Sexual health Women's health
Infertility
Last revised in July 2023
Infertility is the inability to conceive. A couple is regarded as infertile if, after regular sexual intercourse, they have not conceived in 1 year.
Infertility: Summary
- Infertility is the period of time people have been trying to conceive without success, after which formal investigation is justified and possible treatment implemented.
- Over 80% of couples in the general population will conceive within 1 year if the woman is aged under 40 years and they have regular (every 2–3 days) unprotected 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%).
- One in seven UK couples is estimated to have difficulty conceiving (approximately 3.5 million people).
- In the UK, the leading causes of infertility are factors in the man causing infertility (30% of couples), ovulatory disorders (25% of couples), tubal damage (20% of couples), and uterine or peritoneal disorders (10% of couples).
- No identifiable cause is identified in about 25% of couples.
- The presence of factors in both the man and the woman has been reported in about 40% of infertile couples.
- Risk factors for infertility include increasing age, smoking, obesity, occupational risks, excessive alcohol consumption, and the use of certain prescription, over-the-counter, and recreational drugs.
- In addition to the investigations and treatment, psychological stress (for both the woman and the man) may be caused by infertility.
- All couples concerned about their fertility should be offered an initial assessment in primary care to identify those with modifiable risk factors (such as obesity and smoking) and those who need early investigation or referral.
- Referral criteria varies between health authorities.
- For women younger than 36 years with normal history, examination, and investigations in both partners, referral should usually be considered if the couple has not conceived after 1 year.
- Earlier referral should be offered if the woman is 36 years or over or if there is a known clinical cause of infertility or a history of predisposing factors.
- Initial investigations in women include mid-luteal phase progesterone (in all women to confirm ovulation), serum gonadotrophins (in women with irregular menstrual cycles), thyroid function tests (in women with symptoms of thyroid disease), prolactin measurement (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.
- Fertility treatment falls into 3 main types:
- Medical treatment to restore fertility, for example, the use of drugs (such as clomifene) to induce ovulation.
- Surgical treatment to restore fertility, for example, laparoscopy for ablation of endometriosis and surgical correction of epididymal blockage in men with obstructive azoospermia.
- Assisted reproduction techniques (any treatment that deals with means of conception other than vaginal intercourse), for example, intrauterine insemination, in vitro fertilization, and intracytoplasmic sperm injection.
Have I got the right topic?
From age 18 years onwards.
This CKS topic covers the initial assessment and management of a couple concerned about infertility.
This CKS topic does not cover secondary and tertiary care management of infertility, but the three main treatment options (medical treatment, surgical treatment, and assisted conception) are briefly discussed.
This CKS topic does not cover the treatment of impotence. It also does not cover issues around surrogacy or sperm and ovum banking.
There are separate CKS topics on Amenorrhoea, Contraception - assessment, Endometriosis, Erectile dysfunction, Menopause, Polycystic ovary syndrome, Pre-conception - advice and management, and Varicocele.
The target audience for this CKS topic is healthcare professionals working within the NHS in the UK and providing first contact or primary healthcare.
How up-to-date is this topic?
Changes
July 2023 — reviewed. A literature search was conducted in May 2023 to identify evidence-based guidelines, UK policy, systematic reviews, and key randomized controlled trials published since the last revision of this topic. No major changes to clinical recommendations have been made, but the topic has been restructured.
Previous changes
August 2018 — minor update. Citation amended.
April 2018 — reviewed. A literature search was conducted in February 2018 to identify evidence-based guidelines, UK policy, systematic reviews, and key randomized controlled trials (RCTs) published since the last revision of this topic. No changes to clinical recommendations have been made, but the topic has been restructured.
April 2013 — reviewed. A literature search was conducted in February 2013 to identify evidence-based guidelines, UK policy, systematic reviews, and key RCTs published since the last revision of this topic. Information from the National Institute for Health and Care Excellence (NICE) guideline Fertility: assessment and treatment for people with fertility problems (National Collaborating Centre for Women's and Children's Health, 2013) has been added. Minor changes have been made to the recommendations.
March 2012 — minor update. A broken table link was fixed in the section on When to refer.
March 2011 — the topic structure was revised to ensure consistency across CKS topics. No changes to clinical recommendations have been made.
June 2009 — minor typographical error corrected. The Human Fertilisation and Embryology Association is now correctly referred to as the Human Fertilisation and Embryology Authority.
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.
November 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 the MMR (measles, mumps, and rubella) vaccine.
November 2001 — reviewed. Validated in March 2002 and issued in April 2002.
January 1999 — written and replaces the previous guidance on female infertility. Validated in March 1999 and issued in May 1999.
Update
New evidence
Evidence-based guidelines
No new evidence-based guidelines since 1 July 2023.
HTAs (Health Technology Assessments)
No new HTAs since 1 July 2023.
Economic appraisals
No new economic appraisals relevant to England since 1 July 2023.
Systematic reviews and meta-analyses
No new systematic reviews published since 1 July 2023.
Primary evidence
- Jones, C. A., Kulshreshtha, A., Born, K., & Katiyar, P. (2025). Initial assessment of infertility in primary care. bmj, 390. [Abstract]
New policies
No new national policies or guidelines since 1 July 2023.
New safety alerts
No new safety alerts since 1 July 2023.
Changes in product availability
No changes in product availability since 1 July 2023.
Goals and outcome measures
Goals
To support primary healthcare professionals to:
- Assess a couple where there are concerns about infertility.
- Manage a couple where there are concerns about infertility.
- Manage problems that may arise after assisted conception.
Outcome measures
No outcome measures were found during the review of this topic.Audit criteria
No audit criteria were found during the review of this topic.QOF indicators
No QOF indicators were found during the review of this topic.QIPP - Options for local implementation
No QIPP indicators were found during the review of this topic.NICE quality standards
NICE quality standards: Fertility problems
- People who are concerned that it is taking longer than expected to conceive are given advice on the impact that lifestyle can have on their chances of getting pregnant.
- People are referred for specialist consultation if the woman has not conceived after 1 year of intercourse or after 6 cycles of artificial insemination, or earlier in certain circumstances.
- People who are having problems conceiving are offered counselling before, during, and after investigation and treatment for their fertility problems.
- Services analysing semen samples use methods and reference values in accordance with the most recent World Health Organization laboratory manual.
- Women aged under 40 years who meet the criteria for in vitro fertilisation (IVF) are offered 3 full cycles of IVF.
- Women aged 40–42 years who meet the criteria for IVF are offered 1 full cycle of IVF.
- Women having IVF are offered intracytoplasmic sperm injection only if there are severe deficits in semen quality, obstructive azoospermia, non-obstructive azoospermia, or if previous IVF treatment resulted in failed or very poor fertilisation.
- Women having IVF have 1 or 2 embryos transferred according to the woman's or donor's age, the cycle number, and the quality of the embryos.
- People preparing to have treatment for cancer that is likely to result in fertility problems are offered cryopreservation.
Background information
What is it?
- Infertility is a disease of the reproductive system in men or women.
- The National Institute for Health and Care Excellence (NICE) defines infertility as the period of time people have been trying to conceive without success, after which formal investigation is justified and possible treatment implemented [NICE, 2017a].
- The World Health Organization (WHO) defines infertility as the failure to achieve a pregnancy after 12 months or more of regular unprotected sexual intercourse [WHO, 2023].
