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Author Topic: Unexplained Infertility Part 1  (Read 6217 times)
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Unexplained infertility: an update and review of practice

Homerton University Hospital, Homerton Row, London E96SR, UK

Received 22 June 2011; received in revised form 20 February 2012; accepted 23 February 2012. published online 09 March 2012.

Abstract
Of the couples unable to conceive without any identifiable cause, 30% are defined as having unexplained infertility. Management depends on duration of infertility and age of female partner. This review describes and comments on the definition and evidence for the management of unexplained infertility. A literature search was conducted in EMBASE, Medline, Ovid and Cochrane Database of Systematic reviews using the terms ‘infertility’, ‘unexplained infertility’, ‘idiopathic infertility’, ‘definition of infertility’, ‘treatment options’, ‘intrauterine insemination’, ‘ovulation induction’, ‘Fallopian tube sperm’, ‘GIFT’ and ‘IVF’. There is no uniform definition for unexplained infertility. This varies in the literature depending on the duration of infertility and the age of the female partner. The treatment of unexplained infertility is empirical and many different regimens have been used. Among these are expectant management, ovulation stimulation with clomiphene citrate, gonadotrophins and aromatase inhibitors, Fallopian tube sperm perfusion, tubal flushing, intrauterine insemination, gamete intra-Fallopian transfer and IVF. The standard protocol is to progress from low-technology to high-technology treatment options. On the best available evidence, an algorithm for management is suggested. There is a definite need for multicentre randomized controlled trials to identify the best treatment option in unexplained infertility using a standard definition.

Of the couples unable to conceive without any identifiable cause, 30% are defined as having unexplained infertility. The management for unexplained infertility is empirical. There is no uniform definition for unexplained infertility. This varies in the literature depending on the duration of infertility and the age of the female partner. It may arise in two ways: in some couples it may be due to some undetectable factor and in others it may be due to reduced fecundity. The treatment of unexplained infertility is empirical and many different regimens have been used. Among these various treatment options are expectant management, ovulation stimulation with clomiphene citrate, gonadotrophins and other agents, Fallopian tube sperm perfusion, tubal flushing, intrauterine insemination, gamete intra-Fallopian transfer and IVF. There is no definite evidence to show that any one treatment is better than the other. Treatment of unexplained infertility is very much dependent on availability of resources and patients’ age and duration of infertility. The standard protocol is to proceed from low-tech to high-tech treatment options. There is a definite need for multicentre randomized controlled trials to identify the best treatment option in unexplained infertility.


Introduction

Unexplained infertility is a subject on which agreement is rarely found among practitioners. The time was thus felt appropriate to perform a literature search (Medline, EMBASE and Cochrane Database of Systematic Reviews) in the hope that it would point the way to agreement (mainly definition and management) and to promote randomized controlled trials regarding management.

Unexplained infertility usually refers to a diagnosis (or lack of diagnosis) made in couples in whom all the standard investigations such as tests of ovulation, tubal patency and semen analysis are normal. Unexplained infertility is a term that has been applied to as many as 30–40% of infertile couples (Smith et al., 2003). The potential causes of unexplained infertility have been described as disturbances in endocrinological balance, immunology and genetic and reproductive physiology (Pellicer et al., 1998).

A couple is usually referred for investigation after trying unsuccessfully to conceive for a year. For the infertile couple, a ‘diagnosis’ of unexplained infertility may be very frustrating and is often interpreted by them as meaning that if there is no explanation for the cause of infertility, there is, therefore, no effective treatment. Importantly, the prognosis is worse when the duration of infertility exceeds 3years and the female partner is >35 years of age (Collins et al., 1995). If the duration of infertility is less than 2years, the prognosis is relatively good even without therapy, unless the female partner is >35 years. Treatment has generally been indicated if duration is more than 2 years or the female is >35 years (Bhattacharya et al., 2008, Collins et al., 1995). According to the American Society of Reproductive Medicine (ASRM, 1992) standard infertility evaluation includes a semen analysis, post-coital test, assessment of ovulation and a hysterosalpingogram and, if indicated, laparoscopy. However, the Practice Committee bulletin on unexplained infertility (ASRM, 2006) mentioned that the basic evaluation should provide evidence of ovulation, adequate sperm production and patency of Fallopian tubes. Even highly sophisticated tests may fail to detect very subtle abnormalities responsible for subfertility. Although estimates vary, the likelihood that all such tests for an infertile couple are all normal (i.e. that the couple has unexplained infertility) is approximately 15% (Guzick et al., 1994).

