2. Intrauterine insemination: state of the art, 2004 Is new always better? B.J. Cohlen Isala Clinics Zwolle The Netherlands

3. IUI in 2004  Introduction  Strength of evidence  IUI versus timed intercourse  Role of mild ovarian hyperstimulation  Clomiphene or Gonadotropins?  Prevention of muliplets  IUI versus IVF-ET or ICSI  Semen preparation techniques  Prediction of outcome

4. Introduction Piet Kleine Gold & silver medal Olympics 1976 Silver medal Olympics 1980

5. Introduction

7. Is new always better ?

8. Strength of evidence Ideal: large RCTs concealment of allocation multicenter enough power well defined population blinding no drop-outs intention to treat Reality: small trials many retrospective method of randomization? single center inadequate power various mixed subpopulations no blinding many drop outs no intention to treat

9. Strength of evidence Used: Systematic reviews Meta-analyses RCTs only 1a 1b 2b 2a 43 Well designed non randomized controlled trial Well designed quasi experimental Descriptive/cases Experts

10. Stim. Cycle and IUI RCTs to (dis) prove a beneficial effect of IUI and/or MOH Nat. Cycle and IUI Stim. Cycle and Intercourse Nat. Cycle and Intercoure

11. RCTs to (dis) prove a beneficial effect of IUI and/or MOH Nat. Cycle and IUI Nat. Cycle and Intercoure

12. Indications for IUI  Cervical Hostility  Male subfertility  Unexplained subfertility

13. Cervical Hostility, Nat Cy 0.010.1 1 10 1a Glazener 1987 Te Velde 1989 Martinez 1990 Kirby 1991 Check 1995 Total 3.6, 2.0-6.5 Favours timed intercoursefavours IUI

14. Male subfertility, Nat Cy 0.010.1 1 10 1a Favours timed intercoursefavours IUI Kerin 1987 Glazener 1987 Ho 1989 Te Velde 1989 Martinez 1990 Kirby 1991 Total 3.1, 1.5-6.3

15. Unexplained Subfert., Nat Cy 0.010.1 1 10 1a Favours timed intercoursefavours IUI Martinez 1990 Kirby 1991 Total 2.0, 0.56-6.9

16. Natural cycle IUI Effective in couples with: Cervical hostility Male subfertility Not (proven) effective in couples with: unexplained subf. 1a

17. Stim. Cycle and IUI RCTs to (dis) prove a beneficial effect of IUI and/or MOH Nat. Cycle and IUI Stim. Cycle and Intercourse Nat. Cycle and Intercoure

18. Stim. Cycle and IUI RCTs to (dis) prove a beneficial effect of IUI and/or MOH Stim. Cycle and Intercourse

19. Male subfertility, Stim Cy 0.010.1 1 10 1a Evans, 1991 Martinez, 1991 Crosignani, 1994 Nan, 1994 Melis, 1995 Gregoriou, 1996 Total 2.1, 1.3 – 3.5 Favours timed intercoursefavours IUI

20. Unexplained Subfert., Stim Cy 0.010.1 1 10 1a Crosignani, 1991 Evans, 1991 Martinez, 1991 Karlstrom, 1993 Zikopoulos, 1993 Chung, 1995 Gregoriou, 1995 Melis, 1995 Arcaini, 1996 Total Favours timed intercoursefavours IUI 1.9, 1.4 – 2.6

21. Stimulated cycle IUI Effective in couples with: Male subfertility unexplained subf. 1a

22. Stim. Cycle and IUI RCTs to (dis) prove a beneficial effect of IUI and/or MOH Nat. Cycle and IUI Stim. Cycle and Intercourse Nat. Cycle and Intercoure

23. Stim. Cycle and IUI RCTs to (dis) prove a beneficial effect of IUI and/or MOH Nat. Cycle and IUI

24. Male subfertility, IUI 0.010.1 1 10 1a Martinez, 1990 Nulsen, 1993 Arici, 1994 Cohlen, 1998 Goverde, 2000 Total Favours natural cyclefavours MOH 1.4, 0.86-2.4

25. Male subfertility, IUI Total Motile Sperm Count (million) PR per cycle 4 8 12 16 < 55 - 10> 10 nat stim 1b RCT, Cohlen, 1998 *

26. Unexplained subfert, IUI 0.010.1 1 10 1a Martinez, 1990 Murdoch, 1991 Nulsen, 1993 Arici, 1994 Guzick, 1999 Goverde, 2000 Total Favours natural cyclefavours MOH 2.0, 1.4-2.8

