Intrauterine insemination: state of the art, 2004

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Intrauterine insemination state of the art, 2004

• Is new always better?
• B.J. Cohlen
• Isala Clinics Zwolle
• The Netherlands

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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

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Introduction
Piet Kleine Gold silver medal Olympics
1976 Silver medal Olympics 1980
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Introduction
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Introduction
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Is new always better ?
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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
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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
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3
Descriptive/cases
Experts
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RCTs to (dis) prove a beneficial effect of IUI
and/or MOH
Nat. Cycle and IUI
Nat. Cycle and Intercoure
Stim. Cycle and Intercourse
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RCTs to (dis) prove a beneficial effect of IUI
and/or MOH
Nat. Cycle and IUI
Nat. Cycle and Intercoure
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Indications for IUI

• Cervical Hostility
• Male subfertility
• Unexplained subfertility

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Cervical Hostility, Nat Cy
1a
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
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Male subfertility, Nat Cy
1a
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
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Unexplained Subfert., Nat Cy
1a
Martinez 1990 Kirby 1991 Total
2.0, 0.56-6.9
0.01 0.1 1 10
Favours timed intercourse favours IUI
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Natural cycle IUI
Effective in couples with Cervical
hostility Male subfertility Not (proven)
effective in couples with unexplained subf.
1a
1a
1a
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RCTs to (dis) prove a beneficial effect of IUI
and/or MOH
Nat. Cycle and IUI
Nat. Cycle and Intercoure
Stim. Cycle and Intercourse
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RCTs to (dis) prove a beneficial effect of IUI
and/or MOH
Stim. Cycle and Intercourse
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Male subfertility, Stim Cy
1a
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
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Unexplained Subfert., Stim Cy
1a
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
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Stimulated cycle IUI
Effective in couples with Male
subfertility unexplained subf.
1a
1a
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RCTs to (dis) prove a beneficial effect of IUI
and/or MOH
Nat. Cycle and IUI
Nat. Cycle and Intercoure
Stim. Cycle and Intercourse
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RCTs to (dis) prove a beneficial effect of IUI
and/or MOH
Nat. Cycle and IUI
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Male subfertility, IUI
1a
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
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Male subfertility, IUI
1b

RCT, Cohlen, 1998
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Unexplained subfert, IUI
1a
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
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Mild ovarian hyperstimulation
Effective in couples with Mild Male
subfertility Unexplained subfertility
1b
1a
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Clomiphene or Gonadotrophins
1a
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
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Clomiphene or Gonadotrophins
1a
Gonadotrophins are more effective Also more
cost-effective ? Large multicenter RCT ongoing
in the Netherlands
1b
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Prevention of multiplets
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Prevention of Multiplets
2b
Statement IUI in combination with MOH is
cost-effective only when the percentage of
multiplets is kept to a minimum
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Prediction of Multiplets
Can we predict the probability of achieving
multiplets?
No firm evidence ! Retrospective studies - age
of the woman - total number of follicles (gt
11 mm) - Estradiol levels For Instance
Tur et al., 2001
2b
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Total follicle numbers (Gleicher et al., 2000)
2b
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Strategy
Subfertile couples after infertility work-up
Mild male subfertility gt 1 year Unexplained
subfert.gt 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 mm and 4-5 follicles 11
mm and estradiol levels lt 5,000 pmol/L
gt 2-3 follicles 15 mm or gt 4-5 follicles 11
mm or estradiol levels gt 5,000 pmol/L
2b
Cancel cycle -  aspiration of
follicles -  (conversion to IVF/ET)
2a
Proceed with IUI protocol
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Strategy
Subfertile couples after infertility work-up
Mild male subfertility gt 1 year Unexplained
subfert.gt 2 years
Other diagnostic groups Subfertility of a lesser
duration
1a
Start ovarian hyperstimulation with
intrauterine insemination
Different treatment options or expectative
management
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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 mm and 4-5 follicles 11
mm and estradiol levels lt 5,000 pmol/L
gt 2-3 follicles 15 mm or gt 4-5 follicles 11
mm or estradiol levels gt 5,000 pmol/L
Proceed with IUI protocol
Cancel cycle aspiration of follicles
(conversion to IVF/ET)
2a
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IUI versus IVF
IUI baby
IVF baby
10,000
43,000
1b
Van Voorhis et al. Fertil Steril 1998
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IUI versus IVF
IUI baby
IVF baby
5,000
13,000
1b
Goverde et al. Lancet 2000
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IUI versus ICSI, moderate male SF
IUI baby
ICSI baby
9,500
16,000
2b
Philips et al. Hum Reprod 2000
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Semen Preparation techniques
1a

• 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

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Prediction of outcome
1a
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
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The Future
Prognostic modelling
Validation
Implementation
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The Future
2b
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
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The ideal future
Couple with gt 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
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Is new always better ?
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Is new always better ?
Thank you for your attention