- Infertility is classed as [EAU, 2023; WHO, 2023]:
- Primary — in couples who have never conceived.
- Secondary — in couples who have conceived at least once before (with the same or different sexual partner).
- Subfertility generally describes any form of reduced fertility that results in a prolonged duration of unwanted lack of conception [Gnoth, 2005].
How common is it?
- Infertility affects millions of couples worldwide [WHO, 2023].
- It is estimated that approximately one in six people of reproductive age worldwide experience infertility in their lifetime [WHO, 2023].
- A study on global infertility rates was performed in 190 countries from 1990 to 2010 [Mascarenhas, 2012]:
- Of the 48.5 million infertile couples identified, 19.2 million were diagnosed with primary infertility and 29.3 million with secondary infertility.
- The results showed that primary infertility was more common in developed countries, whereas secondary infertility was more common in developing countries.
- A study on global infertility rates was performed in 190 countries from 1990 to 2010 [Mascarenhas, 2012]:
- Infertility affects about one in seven heterosexual couples in the UK (approximately 3.5 million people) [NICE, 2017a].
What are the causes of infertility?
- Infertility is a disease of the reproductive system in men and women [WHO, 2023].
- In the UK, the main causes of infertility are [NICE, 2017a]:
- Factors in the man causing infertility (30% of couples).
- Ovulatory disorders (25% of couples).
- Tubal damage (20% of couples).
- Uterine or peritoneal disorders (10% of couples).
- There is no identifiable cause of infertility in about 25% of couples.
- The presence of disorders in both the man and the woman has been reported in about 40% of infertile couples.
- In the UK, the main causes of infertility are [NICE, 2017a]:
- See the sections on Infertility in women and Infertility in men for more information.
Causes of infertility in women
- Ovulatory disorders
- Anovulation and oligo-ovulation are ovulatory disorders estimated to cause 21% of infertility in women [NICE, 2017a].
- The World Health Organization (WHO) categorizes ovulation disorders into three groups [NICE, 2017a]:
- Group I ovulation disorders are caused by hypothalamic-pituitary failure. They are present in about 10% of women with infertility and include conditions such as hypothalamic amenorrhea (which commonly develops as a result of low body weight or excessive exercise) and hypogonadotropic hypogonadism (cause is unknown in most cases but may be congenital, for example, when associated with anosmia [Kallmann syndrome]). Women typically present with amenorrhoea (primary or secondary), characterized by low gonadotrophins and oestrogen deficiency.
- Group II ovulation disorders are defined as dysfunctions of the hypothalamic-pituitary-ovarian axis. They are present in about 85% of women with infertility and include conditions such as hyperprolactinaemic amenorrhoea and polycystic ovary syndrome (PCOS). PCOS is the most commonly encountered type of Group II ovulation disorder and is responsible for most ovulation disorders. See the CKS topic on Polycystic ovary syndrome for more information.
- Group III ovulation disorders are caused by ovarian failure and are characterized by high gonadotrophins, hypogonadism, and a low oestrogen level. They are present in about 4–5% of women with infertility.
- Other conditions that can cause ovulatory disorders include [BMJ, 2023]:
- Hyperthyroidism and hypothyroidism — may lead to menstrual disorders and ovulatory dysfunction. See the CKS topics on Hyperthyroidism and Hypothyroidism for more information.
- Cushing's syndrome and congenital adrenal hyperplasia — may cause anovulation.
- Chronic debilitating diseases (such as uncontrolled diabetes, cancer, AIDS, end-stage kidney disease, and malabsorption) — may lead to anovulation and amenorrhoea [American Society for Reproductive Medicine, 2004].
- Tubal damage
- Tubal factors account for 14% of the causes of subfertility in women [NICE, 2017a].
- The most common cause of tubal factor infertility is pelvic inflammatory disease (PID) and acute salpingitis [Dun, 2012]. However, all pelvic infections, including appendicitis and diverticulitis, can damage the fallopian tubes [BMJ, 2023].
- Chlamydia trachomatis, Neisseria gonorrhoea, and anaerobic organisms are the most common organisms that infect the lower genital tract and cause PID [Dun, 2012].
- The incidence of tubal damage is about 10–12% after one episode of pelvic infection, 23–35% after two episodes, and 54–75% after three episodes [Dun, 2012].
- The risk of ectopic pregnancy can increase sixfold to sevenfold after an episode of PID [Dun, 2012].
- Endometriosis is commonly associated with infertility, with a 25–40% prevalence in infertile women compared with 0.5–5% in fertile women [NICE, 2017b]. The growth of hormonally responsive endometrial tissue outside the uterus may cause anatomical obstruction of the fallopian tubes. It may also lead to infertility by producing cytokines that may be toxic to sperm or embryos. See the CKS topic on Endometriosis for more information.
- Other factors affecting tubal patency include injury to the fallopian tube due to previous tubal surgeries or sterilization, ischemic nodules, polyps or mucus, tubal spasm, and congenitally abnormal tubes [Ambildhuke, 2022].
- Uterine or peritoneal disorders
- Uterine abnormalities (such as adhesions, polyps, submucous leiomyomas, and septae) have been found in 10–15% of women seeking treatment for fertility problems [NICE, 2017a].
- Uterine fibroids may be the sole cause of infertility in 2–3% of women. Depending on their location in the uterus, fibroids have been implicated in recurrent pregnancy loss and infertility [Freytag, 2021,].
- Peritoneal factors, such as peritubular adhesions, endometriosis, altered tubal motility, and fimbrial end blockage, can also affect tubal patency [Ambildhuke, 2022].
- Unexplained cause
- Unexplained infertility is a diagnosis made by exclusion in couples who have not conceived and in whom standard investigations have not detected any abnormality. It accounts for about 40% of infertility in women and 8–28% of infertility in couples [NICE, 2017a].
Causes of infertility in men
- Testicular failure
- Primary testicular failure is the most common cause of infertility in men due to oligozoospermia and is the cause of non-obstructive azoospermia [NICE, 2017a].
- Testicular failure may be due to factors such as cryptorchidism (undescended testicles), testicular torsion or trauma, orchitis, chromosome disorders (such as Y chromosome deletions and Klinefelter syndrome [XXY]), systemic disease, radiotherapy, or chemotherapy. However, in most cases (66%) the cause is unknown [BMJ, 2022].
- Varicocele is present in almost 15% of the normal population of men, in 25% of men with abnormal semen analysis, and in 35–40% of men presenting with infertility. Clinically detectable varicoceles can be associated with abnormal gonadotrophin levels, impaired spermatogenesis, and histological changes to sperm [EAU, 2023]. See the CKS topic on Varicocele for more information.
- Several endocrinopathies are associated with low testosterone levels, including hyperprolactinaemia and genetic conditions (such as Kallmann syndrome). Clinically significant endocrinopathies are found in only 2% of infertile men [BMJ, 2022].
- Risk factors that alter spermatogenesis through low testosterone levels include obesity and exposure to certain drugs or environmental toxins.
- Obstructive azoospermia
- Obstructive azoospermia is the absence of spermatozoa in the sediment of a centrifuged sample of ejaculate due to obstruction [BMJ, 2022].
