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National Collaborating Centre for Women's and Children's Health (UK). Fertility: Assessment and Treatment for People with Fertility Problems. London (UK): RCOG Press; 2004 Feb. (NICE Clinical Guidelines, No. 11.)

  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

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Fertility: Assessment and Treatment for People with Fertility Problems.

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5Investigation of fertility problems and management strategies

5.1. Semen analysis

WHO criteria for assessing semen quality are based on populations of fertile men and are described as ‘reference’ values rather than ‘normal’ values (Table 5.1).285,287 [Evidence level 4] In the detection of male factor fertility problems, basic semen analysis using the WHO criteria is a sensitive test (sensitivity of 89.6%, i.e. it is likely to detect nine out of ten men who have ‘true’ semen abnormality), but it has poor specificity (an abnormal test result does not always mean there is a true semen abnormality). Analysis of repeat semen samples provides greater specificity in identifying semen abnormalities; a single-sample analysis will falsely identify about 10% of men as abnormal, but repeating the test reduces this to 2%.286 [Evidence level 2b] Definitions relating to semen quality are given in Table 5.2.

Table 5.1. WHO reference values for semen analysis, 2000.

Table 5.1

WHO reference values for semen analysis, 2000.

Table 5.2. Definitions relating to semen quality.

Table 5.2

Definitions relating to semen quality.

Repeat semen measurements from the same individual will vary over time.28,29 This has prompted the suggestion that two285 or three semen samples29 are needed in order to establish a reliable semen profile. However, as the WHO criteria provide a sensitive test (that is, the test is likely to identify most ‘true’ abnormalities), if the semen analysis is normal there is no need for a repeat analysis. To reduce false positives, it is suggested that a repeat semen analysis should be performed only if the result of the first analysis is abnormal.288 Biologically, the optimal time for the second sample is at least three months after the initial sample because the cycle of spermatozoa formation takes about three months to complete.289 [Evidence level 3] However, this delay may cause anxiety and the timing of the second sample should take into consideration the preferences of the man. If azoospermia or severe oligozoospermia is reported in the initial semen analysis, a repeat test should be undertaken within two to four weeks. If the repeat test is reported as normal the semen can be regarded as normal and no further test is needed. However, these men may need further assessment of semen quality if assisted reproduction is being considered.

Men who have two abnormal semen analyses may need further, more detailed, semen assessment. The tests should be interpreted within the clinical context and circumstances of the individual or couple. If azoospermia is confirmed, this should be explained sensitively to the patient, who should be referred for early specialist advice in order to minimise anxiety.

The WHO criteria include assessment for the presence of autoimmune antisperm antibodies as a standard part of semen analysis.287 [Evidence level 4] This analysis is performed using either an immunobead test or a mixed antiglobulin reaction test. However, opinions differ on the reliability of these tests and whether they should be used routinely in the initial investigation of fertility problems.290–293 [Evidence level 3–4] Semen analysis should not include screening for antisperm antibodies because there is no effective treatment in terms of improving male fertility (see Section 6.1).

Sperm function tests vary in their ability to detect defects in the complex processes leading to fertilisation, and are of limited use from a practical point of view.211,294 [Evidence level 4]

The reliability of the WHO reference values, especially that for sperm concentration, in predicting the chance of conception has been questioned.295 [Evidence level 3]

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 fertilising capacity of spermatozoa. Sperm function tests such as computer-assisted semen analysis have not been found to be more predictive. Reliable sperm function tests are urgently required.211,294 [Evidence level 4]

In the UK, low sperm count or quality 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.1,2,296 It is estimated that in between 30% and 50% of men with poor semen quality no cause for this will be identified.297,298 Impaired semen quality, azoospermia and inadequate coitus are contributing factors in nearly 50% of infertile couples.

Abnormal semen characteristics are usually idiopathic (idiopathic oligoasthenoteratozoospermia). Idiopathic semen abnormalities occur in about 26% of infertile men.298 The spermatozoa are mostly dysfunctional and unable to fertilise 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 (nonobstructive azoospermia) or obstruction of the genital tract (obstructive azoospermia).

Hypogonadotrophic hypogonadism, which is a condition caused by hypothalamic or pituitary dysfunction, accounts for less than 1% of male factor fertility problems.296 It results in a deficiency of LH and FSH, which is associated with failure of spermatogenesis and testosterone secretion.

Primary testicular failure is the most common cause of male infertility due to oligozoospermia and is the cause of nonobstructive azoospermia. Testicular failure may be due to cryptorchidism, torsion, trauma, orchitis, chromosome disorders (Klinefelter’s syndrome, Y-chromosome microdeletions), systemic disease, radiotherapy or chemotherapy; however, in the majority of cases (66%) the cause is unknown. The diagnosis is based on reduction in testicular size and elevation of serum FSH levels. There is no effective treatment to restore fertility in primary testicular failure. Men undergoing treatments that cause infertility should be offered the opportunity to cryopreserve semen (see Section 16.1). Alternatively, surgical sperm retrieval with assisted reproduction or donor sperm may be considered (see Section 12.8).

