51 Nick Raine‐Fenning1,2 1 Division of Child Health, Obstetrics and Gynaecology, School of Medicine, University of Nottingham, Nottingham, UK 2 Nuture Fertility, The Fertility Partnership, Nottingham, UK Infertility is the second most common reason for women of childbearing age to visit their general practitioner. As approximately one in seven heterosexual couples have problems conceiving, infertility affects around 3.5 million people in the UK. There has been a small but steady increase in the prevalence of fertility problems and a greater proportion of people now seek help for such problems. Infertility is associated with significant psychological morbidity for both partners and, where there is underlying pathology, physical morbidity too both through the conditions associated with infertility and their associated treatment. If left untreated, infertility can result in stress, depression and emotional distress. However, investigation and treatment is also associated with psychological and physical trauma that is often exacerbated by the length of treatment and the multidisciplinary approach that is involved. Infertility is regarded as an upsetting and difficult life experience for some women, resulting in anxiety and depression comparable to those associated with other serious medical conditions such as heart disease, cancer, hypertension and HIV infection. Infertility is rarely absolute. Unless the male partner has suffered testicular failure and/or does not produce sperm or the woman is menopausal and/or does not have a uterus, conception is usually still possible. It is the chance of conception that really defines fertility and this is very much dependent on how long the couple have been trying, female age and the underlying cause. Subfertility is therefore a more appropriate term for most couples. It is defined by the duration a couple have been trying to conceive without success after which formal investigation is justified and treatment, where indicated, implemented. A woman of reproductive age, who has not conceived after 1 year of unprotected vaginal sexual intercourse, in the absence of any known cause of infertility, should be offered further clinical assessment and investigation along with her partner. Single women and same‐sex couples should be offered formal investigation after six cycles of unsuccessful artificial insemination. Couples should be referred earlier where the woman is 36 years or over or if there is a known clinical cause of infertility or a history of predisposing factors for infertility, including amenorrhoea, oligomenorrhoea, pelvic inflammatory disease or undescended testes. The main causes of infertility in the UK are shown in Table 51.1. Male factor is now the most common cause of primary subfertility closely followed by ovulatory disorders. In about 40% of cases, fertility disorders are found in both the man and the woman. Tubal disease is the most common cause of secondary infertility. Table 51.1 Causes of infertility in the UK. There are no identifiable factors in one in four couples. This does not mean there is no underlying problem and a significant proportion of women will be shown to have low ovarian reserve or other problems if they go on to have assisted conception treatment, which is not only an effective treatment but also provides an informative assessment. The World Health Organization (WHO) categorizes ovulation disorders into three groups based on serum measurements of follicle stimulating hormone (FSH), luteinizing hormone (LH) and estradiol. Group I ovulation disorders (10%) are caused by hypothalamic–pituitary dysfunction or failure, which results in hypo‐oestrogenic amenorrhoea. They are characterized by low gonadotrophins, a normal prolactin and low oestrogen levels. Three conditions are included: hypothalamic amenorrhoea, hypogonadotrophic hypogonadism and hypopituitarism. Hypothalamic amenorrhoea is characterized by secondary amenorrhea with low or normal gonadotrophins and hypo‐oestrogenism. It is often caused by excessive exercise, lean body mass, weight loss, severe dietary restriction, anorexia or bulimia nervosa or chronic illness. The treatment must be aimed at the underlying cause. Hypogonadotrophic hypogonadism is caused by gonadotrophin‐releasing hormone (GnRH) deficiency. Kallmann’s syndrome is congenital and thought to result from the disruption of embryonic migration of GnRH neurones. Acquired causes include central nervous system (CNS) or pituitary tumours, infiltrative diseases, infection, brain/pituitary radiation, pituitary apoplexy, head trauma, and drugs such as glucocorticoids, narcotics and chemotherapy. Hypopituitarism is typically caused by a pituitary tumour or its treatment by surgery and/or radiotherapy but may be due to extra‐pituitary tumours, sarcoidosis, haemochromatosis and Sheehan’s syndrome. The clinical manifestations depend on the cause and both the type and degree of hormonal insufficiency. Patients may be asymptomatic or present with symptoms related to hormone deficiency or a space‐occupying lesion. Group II ovulation disorders (85%) are defined as dysfunction of the hypothalamic–pituitary–ovarian axis. They are characterized by normal oestrogen levels, normal or low FSH levels, and normal or high LH levels. This group of disorders results in anovulatory oligomenorrhoea, predominantly involving women with polycystic ovaries, which are present in about 80–90% of women with oligomenorrhoea and 30% of women with amenorrhoea. Women with polycystic ovaries often have associated clinical symptoms such hyperandrogenism presenting as hirsutism, acne or androgen‐dependent alopecia. Group III ovulation disorders (5%) are caused by ovarian failure, or ovarian insufficiency as it is now called. They are characterized by raised levels of FSH and LH and a low oestrogen. Ovarian insufficiency is often unexplained but may be associated with gonadal dysgenesis, including Turner’s syndrome, or be subsequent to bilateral oophorectomy or treatment with chemotherapy or radiotherapy. The incidence of tubal disease is very dependent on whether the woman has primary or secondary infertility. Primary infertility refers to a woman who has never conceived whilst secondary infertility relates to any previous pregnancy irrespective of whether that resulted in a live birth or not. Women with secondary infertility, especially those who have had an ectopic pregnancy, have a much higher incidence of tubal disease. Uterine and/or peritoneal disorders are the least common cause of infertility but this may, in part, relate to the difficulty in identifying and defining pathology. Endometriosis does not necessarily cause infertility but there is an association with fertility problems, although the cause is not fully established. Even