Although IVF has proven its benefit in the management of unexplained infertility, the technique is associated with high costs, multiple pregnancy, ovarian hyperstimulation (OHSS), and increased perinatal morbidity and mortality [29]. It has therefore been suggested that couples with unexplained infertility may similarly benefit from IUI with or without COH while avoiding these side effects. Numerous studies have been conducted comparing both techniques with various claims of success including some RCTs [30–33].

The updated Cochrane review published in 2012 by Pandian et al. analyzed these RCTs and concluded that there was no significant difference in the live birth rate between IVF and IUI (without COH) in the management of these patients (OR = 1.96; 95 % CI = 0.88–4.36) [22]. Similarly, there was no significant difference in the clinical pregnancy rate between patients treated with IVF and those treated with IUI + COH if these patients were treatment-naive women (OR = 1.10; 95 % CI = 0.60–2.03). However, in pretreated women, IVF was associated with a higher clinical pregnancy rate compared to IUI + COH (OR = 12.78; 95 % CI = 7.54–21.65) [22]. There was also no significant difference in the live birth rate between patients treated with IVF and those treated with IUI + COH if these patients were treatment-naive women (OR = 1.09; 95 % CI = 0.74–1.59), while in pretreated women, IVF was associated with a higher live birth rate compared to IUI + COH (OR = 2.66; 95 % CI = 1.94–3.63) [22]. However, all these data were based on small studies, and the authors suggested that further RCTs are needed before reaching firm conclusions [22] (Table 30.1).

As total fertilization failure (TFF) may be encountered in patients with unexplained infertility treated with IVF due to unexpected problems in either the sperm or the ovum or both, it has been suggested that ICSI may be a more successful line of treatment [21, 34–39]. It has also been suggested that in those couples, splitting the oocytes between IVF and ICSI may help in identifying the cause of infertility besides achieving pregnancy. By subjecting the sibling oocytes to IVF and ICSI, the presence or otherwise of TFF as well as its origin may be determined [40–44].

Many studies compared ICSI to IVF in treatment of unexplained infertility with controversial results. Some studies found that ICSI was associated with higher fertilization rates compared to IVF [35, 40, 41, 45–47], while others found no significant difference [48]. In an attempt to clarify matters, Johnson et al. conducted a meta-analysis of RCTs and found that ICSI increases the fertilization rate and decreases the risk of TFF in couples with well-defined unexplained infertility [23]. The pooled relative risk (RR) per injected oocyte was higher with ICSI than with conventional insemination (RR = 1.49; 95 % CI = 1.35–1.65). The pooled RR of fertilization per retrieved oocyte was also higher with ICSI than with conventional insemination (RR = 1.27; 95 % CI = 1.02–1.58). The authors also found that the pooled RR of TFF was significantly higher with conventional insemination than with ICSI (RR = 8.22; 95 % CI = 4.44–15.23; Table 30.1). The number of subjects needed to be treated with ICSI to prevent one case of TFF was five [23]. Whether ICSI is superior to IVF in terms of clinical pregnancies necessitates RCTs comparing the techniques in two groups of unexplained infertility couples. For ethical reasons, such a study may never be done as no clinician would like to risk TFF in his patients just to conduct such a study.

The cost effectiveness of any medical procedure is important information both from the patient’s and the service provider’s point of view, and the procedures used in the management of couples with unexplained infertility are no exception. In the study of Guzick et al., the estimated cost per pregnancy in these couples was US$ 10,000 for CC and IUI, US$ 17,000 for HMG and IUI, and US$ 50,000 for IVF [7]. Karande et al. reported similar figures with each pregnancy achieved through immediate IVF costing US$ 57,161 compared to US$ 20,019 for patients undergoing their standard management protocol consisting of three CC cycles, followed by three HMG cycles followed by four IVF cycles [49]. The marginal cost was US$ 37,142 per pregnancy higher in the immediate IVF group. Similarly, in a Dutch study, Goverde et al. found that IUI was a more cost-effective treatment than IVF, with each pregnancy ending in a live birth costing US$ 4,511-5,710 for IUI compared to US$ 14,679 for IVF [30]. The marginal cost per live birth was US$ 10,168 greater in IVF than in IUI alone.

A recent study analyzed the cost-effectiveness of performing IVF and ICSI on sibling oocytes (split IVF-ICSI cycle) versus performing IVF only in couples with unexplained infertility [50]. The authors found that if a single cycle was needed to achieve the live birth, an all-IVF-cycle is preferred as the incremental cost-effectiveness ratio (ICER) of split IVF-ICSI or all ICSI (US$ 58,766) does not justify the increased live birth rate (3 %). If two cycles are needed, split IVF/ICSI is preferred as the increased cumulative live birth rate (3.3 %) is gained at an ICER of US$ 29,666 [50].

The cost of achieving one pregnancy by IVF in couples with unexplained infertility compares favorably with the cost of achieving pregnancy by IVF for other indications. In 2001, Collins estimated that the average cost per delivery arising from IVF cycles performed for all indications was US$ 56,419 in the USA and US$ 20,522 in eight other countries [51]. Finally, the high cost of achieving pregnancy through IVF should be considered in the light of the time taken to achieve this pregnancy, which is an important psychological landmark. In the study by Karande et al., the mean time taken to achieve a pregnancy (± SD) was 6.8 ± 3.8 months, 5.7 ± 5.0 months, and 5.8 ± 4.7 months, in patients treated with IVF, with the standard treatment protocol of the authors and for patients who refused to enter in the study, respectively [49].

IVF is an effective treatment for unexplained infertility. The clinical pregnancy and live birth rates are significantly higher than expectant management. It is also more effective than IUI in patients who received previous treatments. In unexplained infertility, ICSI is associated with higher fertilization rates compared to IVF and is more effective in eliminating TFF. IVF is less cost-effective than IUI but this should be seen in the context of time to pregnancy.