Intrauterine insemination: state of the art, 2004 Is new always better? B.J. Cohlen Isala Clinics Zwolle The Netherlands
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
Introduction Piet Kleine Gold & silver medal Olympics 1976 Silver medal Olympics 1980
Introduction
Is new always better ?
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
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
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
RCTs to (dis) prove a beneficial effect of IUI and/or MOH Nat. Cycle and IUI Nat. Cycle and Intercoure
Indications for IUI Cervical Hostility Male subfertility Unexplained subfertility
Cervical Hostility, Nat Cy a Glazener 1987 Te Velde 1989 Martinez 1990 Kirby 1991 Check 1995 Total 3.6, Favours timed intercoursefavours IUI
Male subfertility, Nat Cy a Favours timed intercoursefavours IUI Kerin 1987 Glazener 1987 Ho 1989 Te Velde 1989 Martinez 1990 Kirby 1991 Total 3.1,
Unexplained Subfert., Nat Cy a Favours timed intercoursefavours IUI Martinez 1990 Kirby 1991 Total 2.0,
Natural cycle IUI Effective in couples with: Cervical hostility Male subfertility Not (proven) effective in couples with: unexplained subf. 1a
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
Stim. Cycle and IUI RCTs to (dis) prove a beneficial effect of IUI and/or MOH Stim. Cycle and Intercourse
Male subfertility, Stim Cy a Evans, 1991 Martinez, 1991 Crosignani, 1994 Nan, 1994 Melis, 1995 Gregoriou, 1996 Total 2.1, 1.3 – 3.5 Favours timed intercoursefavours IUI
Unexplained Subfert., Stim Cy a 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
Stimulated cycle IUI Effective in couples with: Male subfertility unexplained subf. 1a
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
Stim. Cycle and IUI RCTs to (dis) prove a beneficial effect of IUI and/or MOH Nat. Cycle and IUI
Male subfertility, IUI a Martinez, 1990 Nulsen, 1993 Arici, 1994 Cohlen, 1998 Goverde, 2000 Total Favours natural cyclefavours MOH 1.4,
Male subfertility, IUI Total Motile Sperm Count (million) PR per cycle < > 10 nat stim 1b RCT, Cohlen, 1998 *
Unexplained subfert, IUI a Martinez, 1990 Murdoch, 1991 Nulsen, 1993 Arici, 1994 Guzick, 1999 Goverde, 2000 Total Favours natural cyclefavours MOH 2.0,
Mild ovarian hyperstimulation Effective in couples with: MildMale subfertility Unexplained subfertility 1b 1a
Clomiphene or Gonadotrophins Favours Clomiphenefavours Gonadotrophins 1a Karlstrom 1993 Balasch 1994 Ecochard 2000 Matorras 1992 Total 2.2, 1.2 – 3.9
Clomiphene or Gonadotrophins Gonadotrophins are more effective Also more cost-effective ? Large multicenter RCT ongoing in the Netherlands 1a 1b
Prevention of multiplets
Prevention of Multiplets Statement: IUI in combination with MOH is cost-effective only when the percentage of multiplets is kept to a minimum 2b
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., b
Total follicle numbers (Gleicher et al., 2000) 2b
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
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
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
IUI versus IVF IUI baby IVF baby $ 10,000$ 43,000 Van Voorhis et al. Fertil Steril b
IUI versus IVF IUI baby IVF baby $ 5,000$ 13,000 Goverde et al. Lancet b
IUI versus ICSI, moderate male SF IUI baby ICSI baby $ 9,500$ 16,000 Philips et al. Hum Reprod b
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, Gradient techniques result in higher recovery rates Also higher Pregnancy rates ? Cochrane review, Boomsma et al., submitted 1a
Prediction of outcome The post-wash TMC can predict non-pregnancy (cut-off level: million) It does not predict pregnancy ! Van Weert et al, in press Sperm morphology is related to IUI outcome ( 4%) Van Waart, a
The Future Prognostic modelling Validation Implementation
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
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
Is new always better ?
Thank you for your attention