IUI 2011 Prof. Dr. Esat ORHON 1

Ovarian stimulation protocols (anti-oestrogens, gonadotrophins with and without GnRH agonists/antagonists) for intrauterine insemination (IUI) in women with subfertility (Review) The Cochrane Library 2011, Issue 6 Cantineau AEP, Cohlen BJ 2

Robust evidence is lacking Gonadotrophins might be the most effective drugs with IUI Low dose protocols are advised – pregnancy rates do not differ from pregnancy rates which result from high dose regimen – the chances to encounter negative effects from ovarian stimulation such as multiples and OHSS 3

Anti-oestrogens Cost effective but less effective when compared to gonadotrophins. Do not prevent multiple pregnancies Have anti-oestrogenic effect on the endometrium Gonadotrophins Most effective drugs for IUI Low dose protocols (50 to 75 IU per day) are advised Pregnancy rates do not seem to differ significantly from pregnancy rates with high dose regimens (> 75 IU per day) whereas the changes to encounter negative effects from ovarian stimulation, such as the risk of multiples and the risk of OHSS might be higher with high dose protocols. GnRH-agonists There seems to be no role in IUI programs Increase costs Increase multiples without increasing the probability of conception Urinary gonadotrophins versus Recombinant products There is no significant difference GnRH-antagonists Whether or not are going to play a role in mild ovarian hyperstimulation/IUI programs needs to be determined in future trials. Letrozole There is no convincing evidence that Letrozole is superior to clomiphene citrate and therefore the cost should be taken into account when using anti-oestrogens. 4

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Synchronised approach for intrauterine insemination in subfertile couples. (Review) The Cochrane Library 2010, Issue 4 Cantineau AEP, Janssen MJ, Cohlen BJ urinary LH surge versus hCG injection OR % CI 0.06 to 18) recombinant hCG versus urinary hCG OR % CI 0.68 to 2.0) hCG versus GnRH agonist OR % CI 0.42 to 3.1 optimum time interval from hCG injection to IUI No significant differences between different timing methods for IUI expressed as live birth rates All the secondary outcomes analysed showed no significant differences between treatment groups. 14

There is no evidence to advise one particular treatment option over another. Since different time intervals between hCG and IUI did not result in different pregnancy rates, a more flexible approach might be allowed. The choice should be based on hospital facilities, convenience for the patient, medical staff, costs and drop-out levels. 15

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Soft versus firm catheters for intrauterine insemination (Review) van der Poel N, Farquhar C, Abou-Setta AM, Benschop L, Heineman MJ The Cochrane Library 2010, Issue 11 three studieslive birth ratesOR % CI 0.65 to 1.35) six studiesclinical pregnancy ratesOR % CI 0.73 to 1.35 ) two studiesmiscarriagesOR % CI (0.49 to 3.22) 22

There was no evidence of a significant effect difference regarding the choice of catheter type for any of the outcomes. On the basis of the evidence available in this review, no specific conclusion can be made regarding the superiority of one catheter class over another. Further adequately powered studies reporting on clinical outcomes (e.g. live birth rate) are required. Additional outcomes such as miscarriage rates and measures of discomfort need to be reported. 23

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Single versus double intrauterine insemination (IUI) in stimulated cycles for subfertile couples (Review) Cantineau AEP, Heineman MJ, Cohlen BJ The Cochrane Library 2010, Issue 11 six studies involving 1785 women. There were no data for the main outcome measure of live birth per couple or ongoing pregnancy rates, and no authors presented comparative data for adverse events. The results of five studies that reported pregnancy rate per couple showed a significant effect of using double insemination OR 1.8, 95% CI 1.4 to

Based on the results of pregnancy rate per couple in five trials, double intrauterine insemination resulted in significant benefit over single intrauterine insemination in the treatment of subfertile couples with husband semen. 31

