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
4/8/2015
March 3rd-4th, 2012
1
Items Addressed
• What is IUI.
•Indications.
•Effectiveness.
•Cost Effectiveness.
• Factors affecting success rate.
•Advantages and complications.
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2
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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3
This interest in IUI is
undoubtedly associated with
the refinement of
techniques for the
preparation of washed
motile spermatozoa.
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4
Semen Preparation Techniques
-Swim up.
-Albumin
-Percoll
-Minipercoll
-Glass wool filtration
-Sephadex separation
-Migration sedimentation
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-Glass blood separation
5
The washing procedures are
necessary to remove
prostaglandins, infectious
agents, antigenic proteins,
non-motile spermatozoa,
leucocytes and immature
germ cells.
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6
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
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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)
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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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
4/8/2015
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Indications
•
•
•
•
•
•
Male factor subfertility
Unexplained infertility
Endometriosis.
Combined ovulatory and ♂ factor
infertility.
Cervical and immunological infertility
Sexual dysfunction infertility.
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
15
The lower reference limit for semen analysis
Volume
PH
Motility
Progressive
Non progressive
Immotile
Vitality
(intact membrane)
Count
Normal forms
1,5ml
7.2
40%
32%
5th centile 95%
CI
(1.4-1.7
(38-42)
(31-34)
58%
(55-63)
15X106
4%
12-16X10 6
(3-4)
WHO Lab Manual of Human Semen 2010
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Male factor Infertility (OAT)
-Oligozoospermia (O)
-Asthenozoospermia (A)
-Tratozoospermia (T)
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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 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
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Male 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.
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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.
4/8/2015
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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
6
between 0.3 and 20X10 .
-Ombelet W et al 2008. Hum. Reprod. Doi:10.1093/humrep/den165
4/8/2015
22
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)
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Infertility work -up
HSG, Laparoscopy, HSCS..
No tubal factor
Washing procedure
IMC< 1 million
Morphology <5%
IMC< 1 million
IMC> 1 million
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
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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When controlled ovarian
hyperstimulation (COH) is
used, IUI becomes
effective compared with TI
Cohlen BJ. Gyn. Obst. Invest ;2005;59:3-13
4/8/2015
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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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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
29
Sexual Dysfunction infertility
•
•
•
•
•
Retrograde ejaculation
Vaginismus
Hypospadius
Impotence
Infrequent Intercourse during fertile
period.
Effectiveness
Controversy still
surrounds the
effectiveness of this very
popular treatment
procedure.
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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 al
Hum Reprod Update, 2009, vol 15 No. 3, 265-277
32
Pregnancy rate per cycle and number needed to treat (NNT)per cycle
Treatment Preg. rate NNT
per cycle
IUI
5
32
CC/IUI*
FSH/IUI
FSH/IUI
IVF
7
4
12
31
14
-25
11
4
95% CI
Source or results
(12.-46) Guzick et al. (1999),
Martinez et al.
(1990) and Steures
et al. (2007)
(7.-100) Deaton et al. (1990)
(15.-7) Steures et al. (2006)
(9.16) Guzick et al. (1999)
(3.7)
Hughes et al. (2004)
*Pregnancy rate per cycle is from Reindollar et al. (2007). NNT is from Deaton et
4/8/2015
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al. (1990) before crossover.
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
4/8/2015
Vol,15, No. 3, 265-277
34
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
4/8/2015
Vol,15, No. 3, 265-277
35
•
•
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
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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IUI / Other modalities
•
•
•
•
•
•
•
Success rate
Singleton live birth rate
Cost-benefit analysis
Complication rate
Invasiveness of the technique
Patient compliancy
Healthcare cost
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:10.1093/humrep/den165
4/8/2015
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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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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 2003. Reprod Biomed Online; 7:485-492
4/8/2015
- Ombelet W. et al 2005. Hum. Reprod. Update ; 11:3-14
41
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.
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Carceau L et al 2002. Hum Reprod; 17:3090-310942
IUI versus IVF
IUI baby
10,000 $
IVF baby
43,000 $
Van Voorhis et al. Fert. Steril 1998
IUI baby
5,000 $
IVF baby
13,000 $
Goverde et al. Lancet 2000
IUI baby
9,500 $
4/8/2015
Philips et al. Hum Reprod 2000
IVF baby
16,000 $
43
IUI baby
IVF baby
1,500 $
5,000 $
4/8/2015
Int J Gynaecol Obstet. 1991 Sep;36(1):49-53
44
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
Live birth rates could not be assessed
Anti –oestrogens versus gonadotrophins combined with intrauterine insemination outcome: pregnancy rate per couple.
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(Contineau AE et al, 2007)
One intrauterine insemination (IUI) versus double IUI in stimulated cycles. Outcome: pregnancy rate per couple.
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(Contineau AE et al, 2003)
47
Embryo Implantation
•
Endometrial thickness/polyps
•
Catheter used
•
Us of aspirin and luteal phase
support
Uterine Polypi
Polypectomy can improve
fertility in subfertile women
with asymptomatic
endometrial polyps.
Kuohung W & Hornstein M 2010. Up T o Date .
49
www.uptodate.com
Number and percentage of pregnancies after
hysteroscopic polypectomy (n=204) (RCT) 4xIUI
Polypectomy
Study (n=101)
P-value
Control (n=103)
Pregnancy
No.
%
<0.001
64
(63,4)
29
(28,2)
RR 2.1 (95% XI 1.5-2.9)
Perez –Medina T et al, 2005. Hum Reprod.
20:1632-1635
50
Laboratory Factors
•
Sperm washing methods
•
Addition of substances in sperm
preparation
•
Fallopian sperm perfusion
•
Effect of abstinence period
•
Immunological male subertility
Advantage
•Easy to perform
•Training is easy
•Less invasive
•Risks are minimal
•Quality control possible
•Costs are minimal
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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
4/8/2015
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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:
http://www.figo2012.org
56
57
IUI versus IVF
IUI baby
IVF baby
10,000 $
43,000 $
Van Voorhis et al. Fert. Steril 1998
IUI baby
5,000 $
IVF baby
13,000 $
Goverde et al. Lancet 2000
4/8/2015
IUI baby
IVF baby
9,500 $
16,000 $
Philips et al. Hum Reprod 2000
58