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Intrauterine insemination: state of the art, 2004

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

  2. 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

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

  4. Introduction

  5. Introduction

  6. Is new always better ?

  7. 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

  8. Strength of evidence • Used: • Systematic reviews • Meta-analyses • RCTs only 1a 1a 1b 2a Well designed non randomized controlled trial 2b Well designed quasi experimental 3 4 Descriptive/cases Experts

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

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

  11. Indications for IUI • Cervical Hostility • Male subfertility • Unexplained subfertility

  12. 1a Cervical Hostility, Nat Cy Glazener 1987 Te Velde 1989 Martinez 1990 Kirby 1991 Check 1995 Total 3.6, 2.0-6.5 0.01 0.1 1 10 Favours timed intercourse favours IUI

  13. 1a Male subfertility, Nat Cy Kerin 1987 Glazener 1987 Ho 1989 Te Velde 1989 Martinez 1990 Kirby 1991 Total 3.1, 1.5-6.3 0.01 0.1 1 10 Favours timed intercourse favours IUI

  14. 1a Unexplained Subfert., Nat Cy Martinez 1990 Kirby 1991 Total 2.0, 0.56-6.9 0.01 0.1 1 10 Favours timed intercourse favours IUI

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

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

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

  18. 1a Male subfertility, Stim Cy Evans, 1991 Martinez, 1991 Crosignani, 1994 Nan, 1994 Melis, 1995 Gregoriou, 1996 Total 2.1, 1.3 – 3.5 0.01 0.1 1 10 Favours timed intercourse favours IUI

  19. 1a Unexplained Subfert., Stim Cy Crosignani, 1991 Evans, 1991 Martinez, 1991 Karlstrom, 1993 Zikopoulos, 1993 Chung, 1995 Gregoriou, 1995 Melis, 1995 Arcaini, 1996 Total 1.9, 1.4 – 2.6 0.01 0.1 1 10 Favours timed intercourse favours IUI

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

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

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

  23. 1a Male subfertility, IUI Martinez, 1990 Nulsen, 1993 Arici, 1994 Cohlen, 1998 Goverde, 2000 Total 1.4, 0.86-2.4 0.01 0.1 1 10 Favours natural cycle favours MOH

  24. PR per cycle nat stim 16 12 8 4 < 5 5 - 10 > 10 Total Motile Sperm Count (million) 1b Male subfertility, IUI * RCT, Cohlen, 1998

  25. 1a Unexplained subfert, IUI Martinez, 1990 Murdoch, 1991 Nulsen, 1993 Arici, 1994 Guzick, 1999 Goverde, 2000 Total 2.0, 1.4-2.8 0.01 0.1 1 10 Favours natural cycle favours MOH

  26. Mild ovarian hyperstimulation Effective in couples with: Mild Male subfertility Unexplained subfertility 1b 1a

  27. 1a Clomiphene or Gonadotrophins Karlstrom 1993 Balasch 1994 Ecochard 2000 Matorras 1992 Total 2.2, 1.2 – 3.9 0.01 0.1 1 10 Favours Clomiphene favours Gonadotrophins

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

  29. Prevention of multiplets

  30. 2b Prevention of Multiplets Statement:IUI in combination with MOH is cost-effective only when the percentage of multiplets is kept to a minimum

  31. 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

  32. 2b Total follicle numbers (Gleicher et al., 2000)

  33. 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 1a Low-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 2b ≤ 2-3 follicles ≥ 15 mmand ≤ 4-5 follicles ≥ 11 mmand estradiol levels < 5,000 pmol/L > 2-3 follicles ≥ 15 mmor > 4-5 follicles ≥ 11 mmor estradiol levels > 5,000 pmol/L 2b Cancel cycle - aspiration of follicles -  (conversion to IVF/ET) 2a Proceed with IUI protocol

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

  35. 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 1a/b 2b ≤ 2-3 follicles ≥ 15 mmand ≤ 4-5 follicles ≥ 11 mmand estradiol levels < 5,000 pmol/L > 2-3 follicles ≥ 15 mmor > 4-5 follicles ≥ 11 mmor estradiol levels > 5,000 pmol/L Proceed with IUI protocol Cancel cycle aspiration of follicles (conversion to IVF/ET) 2a

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

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

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

  39. 1a 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

  40. 1a 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

  41. The Future Prognostic modelling Validation Implementation

  42. 2b 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

  43. 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

  44. Is new always better ?

  45. Is new always better ? Thank you for your attention