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Definition

The ‘diagnosis’ of unexplained infertility is made when tubal patency (hysterosalpingogram and/or laparoscopy), normal ovulatory function (basal body temperature, cervical mucus changes, serum LH surge or mid-luteal progesterone) and normal semen analysis are established.

Infertility is usually described as 1 year of unwanted non-conception with unprotected intercourse in the fertile phase of the menstrual cycle (Evers, 2002). Unexplained infertility may arise in two ways. Some couples may have some subtle, undetected defect in the reproductive process, while in others conception is delayed by chance alone, as the couples fecundity may be on the lower side of the normal distribution.

Should a normal couple who do not conceive within 1 year be defined as having unexplained infertility? Prognostic factors related to a higher cumulative pregnancy rate are duration of infertility less than 2 years, a previous pregnancy in the same relationship and female age <30 years. Controversially, Gnoth et al. (2003) concluded from prospective studies that the question of subfertility must be raised after six cycles of unprotected intercourse without conception regardless of age. On the other hand, it has been stated that, in cases with a good prognosis, couple should be encouraged to wait because they have a similar chance of achieving pregnancy without treatment (Stolwijk et al., 1996, Stolwijk et al., 2000). Cumulative pregnancy rates are generally higher among couples with a shorter duration of infertility (Glazener et al., 1987). Each additional month of infertility beyond the average reduces the chance of pregnancy by 2%, or about 25%/year. Similarly, for each year of the female partner’s age >30, the pregnancy rate is reduced by 9%. The definition of unexplained infertility may vary in women aged >40. The main factor for infertility in this group is reduced ovarian reserve but since this process is not always estimated in the diagnostic approach, many of these women will be diagnosed with unexplained infertility.

According to guidelines from the National Institute for Health and Clinical Excellence (NICE, 2004), failure to conceive after a period of 2 years should be defined as infertility. Couples can be referred for investigations after 1 year. In the general population, of couples attempting conception, 84% will conceive after 1 year and 92% will conceive after 2 years.

An enormous variation in suggested definitions is seen in the literature. Hull et al. (1985) first described the definition of infertility as failure to conceive over a period of 3 years after unprotected intercourse in the face of normal baseline investigations. Later, Collins and Crosignani (1992) wrote of failure to conceive over a period of 1 year after unprotected intercourse in the face of normal investigations. Evers (2002) wrote that infertility is described as 1 year of unwanted non-conception with unprotected intercourse in the fertile phase of the menstrual cycle. Gnoth et al. (2003) defined infertility as failure to conceive after six cycles of unprotected intercourse irrespective of age.


Materials and methods

Literature searches were performed in Medline, Embase, PubMed and Cochrane Library for a systematic review period ranging from 1985 to 2011. A combination of medical subject headings and text words were used to generate sets of citations related to unexplained infertility. The terms used were ‘infertility’, ‘unexplained infertility’, ‘idiopathic infertility’, ‘definition of infertility’, ‘treatment options’, ‘IVF’, ‘intrauterine insemination’, ‘ovulation induction’, ‘Fallopian tube sperm’, ‘GIFT’ and ‘IVF’. These words were combined using ‘AND’ to generate a set of citations relevant to the topic. The reference list of all known primary and review articles were examined to identify cited articles not captured by electronic searches. The results of the search are summarized in Figure 1.
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Prevalence

The proportion of couples suffering from unexplained infertility is popularly quoted as 16% but the range varies from 0% to 37%. In a study (Collins and Rowe, 1989) of 11 Canadian centres where a uniform protocol had been used, the proportion of unexplained infertility ranged from 8% to 37% (in all 470 of 2106 couples, or 22%). These differences were due to differences in the age of the female partners and the duration of infertility, whereas male age, occupation, coital frequency and other factors were not important (Collins and Rowe, 1989). There was a small excess of professional women but that was probably due to an age effect.