- Obstruction may be [BMJ, 2022]:
- Congenital, such as congenital bilateral absence of vas deferens, prostatic cysts (Mullerian cysts), or idiopathic epididymal obstruction.
- Acquired secondary to epididymal or prostatic infections, vasectomy, or complications of surgical procedures (such as inguinal hernia repair or orchiopexy for undescended testicles).
- Related frequently to a mutation in the cystic fibrosis transmembrane regulator gene.
- Obstructive azoospermia is less common than non-obstructive azoospermia and occurs in 20–40% of men with azoospermia [EAU, 2023].
- Ejaculatory and erectile dysfunction
- Ejaculatory disorders result from conditions that interfere with the ejaculation process, a complex physiological process comprising two phases (emission and expulsion) and is mediated by complex neurological and hormonal pathways. Ejaculatory disorders include [EAU, 2023]:
- Premature ejaculation.
- Delayed ejaculation.
- Retrograde ejaculation (semen passing backwards into the bladder).
- Anejaculation (no ejaculation).
- Painful ejaculation.
- Anorgasmia (perceived absence of orgasm, which can give rise to anejaculation).
- Haematospermia (blood in the ejaculate, which may indicate underlying pathology).
- Erectile dysfunction is defined as the persistent inability to attain and maintain an erection sufficient to permit satisfactory sexual performance [Hackett, 2018; EAU, 2023]. See the CKS topic on Erectile dysfunction for more information.
- Erectile and ejaculatory dysfunction may be associated with psychological factors, hypogonadism, spinal cord disease, metabolic and vascular conditions (such as diabetes mellitus), lifestyle factors (such as smoking, excessive alcohol intake, and obesity), and the use of certain drugs [BMJ, 2022].
- Ejaculatory disorders result from conditions that interfere with the ejaculation process, a complex physiological process comprising two phases (emission and expulsion) and is mediated by complex neurological and hormonal pathways. Ejaculatory disorders include [EAU, 2023]:
- Abnormal sperm function and quality
- Conditions or situations that cause abnormal shape (morphology) and movement (motility) of the sperm negatively affect fertility [WHO, 2023].
- Sperm motility can be reduced in men with Kartagener syndrome (immotile cilia syndrome) and those with antisperm antibodies [BMJ, 2022].
- Urogenital tract infections (such as prostatitis, orchitis, and epididymitis) may result in an inflammatory response leading to obstruction or immunogenic spermatogenic dysfunction [BMJ, 2022].
- Anabolic steroids can cause abnormal semen parameters (such as sperm count and shape) [WHO, 2023].
- Unexplained cause
- Unexplained infertility in men is defined as infertility of unknown origin with normal sperm parameters and partner evaluation. It is now believed that idiopathic infertility may be associated with several previously unidentified pathological factors, including endocrine disruption due to environmental pollution, generation of reactive oxygen species (ROS)/sperm DNA damage, or genetic and epigenetic abnormalities [EAU, 2023].
What are the risk factors for infertility?
Risk factors for infertility in women
- Age
- Natural fertility in women declines with age due to dwindling oocyte numbers and poorer oocyte quality [BMJ, 2023].
- The fecundity of women decreases gradually, but significantly, beginning approximately at 32 years and decreasing rapidly after 37 years of age [ACOG/ASRM, 2014].
- Sexually transmitted infections (STIs)
- Chlamydia and gonorrhoea particularly affect fertility by causing damage to the genital anatomy [BMJ, 2023].
- Obesity
- High body fat produces a range of factors, including adipokines and oestrone, that can significantly influence reproductive function [BMJ, 2023].
- Women with a body mass index (BMI) of 30 or over are likely to take longer to conceive compared with women with a normal BMI [NICE, 2017a].
- Women with obesity are at increased risk of infertility and of developing maternal and fetal complications during pregnancy [ASRM, 2021].
- Obesity in women is associated with ovulatory dysfunction, reduced ovarian responsiveness to treatments that induce ovulation, altered oocyte and endometrial function, and lower birth rates after in vitro fertilization [ASRM, 2021].
- Low body weight
- A weight of 10% below normal body weight in most women will cause menstrual irregularities [BMJ, 2023].
- In women with a BMI of less than 19 who have irregular menstruation or are not menstruating, increasing body weight is likely to improve their chances of conception [NICE, 2017a].
- Lifestyle factors
- Smoking is likely to reduce fertility in women [NICE, 2017a].
- 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 [NICE, 2017a].
- Occupational and environmental factors
- Exposure to pesticides, nitrous oxide, metals (lead, cadmium, manganese), solvents, formaldehyde and other occupational and environmental hazards can reduce fertility [NICE, 2017a].
- Drugs
- Some prescription, over-the-counter, and recreational drugs can interfere with fertility. For example:
- Nonsteroidal anti-inflammatory drugs (NSAIDs) may inhibit ovulation [NICE, 2017a].
- Chemotherapy can induce ovarian failure, which may be permanent [Janssen, 2000].
- Metoclopramide, methyldopa, sertraline, fluoxetine, and antipsychotics (such as chlorpromazine, prochlorperazine, haloperidol, and risperidone) can suppress hypothalamic-pituitary function and increase prolactin levels [BMJ, 2023; BNF, 2023].
- Recreational drugs (such as marijuana and cocaine) can adversely affect ovulatory and tubal function [NICE, 2017a].
- Some prescription, over-the-counter, and recreational drugs can interfere with fertility. For example:
Risk factors for infertility in men
- Age
- Sexually transmitted infections (STIs)
- STIs can produce scarring and obstruction of the reproductive tract [BMJ, 2022].
- Obesity
- Obesity contributes to infertility in men. This can be attributed to multiple factors, including reduced testosterone levels and increased aromatisation of testosterone to oestrogen (which has a negative feedback effect on follicle-stimulating hormone production) [BMJ, 2022].
- Men with obesity may exhibit impaired reproductive function. However, additional research is needed to understand further the relationship between obesity in men and reproductive function [ASRM, 2021].
- Obesity is also associated with erectile dysfunction [BMJ, 2022]. See the CKS topic on Erectile dysfunction for more information.
- Lifestyle factors
- There is an association between smoking and reduced semen quality, although this impact on fertility is uncertain [NICE, 2017a].
- Excessive alcohol intake harms semen quality [NICE, 2017a; Ricci, 2017].
- 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 [NICE, 2017a].
- Occupational and environmental factors
- Exposure to pesticides, nitrous oxide, metals (lead, cadmium, manganese), solvents, formaldehyde and other occupational and environmental hazards can reduce fertility [NICE, 2017a].
- Tight underwear
- There is an association between elevated scrotal temperature and reduced semen quality, but it is uncertain whether wearing loose-fitting underwear improves fertility [NICE, 2017a].
- Drugs
- Some prescription, over-the-counter, and recreational drugs can interfere with fertility. For example [BMJ, 2022]:
- Sulfasalazine and some antifungal treatments can adversely affect spermatogenesis.
- Certain antipsychotics, antidepressants, and antihypertensives can cause retrograde ejaculation and orgasmic dysfunction.
- Long-term opiate use can cause hormonal dysregulation and impair bulk semen parameters.
- 5-alpha reductase inhibitors can cause sexual dysfunction.
- Finasteride may impair semen parameters.
