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IUI, Ovarian Stimulation and Complications G. I. Serour, FRCOG, FRCS, FACOG (hon) Professor of Obstetrics and Gynaecology Director, International Islamic.

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Presentation on theme: "IUI, Ovarian Stimulation and Complications G. I. Serour, FRCOG, FRCS, FACOG (hon) Professor of Obstetrics and Gynaecology Director, International Islamic."— Presentation transcript:

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 5/9/20151 ERC/ELG March 3 rd -4 th, 2012

2 Items Addressed 5/9/20152 What is IUI. Indications. Effectiveness. Cost Effectiveness. Factors affecting success rate. Advantages and complications.

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. 5/9/20153

4 4 This interest in IUI is undoubtedly associated with the refinement of techniques for the preparation of washed motile spermatozoa.

5 Semen Preparation Techniques 5/9/ Swim up. -Albumin -Percoll -Minipercoll -Glass wool filtration -Sephadex separation -Migration sedimentation -Glass blood separation

6 5/9/20156 The washing procedures are necessary to remove prostaglandins, infectious agents, antigenic proteins, non-motile spermatozoa, leucocytes and immature germ cells.

7 5/9/20157 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:

8 Patient preparation Natural cycle MOH - CC – hCG -CC – hMG –hCG -rec FSH – hCG -GnRH-hMG (rec. FSH) - hCG

9 Timing of IUI Basal Body Temperature LH Surge ( urine/serum) US

10 Sample for IUI Fresh semen Split ejaculate Different volumes Washed semen +/- - Antioxidants - Platelet Activity Factor - Follicular Fluid.

11 Sites of insemination Intrauterine (IUI) Intracervical (ICI) Intraperitoneal (IPI) Cap insemination Trans cervical / intrafallopian (ITI)

12 5/9/ 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.

13 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. 5/9/ Ombelet W. et al. hum Reprod, 2008, doi: /humrep/den165

14 Indications Male factor subfertility Unexplained infertility Endometriosis. Combined ovulatory and ♂ factor infertility. Cervical and immunological infertility Sexual dysfunction infertility.

15 5/9/ 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. Collins J A et al. Fertil Steril; 1995, 64:22-28 Male Factor Subfertility

16 5 th centile 95% CI Volume1,5ml( P H7.2 Motility40%(38-42) Progressive Non progressive Immotile 32%(31-34) Vitality (intact membrane) 58%(55-63) Count15X X10 6 Normal forms4%(3-4) 5/9/ The lower reference limit for semen analysis WHO Lab Manual of Human Semen 2010

17 5/9/ Oligozoospermia (O) -Asthenozoospermia (A) -Tratozoospermia (T) Male factor Infertility (OAT)

18 Male subfertility 5/9/ 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): Ombelet W et al Hum. Reprod. 12:

19 Male subfertility 5/9/ 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.

20 5/9/ 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.

21 5/9/ 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:

22 5/9/ 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 20X Ombelet W et al Hum. Reprod. Doi: /humrep/den165

23 5/9/ 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:

24 5/9/ A cut off level of: 0.8 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)

25 Infertility work -up No tubal factor HSG, Laparoscopy, HSCS.. Washing procedure IMC> 1 million IMC< 1 million Morphology <5% IVF < 30 % or no fertilization ICSI IUI 4x 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 5/9/ 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. Unexplained infertility Cohen BJ. Gyn. Obst. Invest; 2005,59:3-13

27 5/9/ When controlled ovarian hyperstimulation (COH) is used, IUI becomes effective compared with TI Cohlen BJ. Gyn. Obst. Invest ;2005;59:3-13

28 5/9/ 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

29 5/9/ 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. Cohlen BJ. Gyn. Obst. Invest ;2005;59:3-13 Cervical Factor Infertility

30 Sexual Dysfunction infertility Retrograde ejaculation Vaginismus Hypospadius Impotence Infrequent Intercourse during fertile period.

31 5/9/ Controversy still surrounds the effectiveness of this very popular treatment procedure. Effectiveness

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 5/9/ Crosignani PG et al Hum Reprod Update, 2009, vol 15 No. 3,

33 5/9/ TreatmentPreg. rate per cycle NNT95% CISource or results IUI532(12.-46)Guzick et al. (1999), Martinez et al. (1990) and Steures et al. (2007) CC/IUI*714(7.-100)Deaton et al. (1990) FSH/IUI4-25(15.-7)Steures et al. (2006) FSH/IUI1211(9.16)Guzick et al. (1999) IVF314(3.7)Hughes et al. (2004) Pregnancy rate per cycle and number needed to treat (NNT)per cycle *Pregnancy rate per cycle is from Reindollar et al. (2007). NNT is from Deaton et al. (1990) before crossover.

34 5/9/ 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,

35 5/9/ 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,

36 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

37 Efficacy of IUI 5/9/ Intercourse in natural cycle IUI in 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

38 IUI / Other modalities Success rate Singleton live birth rate Cost-benefit analysis Complication rate Invasiveness of the technique Patient compliancy Healthcare cost

39 Effectivity has been documented in controlled studies under the condition that the inseminating motile count exceeds more than 1 million motile spermatozoa. 5/9/ Ombelet W. et al. Hum Reprod, 2008, doi: /humrep/den165 Unexplained and moderate ♂ factor subfertility

40 5/9/ 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:

41 5/9/ 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 Cost effectiveness

42 5/9/ 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:

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

44 5/9/ IVF baby 5,000 $ Int J Gynaecol Obstet Sep;36(1):49-53 IUI baby 1,500 $

45 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

46 5/9/ 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)

47 5/9/ One intrauterine insemination (IUI) versus double IUI in stimulated cycles. Outcome: pregnancy rate per couple. (Contineau AE et al, 2003)

48 Embryo Implantation Endometrial thickness/polyps Catheter used Us of aspirin and luteal phase support

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

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

51 Laboratory Factors Sperm washing methods Addition of substances in sperm preparation Fallopian sperm perfusion Effect of abstinence period Immunological male subertility

52 5/9/ Easy to perform Training is easy Less invasive Risks are minimal Quality control possible Costs are minimal Advantage

53 5/9/ 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

54 5/9/ 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 Huyser et al 2006

55 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.

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

57 57

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


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