The prevalence of unexplained infertility is still truly debatable because the diagnosis of unexplained infertility is due to lack of a specific test or may be due to misdiagnosis. The most frequent reasons for the latter are endometriosis, mild degrees of tubal infertility, premature ovarian failure and immunological causes. Although these subtle causes may be responsible for so-called unexplained infertility, it may not be in the best interests of the patient to subject them to all these invasive tests. The result may well only fulfil clinical curiosity without helping in better clinical decision making.

Possible reasons for unexplained infertility

The current knowledge of the reproductive system assessment is far from complete. There are many steps which are not routinely evaluated or unavailable, including cervical mucus, capacitation or the ability of spermatozoa to negotiate the uterotubal junction. There is also a need for a test for the acrosome reaction and the ability to bind to and penetrate the zona pellucida. There is no infallible test which can provide fertilization profiles of spermatozoa. Similar limitations are also present in female fertility assessment. Defective oocytes, especially in ageing patients, are an important cause of infertility which is difficult to assess. Tubal patency does not assess the characteristics of bidirectional tubal motility which is important for embryo transport. Tests for the evaluation of the chance for successful implantation are not available. Random delays in conception do not appear to account in a major way for unexplained infertility, whereas a non-random age effect is important. Therefore, the ideal definition for unexplained infertility should be a couple with a real but unobservable defect leading to infertility which may be prolonged and permanent. One study (Gleicher and Barad, 2006) took the extreme view that the term ‘unexplained infertility’ should be abandoned as it is so dependent on the quantity and quality of the diagnostic tests performed. It only remains to speculate whether improved diagnostic accuracy using little-performed and often expensive tests would actually improve the eventual prognosis.



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Treatment options
Expectant management
High spontaneous pregnancy rates have been observed in couples with unexplained in fertility (Eimers et al., 1994, Collins et al., 1995, Snick et al., 1997). However, in another review (Guzick et al., 1998) the average cycle fecundity in the untreated group was 3.8% in six randomized studies and 1.8% in 11 non-randomized trials.

Guidelines from the Royal College of Obstetricians and Gynaecologists (RCOG, 1998) have recommended that couples should have tried expectant treatment before assisted reproductive treatment. The chance of such a pregnancy depends mainly on patient’s age, duration of infertility and history of any other pregnancy in the same relationship.