Obstructive azoospermia is uncommon with a prevalence of less than 2%.1 The diagnosis is based on normal testis size and normal serum FSH levels. This includes conditions such as congenital bilateral absence of vas deferens (CBAVD). CBAVD is commonly associated with cystic fibrosis mutations or renal tract abnormality (e.g. an absent kidney).

Anejaculation is defined as the total failure of seminal emission into the posterior urethra. Retrograde ejaculation is the substantial propulsion of seminal fluid from the posterior urethra into the bladder.299 Anejaculation is a relatively uncommon occurrence in the general population,300 and retrograde ejaculation accounts for about 0.3–2.0% of male fertility problems. Anejaculation and retrograde ejaculation may result from spinal cord injury, transurethral prostatectomy, retroperitoneal lymph node dissection, diabetes mellitus, transverse myelitis, multiple sclerosis or psychogenic (idiopathic) disorders. For example, it has been reported that only 7% of men retained ejaculation after transurethral resection of the prostate.301 [Evidence level 2b] With the advent of ICSI, since only a small number of motile spermatozoa is required for a successful fertilisation,302 both ejaculation disorders can be considered as treatable conditions. [Evidence level 3]

A varicocele is a collection of dilated veins in the spermatic cord and is a common physical anomaly. Varicoceles are found in 11.7% of men with normal semen and 25.4% of men with abnormal semen.303 The mechanism by which varicoceles might impair fertility and spermatogenesis is not clear. Varicoceles may be associated with decreased ipsilateral testicular volume, elevated scrotal temperature and pain, as well as impaired semen quality.303–305

RECOMMENDATIONS

The results of semen analysis conducted as part of an initial assessment should be compared with the following World Health Organization reference values: [GPP]

  • Volume: 2.0 ml or more
  • Liquefaction time: within 60 minutes
  • pH: 7.2 or more
  • Sperm concentration: 20 million spermatozoa per ml or more
  • Total sperm number: 40 million spermatozoa per ejaculate or more
  • Motility: 50% or more motile (grades a* and b**) or 25% or more with progressive motility (grade a) within 60 minutes of ejaculation
  • Vitality: 75% or more live
  • White blood cells: fewer than 1 million per ml
  • Morphology: 15% or 30%***

Screening for antisperm antibodies should not be offered because there is no evidence of effective treatment to improve fertility. [GPP]

If the result of the first semen analysis is abnormal, a repeat confirmatory test should be offered. [B]

Repeat confirmatory tests should ideally be undertaken 3 months after the initial analysis to allow time for the cycle of spermatozoa formation to be completed. However, if a gross spermatozoa deficiency (azoospermia or severe oligozoospermia) has been detected the repeat test should be undertaken as soon as possible. [GPP]

5.2. Assessing ovulation

Regularity of menstrual cycles

Regular menstrual cycles in the range 26 to 36 days are usually indicative of ovulation.306 A review of patient-monitored basal body temperature charts showed that they were not sufficiently reliable for detection of ovulation (see Section 3.2).34–39 Ovulation involves leutinisation of the mature follicle and release of the oocyte. Both are triggered by the LH surge. In practice, testing for release of the oocyte by observing follicle rupture is impractical so ovulation detection is based on the detection of circulating progesterone produced following leutinisation of the follicle. Urinary LH kits used by couples can suggest when ovulation is imminent. Ovulation can be confirmed retrospectively by measurement of serum progesterone in midluteal phase, approximately on day 21 of a 28-day cycle. For women with irregular cycles, this test may need to be performed later in the cycle (e.g. day 28 of a 35-day cycle) and repeated weekly until the next menstrual cycle starts, unless the bleeds are so infrequent that ovulation induction therapy will be needed in any case. Values range from 16 to 28 nmol/l as the lowest limit indicative of ovulation.211,307–309 [Evidence level 2b]

Anovulation and oligo-ovulation are ovulatory disorders that are estimated to cause 21% of female infertility.1 The WHO classifies ovulation disorders into three groups.207

Group 1Hypothalamic pituitary failure (hypothalamic amenorrhoea or hypogonadotrophic hypogonadism)

This group of disorders is characterised by low gonadotrophins, normal prolactin and low oestrogen, and it accounts for about 10% of ovulatory disorders. Failed ovarian follicular development results in hypo-oestrogenic amenorrhoea in this group of disorders.
Group 2Hypothalamic pituitary dysfunction

This group, which is characterised by gonadotrophin disorder and normal oestrogen, accounts for about 85% of ovulatory disorders. This group of disorders results in anovulatory oligo/amenorrhea, predominately involving women with polycystic ovaries. Polycystic ovaries are present in about 80–90% of women with oligomenorrhoea and 30% of women with amenorrhoea.310 In women who have polycystic ovaries, where there are associated clinical symptoms (such as menstrual cycle disturbances, obesity and hyperandrogenism presenting as hirsutism, acne or androgen-dependent alopecia), this is referred to as PCOS. About 30% of the PCOS population is of normal weight.311

