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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: Royal College of Obstetricians & Gynaecologists; 2013 Feb. (NICE Clinical Guidelines, No. 156.)

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Fertility: Assessment and Treatment for People with Fertility Problems.

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11Unexplained infertility

11.1. Introduction

Infertility is described as ‘unexplained’ when standard investigations, including semen analysis, tubal patency tests and assessment of ovulation (see Chapter 6), fail to identify any abnormalities or a specific diagnosis. It is therefore a diagnosis of exclusion. The literature on unexplained infertility is based on studies of heterosexual couples having vaginal intercourse.

Unexplained infertility affects about 15% of the couples seeking medical advice, although in some studies as many as 37% of people are categorized as being infertile for unexplained reasons (Aboulghar et al., 2003; Isaksson & Tiitinen, 2004). The reported incidence varies according to the age and selection criteria in the different studies (Aboulghar et al., 2003; Isaksson & Tiitinen, 2004). As unexplained infertility is a diagnosis of exclusion, it is dependent on the investigations undertaken before the diagnosis is applied (Aboulghar et al., 2003; Isaksson & Tiitinen, 2004). Many of these couples will conceive and go on to have a live birth without treatment. The spontaneous pregnancy rate in couples with unexplained infertility has been reported as 2% to 4% per menstrual cycle (Polyzos et al., 2008; Guzick et al., 1998).

Overall, about 15% of couples diagnosed with unexplained infertility will conceive without treatment within 1 year and 35% within 2 years (Isaksson & Tiitinen, 1998). However, the cumulative pregnancy rate over 3 years without treatment has been reported to be up to 80% in some groups (Guzick et al., 1998; Hull et al., 1985). Age of the woman is the most important predictor of successful conception without treatment with the rates falling at a greater rate after age 30 years (Isaksson & Tiitinen, 1998; Hunault et al., 2004) (see Figure 11.1). Some have suggested that unexplained infertility for more than 3 years is a poor prognostic feature for future chance of pregnancy, while others have not found this (Crosignani et al., 1993; Sundstrom et al., 1997; Isaksson & Tiitinen, 1998). As a result, couples with unexplained infertility are often given advice on lifestyle and successful conception, and told to return in a few months if they have still not become pregnant (this is known as ‘expectant management’), but no active treatment is recommended

Figure 11.1. Probability of a spontaneous live birth without treatment in a woman with either primary (no previous pregnancies) or secondary (previous pregnancies) infertility of 2 years duration, who is having regular intercourse and where she has normal ovulation, patent fallopian tubes and a partner with normal sperm motility (40%) (Hunault et al., 2004).

Figure 11.1

Probability of a spontaneous live birth without treatment in a woman with either primary (no previous pregnancies) or secondary (previous pregnancies) infertility of 2 years duration, who is having regular intercourse and where she has normal ovulation, (more...)

However, expectant management is often not attractive to couples (or their clinicians), both because they have been hoping for a pregnancy for some time and also because there is a preference for active treatment. As a result, a number of therapeutic approaches have been used to actively treat unexplained infertility. They are:

  • ovarian stimulation
  • intrauterine insemination (IUI) (see Chapter 12)
  • in vitro fertilisation (IVF) (see Chapter 15)

This chapter reviews the evidence for the clinical effectiveness of ovarian stimulation for unexplained infertility.

11.2. Ovarian stimulation for unexplained infertility

Introduction

One of the commonly used first-line treatments for unexplained infertility is oral clomifene citrate as it is believed to correct subtle ovulatory dysfunction. However, concerns about the risk of clomifene-induced multiple pregnancies and reports of a possible link with ovarian cancer underline the need to weigh the risks, costs and benefits of this drug. More recently, aromatase inhibitors have been used to stimulate the ovaries in women with unexplained infertility, but there have been some concerns about potential teratogenic effects of these drugs.

Review question

What is the effectiveness and safety of ovarian stimulation agents in women with unexplained infertility?

Description of included studies

Comparison of ovarian stimulating agents versus no ovarian stimulating agents (Table 11.1)

Table 11.1. GRADE findings for comparison of ovarian stimulation agents with no ovarian stimulation agents.

