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.

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.