral (see When to refer).
These recommendations are based on those issued by the National Institute for Health and Clinical Excellence [National Collaborating Centre for Women's and Children's Health, 2004; NICE, 2004].
Measure mid-luteal phase progesterone in all women to confirm ovulation. The sample should be taken 7 days before the expected period (day 21 in a 28-day cycle).
The following additional tests may be needed:
In women with prolonged irregular menstrual cycles, depending on the timing of menstrual periods, serum progesterone may need to be measured later (e.g. on day 28 of a 35-day cycle) to confirm ovulation, and repeated weekly thereafter until the next menstrual cycle starts.
In women with irregular menstrual cycles, measure serum gonadotrophins (follicle-stimulating hormone and luteinizing hormone).
In women with symptoms of thyroid disease, perform thyroid function tests.
In women with an ovulatory disorder, galactorrhoea, or a suspected pituitary tumour, measure prolactin.
Screen for chlamydia.
Mid-luteal phase progesterone levels:
Progesterone is released after luteinization of the follicle (as part of the ovulation process).
Ovulation can be confirmed retrospectively by measurement of serum progesterone in the mid-luteal phase, approximately on day 21 of a 28-day cycle.
Consult your local laboratory regarding the lowest limit indicative of ovulation.
This is of value in women with anovulation or oligo-ovulation. These disorders are estimated to cause 21% of female infertility.
Gonadotrophin measurement can be used to identify three groups of ovulation disorders (defined by the World Health Organization):
Hypothalamic pituitary failure (group 1): characterized by low gonadotrophin, normal prolactin, and low oestrogen levels. This group accounts for about 10% of ovulatory disorders.
Hypothalamic pituitary dysfunction (group 2): characterized by gonadotrophin disorder and a normal oestrogen level. This group accounts for about 85% of ovulatory disorders and includes polycystic ovaries.
Ovarian failure (group 3): characterized by high gonadotrophins and hypogonadism and a low oestrogen level. This group accounts for about 4–5% of ovulatory disorders.
Hyperprolactinaemia is an endocrine disorder caused by increased prolactin secretion from the pituitary gland. This can result in galactorrhoea, irregular menstruation, and infertility.
The incidence of an increased prolactin level in infertile but ovulatory women ranges from 3.8–11.5%.
Prolactin measurement should be reserved for women with symptoms of an ovulatory disorder (e.g. polycystic ovary syndrome), galactorrhoea, or a pituitary tumour.
Thyroid function tests:
Thyroid dysfunction can lead to menstrual and ovulatory disorders associated with infertility:
Abnormal thyroid function has been reported in 1.3–5.1% of infertile women.
Subclinical hypothyroidism has been estimated to occur in 0.88–11.3% of women with ovulation disorders.
Chlamydial testing: a cervical swab or vulvovaginal swab are the specimens of choice. If a speculum examination is not possible, a first-catch urine sample may be taken [BASHH, 2006]. See the CKS topic on Chlamydia - uncomplicated genital for further information.
These recommendations are based on expert opinion from the National Institute for Health and Clinical Excellence (NICE) [National Collaborating Centre for Women's and Children's Health, 2004; NICE, 2004]:
Women with high levels of gonadotrophins are likely to have reduced fertility.
Women with possible fertility problems are no more likely than the general population to have thyroid disease.
NICE recommends that all women scheduled to undergo uterine instrumentation be tested for chlamydia, as infertility investigations may result in iatrogenic pelvic inflammatory disease:
Although the prevalence of Chlamydia trachomatis is only 1.9% in subfertile women, the number of people in whom uncomplicated chlamydia infection is diagnosed has risen steadily since 1993, particularly among those 16–19 years of age [PHLS et al, 2000; National Collaborating Centre for Women's and Children's Health, 2004]. CKS therefore recommends that chlamydia screening be part of the assessment of all women presenting with infertility.
If the test result is positive, women and their partners should be referred for appropriate management and contact tracing [BASHH, 2006].
The Human Fertilisation and Embryology Authority recommends a urine test to screen for chlamydia in both men and women [HFEA, 2007a].
The British Association for Sexual Health and HIV recommend a cervical swab or vulvovaginal swab as the specimens of choice. Both have a sensitivity of 90–95%. Variable sensitivities have been reported using a first-catch urine sample [BASHH, 2006].
Arrange for semen analysis.
If the result of the first semen sample is normal, there is no need to do a repeat confirmatory test.
If the result of the first semen sample is abnormal, order a repeat test:
Testing should ideally be repeated 3 months after the initial test, to allow time for the cycle of spermatozoa to be completed.
