The cause of infertility is unexplained in about 22–28% of all infertile couples. The prognosis for spontaneous pregnancy in such couples is better than in those with diagnosed causes of infertility. Traditional treatment options in this group have included expectant management, clomifene citrate, intrauterine insemination with (super ovulation plus intrauterine insemination) or without (intrauterine insemination) super ovulation and in-vitro fertilisation. Despite being more expensive, empirical clomifene and intrauterine insemination in an unstimulated cycle do not improve the chances of live birth compared with expectant management. Although unlikely to be more effective than no treatment in couples with a reasonably good prognosis, super ovulation plus intrauterine insemination has been shown to be more effective than intrauterine insemination. Any potential advantage of super ovulation plus intrauterine insemination has to be balanced against the relatively high risk of iatrogenic multiple pregnancy. In-vitro fertilisation remains the treatment of choice in longstanding unresolved infertility and, when coupled with the use of elective single embryo transfer, can minimise the risk of multiple pregnancies. Data from randomised trials confirming the superiority of in-vitro fertilisation over expectant management is limited.
Introduction
Infertility has been defined as failure to conceive after regular unprotected sexual intercourse for 1 year. This definition reflects the prognostic approach to this condition, based on the knowledge that, in a general population, 84% of all women are expected to conceive within 1 year of regular unprotected sexual intercourse. This figure rises to 92% after 2 years, and 93% after 3 years. The term ‘unexplained infertility’ refers to infertile couples in whom standard investigations, including tests of ovulation, tubal patency and semen analysis, are normal. The prevalence of unexplained infertility has been shown to vary from 22–28%. A more recent study puts the prevalence among couples attending a fertility clinic to be 21% in women aged under 35 years, and 26% in women over 35 years.
Standard work-up for infertility
The basic fertility work up needs to balance the cost and invasive nature of currently available investigations against their value in informing clinical decision making. The National Institute for Health and Clinical Excellence in the UK and the American Society of Reproductive Medicine in the USA have recommended the following essential tests: semen analysis, assessment of ovulation and evaluation of tubal patency by hysterosalpingogram or laparoscopy. The place of laparoscopy versus hysterosalpingogram continues to be debated, but it is felt that laparoscopy should be considered when severe endometriosis, pelvic adhesions or tubal disease is suspected.
The predictive value of the post-coital test has been questioned, and the result of a randomised-controlled trial has not shown improved pregnancy rates in women undergoing this investigation. Tests of ovarian reserve have been shown to be useful in predicting follicular response to controlled ovarian stimulation in in-vitro fertilisation (IVF), but their role in predicting pregnancy outcomes in infertile women is limited.
Standard work-up for infertility
The basic fertility work up needs to balance the cost and invasive nature of currently available investigations against their value in informing clinical decision making. The National Institute for Health and Clinical Excellence in the UK and the American Society of Reproductive Medicine in the USA have recommended the following essential tests: semen analysis, assessment of ovulation and evaluation of tubal patency by hysterosalpingogram or laparoscopy. The place of laparoscopy versus hysterosalpingogram continues to be debated, but it is felt that laparoscopy should be considered when severe endometriosis, pelvic adhesions or tubal disease is suspected.
The predictive value of the post-coital test has been questioned, and the result of a randomised-controlled trial has not shown improved pregnancy rates in women undergoing this investigation. Tests of ovarian reserve have been shown to be useful in predicting follicular response to controlled ovarian stimulation in in-vitro fertilisation (IVF), but their role in predicting pregnancy outcomes in infertile women is limited.
Causes of unexplained infertility
Standard fertility investigations are far from comprehensive and unable to identify subtle abnormalities in the reproductive pathway. The cause of unexplained infertility is, therefore, likely to be heterogeneous, with proposed causes ranging from endocrinological, immunological and genetic factors. In addition, compromised ovarian reserve is a factor which, while not always captured in the diagnostic pathway, can be responsible for a diagnosis of unexplained infertility in older women.
Some investigators have questioned the validity of the term ‘unexplained infertility’, as it is sensitive to the number, nature and quality of the tests used. Others have argued that the limited number of treatment options, and the overwhelming dependence on assisted reproduction, means that increasing the number of expensive and invasive tests is unlikely to change the treatment strategy in these couples.
Prognosis
Couples with unexplained infertility have a higher chance of spontaneous pregnancy than those where definite barriers to conception have been identified. A number of prognostic models have attempted to determine factors associated with spontaneous livebirth. A synthesis of these models has been produced by Hunault et al. and validated in a Dutch population. Prognostic factors are gradually emerging as key to informing clinical decision-making. The chance of pregnancy leading to live birth is influenced by female age, duration and previous pregnancy. For example, a woman aged 28 years with 2 years of unexplained infertility has been shown to have a 36% chance of conceiving over the next 12 months. The decision to treat a couple with unexplained infertility should, therefore, take into account their chances of spontaneous conception.
Management options
Expectant management
The relatively high possibility of spontaneous pregnancy in unexplained infertility supports the strategy of expectant management (i.e. active medical intervention). Couples are made aware of the fertile period and advised to continue regular unprotected intercourse. Observational data supporting this policy come from a number of sources. Snick et al. reported a cumulative pregnancy rate of 27.4% at 12 months in a cohort of couples seen in primary care, whereas Collins et al. observed a live birth rate of 14.3% at 12 months in the absence of treatment in a secondary- or tertiary-care setting. In a more recent study, most pregnancies occurring in a group of Dutch couples with unexplained infertility were shown to be conceived spontaneously with limited contribution from IVF.