with severe endometriosis, natural conception is still possible and up to 70% of women with mild to moderate endometriosis will conceive without treatment. However, up to 30–50% of women with endometriosis may experience infertility irrespective of the severity of the disease and infertile women are six to eight times more likely to have endometriosis than fertile women. Endometriosis is thought to influence fertility in several ways, including distorted pelvic anatomy, adhesions, pelvic inflammation, altered immune system functioning and impaired implantation. Women with endometriosis may also have endocrine and ovulatory disorders, including luteinized unruptured follicle syndrome, impaired folliculogenesis, luteal phase defect, and premature or multiple LH surges. Adhesions are reported to be the leading cause of secondary infertility in women and are thought to be responsible for approximately 22% (15–40%) of all infertility cases [1]. Adhesions cause infertility by distorting adnexal anatomy and the tubo‐ovarian relationship and/or by preventing or impairing the ability of the fallopian tube to pick up the oocyte at ovulation and then transport it. This may be due to the ovary being encapsulated by adhesions or by adhesions that limit tubal/fimbrial movement. The American Fertility Society classification for adnexal adhesions [2] can be used to quantify the severity of the adhesions, which is predictive of term pregnancy rates. Of patients who have undergone major gynaecological surgery, 60–90% will develop adhesions. Fibroids have been associated with infertility. Intra‐cavity and intramural fibroids are thought to exert a mechanical effect leading to cavity distortion. However, recent data suggest that fibroids may still have a negative effect on fertility even if the cavity appears hysteroscopically normal due to effects on uterine blood flow, impaired embryo implantation or abnormal sperm migration. Despite this, many women with relatively large fibroids conceive without difficulty. Intrauterine adhesions reduce conception. When associated with amenorrhoea, they are referred to as Asherman’s syndrome. The adhesions lead to partial or complete obliteration of the uterine cavity and/or the cervical canal, resulting in menstrual abnormalities and/or recurrent pregnancy loss. Secondary infertility is seen in 43% of women with intrauterine adhesions and may be due to obstruction of sperm into the cervix or prevention of embryo migration and/or implantation. In the UK, seminal fluid analysis is found to be the only cause of infertility in about 20% of couples, and is a contributory factor in a further 25% of couples. However, impaired semen quality, azoospermia and inadequate coitus are contributing factors in nearly 50% of infertile couples. Abnormal semen characteristics are usually idiopathic and occur in 26% of infertile men. The spermatozoa are mostly dysfunctional and unable to fertilize an oocyte but a proportion are often functionally normal. Sperm function may also be impaired by anti‐sperm antibodies. Azoospermia may be due to hypothalamic–pituitary failure, primary testicular failure (non‐obstructive azoospermia) or obstruction of the genital tract (obstructive azoospermia). Primary testicular failure is the most common cause of male infertility due to azoospermia or severe oligozoospermia and may be the result of cryptorchidism, testicular torsion or trauma, orchitis, chromosome disorders (Klinefelter’s syndrome, Y‐chromosome microdeletions), systemic disease, or follow radiotherapy or chemotherapy, although in the majority of cases (66%) the cause is unknown. Obstructive azoospermia is uncommon, with a prevalence of less than 2%. It is often associated with congenital bilateral absence of vas deferens, which itself is commonly associated with cystic fibrosis mutations or renal tract abnormality. Anejaculation and retrograde ejaculation are relatively uncommon but may result from spinal cord injury, prostatectomy, retroperitoneal lymph node dissection, diabetes mellitus, transverse myelitis, multiple sclerosis, or be of psychogenic origin. Varicoceles are more common in men with abnormal semen than men with normal semen (25.4% vs. 11.7%) and are associated with decreased ipsilateral testicular volume. It is unclear if, or why, varicoceles impair fertility and spermatogenesis but any effect is likely to be due to elevated scrotal temperature and impaired semen quality. Given the various causes and presentations of infertility, it is essential that patients are managed as individuals from their initial referral through to their ultimate treatment. Investigations must be directed on the basis of a critical consideration of clinical features and used to inform patient management and counselling. All healthcare practitioners working in fertility must therefore have a comprehensive understanding of tests and treatments and be able to give patients and couples advice on their personal chances of natural and/or assisted conception so that they can make an informed decision as to how to proceed. For the remainder of this chapter I shall refer to the typical management of a heterosexual couple for the simple reason that this reflects most referrals to secondary care. However, same‐sex couples and single women are increasingly seeking advice and treatment and their assessment and management, save the obvious need for donor sperm, is comparable in most instances. Please substitute ‘no partner’ or ‘second female partner’ where relevant when referring to your own clinical practice. Couples who experience problems in conceiving should be seen together because both partners are affected by decisions surrounding investigation and treatment. Furthermore, women have been shown to be more satisfied when seen with their partners. The consultation should start with an understanding of the duration of infertility and the age of the woman or couple. It is important to specifically enquire about sexual history, including the frequency and timing of intercourse. Without this information it is not possible to define ‘subfertility’ and therefore the need for investigation or treatment. Other key factors that influence assessment and treatment include previous pregnancies in the female partner and whether the couple have children together or through a previous relationship. The former influences the tests offered to the woman and her prognosis, while the presence of children invariably has implications for funding. It is also important to assess the couple’s lifestyle as this impacts on their chance of natural conception and influences the success of treatment. Finally, consider any religious or ethical objections the couple may have in respect of their potential treatment. This information