1. IUI, Ovarian Stimulation and Complications
G. I. Serour, FRCOG, FRCS, FACOG (hon)
Professor of Obstetrics and Gynaecology
Director, International Islamic Center for Population Studies and Research , Al-Azhar University
Clinical Director, The Egyptian IVF-ET Center, Maadi, Cairo, Egypt
FIGO President
ERC/ELG
March 3rd-4th, 2012
4/15/2017

2. Items Addressed What is IUI. Indications. Effectiveness.
Cost Effectiveness.
Factors affecting success rate.
Advantages and complications.
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3. The rationale behind intrauterine insemination (IUI) with homologous sperm is bypassing the cervical-mucus barrier and increasing the number of motile spermatozoa with a high proportion of normal forms at the site of fertilization.
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4. This interest in IUI is undoubtedly associated with the refinement of techniques for the preparation of washed motile spermatozoa.
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5. Semen Preparation Techniques
Swim up.
Albumin
Percoll
Minipercoll
Glass wool filtration
Sephadex separation
Migration sedimentation
Glass blood separation
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6. The washing procedures are necessary to remove prostaglandins, infectious agents, antigenic proteins, non-motile spermatozoa, leucocytes and immature germ cells.
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7. Aitken RJ, Clarkson JS et al. Reprod Fertil 1987;81:459-469
This may enhance sperm quality by decreasing the formation of free oxygen radicals after sperm preparation. The final result is an improved fertilizing capacity of the sperm in vitro and in vivo.
Aitken RJ, Clarkson JS et al. Reprod Fertil 1987;81:
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8. For FIGO Faculty Use Only. DO NOT COPY OR DISTRIBUTE.
Patient preparation
Natural cycle
MOH
- CC – hCG
-CC – hMG –hCG
-rec FSH – hCG
-GnRH-hMG (rec. FSH) - hCG 8

9. For FIGO Faculty Use Only. DO NOT COPY OR DISTRIBUTE.
Timing of IUI
Basal Body Temperature
LH Surge ( urine/serum) US 9

10. For FIGO Faculty Use Only. DO NOT COPY OR DISTRIBUTE.
Sample for IUI
Fresh semen
Split ejaculate
Different volumes
Washed semen +/-
- Antioxidants
- Platelet Activity Factor
- Follicular Fluid. 10

11. For FIGO Faculty Use Only. DO NOT COPY OR DISTRIBUTE.
Sites of insemination
Intrauterine (IUI)
Intracervical (ICI)
Intraperitoneal (IPI)
Cap insemination
Trans cervical / intrafallopian (ITI) 11

12. Since IUI programmes are easy to run Cheap and do not need sophisticated equipment IUI is an attractive choice for the treatment of some infertility cases in resource poor countries.
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13. Ombelet W. et al. hum Reprod, 2008 , doi:10.1093/humrep/den165
It is generally accepted that intrauterine insemination (IUI) should be preferred to more invasive and expensive techniques of assisted reproduction and be offered as a first-choice treatment in some cases of subfertility.
Ombelet W. et al. hum Reprod, 2008 , doi: /humrep/den165
4/15/2017

14. For FIGO Faculty Use Only. DO NOT COPY OR DISTRIBUTE.
Indications
Male factor subfertility
Unexplained infertility
Endometriosis.
Combined ovulatory and ♂ factor infertility.
Cervical and immunological infertility
Sexual dysfunction infertility. 14

15. Male Factor Subfertility
In long standing infertility caused by reduced sperm quality expectant treatment seems to be disappointing with a spontaneous conception rate of only 2% per cycle.
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Collins J A et al. Fertil Steril; 1995, 64:22-28

