Abstract
It is estimated that infertility affects 1 in 7 heterosexual couples trying for a child in the United Kingdom. The main causes of infertility are as follows [Figure 5.1]
1 Size of the Problem
It is estimated that infertility affects 1 in 7 heterosexual couples trying for a child in the United Kingdom. The main causes of infertility are as follows [Figure 5.1]:
Unexplained (25%)
Ovulatory disorders (25%)
Tubal factor (20%)
Male factor (30%)
Uterine or peritoneal disorders (10%)[1]
The high proportion of couples with ‘unexplained infertility’ in this review from 2013 differs little from Hull’s classic publication in 1985 [2], even though there has been immense progress in reproductive technology in the interim.
Fertility problems may not be due to a single factor; in about 40% of cases, disorders are found both in the man and woman.
2 Definition of Unexplained Infertility
The term ‘subfertility’ is preferable to ‘infertility’ since few individuals have absolute sterility. Subfertility is usually defined as the inability to conceive after one year of regular unprotected intercourse. This definition is based on the cumulative chance of conception [3][Figure 5.2]. Healthy couples trying to conceive have a 25% chance of conception in the first cycle, 20% in the second, though this falls month-by-month as the most fertile couples achieve pregnancy [4] [Figure 5.3]. By the end of the first year, 85% of couples will have conceived.
Fig. 5.2 Cumulative probability of conceiving a clinical pregnancy by the number of menstrual cycles attempting to conceive for women in different age categories (assuming intercourse occurs at a frequency of 2 times/week). Prospective cohort study of 782 women recruited through 7 European centres (with permission) [3]
Fig. 5.3 Probability of conceiving on the next cycle for a couple who have not yet conceived; shown for female ages of 25, 30, 35 and 40 at the start of the attempt to conceive [4]
If the remaining couples are followed up, half of them will conceive in the second year. Thus these couples could not have had any major fertility problem; they may have been unlucky rather than infertile.
It follows that, in offering fertility investigations promptly after a year, we would expect to find no significant problem in up to half of the couples. They will be labelled as having ‘unexplained’ infertility and their prognosis is good. The standard recommendation to investigate at a year allows ‘triage’ of couples who will need intervention from those who can be reassured.
Unexplained infertility is a diagnosis of exclusion. Infertility is unexplained when the results of standard fertility evaluation are normal. These tests include a semen analysis, assessment of ovulation and tubal patency.
Practitioners should be aware of the limitations of these tests and consider carefully other factors before assigning a diagnosis of genuinely unexplained infertility. ‘Unexplained’ infertility may actually be ‘undiagnosed’.
3 Factors Influencing Fecundity
Female age is a major determinant of fecundity. The cumulative probability of conceiving a clinical pregnancy declines with age as shown in Figure 5.2. Between ages 25 and 30 the overwhelming majority of couples are of high fertility, and only a very small proportion are sterile. However, fecundity drops by the time female age reaches 35 and markedly by 40. The probability of conception in the first cycle falls to below 10% in women of 40 [Figure 5.3]. The same trend affects success rates from treatment. Investigations should therefore be offered earlier to older women, that is, at 6 months if aged over 35.
Currently in the United Kingdom, the average age of women at childbirth is 30 years [5] and demographic changes make age-related subfertility increasingly common.
Other factors that influence conception rates include smoking and obesity, which is increasingly important.
4 Diagnostic Tests
4.1 Male Factor
The assessment of male fertility relies on the semen analysis. Semen analysis results should be compared with the World Health Organization reference values [6]. These values were generated after analyzing a large bulk of data from published studies of recent fathers with time to pregnancy of less than 12 months. These fertile men had a wide range of semen parameters, and the calculated fifth centile was accepted as being the appropriate lower reference for normality. The reference range does not provide a ‘cut-off value’ to categorize men as infertile or fertile; semen parameters should be seen as a continuum.
Semen parameters within the reference range do not guarantee fertility. The prognostic value of semen components is influenced by frequency of sexual activity, the function of accessory sex glands and other unrecognized conditions. Besides, the semen analysis itself does not account for putative sperm dysfunctions such as immature chromatin or fragmented DNA. Therefore, the reference limits should not be over-interpreted to distinguish fertile from subfertile men.
4.2 Ovarian Function
Women undergoing investigations for infertility are usually offered a blood test to measure serum progesterone in the mid-luteal phase of their cycle to confirm ovulation. However, it is debatable whether this adds value to the fertility assessment, as a low value is usually due to mistimed sampling rather than anovulation. A regular menstrual cycle is a good indicator of ovulation, and many women now use home testing to confirm the luteinizing hormone (LH) surge. Moreover, proof of ovulation does not indicate egg quality, nor does it predict ovarian reserve or the likely ovarian response to gonadotrophin stimulation in any future fertility treatment. Infertility that is apparently unexplained warrants a more comprehensive assessment of ovarian function.