It may be appropriate to test earlier (e.g. if the man is very anxious regarding the test result and prefers to have the test done earlier). In these circumstances, or if there is a gross spermatozoa deficiency (azoospermia or severe oligospermia), perform the repeat test within 2–4 weeks.
If the repeat test result is normal, the semen should be regarded as normal and no further testing is required.
Men who have two abnormal semen examination results should be referred for further assessment.
Screen for chlamydia.
Advise that the semen sample [WHO, 1999]:
Should be collected after at least 48 hours but no more than 7 days of sexual abstinence [WHO, 1999].
Ideally, the sample should be collected in a private room near the laboratory. If this is not possible, the sample should be delivered to the laboratory within 1 hour of production.
The specimen should be collected by masturbation and ejaculated into a clean, wide-mouthed glass or plastic container and protected from extremes of temperature (below 20°C or above 40°C).
Emphasize that the semen specimen should be complete.
Interpret by using the World Health Organization reference values.
For chlamydia screening, a first-catch urine sample is reported to be as good as a urethral swab. Urine samples are preferable because they are easy to collect and do not cause discomfort [BASHH, 2006].
The recommendation on semen testing is based on expert opinion from national guidance [National Collaborating Centre for Women's and Children's Health, 2004; NICE, 2004] and the World Health Organization (WHO) Laboratory Manual for the Examination of Human Semen and Sperm–Cervical Mucus Interaction [WHO, 1999].
The WHO criteria are described as 'reference' values rather than 'normal' values and are based on populations of fertile men:
Basic semen analysis using the WHO criteria is sensitive (sensitivity of 89.6% — i.e. the test is likely to detect 9 of 10 men who have 'true' semen abnormality) but has poor specificity (i.e. an abnormal test result does not always mean there is a true semen abnormality) [National Collaborating Centre for Women's and Children's Health, 2004].
Greater specificity can be achieved with repeated testing. A single-sample analysis will falsely identify about 10% of men as abnormal. Repeating the test reduces this to 2%.
To reduce false-positive results, a repeat semen analysis should be performed if the results of the first analysis is abnormal [National Collaborating Centre for Women's and Children's Health, 2004].
The British Association for Sexual Health and HIV recommends that a first-catch urine sample is as good as a urethral swab for testing for chlamydia infection in men [BASHH, 2006].
Do not recommend:
Basal body temperature charts.
Use of ovulation predictor kits.
Screening for antisperm antibodies.
Basal body temperature charts do not reliably predict ovulation [Guermandi et al, 2001; National Collaborating Centre for Women's and Children's Health, 2004].
Ovulation predictor kits are widely available, but there is no evidence that attempts to time sexual intercourse to the menstrual cycle result in improved conception rates [Hargreave and Mills, 1998; Chambers, 1999].
The routine use of postcoital testing has no predictive value for pregnancy rates [National Collaborating Centre for Women's and Children's Health, 2004].
The significance of antisperm antibodies is unclear [National Collaborating Centre for Women's and Children's Health, 2004].
Referral criteria for people presenting with infertility may vary among health authorities.
If the woman is younger than 35 years: in general, consider referral if history, examination, and investigations are normal in both partners and the couple has not conceived after 18 months.
Provide earlier referral for women 35 years of age or older or if an abnormality in the history, examination, or investigations suggests that earlier secondary care involvement is required.
Earlier referral (i.e. duration of infertility less than 18 months) may also be prompted by factors listed in Table 1.
Ensure that the couple have been offered counselling before, during, and after investigation and treatment, regardless of the outcome of these procedures, and explain that fertility problems and their investigation and treatment can cause psychological stress. Usually counselling will be arranged by the specialist infertility team. Infertility counsellors are provided by all licensed clinics in the UK, and the British Infertility Counselling Association (www.bica.net).
|Age older than 35 years||Previous genital pathology|
|Amenorrhoea or oligomenorrhoea||Previous urogenital surgery|
|Previous abdominal or pelvic surgery||Previous sexually transmitted infection|
|Previous pelvic inflammatory disease||Varicocele|
|Previous sexually transmitted infection||Significant systemic illness|
|Abnormal pelvic examination||Abnormal genital examination|
|Known reason for infertility (e.g. prior treatment for cancer)||Known reason for infertility (e.g. prior treatment for cancer)|
The basis for this recommendation is expert advice from national guidance [National Collaborating Centre for Women's and Children's Health, 2004] and a standard textbook [Chambers, 1999]:
Four surveys have reported that most people feel that access to a support group and counselling would be beneficial [National Collaborating Centre for Women's and Children's Health, 2004].