27. Mild ovarian hyperstimulation Effective in couples with: MildMale subfertility Unexplained subfertility 1b 1a

29. Clomiphene or Gonadotrophins 0.010.1 1 10 Favours Clomiphenefavours Gonadotrophins 1a Karlstrom 1993 Balasch 1994 Ecochard 2000 Matorras 1992 Total 2.2, 1.2 – 3.9

30. Clomiphene or Gonadotrophins Gonadotrophins are more effective Also more cost-effective ? Large multicenter RCT ongoing in the Netherlands 1a 1b

31. Prevention of multiplets

32. Prevention of Multiplets Statement: IUI in combination with MOH is cost-effective only when the percentage of multiplets is kept to a minimum 2b

33. Prediction of Multiplets Can we predict the probability of achieving multiplets? No firm evidence ! Retrospective studies:- age of the woman - total number of follicles (> 11 mm) - Estradiol levels For Instance: Tur et al., 2001 2b

34. Total follicle numbers (Gleicher et al., 2000) 2b

35. Strategy Subfertile couples after infertility work-up Mild male subfertility > 1 year Unexplained subfert.> 2 years Other diagnostic groups Subfertility of a lesser duration Start ovarian hyperstimulation with intrauterine insemination Different treatment options or expectative management L ow-dose step-up protocol starting with 50 IU FSH Or 100 mg CC per day No GnRHa Close monitoring with ultrasound (and estradiol) andstrict cancellation criteria ≤ 2-3 follicles ≥ 15 mm and ≤ 4-5 follicles ≥ 11 mm and estradiol levels < 5,000 pmol/L > 2-3 follicles ≥ 15 mm or > 4-5 follicles ≥ 11 mm or estradiol levels > 5,000 pmol/L Proceed with IUI protocol Cancel cycle - aspiration of follicles - (conversion to IVF/ET) 1a 2b 2a

36. Strategy Subfertile couples after infertility work-up Mild male subfertility > 1 year Unexplained subfert.> 2 years Other diagnostic groups Subfertility of a lesser duration Start ovarian hyperstimulation with intrauterine insemination Different treatment options or expectative management 1a

37. Strategy Low-dose step-up protocol starting with 50 IU FSH or 100 mg CC per day / no GnRHa Close monitoring with ultrasound (and estradiol) and strict cancellation criteria ≤ 2-3 follicles ≥ 15 mm and ≤ 4-5 follicles ≥ 11 mm and estradiol levels < 5,000 pmol/L > 2-3 follicles ≥ 15 mm or > 4-5 follicles ≥ 11 mm or estradiol levels > 5,000 pmol/L Proceed with IUI protocol Cancel cycle aspiration of follicles (conversion to IVF/ET) 1a/b 2b 2a

38. IUI versus IVF IUI baby IVF baby $ 10,000$ 43,000 Van Voorhis et al. Fertil Steril 1998 1b

39. IUI versus IVF IUI baby IVF baby $ 5,000$ 13,000 Goverde et al. Lancet 2000 1b

40. IUI versus ICSI, moderate male SF IUI baby ICSI baby $ 9,500$ 16,000 Philips et al. Hum Reprod 2000 2b

41. Semen Preparation techniques Methodological quality of published trials is extremely low IUI outcome after Swim-up versus Gradient techniques: OR with 95% CIs: 0.55, 0.17-1.76 Gradient techniques result in higher recovery rates Also higher Pregnancy rates ? Cochrane review, Boomsma et al., submitted 1a

42. Prediction of outcome The post-wash TMC can predict non-pregnancy (cut-off level: 0.8-5 million) It does not predict pregnancy ! Van Weert et al, in press Sperm morphology is related to IUI outcome (  4%) Van Waart, 2001 1a

43. The Future Prognostic modelling Validation Implementation

44. The Future Prognostic model derived from 3,371 couples and 15,000 cycles: Negative predictors:- increasing maternal age - longer duration of subfertility - male factor present - one-sided tubal pathology - endometriosis - uterine abnormalities - number of treatment cycle Favourable predictors:- cervical factor - ovarian hyperstimulation Steures et al., in press 2b

45. The ideal future Couple with > 2 year subfertility Evidence based Fertility work-up Eimers/Collins Model IUI prediction Model IVF / ICSI Model Spontaneous conception IUI pregnancy Prediction of Multiplets IVF / ICSI pregnancy Cost-effectiveness per live born baby

46. Is new always better ?

48. Thank you for your attention