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Double versus single intrauterine insemination for unexplained infertility: a meta-analysis of randomized trials Nikolaos P. Polyzos, M.D.,a Spyridon Tzioras, M.D., Ph.D.,a Davide Mauri, M.D., Ph.D.,a and Athina Tatsioni, M.D., Ph.D.b, Fertil Steril 2010;94:1261–6 Six randomized trials, involving 829 women, were included in the analysis. Fifty-four (13.6%) clinical pregnancies were recorded for treatment with double IUI and 62 (14.4%) for treatment with single IUI. There was no significant difference between the single and double IUI groups in the probability for clinical pregnancy – (odds ratio, 0.92; 95% confidence interval, 0.58–1.45; P¼0.715) Conclusion: Double IUI offers no clear benefit in the overall clinical pregnancy rate in couples with unexplained infertility. Con 35

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Intra-uterine insemination versus timed intercourse or expectant management for cervical hostility in subfertile couples (Review) Helmerhorst FM, Van Vliet HAAM, Gornas T, Finken MJ, Grimes DA The Cochrane Library 2010, Issue 11 Each study was too small for a clinically relevant conclusion. Only one of the studies provided information on important outcomes such as spontaneous abortion, multiple pregnancies, but none of studies reported on the occurrence of e.g. ovarian hyperstimulation syndrome. There is no evidence from the published studies that intrauterine insemination is an effective treatment for cervical hostility. Given the poor diagnostic and prognostic properties of the postcoital test and the observation that the test has no benefit on pregnancy rates, intrauterine insemination (with or without ovarian stimulation) is unlikely to be a useful treatment for putative problems identified by postcoital testing 37

Clomiphene citrate for unexplained subfertility in women (Review) Hughes E, Brown J, Collins JJ, Vanderkerchove P The Cochrane Library 2010, Issue 1 Data relating to 1159 participants from seven trials were collated. There was no evidence that clomiphene citrate was more effective than no treatment or placebo for live birth (odds ratio (OR) 0.79, 95% CI 0.45 to 1.38; P = 0.41) or for clinical pregnancy per woman randomised both with intrauterine insemination (IUI) – (OR 2.40, 95% CI 0.70 to 8.19; P = 0.16), without IUI – (OR 1.03, 95% CI 0.64 to 1.66; P = 0.91) 38

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Intra-uterine insemination for unexplained subfertility (Review) Veltman-Verhulst SM, Cohlen BJ, Hughes E, Heineman MJ, Te Velde E The Cochrane Library 2010, Issue 11 In the six trials where IUI was compared with TI, both in stimulated cycles, there was evidence of an increased chance of pregnancy – (six RCTs, 517 women: OR 1.68, 95% CI 1.13 to 2.50). A significant increase in pregnancy rate was also found for women where IUI with OH was compared with IUI in a natural cycle – (three RCTs, 415 women: OR 2.33, 95% CI 1.46 to 3.71). However, the trials provided insufficient data to investigate the impact of IUI with or without OH on several important outcomes including live birth, multiple pregnancies, miscarriage and risk of ovarian hyperstimulation. There was no evidence of a difference in pregnancy rate for IUI with OH compared with TI in a natural cycle – (one RCT, 51 women: OR 4.05, 95% CI 0.39 to 41.87). 44

There is evidence that IUI with OH increases the live birth rate compared to IUI alone. The likelihood of pregnancy was also increased for treatment with IUI compared to TI both in stimulated cycles. There is insufficient data on multiple pregnancies and other adverse events for treatment with OH. Therefore, couples should be fully informed about the risks of IUI and OH as well as alternative treatment options. 45

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Cervical insemination versus intra-uterine insemination (Review) Besselink DE, Farquhar C, Kremer JAM, Marjoribanks J, O’Brien PA The Cochrane Library 2010, Issue 11 The search strategy found 232 articles. In two studies 134 women had gonadotrophin-stimulated cycles In two studies 74 women had clomiphene-stimulated cycles. The evidence showed that IUI after 6 cycles significantly improved live birth rates (odds ratio (OR) 1.98, 95% confidence interval (CI) 1.02 to 3.86) pregnancy rates in comparison to cervical insemination. (OR 3.37, 95% CI 1.90 to 5.96) There was no statistically significant evidence of an effect on multiple pregnancies (OR 2.19, 95% CI 0.79 to 6.07) or miscarriages (relative risk (RR) 3.92, 95% CI 0.85 to 17.96). The findings of this review support use of IUI rather than CI in stimulated cycles 53

