Obstetrics and Gynecology International sample. For those with blocked tubes, IVF-ET was found to be a cost-eﬀective practice compared to surgery. In a prospective study, based on cost eﬀectiveness, Karande et al. did not recommend IVF as ﬁrst-line option for infertile couples [28]. In a prospective-randomized study, Goverde et al. found that IUI was as eﬀective as and less costly than IVF in treatment of unexplained and male factor infertility [29]. Peterson et al. reported that four cycles of controlled ovarian hyperstimulation (COH) combined with IUI were superior to IVF and less expensive than single IVF cycle [30]. Even when the same stimulation protocols were used, the cost per pregnancy for IUI was less than half that of IVF [31]. Cohlen et al. conducted a Cochrane review to analyze the eﬀectiveness of IUI versus timed intercourse both in natural and stimulated cycles in cases of male factor infertility [32]. A search of Medline (January 1966-present), EMBASE (http://www.embase.com/), DDFU (http://www.ovid.com/site/catalog/DataBase/893.jsp?top = 2 &mid=3&bottom=7&subsection=10), BIOSIS (Philadelphia, USA), SCI (http://www.thomsonreuters.com/products serv- ices/scientiﬁc/Science Citation Index Expanded) and hand searching of references from identiﬁed studies resulted in 43 studies related to research topic being retrieved. They used 17 studies in the systematic review and their data were pooled in the meta-analysis. In their ﬁnal conclusions, Cohlen et al. reported that IUI with COH was more cost- eﬀective compared to IVF [32]. A more recent study, by Pashayan et al., however, oﬀered evidence that IVF as a ﬁrst-line treatment for couples with unexplained and mild male factor infertility was less costly than IUI followed by IVF (for IUI treatment inability to achieve pregnancy) [33]. 6. The Use of IUI and Concurrent Ovarian Stimulation Which is more eﬀective: IUI in a natural cycle or com- bined with ovarian stimulation? In a meta-analysis that included only randomized controlled trials, Hughes reported a signiﬁcant improvement in fecundity with the use of IUI and follicle stimulating hormone (FSH). He found more than two-fold increase in fecundability for either IUI or FSH treatment alone, while he found a ﬁve-fold increase when IUI and FSH are combined together [34]. In the Cochrane review by Cohlen et al. referenced above, conducted to assess the eﬀectiveness of IUI versus timed intercourse [32], IUI in a natural cycle was compared to IUI combined with controlled ovarian hyperstimulation. Data from four trials were included in the meta-analysis for this comparison. Although there was no signiﬁcant diﬀerence between IUI in natural cycles and IUI combined with ovarian hyperstimulation in cases with male factor infertility, the results suggested increased conception with ovarian hyperstimulation (odds ratio: 1.8 with CI: 0.98– 3.3). In their conclusion, Cohlen et al. recommended the use of IUI in natural cycles for cases with severe semen defect (a total motile sperm count of less than 10 × 106, but with more than 1 × 106 motile sperm after preparation). In cases of less severe semen defect, IUI 3 with ovarian hyperstimulation was recommended. A large randomized study in the US conﬁrmed the eﬀectiveness of combining ovarian stimulation with IUI [35]. The study reported an overall pregnancy rate per couple of 33% for IUI with ovarian stimulation and an overall pregnancy rate of 18% for IUI alone. Data of this study were included in the Cochrane review, discussed above, which was accomplished to assess the eﬀectiveness of IUI in the treatment of unexplained infertility. Verhulst et al. conducted a Cochrane review to assess the eﬀectiveness of IUI in the treatment of unexplained infertility [36]. Their primary search yielded 198 articles related to the topic, but hand searching of their abstracts resulted in 25 trials included in the review. It was found that live birth rate per couple was signiﬁcantly higher when IUI was combined with ovarian hyperstimulation compared to IUI alone (OR 2.07, 95% CI: 1.22–3.5) [36]. However, this review did not ﬁnd studies assessing expectant management versus IUI in unexplained infertility. At the same year of publication as the above Cochrane review, Steures et al. published a randomized clinical trial comparing ovarian hyperstimulation combined with IUI versus expectant management for couples with unexplained infertility [37]. This study reported no higher pregnancy rates for ovarian hyperstimulation combined with IUI overexpectant management in couples with unexplained infertility. The National Institute for Clinical Excellence (NICE) in the United Kingdom recommended, with level I evidence, that when IUI is used to treat male factor infertility, ovarian stimulation should not be oﬀered. This conclusion was based on two trials [29, 32]. Supporting this recommendation is the results of a randomized clinical trial conducted in the Netherlands by Steures et al. [38]. This study reported similar pregnancy rates when IUI alone or IUI combined with ovarian hyperstimulation were used to treat couples with abnormal postcoital tests and poor prognosis for spontaneous pregnancy. For unexplained infertility, both IUI alone and IUI combined with ovarian hyperstimulation appear to be more eﬀective than expectant management alone [39]. What drugs should be used for ovarian hyperstim- ulation combined with IUI? Gonadotropins with and without gonadotropin-releasing hormone (GnRH) ago- nist/antagonist have been studied, along with recombinant human FSH (rFSH). Ragni et al. reported that the daily use of 50 IU of rFSH, combined with a GnRH antagonist, ganirelix, for ovarian stimulation prior to IUI resulted in a live birth rate per couple of 25.7% [40]. When the same dose of rFSH was used on alternate days, rFSH produced a live birth rate of 2.9% [40]. In another study, 50 IU daily of rFSH was found similar to 75 IU daily of urinary FSH (uFSH) in the outcomes of the number of follicles >17 mm and days of stimulation [41]. The clinical pregnancy rates were 12.7% for rFSH and 11.9% for uFSH [41]. Thus, the more expensive rFSH was not a cost-eﬀective drug for induction of ovulation in IUI cycles. Conversely, Demirol and Gurgan compared rFSH to uFSH and hMG in IUI cycles, and found rFSH and IUI produced a clinical pregnancy rate of 25.9% compared to 13.8% for uFSH and 12.5% for hMG [42]. When rFSH