16. WHO Lab Manual of Human Semen 2010
The lower reference limit for semen analysis
5th centile 95% CI
Volume
1,5ml (
P H
7.2
Motility
40%
(38-42)
Progressive
Non progressive
Immotile
32%
(31-34)
Vitality
(intact membrane)
58%
(55-63)
Count
15X106
12-16X10 6
Normal forms 4%
(3-4)
WHO Lab Manual of Human Semen 2010
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17. Male factor Infertility (OAT)
Oligozoospermia (O)
Asthenozoospermia (A)
Tratozoospermia (T)
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18. Male subfertility
In male subfertility IUI with or without COH a pregnancy rate of 10-18% per cycle has been reported.
-Stone BA et al Am. J Obstet Gynecol, 180:
- Ombelet W et al 1995,Hum. Reprod. 10 (Suppl. 1):90-120
- Ombelet W et al Hum. Reprod. 12:
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19. Male subfertility
A Cochrane review showed that IUI is superior to TI, both in natural and in cycles with CoH.
Cohlen BJ et al (Cochrane Review)
Cochrane library, issue 4, update software, Oxford.
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20. IUI in natural cycles should be the treatment of choice in case of male subertility, providing an insemination motile count (IMC) of more than 1 million can be obtained after sperm preparation and in the absence of a triple sperm defect ( according to WHO criteria) .
Cohlen BJ et al (Cochrane Review)
Cochrane library, issue 4, update software, Oxford.
4/15/2017

21. IMC and sperm morphology are the most valuable sperm parameters to predict IUI outcome in male subfertility.
Ombelet W et al Reprod Biomed Online 2003;7:
Duran EH et al , Systematic Review. Hum. Reprod Update ;8:
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22. Ombelet W et al 2008. Hum. Reprod. Doi:10.1093/humrep/den165
There is a trend towards increasing conception rates with increasing IMC, but the cut-off value above which IUI seems to be successful, however varies between 0.3 and 20X106 .
Ombelet W et al Hum. Reprod. Doi: /humrep/den165
4/15/2017

23. (cumulative ongoing PR of 21.9% after three IUI cycles).
In cases with < 1 million motile spermatozoa, IUI remains successful provided the sperm morphology score using strict criteria is 4% or more
(cumulative ongoing PR of 21.9% after three IUI cycles).
Centole GM J. Androl; 18:
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24. 0.8 million motile spermatozoa after washing .
A cut off level of:
million motile spermatozoa after washing .
Metaanalysis (Van Weert et al 2004 )
30-50% Total sperm motility before sperm preparation
( Ombelet W et al 1996
Dickey et al 1999, Montanaro et al
2001, Lee et al, 2002)
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25. Ombelet W et al 2008). ESHRE Monograph , 1: 64-72
Infertility work -up
HSG, Laparoscopy, HSCS..
No tubal factor
Washing procedure
IMC< 1 million
IMC> 1 million
IMC< 1 million
Morphology <5%
IUI 4x
IVF
< 30 % or no fertilization
ICSI
Proposed algorithm of male subfertility treatment at the Genk Institute for fertility Technology (ICM, insemination motile count of the number of motile spermatozoa after washing procedure; HSG, hysterisalpingography; HSCS, hysatero-salpingo-contrast-sonography)
Ombelet W et al 2008). ESHRE Monograph , 1: 64-72

26. Unexplained infertility
Meta –analysis comparing IUI and TI in natural cycles showed no difference in results; therefore, IUI in natural cycles seems ineffective in case of unexplained infertility.
Cohen BJ. Gyn. Obst. Invest; 2005,59:3-13
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27. When controlled ovarian hyperstimulation (COH) is used, IUI becomes effective compared with TI
Cohlen BJ. Gyn. Obst. Invest ;2005;59:3-13
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28. There is evidence that IUI with COH increases the live birth rate compared with IUI alone. The likelihood of pregnancy was also increased for treatment with IUI compared with TI in stimulated cycles.
Verhulst SM et al. Cochrane Database Syst Rev 2006;18::CD001838
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29. Cervical Factor Infertility
The results of a meta-analysis of randomized controlled trials comparing IUI with timed intercourse (TI) for couples with cervical factor infertility showed a significant improved probability of conception for IUI.
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Cohlen BJ. Gyn. Obst. Invest ;2005;59:3-13

