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Current management of unexplained subfertility

Summary

Treatment of infertility has made substantial progress over the last two decades. Infertility is said to be unexplained when a couple do not conceive after 1 year and no definite cause could be diagnosed. Unexplained subfertility poses difficulty in management due to lack of specific abnormality and treatment is generally empiric. In this article, we review the current state of the art efficient and cost-effective infertility care to permit the treatment of a larger number of patients with unexplained subfertility within a reasonable time period.

Introduction

Many couples seeking infertility care do not have identifiable problems to explain their subfertility. Unexplained infertility is lack of conception after one year in couples for whom the results of a standard infertility evaluation are normal. Infertility work up would normally include a semen analysis, a test of tubal patency (hysterosalingogram and/or laparoscopy-hysteroscopy) and assessment of ovulation by serum progesterone.

Treatment – independent fertility trends

Approximately one in five infertile couples have unexplained infertility. This would inevitably include fertile couples who have failed to conceive by chance alone and those with subtle abnormalities as yet undetectable by current standard investigations. Studies of couples with unexplained subfertility who are followed without any treatment report cumulative pregnancy rates between 30% and 80% over three years of follow up depending on female's age, duration of infertility and previous pregnancy history. Therefore, an initial period of expectancy with timed intercourse may be worthwhile, especially in young couples with short duration of infertility (less than 2 years) to make for this spontaneous pregnancy rate. During this period of expectancy, other health problems that may impact fertility or pose some risk during future pregnancy should be. Examples include giving up smoking, abstaining from or at least reducing alcohol consumption to fewer than 5 units per week and optimising pre-existing medical conditions. Normalisation of the female's body mass index should also be encouraged. Both underweight and overweight women are more likely to experience delayed conception and, when pregnant, are at greater risk of miscarriage and premature.

After three years of infertility, the likelihood of spontaneous conception is generally reduced. Expected pregnancy rates were shown to decrease by 9% for every additional year without treatment and by 2% for each year of female age above 26 years and fertility treatment becomes indicated. The monthly fecundity rates after 3 years of infertility in unexplained couples is 1% to 3%.

Management plan

When considering a management strategy for unexplained subfertility, one should consider several issues. These include efficacy over the background incidence of spontaneous conception, cost-effectiveness and adverse effects of the proposed treatment.

The progress of infertility treatment over the last 2 decades has been remarkable and the number of patients who conceive with treatment has increased. The introduction of a number of treatment modalities as intrauterine insemination (IUI), in-vitro fertilisation (IVF) and related techniques has revolutionised the management of unexplained subfertility. Because couples with unexplained subfertility are often frustrated by the protracted course of investigation and the relatively long duration of infertility, it is reasonable to adopt a simple, straight forward, efficient and cost-effective treatment protocol that can be accomplished within a reasonable time frame with minimal physical and economic burden to the subfertile couple.

a) Ovarian stimulation and timed intercourse

Over the past two decades, there has been a marked increase in the use of ovarian stimulation regimens in fertility treatment in general and particularly in the management of unexplained subfertility. The rationale behind this is to overcome a subtle defect in ovulatory function not detected with routine diagnostic studies and/or to enhance the likelihood of pregnancy by increasing the number of eggs available for fertilisation.

The effectiveness of clomiphene citrate (CC) has been demonstrated in the treatment of infertility associated with no or irregular ovulation due to polycystic ovarian syndrome. The efficacy of CC (used in a daily dose ranging between 50 and 150 mg) in treatment of unexplained subfertility has been recently questioned. Whereas in a meta-analysis of eleven randomised controlled trials, there was a statistically significant improvement in pregnancy rate following CC use with the odds of achieving a clinical pregnancy after CC treatment was doubled compared to expectant management, a more recent high quality pragmatic randomised study suggested that CC was not more effective than no treatment. Given the low cost, ease of administration and low risk of side effects associated with its use, CC may represent a worthwhile treatment option Nevertheless, before making this treatment choice, multiple pregnancy risk should be taken into account and thoroughly discussed. Further more, if pregnancy has not been achieved after six ovulatory cycles, further CC treatment is not recommended, as pregnancy rate significantly declines afterwards and alternative means may be more appropriate.