In a Scottish randomised-controlled trial, 17% of women, with a mean age of 32 years and a median duration of infertility of 30 months, had a spontaneous pregnancy leading to live birth after 6 months of expectant management. A health-economic evaluation based on data from the same trial suggests that, despite being more expensive, empirical clomifene citrate and unstimulated intrauterine insemination (IUI) do not offer substantially better outcomes in this context. Dutch data on long-term follow up of couples with an intermediate prognosis, randomised initially to a 6-month period of either expectant management or super ovulation and IUI, show no difference in pregnancy rates between the groups, but an estimated saving of 2616 € in those managed expectantly.
Clomifene citrate
It is believed that oral clomifene citrate acts in unexplained infertility by correcting subtle ovulatory dysfunction and inducing multiple follicular growth. Women have been traditionally advised to start treatment with clomifene citrate at a dose of 50 mg once daily from day 2–6 of a menstrual cycle. A transvaginal ultrasound scan for follicle monitoring is advisable on day 12 to minimise the chance of multiple pregnancy. Couples are advised to have timed intercourse from day 12 of the cycle. Where excessive ovarian response is suspected, the cycle is cancelled and the couple asked to abstain from intercourse until the next period.
The use of clomifene has been popular in couples with unexplained infertility, mainly because it is inexpensive, non-invasive and requires little clinical monitoring. Concerns about multiple pregnancies induced by clomifene and a potential risk of ovarian cancer, however, underline the need to weigh the risks and benefits. In a randomised-controlled trial comparing clomifene with expectant management, live birth rates in the two treatment groups were comparable (OR 0.79, 95% CI 0.45 to 1.38), suggesting no benefit associated with clomifene use. The number needed to harm with clomifene citrate was 33 (i.e. treating 33 more women with clomifene would yield one less live birth compared with a strategy of expectant management).
A Cochrane review by Hughes et al. was unable to show improved pregnancy rates associated with clomifene citrate compared with expectant management after pooling data from two trials (OR 1.03, 95% CI 0.64 to 1.66). Aggregation of data from two studies where clomifene was used along with a human chorionic gonadotrophin (hCG) trigger also failed to show any benefit after active treatment (OR 1.55, 95% CI 0.58 to 4.60). Multiple pregnancy rates were similar in both the groups (OR 1.01, 95% CI 0.14 to 7.19) ( Table 1 ).
| Different interventions | Number of participants ( n = study) | Odds ratio | Confidence interval 95% | Comments | Number of participants ( n = study) | Odds ratio | CI 95% | Comments | Number of participants ( n = study) | Odds ratio | CI 95% | Comments |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Live birth rates | Pregnancy rates | Multiple pregnancy rates | ||||||||||
| IUI v IVF | 113 (1) | 1.96 | 0.88–4.36 | Not applicable | Not applicable | Not applicable | Not applicable | Not applicable | Not applicable | |||
| Expectant management v IVF | 51 (1) | 22 | 2.56–189.37 | 86 (2) | 3.24 | 1.07–9.80 | Heterogeneity I 2 = 80% | Not applicable | Not applicable | Not applicable | ||
| Stimulated IUI v IVF | 234 (2) | 1.09 | 0.74–1.59 | Treatment naive women | 232 (2) | 1.10 | 0.60–2.03 | Treatment naive women | 351 (3) | 0.64 | 0.31–1.29 | |
| Expectant management v IUI | 334 (1) | 1.60 | 0.92–2.78 | 334 (1) | 1.53 | 0.88–2.64 | 334 (1) | 0.50 | 0.04–5.53 | |||
| TI in stimulated cycle v IUI in stimulated cycles | 208 (2) | 1.59 | 0.88–2.88 | Heterogeneity I 2 = 72% | 517 (7) | 1.68 | 1.13–2.50 | 1 study: clomiphene citrate 4 studies: gonadotrophins 1 study: clomiphene citrate and gonadotrophins 1 study: clomiphene citrate or gonadotrophins | 316 (4) | 1.46 | 0.55–3.87 | 1 study: clomiphene citrate 2 studies: gonadotrophins 1 study: clomiphene citrate and gonadotrophins |
| IUI in natural v IUI in stimulated cycles | 396 (4) | 2.07 | 1.22–3.50 | 1 study: clomiphene citrate; 3 studies: gonadotrophins | 396 (4) | 2.14 | 1.26–3.61 | 1 study: clomiphene citrate 3 studies: gonadotrophins | 39 (1) | 3.00 | 0.11–78.27 | |
| Expectant management v IUI in stimulated cycle | 253 (1) | 0.82 | 0.45–1.49 | 253 (1) | 0.80 | 0.45–1.42 | 253 (1) | 2.00 | 0.18–22.34 | |||
| Clomiphene v expectant management | 385 (1) | 0.79 | 0.45–1.38 | 458 (2) | 1.03 | 0.64–1.66 | 385 (1) | 1.01 | 0.14–7.19 | |||
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