is often volunteered and does not require direct questioning. Primary care physicians generally have a good understanding of fertility and in most cases will have performed some tests prior to, or in conjunction with, their referral. Make sure these are available and confirm the couple are aware of the results. Missing a diagnosis of severe oligospermia or azoospermia or failing to realize this until the end of the consultation will mean that much of the conversation was meaningless and will not reassure the couple. Make sure you gather all clinically relevant information and any test results before you see the couple and share these with them at the appropriate time depending on what they show and what the couple know. It is, of course, important to finish by taking a general history from both partners to establish their current and past health, any medications they are using and any known allergies. Having already ascertained the woman’s age and parity, the history should now focus on identifying or excluding an underlying cause of subfertility. Cycle regularity gives an indication of ovulation. Most women (95%) who menstruate every 23–35 days are ovulating. Those with irregular menstrual cycles or who are amenorrhoeic are not ovulating or, if they are, ovulate infrequently. Women with severe premenstrual pain are more likely to have endometriosis or chronic pelvic infection. These conditions may also be associated with chronic pelvic pain and/or deep dyspareunia. All of these symptoms are consistent with pelvic pathology and, in most cases, warrant pelvic and ultrasound examination followed by laparoscopy. Heavy periods may reflect dysfunctional uterine bleeding but could be due to fibroids, adenomyosis, endometriosis or endometrial polyps, all of which may impair implantation. Similarly, intermenstrual or post‐coital bleeding could be hormonal or reflect local or endometrial pathology. Again, these symptoms would be an indication for pelvic and ultrasound examination possibly followed by hysteroscopy and/or laparoscopy depending on the findings. The history should then focus on risk factors for tubal disease and abdomino‐pelvic adhesions. This influences the test of tubal patency that you will offer. Tubal disease and adhesions that may impair the tubo‐ovarian relationship are more common after pelvic infection, sexually transmitted infection, abdomino‐pelvic surgery, particularly that involving the pelvic organs, and ectopic pregnancy irrespective of how it was managed. They may also occur in women with endometriosis. The male history is often redundant, as most couples will be referred with the results of a seminal fluid analysis. Providing this is normal and shows a good number of motile, morphologically normal sperm, there is little value in taking a detailed history from the male partner. However, a specific enquiry regarding any psychosexual problems including erectile or ejaculatory dysfunction is essential. For men who have not had a seminal fluid analysis or those who have been shown to have abnormal results, a more detailed history is indicated. A history of problems with testicular descent, puberty, trauma or surgery, mumps, and past local infection or inflammation may provide a reason for a low sperm count or impaired motility but do not influence current management. Questions about current health, medications and lifestyle are more relevant as they can be modified where necessary in most cases. No cause will be identified in approximately 30–50% of men with poor semen quality. Just like the clinical history, examination of the male and female partner is often unremarkable. It may not even be indicated in some cases and should only be performed if it will influence management. General inspection, both during the consultation and at examination, also provides an opportunity to consider lifestyle issues such as smoking and obesity, which may be readily evident. As a minimum, weight and body mass index (BMI) should be calculated and recorded. This influences management and has implications for funding. Where relevant, a general inspection should be conducted to look for signs of systemic disease, such as thyroid dysfunction, acromegaly and other endocrine disorders, and phenotypic abnormalities. Polycystic ovary syndrome (PCOS) and other causes of hyperandrogenism may manifest with acne and hirsutism. More rarely, insulin resistance may lead to acanthosis nigricans. Virilism can lead to male pattern baldness and clitoromegaly. Breast examination is often not indicated but when performed should include Tanner’s staging. Abdominal examination may reveal scars from previous abdominal surgery. Large pelvic masses including ovarian cysts and fibroids, palpable abdominally, clearly influence management and may militate against a laparoscopic approach if surgery is indicated. However, it is rare to find an unexpected mass or demonstrate abdominal tenderness. Pelvic examination should be considered for women with menstrual dysfunction. Inspection of the vagina and cervix may reveal local pathology that is responsible for irregular or post‐coital bleeding and therefore provides reassurance as this is unlikely to affect fertility or influence management. It also provides an opportunity to take swabs for microbiological assessment if there is a history of sexually transmitted infection or signs and symptoms of current infection. A cervical smear should not be performed opportunistically or if cervical pathology is evident; the latter requires referral for colposcopic examination. Bimanual examination can provide critical information that impacts on investigation and management. A fixed, tender, retroverted uterus is highly suggestive of adhesions and the presence of chronic pelvic inflammation or endometriosis. Such findings warrant an ultrasound scan and, in most cases, an operative laparoscopy with intention to treat any disease and divide any adhesions. In more severe cases, where nodules of endometriosis are visible or palpable or there is evidence of thickening and induration of the uterosacral ligaments, consideration should be given to pelvic MRI to assess the rectovaginal septum and exclude superficial or full‐thickness bowel involvement. Most men do not need to be examined, but where it is considered essential the key examination is that of the genital organs. The scrotum and its contents should be gently palpated to identify the vas deferens and exclude any masses or local pathology. The volume of each testicle should be assessed using an orchidometer and recorded. A prostate examination is rarely needed but if indicated is probably best performed by a urologist. People who experience fertility problems should be treated by a specialist team because this is likely to