Table 11.1

GRADE findings for comparison of ovarian stimulation agents with no ovarian stimulation agents.

One randomised controlled trial (RCT) was identified that was relevant for this review (Bhattacharya et al., 2008). The study randomised women to receive clomifene citrate, expectant management or unstimulated IUI. The expectant management protocol in the study consisted of no active management for six months (that is, no clinic visits or interventions) with general advice given regarding the need for regular intercourse. No specific measures were recommended to the couples. Blinding was not possible in this study. The study included 580 couples, representing an estimated 2826 cycles.

Comparison of different types of ovarian stimulating agents (Table 11.2)

Table 11.2. GRADE findings for comparison of different ovarian stimulation agents.

Table 11.2

GRADE findings for comparison of different ovarian stimulation agents.

One RCT was identified that was relevant for this review (Badawy et al., 2009). The study randomised women to receive letrozole, anazstrozole or clomifene citrate, each with human chorionic gonadotrophin (hCG), and included a non-randomised age-matched group of women as controls (though data on this group is not used in this analysis). Blinding was not performed. The study included 996 couples, representing 1398 cycles.

No RCTs were identified that investigated the effectiveness of clomifene citrate compared with gonadotrophins or with placebo. No randomised controlled studies using a protocol that included gonadotrophin releasing hormone analogues were identified.

A 2010 Cochrane review was not included in this review (Hughes et al., 2010). The Cochrane review included seven studies, six of which did not meet the inclusion criteria for the current review. In two studies women received IUI. One of the studies was a crossover trial with data that could not be separated for each arm and two studies included couples without unexplained infertility (more than 10% in one study and 79% in another). In another study, all women received clomifene citrate before randomisation. The remaining study was included this review (Bhattacharya et al., 2008).

Evidence profile

Two evidence profiles are presented. They are a comparison of:

  • ovarian stimulation agents with no ovarian stimulation agents
  • different types of ovarian stimulation agents.

Evidence statements

Comparison of ovarian stimulation agents vs. no ovarian stimulation agents (Table 11.1)
Live full-term singleton births

There was no significant difference in the number of live births per woman with the use of clomifene citrate compared with expectant management (advice only).

Clinical pregnancies

There was no significant difference in the number of clinical pregnancies with the use of clomifene citrate compared with advice only.

Ovarian hyperstimulation syndrome

No evidence was reported.

Multiple pregnancies

There was no significant difference in the number of multiple pregnancies per woman or per pregnancy when comparing the use of clomifene citrate with advice.

Multiple births

No evidence was reported regarding the number of births from multiple pregnancies when comparing ovarian stimulating agents to non-drug treatment.

Adverse pregnancy outcomes

There was no significant difference in the number of miscarriages or the number of ectopic pregnancies when comparing clomifene citrate to advice.

Congenital abnormalities

No evidence was reported regarding the number of congenital abnormalities when comparing ovarian stimulating agents to non-drug treatment.

Patient satisfaction

Significantly more women receiving clomifene found the process of their treatment acceptable compared with the women who received general pregnancy advice alone. There was no significant difference in the number of women in the two groups who found the outcome of their treatment acceptable.

Anxiety or depression

There was no significant difference in the number of women with anxiety or depression with the use of clomifene citrate without hCG compared with general pregnancy advice alone.

Comparison of different types of ovarian stimulation agents (Table 11.2)
Live full-term singleton births

There were significantly more live births following use of clomifene citrate compared with letrozole.

Similarly, there were more live births following use of clomifene citrate compared with anastrozole though the difference was not statistically significant.

Clinical pregnancies

There was no significant difference in the number of clinical pregnancies per woman following the use of clomifene citrate compared with letrozole or compared with anastrozole.

Ovarian hyperstimulation syndrome

There was no significant difference in the number of cases of ovarian hyperstimulation syndrome (OHSS) following the use of clomifene citrate compared with letrozole or compared with anastrozole.

