IUI, Ovarian Stimulation and Complications G. I. Serour, FRCOG, FRCS, FACOG (hon) Professor of...

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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 03/15/22 1 ERC/ELG March 3 rd -4 th , 2012

Transcript of IUI, Ovarian Stimulation and Complications G. I. Serour, FRCOG, FRCS, FACOG (hon) Professor of...

IUI, Ovarian Stimulation and Complications

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

04/18/23 1

ERC/ELG

March 3rd-4th, 2012

Items Addressed

04/18/23 2

• What is IUI.

•Indications.

•Effectiveness.

•Cost Effectiveness.

• Factors affecting success rate.

•Advantages and complications.

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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This interest in IUI is undoubtedly associated with the refinement of

techniques for the preparation of washed motile spermatozoa.

Semen Preparation Techniques

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-Swim up.

-Albumin

-Percoll

-Minipercoll

-Glass wool filtration

-Sephadex separation

-Migration sedimentation

-Glass blood separation

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The washing procedures are necessary to remove

prostaglandins, infectious agents, antigenic proteins, non-motile spermatozoa, leucocytes and immature

germ cells.

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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;81:459-469

Patient preparation

• Natural cycle

• MOH - CC – hCG -CC – hMG –hCG -rec FSH – hCG -GnRH-hMG (rec. FSH) - hCG

Timing of IUI• Basal Body Temperature

• LH Surge ( urine/serum)

• US

Sample for IUI

• Fresh semen • Split ejaculate• Different volumes• Washed semen +/- - Antioxidants - Platelet Activity Factor - Follicular Fluid.

Sites of insemination

• Intrauterine (IUI)

• Intracervical (ICI)

• Intraperitoneal (IPI)

• Cap insemination

• Trans cervical / intrafallopian (ITI)

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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.

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.

04/18/23 13Ombelet W. et al. hum Reprod, 2008 , doi:10.1093/humrep/den165

Indications • Male factor subfertility• Unexplained infertility• Endometriosis.• Combined ovulatory and ♂ factor

infertility.• Cervical and immunological infertility• Sexual dysfunction infertility.

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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

5th centile 95%CI

Volume 1,5ml (1.4-1.7

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)

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The lower reference limit for semen analysis

WHO Lab Manual of Human Semen 2010

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-Oligozoospermia (O)

-Asthenozoospermia (A)

-Tratozoospermia (T)

Male factor Infertility (OAT)

Male subfertility

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In male subfertility IUI with or without COH a pregnancy rate of 10-18% per cycle has

been reported.

-Stone BA et al 1999. Am. J Obstet Gynecol, 180:1522-1534

- Ombelet W et al 1995,Hum. Reprod. 10 (Suppl. 1):90-120

- Ombelet W et al 1997. Hum. Reprod. 12:1458-1463

Male subfertility

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A Cochrane review showed that IUI is superior to TI,

both in natural and in cycles with CoH.

Cohlen BJ et al 2000. (Cochrane Review)

Cochrane library, issue 4, update software, Oxford.

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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 2000. (Cochrane Review)

Cochrane library, issue 4, update software, Oxford.

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IMC and sperm morphology are the most valuable sperm

parameters to predict IUI outcome in male subfertility.

-Ombelet W et al 2003. Reprod Biomed Online 2003;7:485-492

-Duran EH et al , 2002. Systematic Review. Hum. Reprod Update ;8:373-384

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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 2008. Hum. Reprod. Doi:10.1093/humrep/den165

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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 1997. J. Androl; 18:448-453

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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)

Infertility work -up

No tubal factor

HSG, Laparoscopy, HSCS..

Washing procedure

IMC> 1 millionIMC< 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

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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

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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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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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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

Sexual Dysfunction infertility

• Retrograde ejaculation• Vaginismus• Hypospadius• Impotence• Infrequent Intercourse during fertile

period.

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Controversy still surrounds the

effectiveness of this very popular treatment

procedure.

Effectiveness

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

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Crosignani PG et alHum Reprod Update, 2009, vol 15 No. 3, 265-277

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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) FSH/IUI 12 11 (9.16) Guzick et al. (1999)

IVF 31 4 (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.

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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, 265-277

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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, 265-277

• 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

Efficacy of IUI

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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

IUI / Other modalities

• Success rate • Singleton live birth rate• Cost-benefit analysis• Complication rate• Invasiveness of the technique• Patient compliancy • Healthcare cost

Effectivity has been documented in controlled

studies under the condition that the inseminating motile count exceeds more than 1 million

motile spermatozoa.04/18/23 39

Ombelet W. et al. Hum Reprod, 2008 , doi:10.1093/humrep/den165

Unexplained and moderate ♂ factor subfertility

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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 1997. Hum. Reprod. 12:1458-1463

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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 2003. Reprod Biomed Online; 7:485-492

- Ombelet W. et al 2005. Hum. Reprod. Update ; 11:3-14

Cost effectiveness

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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 2002. Hum Reprod; 17:3090-3109

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IUI versus IVF

IUI baby

IUI baby

IUI baby

10,000 $

5,000 $

9,500 $

IVF baby

IVF baby

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

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IVF baby

5,000 $Int J Gynaecol Obstet. 1991 Sep;36(1):49-53

IUI baby

1,500 $

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

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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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One intrauterine insemination (IUI) versus double IUI in stimulated cycles. Outcome: pregnancy rate per couple.

(Contineau AE et al, 2003)

Embryo Implantation

• Endometrial thickness/polyps

• Catheter used

• Us of aspirin and luteal phase support

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Polypectomy can improve fertility in subfertile women

with asymptomatic

endometrial polyps.Kuohung W & Hornstein M 2010. Up T o Date .

www.uptodate.com

Uterine Polypi

Number and percentage of pregnancies after hysteroscopic polypectomy (n=204) (RCT) 4xIUI

Polypectomy P-value

Study (n=101) Control (n=103)

Pregnancy <0.001

No. 64 29% (63,4) (28,2)RR 2.1 (95% XI 1.5-2.9)

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Perez –Medina T et al, 2005. Hum Reprod. 20:1632-1635

Laboratory Factors• Sperm washing methods

• Addition of substances in sperm preparation

• Fallopian sperm perfusion

• Effect of abstinence period

• Immunological male subertility

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•Easy to perform

•Training is easy

•Less invasive

•Risks are minimal

•Quality control possible

•Costs are minimal

Advantage

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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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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

Complications • Relatively low success rate / cycle.

• PID 0.01-0.2%.*

• 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.

XX FIGO World Congress of Gyn./ and Obs.

FIGO World Congress 2012 website is now

available at:

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IUI versus IVF

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10,000 $ 43,000 $

IUI baby IVF baby

Van Voorhis et al. Fert. Steril 1998

IUI baby

5,000 $

IVF baby

IVF baby

13,000 $

16,000 $IUI baby9,500 $

Goverde et al. Lancet 2000

Philips et al. Hum Reprod 2000