Over many years, the diagnostic criteria for polycystic ovaries and PCOS have been evolving and different researchers have used differing definitions. An international consensus definition of PCOS, which includes a new definition of the polycystic ovary, provides the possibility that future research will be based on a consistent definition. The new definition for the diagnosis of a polycystic ovary (which is usually obtained from an ultrasound scan) requires the presence of at least 12 follicles measuring 2–9 mm in diameter and/or an ovarian volume in excess of 10 cm3.312–314 [Evidence level 3–4] The new definition for the diagnosis of PCOS requires the presence at least two of the following three criteria:312,313 [Evidence level 3–4]
  • oligo- and/or anovulation
  • clinical and/or biochemical hyperandrogenism
  • polycystic ovaries, with the exclusion of other aetiologies.
Reduction in weight and increased pregnancy rates have been reported in obese infertile women who took up lifestyle improvement programmes involving increased exercise and weight loss as compared with conventional management (see Section 3.6).86 [Evidence level 1b]
Group 3Ovarian failure

This group, which is characterised by high gonadotrophins with hypogonadism and low oestrogen, accounts for about 4–5% of ovulatory disorders.

RECOMMENDATIONS

Women who are concerned about their fertility should be asked about the frequency and regularity of their menstrual cycles. Women with regular monthly menstrual cycles should be informed that they are likely to be ovulating. [B]

Women with regular menstrual cycles and more than 2 years’ infertility can be offered a blood test to measure serum progesterone in the midluteal phase of their cycle (day 21 of a 28-day cycle) to confirm ovulation. [B]

Women with prolonged irregular menstrual cycles should be offered a blood test to measure serum progesterone. Depending on the timing of menstrual periods, this test may need to be conducted later in the cycle (for example day 28 of a 35-day cycle) and repeated weekly thereafter until the next menstrual cycle starts. [GPP]

The use of basal body temperature charts to confirm ovulation does not reliably predict ovulation and is not recommended. [B]

Women with irregular menstrual cycles should be offered a blood test to measure serum gonadotrophins (follicle-stimulating hormone and luteinising hormone). [GPP]

Prolactin measurement

Hyperprolactinaemia is an endocrine disorder caused by an increased secretion of prolactin from the pituitary gland, resulting in galactorrhoea, irregular menstruation and possible infertility. The incidence of raised prolactin in infertile but ovulatory women ranges from 3.8% to 11.5%.315–317 [Evidence level 3] There is no significant association between prolactin, progesterone levels and cumulative conception rates in ovulatory women.318,319 [Evidence level 3] Estimation of prolactin levels should be reserved for women with symptoms of an ovulatory disorder, galactorrhoea or a pituitary tumour.

It has recently been proposed that hyperprolactinaemia attributable to macroprolactin, rather than prolactin, may be associated with fertility problems.320–322 [Evidence level 3] However, further research is needed to determine whether women with raised serum prolactin should have macroprolactin excluded.

RECOMMENDATION

Women who are concerned about their fertility should not be offered a blood test to measure prolactin. This test should only be offered to women who have an ovulatory disorder, galactorrhoea or a pituitary tumour. [C]

RESEARCH RECOMMENDATION

Further research is needed to determine whether women with raised serum prolactin should have macroprolactin excluded.

Assessing ovarian reserve

Female fecundability is related to the total number of primordial follicles remaining within the ovaries (referred to as ovarian reserve), which declines with age.323 It would be valuable if reliable estimates of ovarian reserve could be obtained before embarking on fertility therapy such as ovulation induction and IVF in women over the age of 35 years.324,325 [Evidence level 3–4]

Indirect measurements using endocrine markers, such as day-three basal serum follicle-stimulating hormone (FSH) and clomifene citrate challenge test, correlate well with the probability of conception in these populations: women in the infertile population,326,327 women undergoing complex ovulation induction and women participating in assisted reproductive technology cycles.328–331

When ovarian screening was carried out in woman aged over 35 years, women of any age with unexplained infertility and women with one ovary or a poor response to human menopausal gonadotrophin (hMG), one in six women was found to have an abnormal test result.332 [Evidence level 3]

An elevated basal day-three FSH is correlated with diminished ovarian reserve in women aged over 35 years and is associated with poor pregnancy rates after treatment of ovulation induction (6% versus 42%)328 when compared with women with normal ovarian reserve. [Evidence level 2b–3] Poor pregnancy rate after assisted reproduction (2.7%) and high rate of pregnancy loss (71.4%) were also reported in women with elevated basal day-three FSH, regardless of age.333 [Evidence level 3]

A cohort study of 344 women undergoing IVF following pituitary desensitisation showed that basal FSH was a better predictor of cycle cancellation rates and of the number of oocytes collected than age, although age and not basal FSH was independently associated with pregnancy rate.334 Another cohort study of 1045 cycles of women undergoing IVF reported that the combined use of age and basal FSH significantly improved the predictive power of number of oocytes collected, fertilised and embryos transferred. However, age was an independent predictor of pregnancy rate (area under the receiver operating-characteristic curve 0.617 with age alone versus 0.545 with FSH alone, p = 0.002). Increasing age, but not basal FSH, was associated significantly with reduced implantation rate and pregnancy rate. Women aged 40 years or over have the poorest pregnancy outcomes when compared with those aged under aged 35 years and those aged 35–39 years.335 [Evidence level 2b]

A cohort study of 547 women reported that those with poor response to ovarian stimulation and raised basal FSH were more likely to have poor reproductive performance and more likely to experience menopause before the age of 45 years compared with normal responders.336 [Evidence level 2b]