- Hormone treatment, particularly testosterone supplementation or anabolic steroid treatment, can inhibit spermatogenesis and impair fertility.
- Recreational drugs (such as anabolic steroids and cocaine) can adversely affect semen quality [NICE, 2017a].
- Some prescription, over-the-counter, and recreational drugs can interfere with fertility. For example [BMJ, 2022]:
What are the complications of infertility?
Complications of infertility
- Psychological stress (for both the woman and the man) may be caused by infertility in addition to the investigation and treatment [NICE, 2017a].
Complications of assisted conception
- Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic and potentially life-threatening complication of superovulation caused by vasoactive products released by hyperstimulated ovaries [NICE, 2017a].
- The incidence of OHSS varies between different types of fertility treatment, with treatments involving greater degrees of ovarian stimulation being associated with a higher incidence.
- Risk factors include previous history of OHSS, young age, lean physique, polycystic ovary syndrome, and multiple pregnancies.
- 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. Severe manifestations of OHSS can lead to thrombosis, renal and liver dysfunction, and acute respiratory distress syndrome, causing severe morbidity [RCOG, 2016].
- The onset of OHSS can be early (within 9 days after the ovulatory dose of human chorionic gonadotrophin [hCG]) or late (after 9 days, reflecting endogenous hCG stimulation arising from successful implantation).
- Ectopic pregnancy is a possible complication in women undergoing assisted conception.
- The reported rates of ectopic pregnancy after assisted reproduction vary from 0.8-8.6% [Kirk, 2014; Panelli, 2015; Perkins, 2015; Santos-Ribeiro, 2016]. The incidence has decreased over time due to factors such as extended embryo culture and fewer embryos being transferred [Perkins, 2015; Santos-Ribeiro, 2016].
- See the CKS topic on Ectopic pregnancy for more information.
- Pelvic infection is a possible complication of the ovum extraction procedure.
- Pelvic pain and other signs of infection may develop in the weeks after the procedure.
- Infection may be introduced into the ovary during the ovum extraction procedure, which involves passing a needle through the vaginal wall into the ovary.
- Multiple births are the single most significant risk of fertility treatment [HFEA, 2021].
- The risk of a multiple birth is largely determined by the number of embryos transferred back during IVF treatment.
- In the 1990s, the multiple birth rate was around 28% due to the practice of transferring back more than one embryo during treatment.
- In 2007, the ‘One at a time’ campaign was launched to encourage the use of single embryo transfers. Since then, the multiple birth rate has fallen to just 6% in 2019.
- Multiple births remain a health risk for women undergoing IVF treatment and their babies, but the decreasing multiple birth rate means that IVF is a safer treatment.
- The evidence on cancer risk in women who have had fertility treatment is limited and of low quality.
- According to the National Institute for Health and Care Excellence (NICE) [NICE, 2017a]:
- There is no direct association between ovulation induction or stimulation and invasive cancer.
- No association has been found in the short term and medium term between ovulation induction or stimulation and adverse outcomes (including cancer) in children born from ovulation induction.
- Information on long-term health outcomes in women and children is still awaited.
- The absolute risks of long-term adverse outcomes after IVF treatment are low. However, using the available evidence it is not possible to exclude a small increased risk of borderline ovarian tumours.
- A Cochrane systematic review assessed the risk of endometrial cancer in women treated with ovary-stimulating drugs for subfertility, including clomifene citrate and gonadotrophins [Skalkidou, 2017].
- The evidence suggested that exposure to clomifene is associated with an increased risk of endometrial cancer, especially at doses greater than 2000 mg and a high (more than 7) number of cycles. However, the authors pointed out that this may largely be due to underlying risk factors in women who need treatment with clomifene citrate, such as polycystic ovary syndrome, rather than exposure to the drug itself.
- The evidence regarding exposure to gonadotrophins was inconclusive.
- Overall, the quality of the evidence was graded very low due to serious risk of bias and indirectness (non-randomized studies).
- According to the National Institute for Health and Care Excellence (NICE) [NICE, 2017a]:
Assessment
How should I assess a woman who is concerned about infertility?
All couples concerned about fertility should be offered an initial assessment (history and examination) in primary care to identify those who have modifiable risk factors (such as obesity and smoking) and those who need early investigation or referral.
- Take a full medical, sexual, and social history. Ask about:
- Length of time trying to conceive.
- Children born to the woman as well as previous pregnancies and miscarriages (with the same or a different partner).
- Frequency of sexual intercourse, including any difficulties with intercourse — the chances of conception improve with regular (every 2–3 days) 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.
- Frequency and regularity of their menstrual cycles.
- Presence of systemic disease, including thyroid dysfunction, diabetes, and inflammatory bowel disease.
- History of sexually transmitted infections (STIs) or pelvic inflammatory disease (PID).
- The timing and result of their most recent cervical smear test.
- Previous pelvic surgery (for example, appendicitis or ovarian cyst).
- Symptoms that may indicate ovulatory disorders, such as:
- Menorrhagia (abnormally heavy menstrual bleeding).
- Oligomenorrhoea (infrequent or irregular menstrual periods).
- Amenorrhoea (absence of menstruation).
- Dysmenorrhoea (painful periods).
- Galactorrhoea or hirsutism.
- Excessive exercise, weight loss, or psychological distress.
- Symptoms that may indicate uterine, cervical, and peritoneal disorders, including:
- Symptoms of PID or endometriosis, such as dyspareunia (difficult or painful sexual intercourse) and dysmenorrhoea. See the CKS topics on Pelvic inflammatory disease and Endometriosis for more information.
- Intermenstrual or postcoital bleeding.
- Risk factors for infertility, including age (fertility in women decreases with age), lifestyle factors, drug history, occupational hazards, and stress.
- Perform a physical examination.
- Check body mass index (BMI) to assess for obesity (associated with lower fertility). See the CKS topic on Obesity for more information.
- Look for:
- Hirsutism and acne (associated with polycystic ovary syndrome). See the CKS topic on Polycystic ovary syndrome for more information.
- Galactorrhoea (suggestive of hyperprolactinaemia).
- Perform an abdominal examination to identify any mass, such as an ovarian cyst.
- Pelvic examination may identify vaginal infection or tenderness, indicating endometriosis or PID. Bimanual examination may reveal fibroids or an ovarian cyst.
- Vaginal examination may indicate undisclosed sexual difficulties, such as vaginismus.
Basis for recommendation
These recommendations are based largely on the National Institute for Health and Care Excellence (NICE) guideline Fertility problems: assessment and treatment [NICE, 2017a], the British Medical Journal Best Practice guide Infertility in women [BMJ, 2023], and on what CKS considers to be good clinical practice.
How should I assess a man who is concerned about infertility?
All couples concerned about fertility should be offered an initial assessment in primary care to identify those who have modifiable risk factors (such as obesity and smoking) and those who need early investigation or referral.
- Take a full medical, sexual, and social history. Ask about:
- Length of time trying to conceive.
- Children born to the man (with the same or a different partner).
- Frequency of sexual intercourse, including any difficulties with intercourse — the chances of conception improve with regular (every 2–3 days) sexual intercourse.
- History of systemic diseases (for example, cardiac failure, chronic renal failure, neoplasia, uncontrolled diabetes, liver cirrhosis, or thyrotoxicosis).
