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Indications And Patient Selection For IUI
CHAPTER ONE
Surveen Ghumman Sindhu
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Appropriate patient selection is one of the most important factors which determine success of an IUI programme. Many
times treatment is empirical, but it is possible to deduce a section of people in whom this treatment is going to be useful.
The basis of treatment is to improve the quality and quantity of gametes available for fertilization, and to bring them
closer by bypassing factors which depend on deposition of sperms in vagina and transport through cervical mucus to
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upper genital tract. There are several indications for IUI which may be because of male, female or combined factors (Fig.
1.1).
Before taking up the patient for IUI, a complete workup is required to reach the diagnosis, and rule out any
contraindications. If any one of the contraindications is present IUI success rates may be poor (Table 1.1). The cause of
infertility must be established to give a diagnosis to the patient, which is essential to decide if IUI is appropriate therapy.
Patients must be counseled on success rates, other options and risks of IUI.
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INSEMINATION WITH HUSBAND'S FRESH SPERM
MALE FACTOR
RETROGRADE EJACULATION
With retrograde ejaculation, there is re ux of semen backwards from the posterior urethral valve and into the bladder at
the time of ejaculation. These sperms lose their viability due to toxic effects and acidity of urine.
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Figure 1.1: Indications and Patient Selection for IUI
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Table 1.1 Contraindication of IUI
Contraindications
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1. Bilateral tubal block
2. Very severe oligoasthenospermia
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3. Genital tract infection
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Relative contraindication
4. Pregnancy contraindicated in female partners
5. Unexplained genital tract bleeding
1. Tubal pathology
2. Genetic abnormality
3. Pelvic mass
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4. Older women
5. Multiple infertility aetiologies
6. Pelvic surgery
7. Severe illness in one or both partners
8. Recent chemotherapy or radiotherapyContraindications
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IUI has been used in these cases when medical therapy fails especially where there is a good sperm motility.
CAUSE
Diabetes mellitus
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Multiple sclerosis
Damage to innervation of bladder neck can occur during surgery, like transurethral resection of the prostate and
retropubic prostatectomy
Drugs—alfa adrenergic blockers, phenothiazines.
DIAGNOSIS
Demonstration of sperm or detection of fructose in urine following an orgasm.
GOAL OF MANAGEMENT
Alkalinize urine and retrieve sperms, as soon as possible, after ejaculation.
TREATMENT
1. Patient is asked to ejaculate on full bladder. The urinary continence with full bladder entails closure of bladder neck
sphincters and this prevents re ux of ejaculated semen into bladder especially when patient is in upright position.
2. The sperms can be collected from urine for IUI.1
3. Surgical treatment is aimed at restoring sphinteric control.
4. Medical therapy is also possible and aims at increasing sympathetic discharge, or decreasing parasympathetic
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activity at the bladder neck. Alfa adrenergic agents, such as phenyl propanolamine hydrochloride, synephrine and
nidodrin and anticholinergic drugs like brompheniramine, have been tried.
IMPOTENCE OR EJACULATORY DYSFUNCTION
There are a number of reasons for impotence or ejaculatory dysfunction (Table 1.2). The quality of semen is generally
poor in men, who are continent for long periods. The motility is low despite high sperm density. Debris, in ammatory
cells, and bacteria may be found in the sample. They may have recurrent urinary tract infections, which spread on to the
genital tract. The success of treatment depends on sperm quality. In patients with progressive sperm motility of more
than 20-30 per cent, the results of IUI are good. A fecundity rate of 9-36.8 per cent has been reported.2
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Table 1.2 Causes of impotence or ejaculatory dysfunction
• Psychogenic
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• Organic
• Spinal cord injury
• Diabetes mellitus
• Multiple sclerosis
• Atherosclerosis
• Hypo and hyperthyroidism
• Epilepsy
• Renal failure
• Damaged hypogastric nerves during surgery, such as abdominoperineal resection of rectum, retroperitoneal lymph node dissection
and aortoiliac surgery
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• Drug
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TREATMENT
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1. Treat the cause.
2. Intracavernosal injection:
Papavarine hydrochloride
Phenoxybezamine
Phentolamine mesylate
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Prostaglandin.
3. Surgical methods:
Epidydimal sperm aspiration
Hypogastric sperm aspirator
Sperm reservoirs.