It has been reported that direct measures of ovarian function such as inhibin B correlate inversely with age and FSH levels337 and that inhibin B levels are reduced in women with diminished ovarian reserve.338 However, the role of inhibin B in predicting pregnancy outcome is unclear339,340 and needs further evaluation. [Evidence level 3]

One study reported that none of these markers accurately reflected ovarian reserve.341 This study compared follicle numbers in ovarian histology of 22 parous women who undertook the tests before oophorectomy, but the clomifene citrate challenge test was more accurate according to receiver operator characteristic analysis compared with basal FSH and gonadotrophin-releasing hormone agonist stimulation tests.341 [Evidence level 3]

It has been reported that pregnancy rates decline significantly as day-three FSH rises above 15 miu/ml. Very few pregnancies were reported when FSH exceeded 25 miu/ml.329 [Evidence level 3] However, interpretation of basal FSH is subject to great inter-laboratory variation. There appear to be marked differences in ‘normal’ ranges of values of the FSH assay. It is important for each laboratory to define its own normal range of laboratory assays.342 [Evidence level 4]

Tests of ovarian reserve do not currently have the necessary sensitivity or specificity for general application.325

RECOMMENDATIONS

Tests of ovarian reserve currently have limited sensitivity and specificity in predicting fertility. However, women who have high levels of gonadotrophins should be informed that they are likely to have reduced fertility. [C]

Women should be informed that the value of assessing ovarian reserve using inhibin B is uncertain and is therefore not recommended. [C]

Thyroid function tests

Thyroid dysfunction can lead to menstrual and ovulatory disorder associated with infertility.343,344 It has been common practice to screen women with infertility for thyroid dysfunction using thyroid function tests, whether or not symptoms of thyroid disease are present.

Asymptomatic hypothyroidism occurs in up to 7% of the general population.345 Abnormal thyroid function test measurements have been reported in 1.3–5.1% of infertile women.316,346–349 [Evidence level 3] It has been estimated that subclinical hypothyroidism occurs in 0.88–11.3% of women with ovulation disorders.347,348 [Evidence level 3]

RECOMMENDATION

Women with possible fertility problems are no more likely than the general population to have thyroid disease and the routine measurement of thyroid function should not be offered. Estimation of thyroid function should be confined to women with symptoms of thyroid disease. [C]

Endometrial biopsy

Luteal-phase defect has been defined as either a defect of progesterone secretion by the corpus luteum or a defect in endometrial response to hormonal stimulation, resulting in an inadequate endometrium for blastocyst implantation and subsequent pregnancy.350 The defect is estimated to affect 3–20% of the infertile population and 23–60% of women with recurrent miscarriage.351 [Evidence level 3]

There is no consensus of opinion about the diagnosis or effective treatment of luteal-phase defect, and its role as a cause of infertility has been questioned.352,353 The benefit of treatment for luteal-phase defect on pregnancy rates has not been established.354,355 [Evidence level 1b–3]

Traditionally, luteal-phase defect is diagnosed by a timed endometrial biopsy based on a standard set of criteria,356 repeated on at least two occasions. [Evidence level 2b] It has been suggested that diagnosis of luteal-phase defect based on histological dating of endometrial biopsy could be a chance event.355

RECOMMENDATION

Women should not be offered an endometrial biopsy to evaluate the luteal phase as part of the investigation of fertility problems because there is no evidence that medical treatment of luteal-phase defect improves pregnancy rates. [B]

5.3. Screening for Chlamydia trachomatis

Chlamydia trachomatis is present in 11% of the sexually active population aged 19 years or less.357 It is a major cause of pelvic inflammatory disease, leading to chronic abdominal pain, ectopic pregnancy and tubal factor infertility.358,359 Asymptomatic chlamydial infection may go unrecognised and untreated. Although the prevalence of C. trachomatis among subfertile women in the UK is only 1.9%,360 uterine instrumentation carried out routinely as part of the infertility investigation may reactivate or introduce upper tract dissemination of endocervical chlamydial infection, resulting in iatrogenic pelvic inflammatory disease. [Evidence level 2b]

Clinical pelvic infection following hysterosalpingography (HSG) has been reported in up to 4% of cases and in 10% of patients with tubal disease.361 [Evidence level 3] Prophylactic antibiotics are effective in reducing this and should be considered.360,362 [Evidence level 3] Both doxycycline and azithromycin are effective prophylaxis and treatment for chlamydia.363 [Evidence level 1b]

There is evidence that screening for and treating cervical chlamydial infection can reduce the incidence of pelvic inflammatory disease in women at increased risk of chlamydia.364 [Evidence level 1b] The Chief Medical Officer’s Expert Advisory Group on Chlamydia has called for action to reduce the prevalence and morbidity of chlamydial infection. It recommends that consideration be given to screening couples attending fertility clinics and women undergoing procedures requiring instrumentation of the uterus.365 [Evidence level 4] Women who are found to have chlamydial infection should be treated for the infection before proceeding.