30. Sexual Dysfunction infertility
For FIGO Faculty Use Only. DO NOT COPY OR DISTRIBUTE.
Sexual Dysfunction infertility
Retrograde ejaculation
Vaginismus
Hypospadius
Impotence
Infrequent Intercourse during fertile period. 30

31. Effectiveness
Controversy still surrounds the effectiveness of this very popular treatment procedure.
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32. ESHRE Capri Workshop Group
Stimulated IUI is ineffective in male infertility and the effect on other diagnoses is small.
IUI+CC PR 7% /cycle
IUI+ FSH PR 12 %/ cycle
IUI+FSH MP 13 %
Prevention of premature LH | not a major
Luteal phase support | requirement
Crosignani PG et al
Hum Reprod Update, 2009, vol 15 No. 3,
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33. Pregnancy rate per cycle and number needed to treat (NNT)per cycle
Treatment
Preg. rate per cycle
NNT
95% CI
Source or results
IUI 5 32
(12.-46)
Guzick et al. (1999), Martinez et al. (1990) and Steures et al. (2007)
CC/IUI* 7 14
(7.-100)
Deaton et al. (1990)
FSH/IUI 4
-25
(15.-7)
Steures et al. (2006) 12 11
(9.16)
Guzick et al. (1999)
IVF 31
(3.7)
Hughes et al. (2004)
*Pregnancy rate per cycle is from Reindollar et al. (2007). NNT is from Deaton et al. (1990) before crossover.
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34. ESHRE Capri Workshop Group
IUI in stimulated cycles may be considered while waiting for IVF or when in women with patent tubes IVF is not affordable.
ESHRE - Hum Reprod. Update, 2009
Vol,15, No. 3,
4/15/2017

35. ESHRE- Hum Reprod. Update, 2009
In most of these indications, IUI or stimulated ovary/IUI is empiric treatment since it is likely that the majority of infertility involves factors that are untreatable or unknown.
ESHRE- Hum Reprod. Update, 2009
Vol,15, No. 3,
4/15/2017

36. For FIGO Faculty Use Only. DO NOT COPY OR DISTRIBUTE.
Most studies are retrospective.
Studies vary in:
- Comparison of study groups.
- Use or non use of MOH.
- No of inseminations/treatment cycle.
- Different sites of insemination.
-Various methods of sperm preparation.
- Use/non use of additives as antioxidants, platelet activation factor (PAF)…etc 36

37. Efficacy of IUI IUI in Intercourse in natural cycle natural cycle
Intercourse in stimulated cycle
IUI in stimulated cycle
Four comparisons to be performed in RCT to (dis) prove the efficacy of IUI with or without MOH
Cohen BJ and Tournaye H in Macklon NS et al (ed) informa healthcare 2008
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38. For FIGO Faculty Use Only. DO NOT COPY OR DISTRIBUTE.
IUI / Other modalities
Success rate
Singleton live birth rate
Cost-benefit analysis
Complication rate
Invasiveness of the technique
Patient compliancy
Healthcare cost 38

39. Unexplained and moderate ♂ factor subfertility
Effectivity has been documented in controlled studies under the condition that the inseminating motile count exceeds more than 1 million motile spermatozoa.
Ombelet W. et al. Hum Reprod, 2008 , doi: /humrep/den165
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40. A comparable cumulative ongoing PR after three IUI cycles for all couples, providing the IMC was more than 1 million was obtained.
Ombelet W et al Hum. Reprod. 12:
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41. Cost effectiveness
Published data comparing cost of IVF versus IUI indicate that initiating treatment with IUI appeared to be more cost-effective than IVF in most cases of unexplained and moderate male subfertility
- Ombelet W. et al Reprod Biomed Online; 7:
- Ombelet W. et al Hum. Reprod. Update ; 11:3-14
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42. Carceau L et al 2002. Hum Reprod; 17:3090-3109
In a systematic Review Garceau et al (2002) showed that initially treatment with IUI appears to be more cost-effective than IVF in most cases of unexplained and moderate male subfertility.
Carceau L et al Hum Reprod; 17:
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43. IUI versus IVF
IVF baby
IUI baby
43,000 $
10,000 $
Van Voorhis et al. Fert. Steril 1998
IVF baby
IUI baby
13,000 $
5,000 $
Goverde et al. Lancet 2000
IUI baby
IVF baby
9,500 $
16,000 $
4/15/2017
Philips et al. Hum Reprod 2000