- History that may suggest primary testicular failure or obstructive azoospermia, including:
- History of mumps, sexually transmitted infections (STIs), or testicular trauma or torsion.
- Previous urogenital abnormality and treatment (for example, undescended testis or orchidopexy).
- Previous surgery (for example, hernia repair or orchidopexy).
- Ejaculatory or erectile dysfunction.
- Risk factors for infertility, including lifestyle factors, drug history, occupational hazards, and stress.
- Perform a physical examination to identify factors that may contribute to infertility.
- Examine the penis, including a check of the position of the urethral meatus, for structural abnormalities.
- Examine the scrotum and testicles for lumps (which may indicate varicocele, hernia, or cancer); small, soft testes (which may indicate hypogonadism); or undescended testes.
- 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.
Basis for recommendation
These recommendations are based largely on the National Institute for Health and Care Excellence (NICE) guideline Fertility problems: assessment and treatment [NICE, 2017a], the European Association of Urology (EAU) guideline Sexual and Reproductive Health: Male Infertility [EAU, 2023], the British Medical Journal Best Practice guide Male factor infertility [BMJ, 2022], and on what CKS considers to be good clinical practice.
Management
Scenario: Management of infertility
From age 18 years onwards.
How should I advise a couple seeking information on infertility?
- Involve both partners in all aspects of management.
- Provide evidence-based information (verbal and written) to enable them to make an informed decision regarding their care and treatment.
- Ensure the information provided is 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.
- Give women and men general advice on the following:
- Chance of conception
- Advise that over 80% of couples in the general population will conceive within 1 year if the woman is aged under 40 years and they have regular (every 2–3 days) unprotected sexual intercourse. About half of those who do not conceive in the first year will do so in the second year (cumulative pregnancy rate over 90%).
- Inform people who are using artificial insemination to conceive and are concerned about their fertility that over 50% of women under 40 years old will conceive within 6 cycles of intrauterine insemination (IUI). About half of those who do not conceive within 6 cycles of IUI will do so with a further 6 cycles (cumulative pregnancy rate over 75%).
- Advise that fertility in women (and, to a lesser extent) fertility in men declines with age.
- Smoking
- Advise women that smoking (including passive smoking) will likely reduce their fertility and that maternal smoking can harm a developing baby.
- Advise men that smoking affects semen quality (although it is unknown if this adversely affects fertility).
- Discuss the benefits of quitting smoking to general health.
- Offer those who smoke support to help them quit. See the CKS topic on Smoking cessation for more information.
- Alcohol intake
- Advise women that alcohol consumption during pregnancy is not advised as it can adversely affect the foetus.
- Advise men that excessive alcohol consumption may affect semen quality. However, there is no evidence that drinking within recommended safe limits (no more than 14 units per week) has an adverse effect.
- Offer those who drink excessively support to help them quit. See the CKS topic on Alcohol - problem drinking for more information.
- Obesity
- Advise women that a body mass index (BMI) of 30 kg/m2 or over may increase their time to conceive.
- Advise men that a BMI greater than 29 kg/m2 is likely to have reduced fertility.
- Advise women with a BMI of 30 kg/m2 or over who are not ovulating that losing weight is likely to increase their chance of conception.
- Explain that women with obesity are at increased risk of infertility and developing maternal and fetal complications during pregnancy.
- Offer those who are overweight or obese support to help them lose weight. See the CKS topic on Obesity for more information.
- Low body weight
- Advise women with a BMI less than 19 kg/m2 plus either amenorrhoea or irregular menstruation that gaining weight is likely to increase their chance of conception.
- Drugs
- Stress management
- Advise 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.
- Explain that psychological stress (for both the woman and the man) may be caused by infertility as well as the investigation and treatment.
- Offer counselling before, during, and after investigation and treatment, irrespective of the outcome of these procedures.
- Occupational risks
- Advise anyone concerned about occupational risks to their health, including their fertility, to seek specialist advice from occupational health at their place of work or from the Health and Safety Executive website, which provides detailed information on occupational risks.
- Caffeinated beverages
- Advise that no consistent evidence exists of an association between consumption of caffeinated beverages (tea, coffee, and colas) and fertility problems.
- Complementary therapies
- Advise that the effectiveness of complementary therapies for fertility problems has not been adequately evaluated, so further research is needed before such interventions can be recommended.
- Tight underwear
- Advise men that although an elevated scrotal temperature is associated with reduced semen quality, it is uncertain whether wearing loose-fitting underwear improves semen quality.
- Chance of conception
- Give women additional relevant pre-conception advice.
- Folic acid
- Dietary supplementation with folic acid before conception and up to 12 weeks of 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, a higher dose of 5 mg per day is recommended.
- Susceptibility to rubella
- Offer testing for rubella status.
- 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
- Ask about the timing and result of their most recent cervical smear test to avoid delay in fertility treatment.
- Where applicable, offer cervical screening in accordance with the national cervical screening programme guidance.
- See the section on Advice for all women in the CKS topic on Pre-conception - advice and management for more information on these and other pre-conception care that is applicable to all women who are planning a pregnancy.
- Folic acid
- Provide sources of additional information and support.
- Patient information on infertility is available on:
- The NHS website (www.nhs.uk).
- The National Institute for Health and Care Excellence website (www.nice.org.uk).
- The British Fertility Society website (britishfertilitysociety.org.uk).
- Patient support is available from the following charities:
- The British Infertility Counselling Association (www.bica.net).
- Fertility Network UK (fertilitynetworkuk.org).
- The Human Fertilisation and Embryology Authority (www.hfea.gov.uk) provides information on In vitro fertilisation (IVF), clinics, and other fertility treatments from the UK government fertility regulator.
- The NHS website provides an information guide, trying for a baby, to explain how a woman can prepare for a pregnancy, how conception occurs, and how she and her partner can improve her chances of getting pregnant.
- Patient information on infertility is available on:
Basis for recommendation
These recommendations are based largely on the National Institute for Health and Care Excellence (NICE) guideline Fertility problems: assessment and treatment [NICE, 2017a]. The recommendations on obesity are also based on the American Society for Reproductive Medicine (ASRM) Practice Committee report Obesity and reproduction: a committee opinion [ASRM, 2021]. The recommendations on alcohol intake are also based on the UK Chief Medical Officers' Low Risk Drinking Guidelines 2016 [DH, 2016] and on a meta-analysis of semen quality and alcohol intake [Ricci, 2017].
General lifestyle advice
- A Cochrane systematic review assessed the safety and effectiveness of preconception lifestyle advice on fertility outcomes and lifestyle behavioural changes for people with infertility [Boedt, 2021].
- The authors concluded that the review does not provide clear guidance for clinical practice in this area. However, it does highlight the need for high-quality RCTs to investigate preconception lifestyle advice on a combination of topics and to assess relevant effectiveness and safety outcomes in men and women with infertility.
What initial investigations should I arrange in a woman?
Investigate both partners simultaneously to categorize the cause of infertility. Start investigations in couples who have not conceived after 1 year of regular (every 2–3 days) unprotected sexual intercourse. Offer investigations earlier than 1 year to couples identified as less likely to conceive. Early investigations may be prompted by the same factors that prompt early referral.
- Measure mid-luteal phase progesterone in all women to confirm ovulation.