DNA techniques such as polymerase chain reaction and ligase chain reaction for analysis of cervical and urine specimens are highly sensitive and specific for diagnosing chlamydial infection.366–368 [Evidence level 2b]

Chlamydial infection has been implicated in male infertility369 and it may cause epididymitis and obstruction. If chlamydial infection is detected in the female partner, male partners should be notified and treated to limit re-infection and the potential need for retreatment.

The Chief Medical Officer’s Expert Advisory Group on Chlamydia advises referral to genitourinary medicine clinics so that sexual partners can be traced and treated if either partner is found to have chlamydial infection.365 [Evidence level 4]

RECOMMENDATIONS

Before undergoing uterine instrumentation women should be offered screening for Chlamydia trachomatis using an appropriately sensitive technique. [B]

If the result of a test for Chlamydia trachomatis is positive, women and their sexual partners should be referred for appropriate management with treatment and contact tracing. [C]

Prophylactic antibiotics should be considered before uterine instrumentation if screening has not been carried out. [GPP]

5.4. Assessing tubal damage

It is estimated that tubal factors account for 14% of the causes of subfertility in women.1 Tubal blockage involves the proximal part (which is closest to the uterus), the mid part or the distal part (which is furthest from the uterus). Proximal (uterotubal) obstruction occurs in 10–25% of women with tubal disease.370 The results of semen analysis and assessment of ovulation should be known before a test for tubal patency is performed.

Tubal disease includes tubal obstruction and pelvic adhesions due to infection, endometriosis and previous surgery. Endometriosis accounts for about 5% of female infertility.1 It is defined as the presence of endometrial tissue occurring outside the uterine cavity which causes peritoneal lesions, adhesions and ovarian cysts and is associated with pelvic pain, dysmenorrhoea and infertility.

The diagnosis and severity of endometriosis are established by laparoscopy and biopsy using the revised American Fertility Society system,371 which classifies the severity of endometriosis into four stages: stage I (minimal), stage II (mild), stage III (moderate); and stage IV (severe).This classification system is widely used and includes visual assessment, which is subject to inter- and intra-observer error. However, disease severity has not been shown to predict the chance of pregnancy.372,373

An ideal (or ‘gold standard’) test for tubal disease would correctly identify all women with tubal disease. It would be a sensitive test (i.e. all true positives would be identified by a positive test result and a negative test result would rule out disease in all those without disease) and it would also be specific (i.e. the test result would be positive only in women with the disease).

Hysterosalpingography compared with laparoscopy and dye

HSG and laparoscopy with dye are the two most widely used methods to test for tubal pathology. HSG and laparoscopy are both invasive procedures but HSG is less so. Among women whose tubes were found to be patent (unobstructed) using HSG, 18% were found to have tubal obstruction or peritubal adhesions using laparoscopy and a further 34% were found to have endometriosis and/or fibroids.374 However, the detection and treatment of pathology missed by HSG did not increase live birth rates.374 [Evidence level 2b]

The diagnostic accuracy of HSG has been compared with that of laparoscopy and dye in a systematic review of 20 studies that distinguished between tubal obstruction and peritubal adhesions.375 However, only three studies involved judgement of laparoscopy without knowledge of HSG results. Meta-analysis based on these three studies gave pooled estimates of sensitivity and specificity for HSG as a test for tubal obstruction of 0.65 (95% CI 0.50 to 0.78) and 0.83 (95% CI 0.77 to 0.88), respectively.375 [Evidence level 2b] It is estimated that tubal damage accounts for 14% of fertility problems,1 which suggests that when HSG suggests the presence of tubal obstruction this will be confirmed by laparoscopy in only 38% of women. Thus, HSG is a 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 HSG is a reliable indicator of tubal patency.

Results from another review306 suggest that HSG could be used as a screening test for couples with no history of pelvic infection, and if abnormal, confirmatory laparoscopy would follow.376 [Evidence level 2b] Considerable interobserver variability in interpretation of HSGs has been reported, depending on the type of pathology being assessed.377,378 Women with possible comorbidity such as pelvic and tubal diseases may need a laparoscopic assessment.

The choice of laparoscopy as a gold standard in the diagnosis of tubal pathology has been questioned in a cohort study that formed part of the Canadian Infertility Treatment Evaluation Study.379 [Evidence level 3] This study compared the prognostic significance of HSG and laparoscopy using adjusted fecundity rate ratios, which express the probability of spontaneous pregnancy per unit time for women with a particular feature, relative to those without that feature. One-sided occlusion detected using HSG was found to decrease spontaneous pregnancy rates slightly compared to the absence of tubal occlusion at HSG (fecundity rate ratio 0.80) and two-sided occlusion at HSG decreased spontaneous pregnancy rates further (fecundity rate ratio 0.49).379 [Evidence level 3] However, occlusion detected using laparoscopy was associated with even lower spontaneous pregnancy rates (fecundity rate ratio 0.51 for one-sided occlusion and 0.15 for two-sided occlusion).379 [Evidence level 3] Thus, tubal pathology detected at laparoscopy has a stronger effect on future fertility than that detected at HSG.