Multiple pregnancies

There was no significant difference in the number of multiple pregnancies per woman or per pregnancy following the use of clomifene citrate compared with letrozole or compared with anastrozole.

Multiple births

No evidence was reported that compared the number of births resulting from multiple pregnancies after letrozole compared with clomifene citrate, or after anastrozole compared with clomifene citrate.

Adverse pregnancy outcomes

There was no significant difference in the number of miscarriages or ectopic pregnancies per woman or per pregnancy following the use of clomifene citrate compared with letrozole or compared with anastrozole.

Congenital abnormalities

There were no statistically significant differences in the number of congenital abnormalities per woman or per pregnancy when using clomifene citrate compared with letrozole or compared with anastrozole.

Patient satisfaction

No evidence was reported that compared patient satisfaction after clomifene citrate with patient satisfaction after letrozole or anastrozole.

Anxiety or depression

No evidence was reported that compared the number of women with anxiety or depression after clomifene citrate with the number of women with anxiety or depression after letrozole or anastrozole.

Health economics profile

As ovarian stimulation is not effective in women with unexplained infertility it will not be cost effective and thus no further health economic input is required.

Evidence to recommendations

Relative value placed on the outcomes considered

The guideline development group (GDG) considered rates of clinical pregnancies and live full-time singleton births to be important outcomes which allow clinicians to inform couples of their chances of conception and having a baby. The other important outcomes considered in this review were the adverse effects of the treatments. These also must be included in discussion with couples so that they are fully informed of both risks and benefits of treatment.

Consideration of clinical benefits and harms

The evidence for ovarian stimulation agents did not demonstrate any significant difference in the number of clinical pregnancies or live births associated with the use of clomifene citrate compared with expectant management or general pregnancy advice. There were significantly more live births to women who were offered clomifene citrate compared with letrozole, although this was of borderline significance. There was no significant difference in clinical pregnancy rates. The GDG inferred from this that aromatase inhibitors are also no more effective than general pregnancy advice.

The number of ectopic pregnancies and miscarriages did not differ significantly between clomifene citrate and general advice, or between clomifene citrate and letrozole or anastrozole. There was also no reported difference in congenital abnormalities or rates of anxiety or depression.

The evidence demonstrated that treatment with clomifene citrate was more acceptable to women than advice alone. However, the GDG view was that this may have reflected a societal preference for action when faced with unexplained infertility.

The evidence for letrozole or anastrozole reported significantly fewer clinical pregnancies or live births than clomifene citrate alone. There were also no differences in multiple pregnancy or adverse outcomes. The GDG acknowledged that there are ongoing trials investigating the safety of letrozole. The GDG believed, therefore, that the use of aromatase inhibitors could not be recommended in women with unexplained infertility.

After considering all the available evidence, the GDG’s view was that ovarian stimulation with clomifene citrate, letrozole or anastrozole in women with unexplained infertility should not be offered in the NHS in light of the current evidence.

Consideration of health benefits and resource uses

An intervention that is not shown to be effective is not cost effective. An economic evaluation is not required in this case. The use of clomifene citrate and other ovarian stimulation agents costs more to deliver than general pregnancy advice offered on one occasion (‘expectant management’) and there is no evidence that it is more effective in women with unexplained infertility.

Quality of evidence

Despite being reported in RCTs, the data ranged from moderate to very low in quality. Limitations of the studies included a lack of power analysis, mixed populations and ambiguous outcome definitions.

Other considerations

Limitations of the evidence

The GDG was concerned about the limitations in the evidence, specifically with data on congenital abnormalities. There were only a small number of births in each study, which means the comparison was underpowered. The GDG consensus was that the background incidence of congenital abnormalities is 2%.

No studies using random allocation and double blinding reported on clomifene citrate compared with no treatment or compared with a placebo. This may have affected the satisfaction data. The GDG view was that women may report more satisfaction receiving a placebo than general pregnancy advice.

The GDG was unable to make evidence-based recommendations on what specific advice should be given to women as no studies were identified that evaluate this intervention. However, in the absence of evidence, the GDG made recommendations on the advice that should be offered to infertile couples, and in particular what should comprise ‘expectant management’, in Chapter 6 and Chapter 12.