Another study by Evers et al. (1998) checked the treatment-independent pregnancy rate in patients with severe reproductive disorders. This retrospective cohort study showed that spontaneous pregnancy occurred in 76 of 1391 patients on the waiting list. Snick et al. (1997) found that spontaneous pregnancy occurred in the subfertile population with a 27.4% cumulative pregnancy rate after 12 months of untreated observation in primary care. Collins et al. (1995) reported a live-birth rate of 14.3% at 12 months of untreated observation in a secondary/tertiary setting. One study (Gleicher et al., 1996) calculated a spontaneous pregnancy rate of 19.9% after 12 months of observation in a referred population. A spontaneous pregnancy rate of 5.9% was quoted in an unexplained infertility group while on the waiting list (Evers et al., 1998), but this pregnancy rate is much lower in the women who have already had one cycle of IVF. Therefore, the chance of spontaneous pregnancy with expectant management is low but never zero. A recent study (Wordsworth et al., 2011) suggested that, despite being more expensive, existing treatments like empirical clomiphene citrate and natural intrauterine insemination (IUI) do not offer superior live-birth rates compared with expectant management in unexplained infertility. This study compared all three methods for 6 months. Therefore, expectant management does play an important role in a situation where limited resources are available.
Tubal flushing or perturbation
Tubal flushing has proved to be of some use in increasing the chance of pregnancy in unexplained infertility and early stages of endometriosis. (Johnson et al., 2005). The effect of perturbation can be mechanical as well as immunological (Edelstam et al., 1998). It also affects the concentration of peritoneal factors such as cytokines (Oak et al., 1985, Agic et al., 2006). Hysterosalpingo contrast sonography has been well documented in achieving spontaneous pregnancy (Johnson et al., 2005). Oil-based tubal insufflation media have been widely used to investigate tubal patency. A meta-analysis comparing oil-based and water-based media showed that there is significant improvement in pregnancy rate when oil-based media are used (Watson et al., 1994). A prospective randomized trial by Nugent et al. (2002) showed that there is a statistically significantly higher pregnancy rate in couples with infertility randomized to single tubal flush with lipiodol compared with no treatment. This study did not show any significant differences between the mean ages of the patient. Oil-based media have their own relative slowness of absorption that may potentially cause granuloma. However, this complication has not been reported to have long-term consequences (Watson et al., 1994). It has been postulated that an increased pregnancy rate after oil-based tubal flushing may be due to removal of tubal debris (Watson et al., 1994). Another possible explanation is that there is an underlying immunological cause and in vitro it was shown that lipiodol prevents peritoneal mast cell phagocytosis of the spermatozoa (Watson et al., 1994). Lipiodol may be useful in settings where there are limited resources. According to a Swedish study (Edelstam et al., 2008), perturbation is very useful in significantly increasing the clinical pregnancy rate in clomiphene citrate and insemination cycles. The absolute increase in pregnancy rate was 11.7% and the relative increase in pregnancy rate was 465%, or 4.5 times. With the use of lignocaine, treatment was well tolerated. It has been suggested that the combined treatment of clomiphene citrate, perturbation and insemination can be used as the first-line treatment in unexplained infertility (Edelstam et al., 2008).
Fallopian tube sperm perfusion
Fallopian tube sperm perfusion consists of flushing the uterine cavity and the tubes with a sperm-enriched suspension. It helps spermatozoa to pass through the uterine cavity and the Fallopian tubes and ultimately to the pouch of Douglas (Kahn et al., 1993). The use of Fallopian tube perfusion with a sperm-containing medium is either by the laparoscopic approach (Berger, 1987) or with transvaginal tubal catheterization (Jansen and Anderson, 1987, Pratt et al., 1991, Oei et al., 1992). However, tubal flushing requires a certain degree of higher intrauterine perfusion pressure which causes patient discomfort (Baker and Adamson, 1995). There is also risk of infection and tubal trauma whereas the overall result of uterotubal perfusion is no better than traditional IUI. A randomized prospective crossover trial showed that Fallopian sperm perfusion performed using a Foley catheter is significantly less effective than traditional IUI when associated with ovarian stimulation in the treatment of unexplained infertility (Biacchiardi et al., 2004). However, a study done by Ricci et al. (2001) showed in a prospective randomized trial setting that the method of sperm perfusion yields higher pregnancy rates than traditional IUI with no increase in costs and complications. However, it was concluded that there is a need for a larger study before replacing IUI with Fallopian sperm perfusion. NICE guidelines (NICE, 2004), based on management grade A, recommended that, where IUI is used to manage unexplained fertility problems, Fallopian sperm perfusion for insemination with a large volume (4ml) should be offered because it improves pregnancy rates compared with standard insemination techniques (NICE, 2004). However, this method is not at all widely practised in a UK setting.


Intrauterine insemination
The role of IUI in the treatment of unexplained infertility still raises many questions, particularly regarding its superiority in unstimulated cycles over timed intercourse or whether, in addition, ovulation induction should be offered.

Regarding the use of ovulation induction along with IUI in couples with unexplained infertility, women with unexplained infertility have regular ovulatory cycles. The male partner also has normal semen analysis and there is no apparent cervical factor present. There is a hypothesis that increasing the density of the motile spermatozoa available to these eggs may further increase the monthly probability of pregnancy. The use of clomiphene citrate and IUI over IUI alone has not proved to be effective (Hughes et al., 2010).

