Dr H Faruk Buyru İÜ İstanbul Medical Faculty Dept of Obstet&Gynecol

Artificial Insemination Homologous artificial insemination Heterologous artificial insemination Artificial insemination, husband (AIH) Artificial insemination, donor (AID)

Rationale for the use of IUI Vaginal acidity and servical mucus hostility Concentrated, motile, morphologically normal sperm as close as possible to the oocytes

Main Indications for IUI 1. Ejaculatory failure 2. Cervical factor 3. Mild male subfertility 4. Immunological 5. Unexplained infertility 6. Endometriosis 7. Ovulatory dysfunction 8. HIV positive male partner and HIV-negative female partner 9. Combined infertility factors

Assisted reproductive technology in Europe, 2004: results generated from European registers by ESHRE Andersen et al, Hum Reprod 2008 Apr From 29 countries, 785 clinics, 367,066 cycles including: IVF (114,672), ICSI (167,192), frozen embryo (71,997), egg donation (ED, ), PGD/PGS (2701) and, IVM (170) IUI 115,980 cycles (IUI-H, 98,388; IUI-D, 17,592) No of ET: %, %, %, 4 or more 3.3% Singleton 77.2 %, twin 21.7%, triplet 1 % Per Aspiration %Per Transfer % Clinical pregnancy- IVF Clinical pregnancy- ICSI IUI-H clin pregnancy12.6/per cycle

Steps 1. Ovarian stimulation 2. Monitoring of follicular growth and endometrial development 3. Timing of insemination 4. Semen preparation 5. IUI with prepared sperm

Factors Affecting Success Rate Cause of infertility Age of both partners Duration of infertility Treatment cycle rank Sperm parameters

Clomiphene citrate and intrauterine insemination: analysis of more than 4100 cycles Dovey S et al, Hum Reprod 2008 Retrospective cohort study, Boston IVF 4,199 cycles, 1,738 patients, July 2007, CC-IUI Under age 35 years cumulative PRs 24.2 % Ages %Ages % Ages %Above % Younger patients have a higher PR per cycle than older patients The PR per cycle for patients who initiate only one or only two treatment cycles is notably higher than the corresponding per cycle rates for cycles 3 through 9 The drop in success per patient among 41- and 42-year-olds is sharp, but the exceptionally low success rate above age 42 suggests that CC with IUI has virtually no place in their treatment.

Maternal Age An age-related decline in female fecundity has been documented in women undergoing IUI Successful pregnancy rates decrease after age 35 and reduce dramatically after age 40 Plosker et al, Hum Reprod 1994 Tomlinson et al Hum Reprpd 1996

Duration of Infertility The longer the duration of infertility, the lower the pregnancy rates after IUI The pregnancy rate may be seriously compromised when infertility has lasted 3 or more years Nuojua-Huttunen S et al, Hum Reprod 1999 Plosker et al, Hum Reprod 1994 Steures P et al, Fertil Steril 2004

Semen Analysis Characteristics Total motile sperm count > 5 million Kruger morphology 5% Zayed et al, Hum Reprod 1997 Prewashed semen specimen: More than 4% normal sperm morphology, the chances of pregnancy after IUI were significantly increased van Waart et al, Hum Rerprod Update 2001

Threshold for IUI > 5X10 6

W Ombelet et al.. RBM online 2003

Isolated teratozoospermia

Fertil Steril couples, 714 IUI cycles Prospective observational study

IUI used for treating male factor infertility has little chance of success when the; woman is older than 35 years, the number of motile spermatozoa inseminated is <5 x 10(6), normal sperm morphology is <30%

Endometriosis-Related Infertility Controlled Ovarian Hyperstimulation with Intrauterine Insemination vs. In Vitro Fertilization-Embryo Transfer Dmowski et al., F&S 2002

Endometriosis - Conclusion: The pregnancy rate achieved by 1 IVF cyle is higher than cumulative rate of 6 COH-IUI cycles (independent of age and the stage of disease), After 3-4 COH-IUI cycles the success of COH-IUI does not increase, COH-IUI: Mild-moderate endometriosis < 38 years

IUI-How many cycles? 489 cycles OI + IUI Cycle fecundity rate was 0.07 for the first 4 cycles 0.03 for the cycles 94% of pregnancies occured in the first four attemtps Remohi et al; Hum Reprod 1989

COH / IUI : How many cycles? Dickey, 2002 F/S

IUI: How many cycles should we perform? Custers IM et al, Hum Reprod 2008 Multicentre, retrospective cohort analysis Primary outcome: Ongoing pregnancy rate (OPR) per cycle 3714 couples with male, cervical or unexplained subfertility underwent 15,303 cycles of IUI. In 70% of cycles, controlled ovarian hyperstimulation (COH) was used (51% clomiphene-citrate, 19% gonadotropins). Mean OPR rate was 5.6% per cycle. OPR in the seventh, eighth and ninth cycle were 5.1%, 6.7% and 4.6%, respectively. Taking censored patients into account, the calculated COPR was 18% after the third cycle, 30% after the seventh cycle and 41% after the ninth cycle. CONCLUSIONS: OPR in high-order IUI cycles are acceptable, and do not offer a rationale for cancellation before nine cycles. Using this type of very mild COH, it may be reasonable to conduct up to nine cycles.