Expectant management

The GDG discussed what constituted expectant management for groups of women with the diagnosis of unexplained infertility. The GDG concluded that expectant management should consist of supportively offering an individual or couple information and advice about the regularity and timing of intercourse and any lifestyle changes which might improve their chances of conceiving. It does not involve active clinical or therapeutic interventions.

For people having unprotected regular vaginal intercourse conception rates are shown in Figure 5.1. In summary, over 80% of couples where the women is aged 39 years or younger will conceive within 12 months. The figure is over 85% where the woman is less than 35 years old. If the couple continue to have unprotected regular intercourse for another 12 months, making 24 months in total, cumulative pregnancy success rates rise by about a further 15%.

The GDG did note that even after 2 years without a live birth, couples with unexplained infertility still had a chance of natural conception, but the additional cumulative success rates in the third year would be small. In addition, conception rates decline with the age of the woman. The GDG felt that this information should be explained early on to women with the diagnosis of unexplained infertility (see Figure 5.1). Thus, the GDG’s view was that after 2 years of unexplained infertility IVF should be considered. Furthermore, of the 2 years, up to a maximum of 1 year should be included before investigation referal.

The cost effectiveness of IVF under specific circumstances is considered elsewhere (see Chapters 14 and 15) but the GDG consensus view was that women with a diagnosis of unexplained fertility should be told at the start of expectant management that they will be considered for IVF (but it will not necessarily be offered) after a total of 2 years without conception. This provides women diagnosed with unexplained infertility a clear idea of the period of time they should continue with regular unprotected vaginal intercourse before IVF will be considered. The GDG view was that this would represent a positive approach and lessen the anxiety and depression identified in the expectant management group in the trial reported here.

Other groups requiring special consideration

Three separate groups who use either donor or partner insemination to conceive were considered under this heading:

  • people who are unable to, or would find it very difficult to have vaginal intercourse (such as people with with a clinically diagnosed physical disability or psychosexual problem)
  • people who are in same-sex relationships
  • people with conditions that require specific consideration in relation to methods of conception (such as couples where the male is HIV positive).

The term ‘unexplained infertility’ is not normally used in these groups. Nevertheless, the GDG was of the view that in such cases where there was normal ovulation, patent fallopian tubes and normal semenalysis, a failure to conceive after 6 cycles of insemination should be followed by an intervention that would equate to that offered to those people who have been recommended expectant management rather than proceeding directly to IVF. These issues are discussed in more detail in Chapter 12.

Recommendations

NumberRecommendation
113Do not offer oral ovarian stimulation agents (such as clomifene citrate, anastrozole or letrozole) to women with unexplained infertility. [new 2013]
114Inform women with unexplained infertility that clomifene citrate as a stand-alone treatment does not increase the chances of a pregnancy or a live birth. [new 2013]
115Advise women with unexplained infertility who are having regular unprotected sexual intercourse to try to conceive for a total of 2 years (this can include up to 1 year before their fertility investigations) before IVF will be considered. [new 2013]
116Offer IVF treatment (see recommendations 129–130) to women with unexplained infertility who have not conceived after 2 years (this can include up to 1 year before their fertility investigations) of regular unprotected sexual intercourse. [new 2013]
NumberResearch recommendation
RR 21What is the optimum period of expectant management for women of different age groups before invasive treatment such as IVF is considered?
Why this is important
Where there is no known cause for infertility, expectant management increases the cumulative chances of successful conception. However, the chances of a live birth both by natural conception and by using assisted reproductive technology decline with advancing age because of a woman’s decreasing ovarian reserve. The guideline currently recommends a shorter period of expectant management for women who are 36 years or older. This is a very crude cut-off. If there were better evidence it might be possible to customise the period of expectant management based on a woman’s age, including longer periods of expectant management for younger women.
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Copyright © 2013, National Collaborating Centre for Women’s and Children’s Health.

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Bookshelf ID: NBK327760

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