Analysis 1.1. Comparison 1 IUI versus CI in stimulated cycles. Outcome 1 Live birth rate per woman after all treatment cycles. 54

Analysis 1.2. Comparison 1 IUI versus CI in stimulated cycles. Outcome 1 Pregnancy rate per woman after all treatment cycles. 55

Analysis 1.3. Comparison 1 IUI versus CI in stimulated cycles. Outcome 1 Miscarriage rate per woman after all treatment cycles. 56

Analysis 1.4. Comparison 1 IUI versus CI in stimulated cycles. Outcome 1 Multiple pregnancy rate per woman after all treatment cycles. 57

Semen preparation techniques for intrauterine insemination (Review) Boomsma CM, Heineman MJ, Cohlen BJ, Farquhar C The Cochrane Library 2009, Issue 1 Five RCTs, including 262 couples in total, were included in the meta- analysis No trials reported the primary outcome of live birth. There was no evidence of a difference between pregnancy rates (PR) for swim-up versus a gradient or wash and centrifugation technique, nor in the two studies comparing a gradient technique versus wash and centrifugation. There was no evidence of a difference in the miscarriage rate in two studies comparing swim-up versus a gradient technique. 58

Authors’ conclusions There is insufficient evidence to recommend any specific preparation technique. Large high quality randomised controlled trials, comparing the effectiveness of a gradient and/ or a swim-up and/ or wash and centrifugation technique on clinical outcome are lacking. Further randomised trials are warranted. 59

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The influence of the number of follicles on pregnancy rates in intrauterine insemination with ovarian stimulation: a meta-analysis M.M.E. van Rumste, I.M. Custers, F. van der Veen, M. van Wely, J.L.H. Evers, B.W.J. Mol. Human Reproduction Update, Vol.14, No.6 pp. 563–570, studies reporting on cycles. The absolute pregnancy rate was 8.4% for monofollicular and 15% for multifollicular growth. The pooled OR for pregnancy after two follicles as compared with monofollicular growth was 1.6 (99% CI 1.3–2.0), whereas for three and four follicles, this was 2.0 and 2.0, respectively. Compared with monofollicular growth, pregnancy rates increased by 5, 8 and 8% when stimulating two, three and four follicles. The pooled OR for multiple pregnancies after two follicles was 1.7 (99% CI 0.8–3.6), whereas for three and four follicles this was 2.8 and 2.3, respectively. The risk of multiple pregnancies after two, three and four follicles increased by 6, 14 and 10%. The absolute rate of multiple pregnancies was 0.3% after monofollicular and 2.8% after multifollicular growth. 69

CONCLUSIONS Multifollicular growth is associated with increased pregnancy rates in IUI with COH. Since in cycles with three or four follicles the multiple pregnancy rate increased without substantial gain in overall pregnancy rate, IUI with COH should not aim for more than two follicles. One stimulated follicle should be the goal if safety is the primary concern, whereas two follicles may be accepted after careful patient counselling. 70

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Effects and clinical significance of GnRH antagonist administration for IUI timing in FSH superovulated cycles: a meta-analysis Ioannis P. Kosmas, M.D., M.Sc.,a Athina Tatsioni, M.D., Ph.D.,b Efstratios M. Kolibianakis, M.D., Ph.D.,a Willem Verpoest, M.D.,a Herman Tournaye, M.D., Ph.D.,a Josiane Van der Elst, Ph.D., Paul Devroey, M.D., Ph.D.a Fertil Steril 2008;90:367–72 Six comparisons were retrieved including 1,069 patients. Higher pregnancy rates were found in the randomized controlled trials (odds ratio [OR] 1.56, 95% confidence interval [CI] 1.05–2.33) when a GnRH antagonist was added to a gonadotropin superovulated IUI protocol. From the randomized controlled trials of this meta-analysis, it is clear that allowing for follicle growth and avoiding premature LH rise, increased pregnancy rates are observed with GnRH antagonist administration. A parallel trend for multiple pregnancy rates in the GnRH antagonist group was observed, although this did not reach statistical significance. 72

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76 Konuşma Özetleri Kitabı173 Üreme End. Tek. Cer 369 Prof Dr Esat OrhonIUI 2011