A Cochrane review of the role of IUI in unexplained infertility reviewed the data available up to 2011 (Veltman-Verhulst et al., 2009). The use of gonadotrophins alone is associated with a quality-adjusted pregnancy rate of 8%. In a review of 27 studies, it was shown that pregnancy rate/cycle improved from 8% to 18% when IUI was added to gonadotrophin stimulation (Guzick et al., 1998). In another trial, IUI improved fertility in cycles in which chomiphene citrate was combined with gonadotrophins (Arcaini et al., 1996). Veltman-Verhulst et al. (2009) identified one trial which compared natural-cycle IUI with timed intercourse in natural cycle (Bhattacharya et al., 2008). Seven studies were identified which compared stimulated IUI with stimulated timed intercourse (Agarwal and Mittal, 2004, Arcaini et al., 1996, Chung et al., 1995, Crosignani et al., 1991, Janko et al., 1998, Karlström et al., 1993, Melis et al., 1995). Agarwal and Mittal (2004) was included in the review but excluded from primary analysis due to severely unbalanced groups due to high dropout. Only two (Melis et al., 1995, Chung et al., 1995) out of the six studies actually reported live-birth rate/couple (OR 1.59, 95% CI 0.88–2.88) (Table 3). There was no statistically significant difference between the two groups. In the study conducted by Melis et al. (1995), patients had previous fertility treatments, which indicates the heterogeneity among the studies. There was no significant difference in pregnancy rates between the two groups.

Table 3. Comparison of IUI treatment options.



Treatments compared

Clinical pregnancy/woman

Live birth/woman

Study


Natural IUI versus timed intercourse or expectant management 1.53 (0.88–2.64) 1.60 (0.92–2.Cool Bhattacharya et al. (2008)
Stimulated IUI versus natural IUI 2.14 (1.26–3.61) 2.7 (1.22–3.55) Murdoch et al., 1991, Arici et al., 1994, Guzick et al., 1998, Goverde et al., 2000
Stimulated IUI versus stimulated timed intercourse 1.68 (1.13–2.50) 1.59(0.88–2.88) (Chung et al., 1995, Melis et al., 1995) Crosignani et al., 1991, Karlström et al., 1993, Chung et al., 1995, Melis et al., 1995, Arcaini et al., 1996, Janko et al., 1998
Stimulated IUI versus timed intercourse 4.05 (3.9–41.87) (Deaton et al., 1990) 0.82 (0.45–1.49) (Steures et al., 2006) Deaton et al., 1990, Steures et al., 2006
 0.61 (0.25–1.47) (Steures et al., 2006)   
Natural IUI versus stimulated timed intercourse 1.77 (1.01–3.44) 1.95 (1.10–3.44) Bhattacharya et al. (2008)

Values are OR (95% CI). IUI=intrauterine insemination.

Data from Wordsworth et al. (2011) are not included as at the time of writing the study is awaiting assessment from Cochrane review.



In the Cochrane review, stimulated cycle IUI was compared with IUI in a natural cycle (Veltman-Verhulst et al., 2009). A significant increase was found in pregnancy rate/woman (OR 2.14, 95% CI 1.26–3.61) in favour of stimulated cycle (Goverde et al., 2000; Guzick et al., 1999; Arici et al., 1994, Murdoch et al., 1991; Table 3). The pregnancy rate of Arici et al., 1994, Murdoch et al., 1991 were combined with the live-birth data of Goverede and Guzick; they did not present clinical pregnancy data. These trials did not provide enough data regarding the adverse outcomes like multiple pregnancy, ovarian hyperstimulation or miscarriage rate. IUI with prepared spermatozoa does not increase the chance of anti-sperm antibodies (Horvath et al., 1989). Although all these previous studies have shown improved pregnancy rate with ovulation induction and IUI, more recent studies by Steures et al. (2006) and Bhattacharya et al. (2008) have seriously questioned the effect of IUI with or without ovarian stimulation when compared with 6 months of expectant management.