A meta-analysis of 23 test evaluation studies found that the discriminative capacity of chlamydial antibody testing, using enzyme-linked immunosorbent assay (ELISA), immunofluorescence or microimmunofluorescence is comparable to that of HSG in the diagnosis of tubal pathology.380 [Evidence level 2b] Elevated titres of chlamydial antibodies in women were significantly associated with tubal disease.381 The titre of chlamydial antibodies has also been reported to be more accurate in predicting severe tubal pathology than unspecified tuboperitoneal abnormalities.382 However, it has been reported that the negative predictive value for pelvic pathology from the use of clinical features in addition to the chlamydial antibody titre is not significantly higher than that from the chlamydial antibody titre alone at 53%; this may not justify the avoidance of a diagnostic and confirmatory laparoscopy.383 [Evidence level 3]

A cohort study found that chlamydial antibody levels are quantitatively related to severity and extent of tubal pelvic damage. An elevated chlamydial antibody titre result is significantly associated with poor live birth rates, but not pregnancy rates.384 [Evidence level 2b] However, the chance of conception with or without tubal surgery is related to the degree of damage found at laparoscopy, with the chlamydial antibody titre adding no further diagnostic value.385 [Evidence level 2b]

Hysterosalpingo-contrast-sonography compared with laparoscopy and dye or hysterosalpingography

Evaluative studies of hysterosalpingo-contrast-sonogaphy (HyCoSy) showed good statistical comparability and concordance with HSG and laparoscopy combined with dye.386 [Evidence level 1b] HyCoSy is well-tolerated and can be a suitable alternative outpatient procedure.387 [Evidence level 1b] HyCoSy using contrast agent Infoson® appears to be more efficient than saline solution in detecting tubal obstruction.388 [Evidence level 1b]

Fertiloscopy and falloposcopy

Fertiloscopy is a relatively new procedure, defined as the combination in one investigation of transvaginal hydropelviscopy, dye test, optional salpingoscopy and hysteroscopy performed under local anaesthesia or neuroleptanalgesia.389 Diagnostic fertiloscopy has also been used to identify tubal pathology as an alternative to laparoscopy.389 [Evidence level 3] However, the procedure is not without risk, and bowel390 and rectal injuries389 following fertiloscopy have been reported. [Evidence level 3] The diagnostic accuracy of fertiloscopy in comparison to HSG and laparoscopy needs further evaluation.

Falloposcopy is defined as transvaginal microendoscopy of the fallopian tubes and direct visualisation of the entire fallopian tube lumen.391 It has been suggested that it may be a more discriminatory test of tubal pathology because women with normal fallopian tubes at falloposcopy achieve higher spontaneous pregnancy rates (27.6%) than those with mild or severe endotubal lesions (11.5% to 0%).392 In another study, the management plan was changed in 90% of women following falloposcopy and 24% conceived naturally.393 [Evidence level 3] However, further diagnostic evaluation studies are required, and technical problems with falloposcopy limit the use of the procedure in routine clinical practice.394,395

Tubal flushing

The potential therapeutic effect of diagnostic tubal patency testing has been debated for over 40 years. Tubal flushing might involve water- or oil-soluble media. Current practice usually involves water-soluble media when tubal flushing is performed at laparoscopy. A systematic review of eight RCTs showed a significant increase in pregnancy rates with tubal flushing using oil-soluble contrast media when compared with no treatment (OR 3.57, 95% CI 1.76 to 7.23). Tubal flushing with oil-soluble contrast media was associated with an increase in the odds of live birth (OR 1.49, 95% CI 1.05 to 2.11), but not pregnancy rates (OR 1.23, 95% CI 0.95 to 1.60) when compared with tubal flushing with water-soluble media.396 [Evidence level 1a] There were no significant differences in miscarriage, ectopic pregnancy and infection rates between tubal flushing with oil or water, or between oil plus water media versus water media only.396 [Evidence level 1a] There were no trials assessing tubal flushing with water-soluble media versus no treatment.

The potential consequences of extravasations of oil-soluble contrast media into the pelvic cavity and fallopian tubes may be associated with anaphylaxis and lipogranuloma.

RECOMMENDATIONS

Women who are not known to have comorbidities (such as pelvic inflammatory disease, previous ectopic pregnancy or endometriosis) should be offered hysterosalpingography (HSG) to screen for tubal occlusion because this is a reliable test for ruling out tubal occlusion, and it is less invasive and makes more efficient use of resources than laparoscopy. [B]

Where appropriate expertise is available, screening for tubal occlusion using hysterosalpingo-contrast-ultrasonography should be considered because it is an effective alternative to hysterosalpingography for women who are not known to have comorbidities. [A]

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. [B]

RESEARCH RECOMMENDATIONS

Further research is needed to ascertain the value of fertiloscopy and falloposcopy in the investigation of couples who experience problems with fertility.

Further randomised controlled trials are needed to evaluate the potentially therapeutic effects of tubal flushing with water-soluble media.

5.5. Assessing uterine abnormalities

Uterine abnormalities such as adhesions, polyps, submucous leiomyomas and septae have been found in 10% to 15% of women seeking treatment for fertility problems.398 Compared with HSG, hysteroscopy is recognised as the ‘gold standard’ test for identifying uterine abnormalities as it allows direct visualisation of the uterine cavity.399 [Evidence level 2b]

Opinions differ as to whether hysteroscopy should be considered as a routine investigation in addition to HSG and laparoscopy and dye in the infertile couple. A causal relationship between leiomyoma and infertility has not been established.400 [Evidence level 2b] In women undergoing assisted reproduction, the presence of uterine leiomyoma is associated with a reduced chance of clinical pregnancy or delivery.401,402 [Evidence level 2b–3] However, the effectiveness of surgical treatment of uterine abnormalities to enhance pregnancy rates is not established.