improve the effectiveness and efficiency of treatment and improves satisfaction. Serum FSH and LH should be checked in the early follicular phase between days 2 and 5 of the menstrual cycle. The levels of these hormones cannot be interpreted in the absence of serum estradiol and all three tests are needed to assess hypothalamic–pituitary–ovarian function. Most women have normal FSH, LH and estradiol levels. Low FSH and LH levels in conjunction with a low estradiol suggest hypogonadotrophic hypogonadism and type I anovulation. Thyroid function and prolactin should be checked along with other hormones depending on the clinical picture. Elevated serum LH or a raised LH/FSH ratio are no longer used to diagnose PCOS but may provide prognostic information so should be noted and recorded. An early follicular phase FSH level above 15 IU/L is very suggestive of impaired reserve whilst levels persistently above 30 IU/L are consistent with ovarian failure. The National Institute for Health and Care Excellence (NICE) [3] states that the FSH should be less than 9 IU/L and that levels above this cut‐off indicate impaired ovarian reserve. However, there are more accurate tests for ovarian reserve, namely antral follicle counts and serum anti‐Müllerian hormone (AMH) levels. These have been used to triage treatment as they provide some information about egg quality. However, this requires more research and, at present, there is insufficient evidence to preclude treatment or fast‐track patients on the basis of an ovarian reserve test. NICE suggests that a total antral follicle count of four or less, AMH level of 5.4 pmol/L or less, and FSH level above 8.9 IU/L are predictive of a low response. Age, although not an independent factor, must always be considered under such circumstances as many younger women conceive naturally or after treatment despite having seemingly poor ovarian reserve.At present, NICE suggests any of the three tests may be used but most fertility experts rely on antral follicle counts and serum AMH and not FSH unless the latter is significantly raised. Women with a regular cycle should have a mid‐luteal progesterone to confirm ovulation, but a day 21 progesterone is only relevant for women with a 28‐day cycle. There is little value in measuring serum progesterone in a women with amenorrhoea or oligomenorrhoea and it is better to assume anovulation. Thyroid function and prolactin should be checked under such circumstances along with tests to exclude PCOS. Thyroid function and prolactin are not indicated in women with a regular cycle unless there are associated clinical features. The use of basal body temperature charts to confirm ovulation does not reliably predict ovulation and is not recommended. Current rubella immunity should be checked and the woman immunized where necessary. Treatment should be delayed for at least 1 month during which time the couple should avoid intercourse or use appropriate contraception. Immunity should be rechecked and treatment then offered. Some women do not mount an immune response despite repeated immunization. Ultrasound is not indicated for all patients at initial assessment. It should be reserved for women with menstrual dysfunction, abdominal or pelvic pain, dysmenorrhoea or dyspareunia or where pathology is suspected on examination. In such cases, it may reveal fibroids (Fig. 51.1), adenomyosis, endometrial polyps, hydrosalpinges, or ovarian cysts including an endometrioma (Fig. 51.2), which provides a non‐invasive diagnosis of endometriosis. Fig. 51.1 Rendered three‐dimensional ultrasound scan showing a type 0 fibroid in the endometrial cavity. (See also colour plate 51.1) Fig. 51.2 Typical unilocular cyst with ‘ground glass’ contents consistent with an endometrioma. Ultrasound can also be used to diagnose the polycystic ovary and should be performed in any woman with an irregular cycle and/or hyperandrogenism, along with serum testosterone and sex hormone‐binding globulin to allow the free androgen index to be calculated. Women with high levels and those with signs of virilism should also have other androgens checked, including androstenedione and dehydroepiandrosterone sulfate as well as 17‐hydroxyprogesterone if relevant. Ultrasound can also be used to count the number of antral follicles, as outlined above, and provide an objective assessment of ovarian reserve but this is typically reserved for women considering assisted conception as it provides information about the likely response to controlled ovarian stimulation. The last investigation, but arguably one of the most important, is a test of tubal patency. The results of semen analysis and assessment of ovulation should be known before a test for tubal patency is performed. Hysterosalpingography (HSG) and laparoscopy with dye are the two most widely used methods to test for tubal pathology. Both are invasive procedures but HSG is less so. However, laparoscopy is more accurate and therefore the gold standard. When HSG suggests the presence of tubal obstruction this is confirmed by laparoscopy in only 38% of women. HSG is therefore not a reliable indicator of tubal occlusion. However, when HSG suggests that the tubes are patent, this will be confirmed at laparoscopy in 94% of women, and so is a reliable indicator of tubal patency. Women who are not known to have comorbidities should therefore be offered HSG to screen for tubal occlusion because this is a reliable test for ruling out tubal occlusion and it is less invasive than laparoscopy. Women who are thought to have comorbidities should be offered laparoscopy and dye so that tubal and other pelvic pathology can be assessed at the same time [3]. Comorbidities include pelvic inflammatory disease, previous ectopic pregnancy, pelvic adhesions, and endometriosis. Hysterosalpingo‐contrast ultrasonography is an alternative to HSG for women who are not known to have comorbidities since it is as effective but requires appropriate expertise. Chlamydial antibody testing is comparable to HSG in the diagnosis of tubal pathology [4]. Elevated titres of chlamydial antibodies are significantly associated with tubal disease, with higher titres predicting more severe tubal pathology. Negative titres do not justify avoidance of a test of tubal patency but support HSG as opposed to laparoscopy unless there are clinical features or a history suggestive of past sexually transmitted infection or pelvic inflammatory disease. Women undergoing HSG or any procedure requiring instrumentation of the uterus must be screened for Chlamydia or offered prophylactic antibiotics. Women who are screened and found to have chlamydial infection, and their sexual partners, should be referred for appropriate management with treatment and contact tracing before proceeding with