Single versus double IUI for unexplained infertility has been examined in recent study (Bagist et al., 2010). This study have shown there is no clear benefit of double over single inseminations in the overall clinical pregnancy rate in couples with unexplained infertility. In unexplained infertility, there is controversy regarding the best treatment option. In the case of unexplained infertility, ovarian stimulation and IUI are stated as ‘effective treatment’ by the RCOG (1998). Later, these recommendations were described as ‘not a natural choice’ (Stewart, 2003) and the recommendations made by the guideline were questioned. This paper actually asked for a trial in couples with unexplained infertility, with stimulated IUI with uni- or bifollicular response, versus no treatment. Where IUI is used to manage unexplained fertility problems, both stimulated and unstimulated IUI is more effective than no treatment. However, it has been suggested that ovarian stimulation should not be offered, even though it is associated with higher pregnancy rates than unstimulated IUI, because it carries a risk of multiple pregnancy (NICE, 2004). Treatment cost was evaluated by Philips et al. (2000) and showed that stimulated IUI is more cost effective than IVF. However, no account was taken of the cost of management of the complicated pregnancy and perinatal period associated with multiple pregnancies. The long-term mortality and morbidity was not considered in this study. The study reported by Zikopoulos et al. (1993) is well designed to attempt the question of the use of stimulated IUI in unexplained infertility. They showed that cycle fecundity for stimulated IUI or ovarian stimulation with timed intercourse of 0.11 was significantly higher than that achieved with timed intercourse in a natural cycle (P<0.01). This study, however, reports a multiple-pregnancy rate of 36%, including a set of triplets.

Gamete intra-Fallopian transfer

Gamete intra-Fallopian transfer (GIFT) involves the collection of oocytes and transferring oocytes and spermatozoa directly into the Fallopian tube. The hypothesis behind transferring the gametes directly into the Fallopian tube is provision of a more physiological environment than in an in-vitro culture media. A large multicentre trial was conducted by the European Society of Human Reproduction and Embryology in 444 patients over 649 cycles (Crosignani et al., 1991). There was no statistically significant difference among the five treatment modalities (per cycle: ovulation induction 15%, ovulation induction/IUI 27%, ovulation induction/intraperitoneal insemination 27%, GIFT 28% and IVF 26%). The main criticism of this study is lack of a control group.
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IVF

IVF is an accepted method of treatment for unexplained infertility. It is expensive and invasive, but it is considered as the most effective method. The average success rate for IVF treatment using fresh eggs in the UK is 28.2% for women <35, 23.6% for women aged 35–37, 18.3% for women aged 38–39 and 10.6% for women aged 40–42 (published in conjunction with the 2006–2007 Human Fertilisation Embryology Authority (HFEA, 2006–2007) guide to infertility, treatment and success, data based on treatment carried out between 1 April 2003 and 31 March 2004). Similarly, the American Society for Reproductive Medicine/Society for Assisted Reproductive Technology Registry (ASRM/SART) reported a live-birth rate among women with unexplained infertility of 30.4% (Practice Committee of ASRM, 2006). This procedure helps with ovarian dysfunction, cervical factors, sperma and egg interaction and sperma and egg transport. However increased success rate with IVF comes with a price of high multiple-pregnancy rates (25%) (ESHRE Campus Report, 2001). Since then, multiple-pregnancy rates in IVF have been better controlled by reduced numbers of embryos transferred. HFEA declared that the maximum multiple-birth rate should not be more than 24%. This view was already reinforced in European countries (ESHRE, 2003). All clinics in the UK had to reduce the multiple-pregnancy rates in the first year to below 24%. This will be lowered periodically, with an overall aim of no more than 10% multiple births out of all live births. Ovarian hyperstimulation is also a seriously life-threatening complication and in a gonadotrophin-releasing hormone agonist cycle this may be 6–14% (Templeton et al., 2000).

Spontaneous pregnancies are quite common in couples with unexplained infertility (Lenton et al., 1977, Collins and Rowe, 1989, Snick et al., 1997). A single cycle of IVF has been compared with expectant management in two trials (Hughes et al., 2004, Soliman et al., 1993). A Cochrane review (Pandian et al., 2005) on the role of IVF in unexplained infertility showed higher pregnancy rates than expectant management (OR 3.24, 95% CI 1.07–9.80). Live-birth rate/woman with a single cycle of IVF was also significantly higher than with expectant management (OR 22.0, 95% CI 2.56–189.38; Table 4; Hughes et al., 2004).

