IUI, Ovarian Stimulation and Complications
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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

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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

ERC/ELG

March 3rd-4th, 2012


Items addressed
Items Addressed

  • 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.


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


Semen preparation techniques
Semen Preparation Techniques refinement of techniques for the preparation of washed motile spermatozoa.

  • Swim up.

  • Albumin

  • Percoll

  • Minipercoll

  • Glass wool filtration

  • Sephadex separation

  • Migration sedimentation

  • Glass blood separation


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


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
Patient preparation of free oxygen radicals after sperm preparation. The final result is an improved fertilizing capacity of the sperm in vitro and in vivo.

Natural cycle

MOH

- CC – hCG

-CC – hMG –hCG

-rec FSH – hCG

-GnRH-hMG (rec. FSH) - hCG


Timing of iui
Timing of IUI of free oxygen radicals after sperm preparation. The final result is an improved fertilizing capacity of the sperm in vitro and in vivo.

Basal Body Temperature

LH Surge ( urine/serum)

US


Sample for iui
Sample for IUI of free oxygen radicals after sperm preparation. The final result is an improved fertilizing capacity of the sperm in vitro and in vivo.

Fresh semen

Split ejaculate

Different volumes

Washed semen +/-

- Antioxidants

- Platelet Activity Factor

- Follicular Fluid.


Sites of insemination
Sites of insemination of free oxygen radicals after sperm preparation. The final result is an improved fertilizing capacity of the sperm in vitro and in vivo.

Intrauterine (IUI)

Intracervical (ICI)

Intraperitoneal (IPI)

Cap insemination

Trans cervical / intrafallopian (ITI)


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.

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


Indications
Indications (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.

Male factor subfertility

Unexplained infertility

Endometriosis.

Combined ovulatory and ♂ factor infertility.

Cervical and immunological infertility

Sexual dysfunction infertility.


Male Factor Subfertility (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.

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


Who lab manual of human semen 2010

The lower reference limit for semen analysis (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.

WHO Lab Manual of Human Semen 2010


Male factor Infertility (OAT) (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.

  • Oligozoospermia (O)

  • Asthenozoospermia (A)

  • Tratozoospermia (T)


Male subfertility
Male subfertility (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.

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 subfertility1
Male subfertility (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.

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.


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.


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


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


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


A cut off level of: successful provided the sperm morphology score using strict criteria is 4% or more

0.8 million motile spermatozoa after washing .

Metaanalysis(Van Weert et al 2004 )

30-50% Total sperm motility before sperm preparation

( OmbeletW et al 1996

Dickey et al 1999, Montanaro et al

2001, Lee et al, 2002)


Infertility work -up successful provided the sperm morphology score using strict criteria is 4% or more

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


Unexplained infertility successful provided the sperm morphology score using strict criteria is 4% or more

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


When controlled ovarian hyperstimulation (COH) is used, IUI becomes effective compared with TI

Cohlen BJ. Gyn. Obst. Invest ;2005;59:3-13


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


Cervical Factor Infertility rate compared with IUI alone. The likelihood of pregnancy was also increased for treatment with IUI compared with TI in stimulated cycles.

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


Sexual dysfunction infertility
Sexual Dysfunction infertility rate compared with IUI alone. The likelihood of pregnancy was also increased for treatment with IUI compared with TI in stimulated cycles.

Retrograde ejaculation

Vaginismus

Hypospadius

Impotence

Infrequent Intercourse during fertile period.


Effectiveness rate compared with IUI alone. The likelihood of pregnancy was also increased for treatment with IUI compared with TI in stimulated cycles.

Controversy still surrounds the effectiveness of this very popular treatment procedure.


Eshre capri workshop group
ESHRE Capri Workshop Group rate compared with IUI alone. The likelihood of pregnancy was also increased for treatment with IUI compared with TI in stimulated cycles.

  • 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, 265-277


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.


ESHRE Capri Workshop Group cycle

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


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. empiric treatment since it is likely that the majority of infertility involves factors that are untreatable or unknown.

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
Efficacy of IUI empiric treatment since it is likely that the majority of infertility involves factors that are untreatable or unknown.

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
IUI / Other modalities empiric treatment since it is likely that the majority of infertility involves factors that are untreatable or unknown.

Success rate

Singleton live birth rate

Cost-benefit analysis

Complication rate

Invasiveness of the technique

Patient compliancy

Healthcare cost


Unexplained and moderate ♂ factor subfertility empiric treatment since it is likely that the majority of infertility involves factors that are untreatable or unknown.

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:10.1093/humrep/den165


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


Cost effectiveness for all couples, providing the IMC was more than 1 million was obtained.

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


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


IUI versus IVF initially treatment with IUI appears to be more cost-effective than IVF in most cases of unexplained and moderate male subfertility.

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 $

Philips et al. Hum Reprod 2000


IUI baby initially treatment with IUI appears to be more cost-effective than IVF in most cases of unexplained and moderate male subfertility.

1,500 $

IVF baby

5,000 $

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


Factors affecting iui success
Factors affecting IUI success initially treatment with IUI appears to be more cost-effective than IVF in most cases of unexplained and moderate male subfertility.

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


Live birth rates could not be assessed initially treatment with IUI appears to be more cost-effective than IVF in most cases of unexplained and moderate male subfertility.

Anti –oestrogens versus gonadotrophins combined with intrauterine insemination outcome: pregnancy rate per couple.

(Contineau AE et al, 2007)


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

(Contineau AE et al, 2003)


Embryo implantation
Embryo Implantation stimulated cycles. Outcome: pregnancy rate per couple.

Endometrial thickness/polyps

Catheter used

Us of aspirin and luteal phase support


Uterine Polypi stimulated cycles. Outcome: pregnancy rate per couple.

Polypectomy can improve fertility in subfertile women with asymptomatic

endometrial polyps.

Kuohung W & Hornstein M 2010. Up T o Date . www.uptodate.com


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

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


Laboratory factors
Laboratory Factors polypectomy (n=204) (RCT) 4xIUI

Sperm washing methods

Addition of substances in sperm preparation

Fallopian sperm perfusion

Effect of abstinence period

Immunological male subertility


Advantage polypectomy (n=204) (RCT) 4xIUI

  • Easy to perform

  • Training is easy

  • Less invasive

  • Risks are minimal

  • Quality control possible

  • Costs are minimal


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


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
Complications and trypsin for removing HIV and hepatitis C virus from semen seems to be very promising.

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
XX FIGO World Congress of Gyn./ and Obs. and trypsin for removing HIV and hepatitis C virus from semen seems to be very promising.

FIGO World Congress 2012 website is now available at:

http://www.figo2012.org


THANK YOU and trypsin for removing HIV and hepatitis C virus from semen seems to be very promising.

57


Iui versus ivf
IUI versus IVF and trypsin for removing HIV and hepatitis C virus from semen seems to be very promising.

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 $

Philips et al. Hum Reprod 2000


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