Female age is the best initial predictor of fertility potential. Follicle stimulating hormone (FSH), antral follicle count (AFC) and anti-Mullerian hormone (AMH) are generally the tests used to assess ovarian reserve.
FSH measurement is widely used as a marker of ovarian reserve but has serious limitations. FSH varies throughout a woman’s cycle and measurement must therefore be standardized by sampling in the early follicular phase. Moreover, FSH fluctuates from cycle to cycle, and these fluctuations become wider as ovarian reserve diminishes. Persistently raised FSH is a late marker of ovarian insufficiency. FSH should not be used independently as an exclusion criterion for low ovarian reserve in unexplained infertility. It is suitable as a screening test for counselling purposes and further diagnostic steps are needed.
The number of small antral follicles, sized 2–10 mm, in both ovaries as measured by ultrasound is clearly related to reproductive age and could well reflect the size of the remaining primordial follicle pool. Before the age of 37, the mean yearly decline of AFC is 4.8% compared with 11.7% thereafter [7]. AFC does not appear to provide added predictive value beyond AMH [8]. It may well be used as a screening test for possible ‘poor responders’ but not as a solitary test to exclude low ovarian reserve in unexplained infertility. Moreover, it is relatively expensive, requiring transvaginal ultrasound by a skilled operator.
AMH appears to be a more stable predictor of ovarian reserve as it does not fluctuate significantly through the menstrual cycle and is not operator-dependent. One should be aware of the different laboratory assays in use and interpret the results in the context of the woman’s age and history. It is not uncommon to see discrepancy between AMH and FSH where, without the result of low AMH, the subfertility would otherwise be unexplained.
4.3 Tubal Factor
Confirmation of tubal patency is the last in the triumvirate of standard investigations for subfertility. Hysterosalpingography (HSG) and Hysterosalpingo-contrast sonography (HyCoSy) are considered as first-line tests for tubal patency. Both are substitutes for laparoscopy which is widely accepted as the gold standard for diagnosing tubal occlusion and other pelvic pathology.
A systematic review with meta-analysis studied the diagnostic accuracy of HSG and HyCoSy in comparison with laparoscopy [9]. In nine studies all patients underwent HSG in addition to HyCoSy and laparoscopy allowing direct comparison of accuracy. The estimates of sensitivity and specificity were 0.95 (95% CI:0.78–0.99) and 0.93 (95% CI:0.89–0.96) for HyCoSy and 0.94 (95% CI:0.74–0.99) and 0.92 (95% CI:0.87–0.95) for HSG respectively. In conclusion, HyCoSy performs similarly to HSG. However, the technique of HyCoSy has the advantage of visualizing the ovaries, myometrium and the fallopian tubes in a single study; this can yield relevant findings such as polycystic ovarian morphology or suspected endometriosis.
Patent fallopian tubes on HSG or HyCoSy do not confirm that ovum pick-up will occur. HSG has almost no value in the detection of peritubal adhesions [10]. In a study to assess the value of laparoscopy in 265 subfertile women with normal HSG, 51% of laparoscopies were normal, whereas 49% had abnormal findings including endometriosis, adnexal adhesions, subserosal fibroids, ovarian neoplasms and salpingitis isthmica nodosa [11]. A history of dysmenorrhoea or dyspareunia increased the likelihood of detecting endometriosis from 41% to 64% and 69% respectively. The presence of both symptoms increased the likelihood to 83%. A careful history and pelvic examination is crucial before selecting the best test to confirm tubal patency.
5 Undiagnosed Subfertility
Diagnostic tests currently available are not exhaustive. Other subtle causes that have been proposed as underlying unexplained infertility include: tubal abnormal peristaltic or cilial activity, altered cervical mucus, genetic abnormalities, cytological abnormalities in oocytes, abnormal secretion of endometrial proteins, abnormalities in uterine perfusion and contractility, altered cell mediated immunity or abnormal T-cell and natural killer activity, abnormal follicle growth or reduced growth hormone sensitivity. Many of these abnormalities have been found in couples of normal fertility and proposed correction of the abnormality has not always been shown to improve fertility.
A balance needs to be struck between thorough and speculative investigation, accepting that subtle causes of subfertility may not be detectable, and moving on to management of the situation.
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