further investigation. Women with no risk factors for tubal disease can be offered ovulation induction or intrauterine insemination without a test of tubal patency. Tubal assessment should be performed after three cycles if treatment has been unsuccessful. Women with a history suggestive of tubal damage should be offered tubal assessment before treatment. However, all women may choose to have a test of tubal patency prior to treatment if they prefer this approach. Women should not be offered hysteroscopy on its own as part of the initial investigation unless clinically indicated because the effectiveness of surgical treatment of uterine abnormalities on improving pregnancy rates has not been established. The routine use of post‐coital testing of cervical mucus in the investigation of fertility problems is no longer recommended because it has no predictive value on pregnancy rate. Semen analysis is the primary assessment tool for male fertility and outweighs all other tests, and should be compared with the WHO reference values [5] (Table 51.2). Variations in laboratory techniques significantly influence the reliability of the results of semen analysis and so the accuracy of the result is dependent on following accredited methods of analysis that should be regularly audited and subject to quality control. Screening for anti‐sperm antibodies should not be offered, as there is no evidence of effective treatment to improve fertility. Table 51.2 World Health Organization reference values for seminal fluid analysis. Oligospermia is used to describe seminal fluid analyses where the concentration of spermatozoa is below the lower reference limit. Asthenozoospermia and teratozoospermia refer to the percentage of progressively motile and morphologically normal spermatozoa, respectively. Oligoasthenoteratozoospermia therefore refers to seminal fluid analyses showing a low number of spermatozoa with reduced progressive motility and normal morphology. Azoospermia refers to the total absence of spermatozoa in the ejaculate. However, the reliability of the WHO reference values and their ability to predict conception has been questioned and, unless there is azoospermia, the predictive value of subnormal semen variables is limited. No functional test has yet been established that can unequivocally predict the fertilizing capacity of spermatozoa, including sperm function tests such as computer‐assisted semen analysis. If the result of the first semen analysis is abnormal it should be repeated. The repeat test should be undertaken 3 months after the initial analysis to allow for a cycle of spermatogenesis unless there is azoospermia or severe oligozoospermia, when it should be repeated as soon as reasonably possible. This is important because a single‐sample analysis will falsely identify about 10% of men as abnormal. Repeating the test reduces this to 2%. Male infertility due to severe oligozoospermia and azoospermia has been associated with a number of genetic factors, including numerical and structural chromosomal abnormalities, microdeletions of the Y chromosomes and mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, commonly associated with congenital vas deferens abnormalities. Men with severe oligozoospermia and azoospermia should be offered genetic testing and counselling before undergoing fertility treatment. Men with azoospermia or severe oligozoospermia should should also have a full endocrine profile to exclude testicular failure or hypothalamic–pituitary–testicular dysfunction. As a minimum, it is essential to check serum levels of FSH, LH and testosterone along with thyroid function and prolactin. More detailed assessments may be needed depending on the result of these tests but should be performed in conjunction with an endocrinologist. Men with severe oligozoospermia should consider freezing sperm for subsequent use provided they have been shown to have an apparently normal karyotype. Choice is an integral part of any decision‐making process. Patients should have access to evidence‐based information that they can use to inform decisions regarding their care and treatment. Verbal information should be supplemented with written information or audio‐visual media and provided in a form that is accessible to people who have additional needs and those who do not speak or read English. The NICE quality standard [6] describes a concise set of statements that summarizes what the best possible care should comprise, states that previous children, sexual orientation and relationship status should not be a factor in determining eligibility for treatment, and that counselling should be available throughout treatment. People who are concerned that it is taking longer than expected to conceive should be given advice on the impact that lifestyle can have on their chances of getting pregnant. Both partners should be informed that the effects of caffeinated beverages (tea, coffee and carbonated drinks) on fertility is unclear. Some prescription, over‐the‐counter and recreational drugs may interfere with male and female fertility and so should be disclosed to the healthcare practitioner. The same is true of occupations, especially those that involve exposure to chemicals or excess heat. Patients should be offered lifestyle advice and access to specialist services and consultation, where appropriate, to address factors that influence fertility and the success of treatment such as body weight, smoking, drinking and drug use. The relationship between psychological stress and fertility problems is complex and the individual response to stress situations is variable. Work‐related stress may reduce conception rates and psychological stress can negatively affect a couple’s relationship and libido, which may impact on their chance of conception. Couples undergoing fertility tests and treatment have been shown to experience a higher frequency of male sexual disturbances, including loss of libido and a decrease in the frequency of sexual intercourse. Both partners should therefore be informed that stress in the male and/or female partner can affect the couple’s chance of conception and their relationship. All efforts should be made to limit stress wherever possible. The effectiveness of complementary therapies, for both men and women, has not been properly evaluated and further research is needed before such interventions can be recommended. Women with unexplained subfertility should not be offerred oral ovarian stimulation agents such as clomifene citrate, anastrozole or letrozole. Clomifene citrate, as a stand‐alone treatment, does not increase the chances of a pregnancy or a live birth. Rather, they should be reassured and given advice on natural conception and the timing and frequency of sexual intercourse. They