Ultrasound of the pelvis

Compared with bimanual pelvic examination, transvaginal ultrasound enables pelvic anatomy to be identified with more accuracy and reliability. Ultrasound can be used in the evaluation of pelvic pathology, such as endometriosis, endometrioma, cysts, polyp, leiomyoma, adnexal and ovarian abnormality, where such abnormalities are present.403–405 [Evidence level 2b–3]

The diagnostic criteria for polycystic ovaries and PCOS, in which ultrasonic parameters have an important role, have been evolving over many years, and have recently been clarified in an international consensus statement (see Section 5.2).

RECOMMENDATION

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. [B]

RESEARCH RECOMMENDATION

The role of pelvic ultrasound in women who are not suspected to have pelvic pathology requires further evaluation.

5.6. Postcoital testing of cervical mucus

The value of postcoital testing of cervical mucus for the presence of motile sperm is controversial and is a subject of continuing debate.406–411

It has been reported that the postcoital test is an effective predictor of conception where defined female causes of infertility are absent and duration of infertility is less than three years.412 [Evidence level 3] However, a systematic review of 11 observational studies (n = 3093 women) showed that the postcoital test has poor predictive power of fertility and lacks validity.413 [Evidence level 3] One RCT (n = 444) compared cumulative pregnancy rates between couples offered a postcoital test versus couples who were not offered this test as part of their infertility investigation. No significant differences were shown in their respective cumulative pregnancy rates (49%, 95% CI 42% to 55% in the intervention group versus 48%, 95% CI 42% to 55% in the control group). The couples offered postcoital tests in this RCT also had more tests and treatments than those in the control group.414 [Evidence level 1b]

It has been suggested that results of postcoital testing may have little influence on treatment strategy in the light of the widespread use of assisted reproduction techniques (for example, IUI and IVF) for fertility problems associated with sperm-cervical mucus interaction. In addition, the lack of a reliable sperm function test may render post-coital testing unnecessary.410 [Evidence level 4]

RECOMMENDATION

The routine use of postcoital testing of cervical mucus in the investigation of fertility problems is not recommended because it has no predictive value on pregnancy rate. [A]

5.7. Strategies for management of fertility problems

The investigation of people with fertility problems will lead to a number of possible diagnostic categories. Each diagnostic category tends to have its own management strategy but these strategies are based on a core of techniques that apply across many conditions. This applies particularly to the techniques involved in assisted reproduction. The importance of psychological support and counselling applies at every stage of the management strategy and process (see Section 4.2). Diagnostic categories and their corresponding management strategies are described below, and the individual techniques are described in subsequent chapters.

Male factor fertility problems

Techniques for managing ejaculatory failure (anejaculation and retrograde ejaculation) are discussed in Section 6.3.

Semen quality can be marginally improved by lifestyle or medical measures (see Chapters 3 and 6) but natural pregnancy is rare because the spermatozoa remain predominantly dysfunctional.

Endocrine therapy for hypothalamic–pituitary failure and reconstructive surgery in selected cases of obstructive azoospermia may restore fertility by returning functional spermatozoa to the semen and natural pregnancy is feasible (see Chapter 6). In nonobstructive azoospermia there are foci of spermatogenesis in about 50% of cases but there is little potential for restoring fertility. However, in some cases lifestyle measures (see Chapter 3) may return sperm to the ejaculate and thereby avoid the need for surgical sperm recovery. Cases of irreversible obstructive azoospermia and nonobstructive azoospermia are managed by surgical sperm recovery from the epididymis or testis (see Section 12.8) followed by ICSI (see Chapter 13) because of the immaturity of the recovered sperm.

Leucocytospermia has been associated with adverse effects on semen parameters and function.415,416 Antibiotics have been considered in the treatment of leucocytospermia (see Chapter 6).

Surgical treatment for varicocele is discussed in Section 6.2.

A specific male factor should be identified and corrected where possible to try to initiate natural pregnancy. As this is seldom feasible, the man’s sperm is normally used for assisted reproduction, to avoid the need to consider sperm donation. However, an improvement in semen quality may reduce the complexity, costs and potential risks of future assisted reproduction for both partners and any resulting children.

Assisted reproduction methods are indicated by the quantity and quality of spermatozoa that can be isolated by semen preparation techniques. While IUI (see Chapter 10) or IVF (see Chapter 11) are feasible in mild–moderate oligozoospermia, ICSI (see Chapter 13) is usually required to achieve fertilisation, especially in moderate–severe oligozoospermia, asthenozoospermia or teratozoospermia. As there are no reliable sperm function tests, different sperm quality criteria are used by different clinics when considering allocating couples to treatments such as IUI, IVF or ICSI. There is no evidence or even consensus-based recommendations for good practice to support any particular sperm quality criteria for ICSI or other forms of assisted reproduction.