4. Penile vibrator.
5. Rectal electrostimulation.
Autonomic hyper-re exia may occur in men with spinal cord injury, leading to a raised blood pressure following
orgasm. This can be treated by drugs. Retrogade ejaculation is occasionally seen, hence culture medium should be
instilled into the bladder prior to the procedure. Urine must be collected and processed.
Penile vibrator or electrostimulator: The penile vibrator or electrostimulators are effective and safe. Electro-ejaculation,
with stepwise application of ART, is effective in treating anejaculatory infertility. Intrauterine insemination, with the least
expensive monitoring protocol, should be used for most couples, as use of more expensive monitoring has not shown
improved results. Female management protocol, and etiology of an ejaculation does not affect results. Patients
undergoing IVF had higher cycle fecundity (37.2%), than did those undergoing IUI.(32.5%) It is cost-effective to bypass IUI
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and proceed directly to IVF, in men who require anesthesia for electro-ejaculation, and in those with a total inseminated
motile sperm count < 4 million.3
Per cutaneous vasal sperm aspiration (PVSA): In a study IUI was performed in 26 men with anejaculation after
percutaneous vasal sperm aspiration. A pregnancy rate of 73.1 per cent was achieved. Values for sperm variables were
acceptable and as follows: motility, 78.6 per cent; progressive motility, 60.4 per cent; density, 37.6 × 106 cells/mL; total
count, 35.2 × 106 cells; and abnormal sperm, 18.6 per cent. Percutaneous vasal sperm aspiration may obtain high
motility sperms, and combined with IUI, is an effective treatment for male infertility with an ejaculation.
HYPOSPADIAS
Here deposition of semen occurs outside the vagina or much away from the os. However, hypospadius is usually
repaired in infancy.
HYPOSPERMIA
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The term should only be used if the volume is consistently less, and it is ensured that there is no spillage. Low volume
could be because of inadequate sexual stimulation, in which case the semen may be collected from home.
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Need for IUI in such cases exists because:
1. The very small volume of ejaculate may be deposited away from the cervix.
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2. Small volume of seminal plasma is inadequate to change pH of upper vagina, and the acidic pH of vagina destroys the
sperms.
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NON LIQUEFYING OR HIGHLY VISCOUS SEMEN
Increased viscosity impedes the escape of sperms from the ejaculate into the cervical canal before destruction by
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vaginal acidity occurs. Enzymatic digestion of mucus is possible by plasmin or chymotrypsin. Mechanical methods may
be employed to break tenacious mucus threads while preparing sperms. After adding culture medium, the sample is
repeatedly aspirated and expelled through a hypodermic needle of 18 G size. Alternatively a pipette can be used.
However, there may be portions of highly viscous ejaculate which have normal viscosity.
The overall pregnancy rate, when viscosity was increased, was 14 per cent vs 11.8 per cent for normal semen.
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However 62.5 per cent pregnancies miscarried in the rst trimester; with no miscarriage in the normal semen group. The
high miscarriage rate, in couples with semen hyperviscosity, may be attributed to biophysical alterations or chemical
changes of the ejaculate that could impact sperm quality, despite normal sperm parameters on semen analysis.4
SUBNORMAL SEMEN PARAMETERS
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The cause of infertility in oligoasthenospermia is decreased availability of motile sperms required for fertilization.
Oligospermia: In patients with oligoasthenozoospermia the normal motile sperm fraction is selected out during the
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preparation and is selectively deposited in the uterine cavity. They bypass the vaginal acidity and cervical mucus and
reach the fallopian tube in numbers greater than what would have been otherwise possible.
Teratospermia: With teratozoospermia the motility is decreased because of abnormal morphology. Also the ability of
sperm to bind to the zona may be altered. Sperm preparation and insertion into the uterine cavity is not going to improve
the fertilization rates unless adequate amount of normal motile sperms are selected out while preparing the sample.
Sperm preparation with more than 1 × 106 motile sperms is needed.
Patients with severe male factor infertility like sperm count of less than 5 million, or more than two abnormal
parameters, have poor results.5 With mild male factor infertility, the pregnancy rates of IUI are comparable to IVF.6
HIV INFECTION
Recently insemination of HIV negative women with processed semen sample of HIV positive partners has been carried
out to reduce the risk of transfer. Sperm washing can signi cantly reduce the virus load7 However, documentation of
testing of sperm preparation by PCR on each sample is a must before insemination. In a recent study 740 serodiscordant
HIV positive couples no seroconversion of female partner was observed with IUI or ICSI.8
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FEMALE FACTOR
CERVICAL FACTOR
The cervical mucus plays an important role in fertility.