should be offered in vitro fertilization (IVF) treatment if they have not conceived after 2 years, including up to 1 year before their fertility investigations, of regular unprotected sexual intercourse. Couples with mild male factor infertility and minimal and mild endometriosis should be treated in exactly the same way. While it is possible to adopt a generic approach to fertility treatment, it is paramount to individualize care and consider the underlying cause. Women who are not ovulating should be managed according to the likely problem. The management of women with hypothalamic hypogonadism is totally dependent on whether there are issues with weight, stress, thyroid disease or hyperprolactinaemia. They should not be offered ovulation induction until these issues are addressed as it is unlikely to work. Furthermore, correction or moderation of the underlying cause often leads to resumption of ovulation, mitigating the need for treatment. This is a safer and more practical approach. A specific male factor should be identified and corrected where possible. Where indicated, ovulation induction should be offered. The aim is to induce a monofollicular response to insure this occurs, and a multifollicular response is avoided, all patients undergoing ovulation induction should have ultrasound monitoring through their first cycle of treatment. This ensures they are taking a dose that minimize the risk of multiple pregnancy. Differentiating between the three causes of Group I ovulation disorders is essential as it governs the approach to ovulation induction and is prognostic of treatment outcome. Treatment may involve lifestyle modifications (normalizing weight and exercise regimes), pulsatile GnRH, or gonadotrophin therapy with human menopausal gonadotrophin (hMG). Lifestyle modifications are more appropriate for hypothalamic amenorrhoea while pulsatile GnRH is recommended for patients with hypothalamic hypogonadism as it is more physiological and induces monofollicular ovulation. However, neither of these strategies is appropriate for patients with hypopituitarism. In this circumstance, gonadotrophins need to be directly replaced and this requires the administration of both FSH and LH. This is usually achieved through the use of hMG, which contains both hormones in a ratio of 1 : 1. This approach is very successful in women with hypogonadotrophic hypogonadism and hypothalamic amenorrhoea, resulting in cumulative conception rates of 82.1% and 65.4% and cumulative live‐birth rates of 95.0% and 85.3%, respectively, over the course of a year. Women with Group II ovulation disorders should be offered clomifene citrate, metformin or a combination of these. Clomifene citrate should not normally be continued for longer than 6 months as there are more effective treatment options. Women prescribed metformin should be informed of the side effects associated with its use, such as nausea, vomiting and other gastrointestinal disturbances. These can be lessened by reducing the dose, taking the medication with food, or through the use of a slow‐release formulation. Women with a Group II ovulation disorder and BMI over 30 should be encouraged to lose weight as this alone may restore ovulation; if it does not, it will improve their response to ovulation induction agents and have a positive impact on pregnancy outcomes. Women who prove resistant to increasing doses of clomifene citrate should be offered laparoscopic ovarian drilling, combined treatment with clomifene citrate and metformin if not already offered as first‐line treatment, or gonadotrophins. Concomitant treatment with GnRH agonist, pulsatile GnRH, growth hormone and/or hMG during ovulation induction in women with PCOS who do not respond to clomifene citrate is not recommended because there is no evidence they improve pregnancy rates. Tamoxifen and aromatase inhibitors may be used as alternatives to clomifene. Women with Group III ovulation disorders require treatment with donor eggs. The use of donor oocytes is also effective for certain cases of IVF treatment failure, where there is evidence of poor oocyte quality or poor response to ovarian stimulation, and where there is a high risk of transmitting a genetic disorder to the offspring. Tubal surgery has largely been replaced by IVF. It still has a role in select cases and in women who do not want IVF or who are unable to self‐fund treatment. It should only be offered in centres where appropriate expertise is available. For women with mild tubal disease, tubal surgery may be more effective than no treatment. For women with proximal tubal obstruction, selective salpingography plus tubal catheterization, or hysteroscopic tubal cannulation, may improve the chance of pregnancy. In women undergoing IVF, the presence of hydrosalpinx is associated with early pregnancy loss and poor implantation and pregnancy rates. Hydrosalpinges large enough to be visible on ultrasound are associated with the poorest outcome, including increased miscarriage rates. Women with hydrosalpinges should therefore be offered treatment before IVF because this improves the chance of a live birth. Various surgical treatments including salpingectomy, salpingostomy, proximal tubal ligation or clipping, and transvaginal aspiration have all been used to improve IVF outcome. Laparoscopic salpingectomy has been shown to increase ongoing pregnancy rates following IVF by about 50% and is therefore the current standard treatment, although laparoscopic proximal tubal ligation/clipping has a similar effect. Transvaginal aspiration does not improve outcome. The hysteroscopic placement of Essure® intratubal devices to occlude the fallopian tube and prevent leakage of fluid back into the uterine cavity is not effective and is associated with lower ongoing pregnancy rates (26.2%) than after laparoscopic salpingectomy (55.8%). A hysteroscopic approach may still be valid in women who cannot undergo laparoscopic salpingectomy as there is no alternative, but there is no evidence to show benefit. Fertility can be improved by the division of adhesions. Pregnancy rates increase by 38–52% in previously infertile patients following laparotomy with adhesiolysis. In women with infertility as a result of adnexal adhesions, pregnancy rates of 32 and 45% at 12 and 24 months, respectively, have been reported following adhesiolysis, compared with 11 and 16% at corresponding time intervals in untreated women. Higher pregnancy rates (12% vs. 29%) have also been reported 3 years after tubal surgery. Division of adhesions around the ovary has also been shown to increase pregnancy rates by over 50%. Adhesions re‐form in most patients (mean 85%) regardless of the method of adhesiolysis used or the type of adhesion being lysed. Women must be made aware of