If only nonviable spermatozoa are isolated from the semen, surgical sperm recovery from the testis may be required to obtain viable sperm for IVF and/or ICSI (see Section 12.8). Alternatively, assisted reproduction uses sperm isolated from the semen or urine following physical methods involving vibration or electrostimulation to induce ejaculation (see Section 12.3).

Donor insemination (see Chapter 14) is an alternative treatment option for male factor subfertility, and is the principal option for the one in 200 of infertile men (and their partners) who have no sperm because of anorchia or complete germ-cell aplasia.

World Health Organization Group I ovulation disorders

Women with this problem will include those with low body weight and restoration of body weight may help to resume ovulation and restore fertility (see Section 3.6). Otherwise, treatment for this group of women has included GnRH, a hypothalamic hormone which, if given in pulses, induces the appropriate release of the pituitary gonadotrophin hormones FSH and LH (see Section 7.9). Alternatively, women can be treated with gonadotrophins (see Section 7.4).

World Health Organization Group II ovulation disorders

Treatment strategies in women with WHO Group II ovulation disorders, such as PCOS, include three established options. These options are the use of oral anti-oestrogens, the use of ovarian drilling and the use of injectable gonadotrophins. Another option is the use of oral metformin, which is not currently licensed for this indication. These treatment options are discussed in detail in Chapter 7.

World Health Organization Group III ovulation disorders

Ovarian failure and its management by oocyte donation are discussed in Chapter 15.

Hyperprolactinaemia

Where a diagnosis of hyperprolactinaemia is made, the management must include investigation to exclude the presence of a pituitary adenoma or extrapituitary tumours, which would require specific management before proceeding with fertility treatment. Dopamine agonists are widely used in the treatment of hyperprolactinaemia.417 There are several newer dopamine agonists but the effects of these on reproductive outcomes has not been evaluated fully, and their safety in women intending to become pregnant has not been established (see Section 7.10).

Tubal disease

The management of tubal disease traditionally involved surgery but IVF has become the predominant approach in recent years. The surgical approaches to management of tubal disease are discussed in Chapter 8. The management of tubal disease by IVF does not generally differ from the use of IVF for other indications (see Chapter 11).

Endometriosis

In the management of fertility problems associated with endometriosis, it is widely accepted that minimal and mild endometriosis may be considered equivalent to unexplained infertility and managed accordingly (see below). Medical management, in the absence of pelvic pain, is no longer thought to be an appropriate strategy (see Section 9.1). Surgical management by the ablation of endometriotic lesions and the removal of endometriomas is an established approach (see Section 9.2) but many women with endometriosis of all severities choose to have IVF treatment (see Chapter 11).

Uterine abnormalities

Uterine abnormalities such as adhesions, polyps, submucous leiomyomas and septae may be associated with infertility but their role in causing infertility is not clear. Surgical approaches to management of uterine abnormalities are discussed in Chapter 8.

Unexplained fertility problems

Unexplained (idiopathic) 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 female infertility418 and 8–28% of infertility in couples.1,3 In couples with unexplained infertility, the chance of spontaneous conception will relate to the duration of infertility (see Section 3.1). The spontaneous cumulative pregnancy rate has been estimated to lie between 33% and 60% at three years419,420 and 36% at seven years, although this will be influenced by other known prognostic factors such as the age of the woman.421–425 [Evidence level 2b–3] Data based on follow-up studies showed that the prognosis for pregnancy remained high without treatment until after three years duration of unexplained infertility. With longer duration of infertility, the prognosis falls by 25% per year and the prognosis is much poorer in women aged 35 years or over.422

Many couples who have unexplained fertility problems will be managed expectantly initially and further management is essentially empirical and arises mainly from the time factor.426. Anti-oestrogens (usually clomifene citrate; see Section 7.1) and IUI (see Chapter 10) are usually used as intermediate options, with the final stage of management being IVF treatment (see Chapter 11). There is no evidence to suggest that ICSI improves pregnancy rates above those achieved with IVF in unexplained fertility problems (see Section 13.3).

Four further treatments that have been used in the management of unexplained infertility are tubal flushing (see Section 5.4), medical treatment with danazol or bromocriptine (see Section 7.10) and fallopian sperm perfusion (see Section 10.5).

Grade a: rapid progressive motility (sperm moving swiftly, usually in a straight line).

Grade b: slow or sluggish progressive motility (sperm may be less linear in their progression).

Currently being reassessed by the World Health Organization. In the interim, the proportion of normal forms accepted by laboratories in the United Kingdom is either the earlier World Health Organization lower limit of 30% or 15% based on strict morphological criteria.

Footnotes

*

Grade a: rapid progressive motility (sperm moving swiftly, usually in a straight line).

**

Grade b: slow or sluggish progressive motility (sperm may be less linear in their progression).

***

Currently being reassessed by the World Health Organization. In the interim, the proportion of normal forms accepted by laboratories in the United Kingdom is either the earlier World Health Organization lower limit of 30% or 15% based on strict morphological criteria.

Copyright © 2004, National Collaborating Centre for Women’s and Children’s Health.

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The use of registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant laws and regulations and therefore for general use.

Bookshelf ID: NBK45923
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