Evidence from two RCTs indicates that group psychological interventions prevent distress and improve pregnancy rates (55% in a cognitive behavioural therapy group versus 54% in a support group versus 20% in a routine care group) in women with infertility of less than 2 years' duration [National Collaborating Centre for Women's and Children's Health, 2004].
Assessments in secondary and tertiary care:
Investigations in women normally include tubal patency tests:
Women who are not known to have comorbid conditions (e.g. pelvic inflammatory disease, endometriosis, or previous ectopic pregnancy) should be offered hysterosalpingography or hysterosalpingo-contrast ultrasonography.
Women thought to have comorbid conditions should be offered diagnostic laparoscopy and dye so that tubal and other pelvic abnormalities can be assessed at the same time.
Investigations in men include an assessment of the sperm, starting with a review of results obtained from primary care investigations:
In men with abnormal sperm, a more detailed examination is done, which may include microbiological tests, sperm culture, endocrine tests, imaging of the urogenital tract, and testicular biopsy.
Types of infertility treatment:
There are three main types of fertility treatment (see Types of infertility treatment):
Further information on many aspects of infertility treatments can be found on the website of the Human Fertilisation and Embryology Authority (HFEA, www.hfea.gov.uk). This body is responsible for regulating all NHS and private clinics offering infertility treatments to ensure compliance with the Human Fertilisation and Embryology Act 1990:
Information provided by the HFEA to patients, donors, and healthcare professionals includes:
The HFEA guide to infertility, which is written for people who are having or considering fertility treatment.
Detailed information on all UK fertility clinics, including the services they provided and their success rates.
Examples of medical treatments for infertility are [National Collaborating Centre for Women's and Children's Health, 2013]:
Ovulation induction with anti-oestrogen drugs:
Clomifene is an effective treatment for anovulation and may be used in selected women.
Metformin may be added in women with polycystic ovary syndrome and a body mass index greater than 25 kg/m2 who are unresponsive to clomifene.
These may be offered to women with clomifene-resistant anovulatory infertility, but they carry a significant risk of multiple pregnancy.
They are also effective in improving fertility in men with hypogonadotropic hypogonadism.
Pulsatile gonadotrophin-releasing hormone and dopamine agonists are other treatments that induce ovulation.
Dopamine agonists can be considered for women with ovulatory disorders secondary to hyperprolactinaemia.
Examples of surgical treatment of infertility include :
Tubal microsurgery may be effective in women with mild tubal disease. Tubal catheterization or cannulation improves the chance of pregnancy in women with proximal tubal obstruction.
Surgical correction of epididymal blockage in men with obstructive azoospermia is likely to restore patency of the duct and improve fertility.
Assisted conception is treatments that deal with means of conception other than normal coitus. National success rates for various treatments can be found on the Human Fertilisation and Embryology Authority (HFEA) website (www.hfea.gov.uk). Success rates for individual clinics can also be found on the HFEA site.
Intrauterine insemination (IUI):
In this process, which is timed to coincide with ovulation, sperm is placed in the woman's uterus using a fine plastic tube. Low doses of ovary-stimulating hormones
The National Institute for Health and Clinical Excellence (NICE) recommends that couples with mild male factor fertility problems, unexplained fertility problems,
In vitro fertilization (IVF):
This involves retrieval of one or more eggs, which are mixed with sperm and incubated for 2–3 days; the resultant embryo is then injected into the uterus via the cervix.
NICE recommends that all 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 (e.g. azoospermia or bilateral tubal occlusion) or who have infertility of at least 3 years' duration be offered up to three stimulated cycles of IVF.
In response, the Department of Health recommends that from April 2005, each primary care trust offer all women aged 23–39 years who meet the NICE clinical criteria at least one full cycle of IVF. In the longer term, it is expected that primary care trusts will progress towards fully implementing NICE guidance. Priority will be given to couples who do not already have a child living with them [DH, 2004a].
About 25% of IVF treatments are funded by the NHS [HFEA, 2006a].
Intracytoplasmic sperm injection (ICSI):
This involves injecting an individual sperm directly into the egg, to bypass natural barriers that prevent fertilization.
ICSI represents 44% of all IVF treatment in the UK [HFEA, 2006a].
This is the insemination of sperm, from a donor, into a woman via her vagina into the cervical canal or into the uterus itself (IUI).
In some cases, low doses of ovary-stimulating hormones are used in conjunction with donor insemination, with the aim of increasing pregnancy rates.