The preovulatory cervical mucus is receptive and allows entry of sperms into the uterus
It protects the sperm from vaginal acidity
It serves as a sperm reservoir, from which there is continuous slow release of sperms, which remain available for the
egg
There is initiation of capacitation of sperms in the cervical mucus.
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At microscopic levels the cervical mucus appears to be a loose network of bres with uid lled interstitial spaces.
These spaces are small, compared with the sperm, so the sperm must be motile to push its way through the mucus.
Cervical mucus limits the passage of motile sperms, lters out the non-motile cells and debris, and prevents passage of
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seminal plasma into the uterus. If the cervical mucus is scanty or hostile, due to immunological factors, the sperm may
not ascend into the uterine cavity. This could occur if there is:
History of cervical cone biopsy or amputation
Radical cauterization
Tumors of cervix
Severe cervical stenosis
Chronic endocervicitis
Inspissated cervical mucus.
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IUI helps to bypass these hostile factors. It has been observed that only 0.1 per cent of the sperms placed in the
vagina are present in the cervical canal one hour after insemination.9 Direct deposition of motile sperms in the uterine
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cavity can reverse this situation, and increase the chances of pregnancy. It resulted in a 14 per cent fecundity rate, which
increased to 17 per cent with controlled ovarian stimulation (COS). Ongoing pregnancy rates were only marginally better
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when controlled ovarian stimulation is used (9.7% vs 12.7%).10 COS does not give an advantage with cervical factor
infertility according to recent study.11 However, the predictive value of postcoital test is questionable, hence raising
doubts about the existence of cervical factor.12
OVULATORY DYSFUNCTION
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Results of pregnancy improve if IUI is performed instead of timed intercourse, along with controlled ovarian stimulation,
in women with ovulatory dysfuncion.
ENDOMETRIOSIS
IUI with ovulation induction can be tried in mild endometriosis. However, in these patients the success rate of IUI remains
poor in comparison to IUI done for indications like mild male factor or unexplained infertility. The mean fecundity rates
remain between 7-18 per cent depending on the severity of endometriosis. In patients with severe endometriosis, results
of IUI are poor because of tubal factor and it is recommended that IVF be done directly. The clinical PR per cycle was
comparable in women with minimal, or mild, endometriosis treated laparoscopically (21% and 18.9%, respectively), and in
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women with unexplained infertility (20.5%), when COS and IUI was done.13
COS and IUI should be the second line of treatment after surgery, in the absence of speci c indication for IVF. The
nancial and psychological strain is signi cantly more with IVF. Attempts at IUI should be limited to 3 to 6 cycles as
success rates decrease thereafter. Those with severe endometriosis should directly be taken up for IVF as results of COS
and IUI are poor.
FACTORS COMMON TO BOTH MALE AND FEMALE
IMMUNOLOGICAL INFERTILITY
In the males antisperm antibodies are found in the serum and seminal uid, while in the females they can be found in
serum, cervical mucus, tubal uid, follicular uid and peritoneal uid. There is an increased incidence of these antibodies
in infertility.
CAUSES
Causes in men are usually testicular trauma or obstruction to the male genital tract. In women a break in the vaginal
epithelium, peritoneal instillation, or anal and oral intercourse, may cause development of antibodies. Local antibodies
are more important in causing infertility than the ones found in the serum. These antibodies can prevent binding of
sperm to zona pellucida. They also impair sperm movement.
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Various treatments, like prolonged use of condoms, immunosuppression with steroids and laboratory procedures, to
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wash sperms to remove antibodies from the surface of the sperms have been tried without too much success.
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Both IUI and IVF yielded unexpectedly high pregnancy rates in this selected group of patients, with long-standing
infertility due to sperm surface antibodies (predominantly IgG). Since cost bene t analysis comparing superovulation IUI
with IVF may favour a course of four IUI cycles, superovulation IUI is advocated as the rst line therapy in male
immunological infertility.14 If antibodies are found in cervical mucus IUI helps to bypass them.
UNEXPLAINED INFERTILITY
Unexplained infertility is a diagnosis made when a couple fails to establish pregnancy despite there being no obvious
cause. The diagnostic protocol should show a normal laboratory assessment of ovulation, evaluation of tubal patency
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and semen analysis. It is diagnosed as cause of infertility in 15 per cent couples.