b) Superovulation and Intrauterine Insemination (IUI)

For patients who do not achieve a pregnancy whilst on CC, the next appropriate step in the treatment protocol consists of ovulation induction using injectable gonadotrphins (superovulation or controlled ovarian stimulation – COS) and IUI. The rationale behind IUI is to increase the density of motile sperm reaching the ampullary segment of the fallopian tube and overcome an undiagnosed cervical factor. Bringing together more than one mature oocyte and a great number of highly motile sperm would enhance the chances of pregnancy for treated patients. Thus, pregnancy rates between 10% to 18% can be expected after each COS/IUI treatment cycle, with a cumulative pregnancy rate of approximately 25%-30% after three cycles. Moreover, studies have demonstrated the cost-effectiveness of COS/IUI treatment before resorting to more invasive and expensive forms of assisted conception. Finally, when attempting COS/IUI, risks of superovulation, which include ovarian hyperstimulation and increased risk of multiple pregnancy, must be carefully considered.

c) In Vitro Fertilisation (IVF) and related techniques

Continuing COS/IUI treatment for more than three cycles is often less rewarding. Studies have shown that the effectiveness of ovarian stimulation with exogenous gonadotrophins decreases after two to four cycles. Failure to conceive after three or a maximum of four trials of COS/IUI should prompt serious consideration of the next step in the treatment protocol – IVF. The rationale for such approach is clear; unexplained subfertility in this subset of patients may be due to a fundamental defect in oocyte pick-up by the fallopian tubes, in fertilisation or in embryo transfer to the uterus – factors readily overcome through IVF.

Encouraging pregnancy rates approaching 45% per treatment cycle can be achieved with IVF and embryo transfer among patients with unexplained who fail to conceive with COS/IUI. Furthermore, it may also have a diagnostic value in some of these cases because occult defects in the oocyte or sperm fertilisation potential may be uncovered during an IVF cycle and would feature as reduced fertilisation or abnormal embryo development. Between 15% and 30% of couples having IVF for unexplained infertility may exhibit absent or low fertilisation after conventional IVF, a possible explanation for their unexplained infertility. This group would benefit from the addition of the technique intracytoplasmic sperm injection (ICSI) to their treatment. ICSI was originally introduced for the treatment of severe male factor infertility. However, it was shown in randomised studies that couples with unexplained subfertility failing to conceive with IUI and undergoing IVF have an 11% to 22% risk of total fertilisation failure of retrieved oocytes and that this problem can be largely overcome by using ICSI in at least some, if not all, oocytes. Injecting a sperm directly into the oocyte can circumvent some of the difficulties that may encounter the sperm during the process of fertilisation and further enhance cycle outcome.

IVF with or without ICSI has been shown to be a more cost-effective treatment after failure of 3 COS/IUI cycles. The cost-effectiveness of IVF is likely to improve as success rates show continued improvements over the course of time. In addition, the usefulness of embryo selection and practices to reduce the likelihood of multiple pregnancies, without reduction in pregnancy rates, will undoubtedly enhance cost-effectiveness.

Treatment outcome

Based on this management plan, about 80% of couples who proceed through all treatment steps can expect to conceive within a time frame of 18-24 months. This algorithm will also identify a group of patients who may need a different treatment approach such as the use of donated oocytes in patients with markedly reduced ovarian reserve.

Patients should be counselled that an 80% chance of conception could only be expected for couples who stay in the course of treatment. Moreover, to achieve this high chance of conception, this treatment algorithm, ideally, should be provided through a fully integrated system of service that guarantees smooth transition from one step to the next to all patients. It should also be remembered that the optimal treatment strategy needs to be based on couple characteristics such as female age, duration of subfertility, treatment efficacy, side-effect profile and cost considerations.

Conclusion

Advances in reproductive technology have enabled the successful treatment of an increasing number of subfertile couples. This pragmatic cost-effective and time-efficient protocol for management of unexplained subfertility is likely to benefit the majority of couples whom are fully investigated but remain disappointed by the long delay of conception and lack of any obvious cause for their infertility.

Useful contact

Infertility Network UK

Tel: 0800 008 7464

Website: www.infertilitynetworkuk.com

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