Table 4. Comparison of IVF treatment options.



Treatments compared

Clinical pregnancy/woman

Live birth/woman

Study


IVF versus expectant management NA 22.0 (2.56–189.33) Hughes et al. (2004)
IVF versus IUI NA 1.96 (0.88–4.36) Goverde et al. (2000)
IVF versus IUI with ovarian stimulation NA 1.15 (0.55–2.42) Goverde et al. (2000)
IVF versus GIFT 2.14 (1.08–4.22) 2.57 (0.93–7.08) (Raneiri et al., 1995) Tanbo et al., 1990, Raneiri et al., 1995

Values are OR (95% CI). GIFT=gamete intra-Fallopian transfer; IUI=intrauterine insemination.



Goverde et al. (2000) concluded that there is no significant difference in live birth/woman between IVF and IUI without (OR 1.96, 95% CI 0.88–4.4) or with (OR 1.15, 95% CI 0.55–2.42) ovarian stimulation (Table 4). Multiple-pregnancy rate and ovarian hyperstimulation syndrome rate were also considered in this trial. There was no significant difference between IVF and IUI with stimulation. Two trials compared the role of IVF with GIFT in unexplained infertility (Raneiri et al., 1995, Tanbo et al., 1990). Both studies reported pregnancy rate/woman as an outcome. There was no significant difference in live-birth rates (OR 2.57, 95% CI 0.93–7.08) but a difference in the clinical pregnancy rates between IVF and GIFT in favour of IVF (OR 2.14, 95% CI 1.08–4.22; Table 4). Raneiri et al. (1995) reported live-birth rate/woman as an outcome in the study whereas clinical pregnancy/woman was the end point in Tanbo et al. (1990). All the trials included in the Cochrane review have their own limitations. Most trials were poor in their methodology. Most of the trials considered pregnancy rate/cycle as an end point whereas live-birth rate/woman is the most important outcome for any treatment. A large trial with adequate power should establish the effective role of IVF in the treatment of unexplained infertility.

Is IVF treatment superior to FSH/IUI? There is also the question of cost effectiveness to be considered. The gonadotrophin-stimulated IUI technique for unexplained infertility is better than no treatment. Two randomized trials compared gonadotrophin-stimulated IUI with IVF in cases of unexplained infertility. Crosignani et al. (1991) showed birth rates of 24.5% and 22.9%, respectively, when two cycles of each treatment were being offered to the couple. But valid live birth or pregnancy could not be extracted; therefore, this study was excluded from final analysis in the Cochrane review by Pandian et al. (2005). An Amsterdam trial evaluated a treatment plan involving six cycles of unstimulated and stimulated IUI or IVF (Goverde et al., 2000). Patients involved were diagnosed with either unexplained infertility or mild male infertility. This trial had a low pregnancy rate/cycle with IVF and a multiple-pregnancy rate of 21%. Withdrawal rate was higher in IVF cycles (42%) than FSH/IUI cycles (16%). The clinical effectiveness between FSH/IUI and IVF treatment of unexplained infertility were small. Cost effectiveness of primary offer of IVF versus primary offer of IUI followed by IVF in couples with unexplained or mild male factor subfertility has been evaluated (Pashayan et al., 2006). They used a mathematical model to estimate comparative clinical and cost efficacy of both approaches. They used average success rates rather than age- and indication-specific live-birth rates. They highlighted the cost effectiveness of frozen embryo transfer cycles associated with an IVF cycle. An interesting randomized controlled trial comparing programmes with and without the inclusion of FSH/IUI advocated that FSH/IUI treatment was of no added value (Reindollar et al., 2010).

The role of IVF in unexplained infertility has not been properly evaluated. Adverse events and cost effectiveness of different treatment should be evaluated before coming to any conclusion. For women over 40 years old, a study (Tsafrir et al., 2009) reviewed first-line treatment for unexplained infertility. Clomiphene citrate was ineffective and the success rate of gonadotrophins in IUI cycles was less than 5% in this study. Chance of pregnancy reduces every year after the age of 40; therefore, this study recommended that all women should be referred for IVF after a short trial of gonadotrophins and IUI.