- Offer a blood test to measure serum progesterone in the mid-luteal phase of the cycle (day 21 of a 28-day cycle) even if the woman has regular menstrual cycles.
- Screen for chlamydia.
- Before undergoing uterine instrumentation, women should be offered screening for Chlamydia trachomatis using an appropriately sensitive technique.
- If the result is positive, the woman and her sexual partner(s) should be referred for appropriate management with treatment and contact tracing.
- Prophylactic antibiotics should be considered before uterine instrumentation if screening has not been done.
- See the section on Testing to confirm the diagnosis in the CKS topic on Chlamydia - uncomplicated genital for more information.
- The following additional tests may be needed:
- Serum progesterone (in women with prolonged irregular menstrual cycles) — depending on the timing of menstrual periods, serum progesterone may need to be measured later (for example, on day 28 of a 35-day cycle) to confirm ovulation and repeated weekly after that until the next menstrual cycle starts.
- Gonadotrophin measurement (in women with irregular menstrual cycles) — gonadotrophin (follicle-stimulating hormone and luteinizing hormone) measurements are of value in women with anovulation or oligo-ovulation. They can be used to identify ovulation disorders.
- Thyroid function tests (in women with symptoms of thyroid disease).
- Prolactin measurement (in women with symptoms of an ovulatory disorder [for example, polycystic ovary syndrome], galactorrhoea, or a suspected pituitary tumour).
- The following investigations are not recommended:
- Endometrial biopsy — there is no evidence that medical treatment of luteal phase defects improves pregnancy rates.
- Basal body temperature charts — they do not reliably predict ovulation.
- Use of ovulation predictor kits — there is no evidence that attempts to time sexual intercourse to the menstrual cycle result in improved conception rates. Furthermore, there is evidence that the use of these kits causes stress.
- Postcoital testing of cervical mucus — has no predictive value for pregnancy rates.
Basis for recommendation
These recommendations are based on the National Institute for Health and Care Excellence (NICE) guideline Fertility problems: assessment and treatment [NICE, 2017a] and the European Association of Urology (EAU) guideline on Sexual and Reproductive Health [EAU, 2023].
What initial investigations should I arrange in a man?
Investigate both partners simultaneously to categorize the cause of infertility. Start investigations in couples who have not conceived after 1 year of regular (every 2–3 days) unprotected sexual intercourse. Offer investigations earlier than 1 year to couples identified as less likely to conceive. Early investigations may be prompted by the same factors that prompt early referral.
- Arrange for semen analysis.
- Give clear written and verbal instructions concerning the collection of the semen sample:
- The specimen should be collected by masturbation; ejaculated into a clean, wide-mouthed container made of plastic from a batch that has been confirmed to be non-toxic for spermatozoa; and protected from extremes of temperature (below 20°C or above 37°C).
- The specimen should be collected after a minimum of 2 days and a maximum of 7 days of sexual abstinence.
- Ideally, the sample should be collected in a private room near the laboratory to avoid exposure of the semen sample to fluctuations in temperature and to control the time between collection and analysis.
- If the man, for any reason, must collect the sample at another place, the specimen container should be kept close to the body under the clothes (for example, in the armpit) during transport and should be delivered to the laboratory, preferably within 30 minutes after collection and at least no longer than 50 minutes after collection.
- Emphasize that the semen sample needs to be complete and that the man should report any loss of any fraction of the sample.
- The results should be interpreted using the most recent World Health Organization (WHO) reference values for human semen characteristics.
- 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, for example, if the man is very anxious about 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), repeat the test within 2–4 weeks.
- If the repeat test result is normal, regard the semen as normal; no further testing is required.
- Refer men with two abnormal semen examination results to secondary care for further assessment.
- Give clear written and verbal instructions concerning the collection of the semen sample:
- Screen for chlamydia.
- See the section on Testing to confirm the diagnosis in the CKS topic on Chlamydia - uncomplicated genital for more information.
- The following tests are not recommended:
- Screening for antisperm antibodies — there is no evidence of effective treatment to improve fertility.
Basis for recommendation
These recommendations are based largely on the National Institute for Health and Care Excellence (NICE) guideline Fertility problems: assessment and treatment [NICE, 2017a], the European Association of Urology (EAU) guideline on Sexual and Reproductive Health [EAU, 2023], and World Health Organization (WHO) publication WHO laboratory manual for the examination and processing of human semen (Sixth Edition) [WHO, 2021].
Investigating both partners simultaneously
- The EAU advises that parallel assessment of the fertility status should be included during the diagnosis and management of the infertile man, since this might determine decision-making in terms of timing and therapeutic strategies, for example, the choice between assisted reproductive technology or surgical intervention.
When should I refer a couple presenting with infertility?
Referral criteria for people presenting with infertility may vary between health authorities. Refer to local guidelines.
- In women younger than 36 years of age:
- In general, consider referring the couple for additional investigations and management if history, examination, and investigations are normal in both partners and the couple has not conceived after 1 year.
- Consider earlier referral if the following factors are present:
- In women:
- Age 36 years and older (refer after 6 months).
- Amenorrhoea or oligomenorrhoea.
- Previous abdominal or pelvic surgery.
- Previous pelvic inflammatory disease.
- Previous sexually transmitted infection (STI).
- Abnormal pelvic examination.
- Known reason for infertility (for example, prior treatment for cancer).
- In men:
- Previous genital pathology.
- Previous urogenital surgery.
- Previous STI.
- Varicocele.
- Significant systemic illness.
- Abnormal genital examination.
- Two abnormal semen examination results.
- Known reason for infertility (for example, prior treatment for cancer).
- In women:
- Ensure that the couple is offered counselling before, during, and after investigation and treatment regardless of the outcome of these procedures.
- Psychological stress (for both the woman and the man) may be caused by infertility as well as the investigation and treatment.
- 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).
Additional investigations and management
- Following referral, additional investigations may be undertaken.
- Investigations in women normally include tubal patency tests.
- Women who are not known to have comorbid conditions (such as pelvic inflammatory disease, endometriosis, or previous ectopic pregnancy) are offered hysterosalpingography or hysterosalpingo-contrast ultrasonography.
- Women thought to have comorbid conditions are offered diagnostic laparoscopy and dye so that tubal and other pelvic abnormalities can be assessed simultaneously.
- Investigations in men may 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.
- Investigations in women normally include tubal patency tests.
- Fertility treatment falls into 3 main types:
- Medical treatment to restore fertility.
- Clomifene (an anti-oestrogen drug) is an effective treatment for anovulation and may be used in selected women.
- Gonadotrophins may be offered to women with clomifene-resistant anovulatory infertility. 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.
- Surgical treatment to restore fertility. This includes:
- Tubal microsurgery in women with mild tubal disease — tubal catheterization or cannulation improves the chance of pregnancy in women with proximal tubal obstruction.
- Surgical ablation, or resection of endometriosis plus laparoscopic adhesiolysis in women with endometriosis.
- Surgical correction of epididymal blockage in men with obstructive azoospermia — this is likely to restore patency of the duct and improve fertility.
- Assisted reproduction techniques (any treatment that deals with means of conception other than vaginal intercourse). These include:
- 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 (oral anti-oestrogens or gonadotrophins) might be given (stimulated IUI) to maximize pregnancy rates.