44. Int J Gynaecol Obstet. 1991 Sep;36(1):49-53
IUI baby
1,500 $
IVF baby
5,000 $
Int J Gynaecol Obstet Sep;36(1):49-53
4/15/2017

45. Factors affecting IUI success
For FIGO Faculty Use Only. DO NOT COPY OR DISTRIBUTE.
Factors affecting IUI success
Age of the female.
Natural cycle versus MOH
Number of inseminations
Number of IUI treatment cycles.
Site of insemination
Exact timing of IUI
Factors affecting embryos implantation
Laboratory factors 45

46. Live birth rates could not be assessed
Anti –oestrogens versus gonadotrophins combined with intrauterine insemination outcome: pregnancy rate per couple.
(Contineau AE et al, 2007)
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47. One intrauterine insemination (IUI) versus double IUI in stimulated cycles. Outcome: pregnancy rate per couple.
(Contineau AE et al, 2003)
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48. For FIGO Faculty Use Only. DO NOT COPY OR DISTRIBUTE.
Embryo Implantation
Endometrial thickness/polyps
Catheter used
Us of aspirin and luteal phase support 48

49. Kuohung W & Hornstein M 2010. Up T o Date . www.uptodate.com
Uterine Polypi
Polypectomy can improve fertility in subfertile women with asymptomatic
endometrial polyps.
Kuohung W & Hornstein M Up T o Date .

50. Number and percentage of pregnancies after hysteroscopic polypectomy (n=204) (RCT) 4xIUI
P-value
Study (n=101)
Control (n=103)
Pregnancy
<0.001
No. 64 29 %
(63,4)
(28,2)
RR 2.1 (95% XI )
Perez –Medina T et al, Hum Reprod. 20:

51. For FIGO Faculty Use Only. DO NOT COPY OR DISTRIBUTE.
Laboratory Factors
Sperm washing methods
Addition of substances in sperm preparation
Fallopian sperm perfusion
Effect of abstinence period
Immunological male subertility 51

52. Advantage Easy to perform Training is easy Less invasive
Risks are minimal
Quality control possible
Costs are minimal
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53. Many studies have shown that appropriate sperm processing may reduce the risk of HIV, transmission through IUI and IVF/ICSI.
Balet et al 1998, Ohl et al 2005, Manigart et al 2006,
Garrido et al 2002, Savasi et al 2007
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54. A Novel washing method combining multiple density gradients and trypsin for removing HIV and hepatitis C virus from semen seems to be very promising.
Loskutoff et al 2005.
Huyser et al 2006
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55. For FIGO Faculty Use Only. DO NOT COPY OR DISTRIBUTE.
Complications
Relatively low success rate / cycle.
PID %.* MP
Prematurity & low birth weight.**
* Dodson and Haney, 1991
*Ombelet et al 1995
**Wong et al 2002, Gaudoin et al 2003, Ombelet et al 2006. 55

56. XX FIGO World Congress of Gyn./ and Obs.
FIGO World Congress 2012 website is now available at:

57. THANK YOU 57 57

58. IUI versus IVF
IUI baby
IVF baby
10,000 $
43,000 $
Van Voorhis et al. Fert. Steril 1998
IVF baby
IUI baby
13,000 $
5,000 $
Goverde et al. Lancet 2000
IUI baby
IVF baby
9,500 $
16,000 $
4/15/2017
Philips et al. Hum Reprod 2000