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Discussion

Unexplained infertility is a common diagnosis affecting up to 30% of infertile couples after a standard investigation protocol (Templeton and Penny, 1982). Any good clinical practice decision is dependent on three essential criteria: (i) clinical experience; (ii) perspective of patient’s presentation (duration of infertility); and (iii) evidence. Doctors gather their knowledge from clinical experience and care-giving experience to specific communities and by regularly updating their knowledge with scientific evidence. The patient’s own clinical experience is also influenced by geography, finance and culture.

Clomiphene citrate has been used in unexplained infertility as a low-technology, cheap, easily available medicine but its efficacy is doubtful as systematic review (Athaullah et al., 2002) did not show any advantage of using clomiphene citrate over placebo. So is ovarian stimulation a rational and justified answer to unexplained infertility? There has to be a subtle balance between risk of multiple pregnancy and cost effectiveness of the treatment.

NICE (2004) has recommended IUI as a treatment option in unexplained infertility. A study by Philips et al. (2000) showed that stimulated IUI is more cost effective than IVF per pregnancy. But this study did not address the expenses due to perinatal mortality, morbidity or maternal complications due to multiple pregnancies. IUI has a disadvantage as multifollicular development leads to cycle cancellation because of risk of multiple pregnancies. Therefore, more recent studies, such as Steures et al., 2006, Bhattacharya et al., 2008, seriously questioned the role of IUI stimulated or unstimulated over 6 months of expectant management. However, if ovarian stimulation for IUI is aimed at producing no more than two large follicles, the multiple-pregnancy rates can be significantly reduced without seriously comprising the overall pregnancy rate.

IVF has the advantage of a proven record of success, resulting in an increased pregnancy rate in patients with unexplained infertility. The present environment in favour of selective offer of single-embryo transfer and the legal limit of double-embryo transfer reduces the chance of multiple pregnancies. The most serious and potential risk in the IVF procedure is ovarian hyperstimulation syndrome, but selection of patients, with use of antagonist protocol, gonadotrophin-releasing hormone agonist as a trigger and a successful embryo-freezing programme, may reduce the risk significantly (Papanikolaou et al., 2011).

The clinical question to be addressed is how to achieve the best outcome possible for the patient. There is no definite answer as to what should be the best approach to the management of the couples with unexplained infertility. The availability of resources, the age of the patient and the duration of the infertility all need to be considered while planning the treatment policy with available best evidence. The current review of evidence suggests the policy of progression from low- to high-technology treatment for unexplained infertility. According to the evidence available, IVF is probably the best option for women who are more than 40 years of age but this review suggests that two cycles of gonadotrophin stimulation and IUI are considered before offering the IVF treatment option. In younger women, treatment policy should follow in a stepwise manner of expectant management followed by stimulated IUI, and if these options fail, then a final resort to IVF. The NICE guideline on fertility assessment (NICE, 2004) highlighted recommended treatment with IUI in unexplained infertility for six cycles based on grade A recommendation. Based on the best available evidence, an algorithm for the management of unexplained infertility is suggested (Figure 2).
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Figure 2.

Suggested unexplained infertility management protocol. HMG=human menopausal gonadotrophin; IUI=intrauterine insemination; OI=ovulation induction..

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There is a definite need for more good evidence. A large multicentre study involving different treatment modalities probably is able to answer the clinical questions. There is also need for research to identify the subtle causes of infertility and reduce the prevalence of unexplained infertility. Wider use of tests to check ovarian reserve may be a way forward to reduce the percentage of diagnosis of unexplained infertility among couples seeking treatment. Properly planned research only can resolve the issues regarding the ideal management plan for unexplained infertility, but until then debate continues about the prevalence, definition and optimum treatment options.

In summary, a uniform definition for unexplained infertility is needed. There is need for research to identify more subtle causes of infertility. The best approach to the management of the couple should be based upon the availability of resources, the age of the patient and the duration of infertility.

There is need for multicentre randomized controlled trials for different modalities of treatment in unexplained infertility
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