Comparison Success rates Cost-benefit analysis Complication rates The invasiveness of the techniques Couple compliance

Cost Initiating treatment with IUI appeared to be more cost-effective than IVF most cases of unexplained and moderate male subfertility Goverde AJ et al, Lancet 2000 Karande VC et al, Fetil Steril 1999 Philips Z et al, Hum Reprod 2000 Van Voorhis BJ, Fertl Steril 1998 Nuojua-Huttunen S et al; Hum Reprod 1999

COST: IVF / IUI Before IVF Cohlen (2005) Gynecol Obstet Invest Review Cervical factor, male factor (TMS> 10 million), unexplained infertility Gonadotropins are more effective than CC Mild ovarian hyperstimulation + IUI is more cost- effective than IVF

Cost-effectivity in tubal factor infertility MildModerateSevere Surgery IVFSurgery IVFSurgery IVF Cost-effectivity in endometriosis MildModerateSevere Surgery IVFSurgery IVFSurgery IVF Philips, Hum Reprod, 2000 Cost per pregnancy (£)

IUI / IVF: Cost-effectiveness Van Voorhis et al (1998) Fertil Steril

Outcome: Per live birth-producing pregnancy IVF: £ Unstimulated-IUI + IVF: £ Stimulated-IUI + IVF: £ Hypothetical cohort of 100 couples: Compared with primary offer IVF, 6 cycles of “U-IUI” or of “S-IUI” wolud cost an additional £ and £ , representing an opportunity cost of 54 and 136 additional IVF cycles and 14 to 35 live birth-producing pregnancies respectively

For couples with unexplained and mild male factor subfertility, primary offer of a full IVF cycle is less costly and more cost-effective than providing IUI (of any modality) followed by IVF

Intra-uterine insemination for male subfertility Bensdorp AJ, Cohlen BJ, Heineman MJ, Vandekerckhove P Cochrane Syst Rev, IUI versus TI both in natural cycles no evidence of difference (Peto OR 5.3, 95% CI 0.42 to 67) No statistically significant of difference between pregnancy rates (PR) per couple for IUI + OH versus IUI could be found (Peto OR 1.47, 95% CI 0.92 to 2.37) IUI versus TI both in stimulated cycles there was no evidence of statistically significant difference (Peto OR 1.67, 95% CI 0.83 to 3.37) Conclusion: There was insufficient evidence of effectiveness to recommend or advise against IUI with or without OH above TI, or vice versa

Intra-uterine insemination for unexplained subfertility Verhulst SM, Cohlen BJ, Hughes E, te Velde E, Heineman MJ Cochrane Syst Revc IUI vs 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 live birth rate was found for women where IUI with OH was compared with IUI in natural cycle (four RCTs, 396 women: OR 2.07, 95% CI 1.22 to 3.50). There is evidence that intra-uterine insemination (IUI) improves the odds of becoming pregnant for couples with unexplained subfertility compared to timed intercourse. The addition of fertility drugs to IUI treatment to induce ovulation also improves the chances

Ovarian stimulation protocols (anti-oestrogens, gonadotrophins with and without GnRH agonists/antagonists) for intrauterine insemination (IUI) in women with subfertility Cantineau AEP, Cohlen BJ, Heineman MJ Cochrane Syst Rev Forty three trials involving 3957 women The review compared different drugs for ovarian hyperstimulation showing that injections result in higher pregnancy rates compared with oral medication. However, the evidence for this result is not very strong. This review does not answer the question whether the addition of GnRH agonist or antagonist is use ful.

Advantages of IVF over IUI Higher pregnancy rates Knowledge obtained about fertilization of oocytes Cryopersarvation of spare embryos Severe male-factor infertility Severe endometriosis Tubal damage

Should we still perform IUI as IVF-ICSI is promoting so quickly? All treatment options, side effects, risks and costs should be discussed with the couples IVF/ICSI is more invasive Couples should be informed about the real success rates HFB

Conclusion IUI is relatively an effective method of teratment for certain groups of subfertile couples IUI is less invasive and cheaper than IVF Careful selection of patients is important Patent Fallopian tubes No endometriosis of moderate and severe degree No severe degree of male-factor infertility IVF should be carried out with couples after 4 cycles

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