this and, even when successful, that fallopian tubes may become blocked again. If natural conception does occur in women with tubal disease and/or adhesions, there is a higher risk of that pregnancy being ectopically located. This is also true after tubal surgery and adhesiolysis. The risk is thought to be around 10% but will vary depending on individual circumstances. Any woman with tubal disease or adhesions who does conceive should seek early referral and an ultrasound scan around 7 weeks’ gestation or sooner in the event of any symptoms of ectopic pregnancy, of which they should be fully informed. Infertile women with large fibroids or submucosal/intramural fibroids that affect the uterine cavity are often offered myomectomy. However, there is no robust evidence to show this is effective. Women may decide to avoid myomectomy and this is reasonable. Uterine artery embolization has been used but its effects on fertility are unclear and it can lead to premature menopause or impaired ovarian reserve and persistent amenorrhoea. These complications are unpredictable but more common in older women and may result from non‐target embolization. Whilst endometrial polyps are likely to negatively impact on fertility and impair implantation, the evidence for this is far from clear and there are no randomized controlled trials to show polypectomy is beneficial. However, polypectomy is a relatively straightforward procedure with minimal risks that can often be performed as an outpatient procedure and should be offered to all women with a polyp prior to treatment. Broad‐based polyps often recur and may need to be formally resected rather than simply avulsed or blindly curetted to reduce this happening. Women with amenorrhoea and intrauterine adhesions should be offered hysteroscopic adhesiolysis because this is likely to restore menstruation and improve the chance of pregnancy. However, the key to intrauterine adhesions is their prevention rather than their subsequent treatment. They most commonly occur following uterine instrumentation of a pregnant uterus. Women of childbearing age who wish to preserve their fertility should be made aware of the risk at the time of evacuation of retained products and offered alternative management, especially if they require repeated procedures. Hysteroscopy provides a minimally invasive way to remove polyps and submucosal fibroids and divide intrauterine adhesions. There is no robust evidence to show this improves fertility but their presence does impair implantation and there is a biological rationale as to why their removal may improve fertility. There are no treatments for adenomyosis that improve fertility. Treatment should be based on symptom control. GnRH agonists can be used but there are no data to show they lead to an increase in spontaneous pregnancy or improve the outcome of IVF. Suppression of ovarian function to improve fertility in minimal–mild endometriosis is not effective and should not be offered for this indication alone. There is no evidence of its effectiveness in more severe disease. Indeed, more harm than good may result from treatment, because of adverse effects and the lost opportunity to conceive. Ablation of endometriotic lesions plus adhesiolysis to improve fertility in minimal–mild endometriosis is effective and improves ongoing pregnancy and live‐birth rates but the role of surgery for moderate–severe disease is uncertain and there are no randomized controlled trials or meta‐analyses to inform management. When surgery is performed, laparoscopy is preferred to laparotomy as it is associated with pregnancy rates of 54–66% compared with 36–45% after laparotomy in women with moderate and severe endometriosis. Women with ovarian endometriomas should be offered laparoscopic cystectomy because this improves the chance of pregnancy. Laparoscopic cystectomy for ovarian endometriomas is better than drainage and coagulation as it reduces symptoms and the risk of recurrence. Excision of the endometrioma capsule increases the postoperative spontaneous pregnancy rate, compared with drainage and electrocoagulation of the endometrioma wall. Nevertheless, both techniques carry potential risks for ovarian reserve, either by removal of normal ovarian tissue during excision or by thermal damage to the ovarian cortex during ablation. It should also be noted that there is no evidence that cystectomy prior to treatment with assisted reproductive technologies improves pregnancy rates in infertile women with endometrioma larger than 3 cm. In this case, cystectomy should only be considered to improve endometriosis‐associated pain or the accessibility of follicles. IVF is appropriate treatment, especially if tubal function is compromised, there is also male factor infertility and/or other treatments have failed. Whilst IVF pregnancy rates are lower in women with endometriosis than in those with tubal infertility, endometriosis does not appear to adversely affect pregnancy rates. Treatment with a GnRH agonist for 3–6 months before IVF in women with endometriosis may increase the rate of clinical pregnancy. The complete surgical removal of endometriosis may also improve live‐birth rate in infertile women with AFS/ASRM stage I/II endometriosis undergoing laparoscopy prior to treatment with assisted reproductive technologies although the benefit is not well established. Intrauterine insemination, with or without ovarian stimulation, is no longer recommended for people with unexplained infertility, mild endometriosis or mild male factor infertility who are having regular unprotected sexual intercourse. Intrauterine insemination may be considered in exceptional circumstances such as when people have social, cultural or religious objections to IVF. Unstimulated intrauterine insemination may benefit couples who are unable, or would find it very difficult, to have vaginal intercourse because of a clinically diagnosed physical disability or psychosexual problem. Unstimulated intrauterine insemination with donor sperm, often referred to as donor insemination, is the recommended treatment for men with azoospermia due to testicular failure or severe deficits in semen quality who do not wish to undergo ICSI. Donor insemination may also be considered where there is a high risk of transmitting a genetic disorder or infectious disease to the offspring or the latter to the woman from the man. It may also be used for couples with severe rhesus isoimmunization. Donor insemination is the treatment of choice for people in same‐sex relationships and single women. However, as these individuals invariably have to self‐fund their treatment, some elect to have IVF with donor sperm. People who have not conceived after six cycles of donor or partner insemination, despite evidence of