- In vitro fertilization (IVF) — involves retrieval of one or more ova combined with sperm and incubated for 2–3 days; the resultant embryo is then injected into the uterus via the cervix. This method is suitable for women who have blocked fallopian tubes, men with a minor degree of subfertility, and couples who have been diagnosed with unexplained infertility or have been unsuccessful with other techniques (such as ovulation induction or IUI).
- Intracytoplasmic sperm injection (ICSI) — involves injecting an individual sperm directly into the ovum to bypass natural barriers that prevent fertilization. The embryo is then transferred into the uterus. This method is suitable when the man has a very low sperm count or problems maintaining an erection and ejaculation (such as diabetes or spinal cord injury).
- Donor insemination — involves insemination of sperm, from a donor, into a woman via her vagina into the cervical canal or into the uterus itself (IUI). This method 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. It is also considered in couples where there is no male partner.
- Oocyte donation — involves stimulation of the donor's ovaries and collection of ova. The donated ova 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. This method is considered for women with ovarian failure (premature or after radiotherapy or chemotherapy); those with 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 (embryo donation).
- Medical treatment to restore fertility.
- Further information on many aspects of infertility treatments can be found on the Human Fertilisation and Embryology Authority (HFEA) website (www.hfea.gov.uk).
- The HFEA 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:
- Information on potential treatments and their success rate.
- Detailed information on all UK fertility clinics, including the services they provide and their success rates.
Basis for recommendation
These recommendations are based on the National Institute for Health and Care Excellence (NICE) guideline Fertility problems: assessment and treatment [NICE, 2017a] and The American College of Obstetricians and Gynecologists Committee on Gynecologic Practice and The Practice Committee of the American Society for Reproductive Medicine (ACOG/ASRM) expert opinion Female age-related fertility decline [ACOG/ASRM, 2014].
How should I manage complications that may occur after assisted conception?
- Ovarian hyperstimulation syndrome (OHSS) is a potentially life-threatening complication of superovulation.
- Symptoms and signs include:
- Mild — abdominal bloating and mild abdominal pain.
- Moderate — nausea and vomiting and increased abdominal discomfort.
- Severe — oliguria, generalized oedema, abdominal pain and/or distension (caused by enlarged ovaries and acute ascites), and hydrothorax (occasionally).
- Critical — oligo/anuria, tense ascites or large hydrothorax, thromboembolism, and acute respiratory distress syndrome.
- If a woman presents with these symptoms and signs:
- Consider alternative diagnoses, such as complications of an ovarian cyst (torsion, haemorrhage), pelvic infection or abscess, intra-abdominal haemorrhage, ectopic pregnancy, bowel perforation, or appendicitis.
- If OHSS is suspected, seek urgent advice from the specialist unit. The severity of OHSS can worsen over time, and even initially mild presentations should be kept under review.
- Symptoms and signs include:
- Other possible complications that may occur after assisted conception include:
- Ectopic pregnancy — see the CKS topic on Ectopic pregnancy for more information on when to suspect an ectopic pregnancy and how to manage the woman.
- Pelvic infection — see the CKS topic on Pelvic inflammatory disease for management information.
- Multiple pregnancy — the National Institute for Health and Care Excellence (NICE) guideline on Twin and triplet pregnancy covers the care that should be offered to women with a twin or triplet pregnancy in addition to the routine care that is offered to all women during pregnancy.
Basis for recommendation
These recommendations are based on the National Institute for Health and Care Excellence (NICE) guideline Fertility problems: assessment and treatment (full guideline) [NICE, 2017a] and the Royal College of Obstetricians and Gynaecologists (RCOG) guideline The management of ovarian hyperstimulation syndrome [RCOG, 2016].
Supporting evidence
The recommendations in this CKS topic are based largely on the National Institute for Health and Care Excellence (NICE) guideline Fertility problems: assessment and treatment [NICE, 2017a], the European Association of Urology (EAU) guideline on Sexual and Reproductive Health [EAU, 2023] and the British Medical Journal Best Practice guides Infertility in women [BMJ, 2023] and Male factor infertility [BMJ, 2022]. For a detailed discussion of the evidence NICE used to base their recommendations, see the full NICE guideline (available at www.nice.org.uk). The rationale for individual recommendations is outlined in the relevant basis for recommendation sections of the topic.
How this topic was developed
This section briefly describes the processes used in developing and updating this topic. Further details on the full process can be found in the About Us section and on the Clarity Informatics website.
Search strategy
Scope of search
A literature search was conducted for guidelines, systematic reviews and randomized controlled trials on primary care management of infertility.
Search dates
February 2018 - May 2023
Key search terms
Various combinations of searches were carried out. The terms listed below are the core search terms that were used for Medline.
- exp Fertility/, exp Infertility, Female/, exp Infertility/, exp Infertility, Male/, fertility.tw., infertility.tw., subfertility.tw., (fertility adj2 problem$).tw., (reproduct$ adj2 problem$).tw., (reproduct$ adj2 dysfunction).tw., (involuntary adj childlessness).tw., (delay$ adj2 conception).tw.
Sources of guidelines
- National Institute for Health and Care Excellence (NICE)
- Scottish Intercollegiate Guidelines Network (SIGN)
- Royal College of Physicians
- Royal College of General Practitioners
- Royal College of Nursing
- NICE Evidence
- World Health Organization
- Guidelines International Network
- TRIP database
- Agency for Healthcare Research and Quality
- National Health and Medical Research Council (Australia)
- Royal Australian College of General Practitioners
- British Columbia Medical Association
- Canadian Medical Association
- Alberta Medical Association
- Michigan Quality Improvement Consortium
- Singapore Ministry of Health
- National Resource for Infection Control
- RefHELP NHS Lothian Referral Guidelines
- Medline (with guideline filter)
- Driver and Vehicle Licensing Agency
- NHS Health at Work (occupational health practice)
Sources of systematic reviews and meta-analyses
- The Cochrane Library:
- Systematic reviews
- Protocols
- Database of Abstracts of Reviews of Effects
- Medline (with systematic review filter)
- EMBASE (with systematic review filter)
Sources of health technology assessments and economic appraisals
- NIHR Health Technology Assessment programme
- The Cochrane Library:
- NHS Economic Evaluations
- Health Technology Assessments
- Canadian Agency for Drugs and Technologies in Health
- International Network of Agencies for Health Technology Assessment
Sources of randomized controlled trials
- The Cochrane Library:
- Central Register of Controlled Trials
- Medline (with randomized controlled trial filter)
- EMBASE (with randomized controlled trial filter)
Sources of evidence based reviews and evidence summaries
Sources of national policy
- Department of Health
- Health Management Information Consortium (HMIC)
Patient experiences
Sources of medicines information
The following sources are used by CKS pharmacists and are not necessarily searched by CKS information specialists for all topics. Some of these resources are not freely available and require subscriptions to access content.
Stakeholder engagement
Our policy
The external review process is an essential part of CKS topic development. Consultation with a wide range of stakeholders provides quality assurance of the topic in terms of:
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Our policy
Scoping a literature search, and reviewing the evidence for CKS is a methodical and systematic process that is carried out by the lead clinical author for each topic. Relevant evidence is gathered in order that the clinical author can make fully informed decisions and recommendations. It is important to note that some evidence may be excluded for a variety of reasons. These reasons may be applied across all CKS topics or may be specific to a given topic.