Donor insemination is considered when the man has no, or very few, sperm on testicular biopsy or surgical extraction; has had a vasectomy, and reversal has failed or not been tried; or has an infectious disease, such as HIV; or where there is a high risk of transmitting a genetic disorder to the offspring.
This involves stimulation of the donor's ovaries and collection of eggs. The donated eggs are then fertilized by the recipient's partner's sperm. After 2–3 days, the embryos are transferred to the uterus of the recipient via the cervix, after hormonal preparation of the endometrium.
Oocyte donation is considered for women who have ovarian failure (premature or after radiotherapy or chemotherapy); those who have had bilateral oophorectomy; those with gonadal dysgenesis, including Turner's syndrome; and when the risk of transmitting a genetic disorder is high. It is also used in certain cases of IVF failure.
Couples who have had successful IVF or ICSI may decide to donate their spare embryos to help other infertile couples [HFEA, 2004b].
Gamete intrafallopian transfer (GIFT):
Evidence is insufficient to recommend GIFT over IVF in couples with unexplained infertility problems or male factor fertility problems.
This information is based on national guidance [National Collaborating Centre for Women's and Children's Health, 2004].
Depending on the treatment, problems that may occur with assisted conception include:
Ovarian hyperstimulation syndrome:
Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic and potentially life-threatening complication of superovulation [National Collaborating Centre for Women's and Children's Health, 2004]:
OHSS can occur after any form of supraphysiological ovarian stimulation, including clomifene and gonadotrophin ovulation induction.
Mild forms of OHSS are common and affect up to 33% of in vitro fertilization (IVF) cycles. Moderate or severe OHSS complicates 3–8% of IVF cycles [RCOG, 2006]. Severe manifestations of OHSS can lead to thrombosis, renal and liver dysfunction, and acute respiratory distress syndrome, causing serious morbidity.
Onset of OHSS can be [RCOG, 2006]:
Early: within 9 days after the ovulatory dose of human chorionic gonadotrophin (hCG).
Late: after 9 days, reflecting endogenous hCG stimulation arising from successful implantation.
Symptoms and signs include:
Feeling unwell, nausea, vomiting.
Abdominal pain, distension, or both, caused by enlarged ovaries and acute ascites.
Bowel disturbance: constipation or diarrhoea.
Dark, concentrated urine due to reduced renal perfusion and low urine output.
Dyspnoea due to splinting of the diaphragm secondary to ascites or pleural effusion.
Leg and vulval oedema.
Consider alternative diagnoses, such as complications of an ovarian cyst (torsion, haemorrhage), pelvic infection, intra-abdominal haemorrhage, ectopic pregnancy, and appendicitis [RCOG, 2006].
Seek urgent advice from a specialist unit if OHSS is suspected. The severity of OHSS can worsen over time, and even initially mild presentations should be kept under review [RCOG, 2006].
Ectopic pregnancy occurs in about 4% of pregnancies after assisted conception [Braude and Rowell, 2003]:
Heterotopic (one embryo in the uterus and one in the tube) pregnancy is rare naturally (1 in 30,000 pregnancies), but the rate may be as high as 1 in 100 pregnancies in women who have had assisted conception [Tal et al, 1996].
The egg extraction procedure poses a risk of pelvic infection. As a result, pelvic pain and other signs of infection may develop in the weeks after the procedure:
Infection might be introduced into the ovary during the extraction procedure, which involves passing a needle through the vaginal wall into the ovary.
The risk of serious pelvic infection is likely to be less than 1 in 500 procedures.
Multiple pregnancy is the greatest health risk associated with fertility treatment:
The risk of multiple birth is high with in vitro fertilization (IVF):
In the UK, 1 in 4 births after IVF (including intracytoplasmic sperm injection [ICSI]) result in twins or triplets. In contrast, the incidence is 1 in 80 births after natural conception.
40% of IVF babies are twins. The numbers of multiple births from IVF has risen by 41% from 1995 to 2003.
The high incidence of multiple births is due to current embryo transfer practices — most women have two embryos transferred during IVF.
Multiple pregnancy poses increased risks:
Up to 25% of women carrying more than one baby have pregnancy-induced high blood pressure and are 2–3 times more likely to get diabetes than those with singleton pregnancies.
The risk of death, although low, is double for women expecting twins compared with singleton pregnancies.
Twins and triplets have much higher risks of ill health and death compared to singletons:
Around half of all twins and 90% of triplets are born prematurely or with low birth weight. The risk of death in the first week of life is five times higher for twins and nine times higher for triplets than for singletons.
Twins have a four times higher risk of cerebral palsy than singletons (around 8 in 1000 twins are affected).
Ovarian hyperstimulation syndrome
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