normal ovulation, tubal patency and semen analysis, can be offered IVF or a further six cycles of unstimulated intrauterine insemination. NICE recommends that women under 40 who have been trying to get pregnant for 2 years should be offered three full cycles of IVF. Women aged between 40 and 42 who have been trying for two or more years and have not previously received IVF or have low ovarian reserve should be offered one full cycle of treatment. The overall chance of having a live birth after IVF treatment falls with rising female age and also decreases as the number of unsuccessful cycles increases. ICSI is indicated and should only be offered if there are severe deficits in semen quality, obstructive azoospermia, non‐obstructive azoospermia or if previous IVF treatment resulted in failed or very poor fertilization. People experiencing fertility problems should be offered counselling because fertility problems themselves, and the investigation and treatment for fertility problems, can cause emotional stress. Counselling should be offered before, during and after investigation and treatment. People who experience fertility problems should be informed that they may find it helpful to contact a fertility support group. There are several patient organizations and support groups available throughout the UK that offer general or specific advice. Fertility Fairness, formerly the National Infertility Awareness Campaign, has campaigned for people to have comprehensive and equal access to a full range of appropriate NHS investigations and treatments for infertility, including the right to access up to three full cycles of IVF treatment free on the NHS [10]. The welfare of the child who may be born as a result of fertility treatment, including the need of that child for supportive parenting, and of any other child who may be affected by the birth must be considered prior to offering treatment in accordance with Human Fertilisation and Embryology Authority (HFEA) regulations [11]. Each patient should be assessed to decide whether there is a risk of significant harm or neglect to any child. Over 80% of couples will conceive within 1 year if the woman is aged under 40 years and they have regular sexual intercourse every 2–3 days. Half of the couples who do not conceive in the first year will conceive in the second year such that the cumulative pregnancy rate over 2 years is over 90%. A prospective cohort of women aged 35–39 years, from the European Fecundability Study, suggested even higher rates of conception after 2 years (Table 51.3). Pregnancy rates did decrease with increases in female age. Men aged 40 years having intercourse twice per week have approximately 10% lower cumulative success rates compared with men aged 35 years over the same time period. All subfertile patients should therefore be made aware that female fertility and, albeit to a lesser extent, male fertility decline with age [12]. Table 51.3 Cumulative probability of conceiving a clinical pregnancy by number of menstrual cycles based on female age. Source: National Institute for Health and Care Excellence [3]. Coital frequency also influences conception rates. At least 94% and 77% of fertile women aged 35 years and 38 years, respectively, conceive after 3 years of trying if they have intercourse two or three times per week. Conception rates within 12 months fall from 92% for women aged 19–26 years to 86% for women aged 27–34 years and 82% for women aged 35–39 years for couples having intercourse twice per week. Conception rates fall further to 85%, 76% and 71%, respectively, for couples having intercourse once per week. Furthermore, sperm motility is highest in semen emission every 3–4 days on average. Coitus every 2–3 days is therefore likely to maximize the overall chance of natural conception, as spermatozoa survive in the female reproductive tract for up to 7 days after insemination. In terms of timing, most pregnancies can be attributed to sexual intercourse during a 6‐day period starting 5 days before ovulation and including the day of ovulation, with the highest estimated conception rates associated with intercourse 2 days before ovulation. NICE suggests that most women typically achieve success rates of 20–35% per cycle with a cumulative success of 45–53% after three full cycles of IVF, which is why it recommends three IVF cycles as it is both the most cost‐effective and clinically effective number for women under the age of 40. Patient and public engagement has shown that many patients think that an 80% chance of getting pregnant through IVF is excellent and anything less than 50% is poor. However, these figures need to be considered and directly compared with natural fecundity as young healthy couples only have around a 20% chance of conceiving naturally in a month. Although NICE has made its recommendations clear, funding for fertility treatment and assisted conception is ultimately determined by clinical commissioning groups (CCGs). Different CCGs use different eligibility criteria, with female age, BMI, previous children, relationship status and sexuality all deciding factors. Most CCGs do not offer funding for women who are overweight (BMI >30 kg/m2) and all have an upper age cut‐off that varies from 35 to 43 years. Most CCGs will not support couples who have children irrespective of whether these were conceived together or with a different partner.
Subfertility
Importance
Definition: what is infertility?
Aetiology
Cause
Prevalence (%)
Primary
Secondary
Unexplained
25
20
Ovulatory disorders
25
15
Tubal disease
20
40
Male factors
30
20
Uterine or peritoneal disease
10
5
Ovulatory disorders
Group I ovulation disorders
Group II ovulation disorders
Group III ovulation disorders
Tubal disease
Uterine and/or peritoneal disorders
Male factor
Principles of management
Take a critical history
Female
Male
Perform a relevant examination
Female
Male
Perform directed investigations
The female partner
The male partner
Semen volume: ≥1.5 mL
pH: ≥7.2
Sperm concentration: ≥15 million per mL
Total sperm number: ≥39 million per ejaculate
Total motility (progressive and non‐progressive motility): ≥40% motile or ≥32% with progressive motility
Vitality: ≥58% live spermatozoa
Sperm morphology: ≥4% normal forms
Treat patients as individuals
Lifestyle measures
Reassurance
Treat the cause
Male factor
Ovulation induction
Tubal disease and adhesions
Uterine factors
Endometriosis and peritoneal disease [7–9]
Intrauterine insemination
Assisted conception
Counselling and support
Welfare of the child
Prognosis
Natural conception
Age (years)
Pregnant after 1 year (12 cycles) (%)
Pregnant after 2 years (24 cycles) (%)
19–26
92
98
27–29
87
95
30–34
86
94
35–39
82
90
Assisted conception
Funding
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