Studies identified during literature searches are reviewed to identify the most appropriate information to author a CKS topic, ensuring any recommendations are based on the best evidence. We use the principles of the GRADE and PICOT approaches to assess the quality of published research. We use the principles of AGREE II to assess the quality of published guidelines.
Standard exclusions for scoping literature:
- Animal studies
- Original research is not written in English
Possible exclusions for reviewed literature:
- Sample size too small or study underpowered
- Bias evident or promotional literature
- Population not relevant
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Organizational, behavioural and financial barriers
Our policy
The CKS literature searches take into consideration the following concepts, which are discussed at the initial scoping of the topic.
- Feasibility
- Studies are selected depending on whether the intervention under investigation is available in the NHS and can be practically and safely undertaken in primary care.
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We also evaluate and include evidence from NICE accredited sources which provide economic evaluations of recommendations, such as NICE guidelines. When a recommended action may not be possible because of resource constraints, this is explicitly indicated to healthcare professionals by the wording of the CKS recommendation.
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Although particular attention is given to interests that could result in financial gains or losses for the individual, competing interests may also arise from academic competition or for political, personal, religious, and reputational reasons. An individual is not obliged to seek out knowledge of work done for, or on behalf of, the healthcare industry within the departments for which they are responsible if they would not normally expect to be informed.
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Any individual (or organization) involved in developing, reviewing, or commenting on clinical content, particularly the recommendations should declare competing interests. This includes the authoring team members, expert advisers, external reviewers of draft topics, individuals providing feedback on published topics, and Editorial Steering Group members. Declarations of interest are completed annually for authoring team and editorial steering group members, and are completed at the start of the topic update and development process for external stakeholders.
Competing interests declared for this topic:
None.
References
- ACOG/ASRM (2014) Female age-related fertility decline. Committee Opinion No. 589. Fertility and Sterility 101(3), 633-634. [Abstract] [Free Full-text]
- Ambildhuke. K., Pajai. S., Chimegave. A., et al. (2022) Review of Tubal Factors Affecting Fertility and its Management. Cureus 14(11), e30990. [Free Full-text]
- American Society for Reproductive Medicine (2004) Current evaluation of amenorrhea. Fertility and Sterility. 82(1), 266-272. [Abstract]
- American Society for Reproductive Medicine (2021) Obesity and reproduction: a committee opinion. Fertility and Sterility 116(5), 1266-1285. [Abstract] [Free Full-text]
- BMJ Best practice (2022) Male factor infertility. BMJ Publishing Group. http://www.bestpractice.bmj.com
- BMJ Best Practice (2023) Infertility in women. BMJ Publishing Group. http://bestpractice.bmj.com
- BNF (2023) British National Formulary. National Institute for Health and Care Excellence. https://bnf.nice.org.uk
- Boedt, T., Vanhove, A. C., Vercoe, M. A., et al. (2021) Preconception lifestyle advice for people with infertility (Cochrane Review/Cochrane Intervention Protocol). Issue 04. John Wiley & Sons, Ltd. http://www.cochranelibrary.com [Free Full-text]
- DH (2016) UK Chief Medical Officers' low risk drinking guidelines. Department of Health. http://www.gov.uk [Free Full-text]
- Dun, E. C. and Nezhat, C. H. (2012) Tubal factor infertility: diagnosis and management in the era of assisted reproductive technology. Obstetrics and gynecology clinics of North America, 39(4), 551–566 39(4), 551-566. [Abstract] [Free Full-text]
- EAU (2023) Sexual and Reproductive Health. European Association of Urology. http://uroweb.org [Free Full-text]
- Freytag, D., Günther, V., Maass, N. and Alkatout, I. (2021) Uterine Fibroids and Infertility. Diagnostics (Basel) 11(8), 1455. [Abstract] [Free Full-text]
- Gnoth, C., Godehardt, E., Frank-Herrmann, P., et al. (2005) Definition and prevalence of subfertility and infertility. Human Reproduction 20(5), 1144-1147. [Abstract]
- Hackett, G., Kirby, M., Wylie, K., et al. (2018) British Society for Sexual Medicine Guidelines on the Management of Erectile Dysfunction in Men-2017. Journal of Sexual Medicine, 1-28. [Abstract]
- HFEA (2021) Fertility treatment 2019: trends and figures. Human Fertilisation and Embryology Authority. http://www.hfea.gov.uk [Free Full-text]
- Janssen, N.M. and Genta, M.S. (2000) The effects of immunosuppressive and anti-inflammatory medications on fertility, pregnancy, and lactation. Archives of Internal Medicine 160(5), 610-619. [Abstract]
- Kirk. E., Bottomley. C., Bourne. T. (2014) Diagnosing ectopic pregnancy and current concepts in the management of pregnancy of unknown location. Human Reproduction Update 20(2), 250-261. [Abstract] [Free Full-text]
- Mascarenhas, M. N., Flaxman, S. R., Boerma, T., et al. (2012) National, regional, and global trends in infertility prevalence since 1990: a systematic analysis of 277 health surveys. PLoS Medicine 9(12), e1001356. [Abstract] [Free Full-text]
- NICE (2014) Fertility problems. Quality standard [QS73]. National Institute for Health and Care Excellence. http://www.nice.org.uk [Free Full-text]
- NICE (2017a) Fertility problems: assessment and treatment. National Institute for Health and Care Excellence. http://www.nice.org.uk [Free Full-text]
- NICE (2017b) Endometriosis: diagnosis and management. National Institute for Health and Care Excellence. http://www.nice.org.uk [Free Full-text]
- Panelli, D., Phillips, C. and Brady, P. (2015) Incidence, diagnosis and management of tubal and nontubal ectopic pregnancies: a review. Fertility Research And Practice 1, 15. [Free Full-text]
- Perkins, K.M., Boulet, S.L., Kissin, D.M. and Jamieson, D.J. (2015) Risk of ectopic pregnancy associated with assisted reproductive technology in the United States, 2001-2011. Obstetrics And Gynecology 125(1), 70-78. [Abstract] [Free Full-text]
- RCOG (2016) The Management of Ovarian Hyperstimulation Syndrome. Royal College of Obstetricians and Gynaecologists. http://www.rcog.org.uk [Free Full-text]
- Ricci, E., Al Beitawi, S., Cipriani, S., et al. (2017) Semen quality and alcohol intake: a systematic review and meta-analysis. Reproductive Biomedicine Online 34(1), 38-47. [Abstract]
- Santos-Ribeiro, S., Tournaye, H. and Polyzos, N.P. (2016) Trends in ectopic pregnancy rates following assisted reproductive technologies in the UK: a 12-year nationwide analysis including 160 000 pregnancies. Human Reproduction 31(2), 393-402. [Abstract] [Free Full-text]
- Skalkidou, A., Sergentanis, T.N., Gialamas, S.P., et al. (2017) Risk of endometrial cancer in women treated with ovary-stimulating drugs for subfertility (Cochrane Review). Issue 3. John Wiley & Sons, Ltd. http://www.cochranelibrary.com [Free Full-text]
- WHO (2021) WHO laboratory manual for the examination and processing of human semen. World Health Organization. http://www.who.int [Free Full-text]
- WHO (2023) Infertility. World Health Organization. http://www.who.int [Free Full-text]