RATIONALE OF TREATMENT
Since these patients have reduced reproductive capacity, it may take longer for them to conceive. Their monthly
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fecundity is 3 per cent compared to 20 per cent for normal fertile couples. Thus most couples of unexplained infertility
will conceive, given time. Their chance of successful pregnancy, without any intervention, is as high as 60 per cent in 3
years. Viewed from this aspect, the rationale of treatment in unexplained infertility is to increase the monthly probability
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of pregnancy, hence reducing time interval for conception and identifying, early, couples who may not respond to
treatment. Superovulation with intrauterine insemination, and in vitro fertilization (with or without intracytoplasmic sperm
injection), have been known to increase the chance of pregnancy.
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The therapy consists of three basic management principles:
1. Increasing availability of gametes by ovulation induction and IUI.
2. Improving gamete quality.
3. Bringing gametes together by IUI and IVF.
Defects in folliculogenesis, gamete development, fertilization and embryo implantation may be responsible for
unexplained infertility. The rationale of empirical therapy is to reduce, or bypass, as many causative factors, as possible.
ART techniques are used to overcome known de ciencies, such as using IVF to circumvent damaged fallopian tubes.
Because these techniques are based upon enhancement and/or substitution, they can be applied to unexplained
infertility patients, with the hope that what is being enhanced or substituted, is the element responsible for the infertility.
To enhance the decreased reproductive capacity in couples with unexplained infertility the number of gametes can be
increased. Ovulation induction, besides increasing number of gametes, helps in removing subtle defects of ovulation
which may be responsible for unexplained infertility. Increasing density of motile sperms in semen, prepared for IUI,
might increase probability of pregnancy. Hence the ovulatory and male factors are enhanced while the cervical factor is
bypassed.
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COH, with clomiphene, combined with intrauterine insemination, is tried in cases of unexplained infertility. Since
clomiphene is a safe drug, a 3 month trial with clomiphene is recommended.
E cacy of IUI: Controlled ovarian hyperstimulation (COH), without IUI, leads to success in unexplained infertility, but
success rates improve when combined with IUI. It is well established that IUI gave better pregnancy rates than timed
intercourse (TI), both in stimulated and natural cycle.15
In a retrospective analysis of 45 published reports, success rates were analysed as pregnancy rate per initiated cycle
(Table 1.2). Addition of IUI to superovulation improved results. Use of gonadotropins, in place of clomiphene citrate
improved pregnancy rates from 8.3 per cent to 17 per cent16 (Table 1.3).
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Table 1.3 E cacy of treatment in unexplained infertility
Treatment
Combined Pregnancy Rates Perinitiated Cycle (%)
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1.3%
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3.8%
CC
5.6%
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CC with IUI
8.3%
HMG
7.7%
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HMG with IUI
17.1%
IVF
20.7%
Gonadotropins may be preferred in older patients, or where clomiphene has failed, as it produces greater number of
follicles. It is also free from antiestrogenic effect of clomiphene. Three cycles of gonadotropins, combined with
intrauterine insemination, may be tried.
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However, controversy exists as to whether the success is attributable to ovarian stimulation and close monitoring of
the cycle. Of all the etiologies of infertility, unexplained infertility gave the best results with IUI in terms of overall
fecundity of 22 per cent.17
INSEMINATION WITH HUSBAND'S FROZEN SEMEN
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Freezing of husband's semen is indicated in the following conditions:
1. Absentee husband.
2. Anti neoplastic treatment.
3. Vasectomy.
4. Poor semen parameters.
5. Drug therapy: Drugs that are detrimental to testicular function—Alcohol, cocaine, colchicines, niridazole, methadone,
heroin, lead, diethylstil-besterol, sulphasalazine, tobacco, trinitrotoluene.
INSEMINATION WITH DONOR SPERMS
The use of cryopreserved sperms in donor insemination, is now mandatory to minimize transmission of HIV.
The indications are:
1. Azoospermia.
2. Severely subnormal semen parameters.
3. Persistent IVF/ICSI failures.
4. Hereditary disease in father.
5. Rhesus isoimmunization.
. Patient unable to afford the cost of IVF.
Obstructive azoopsermia can now be treated with ICSI after recovering sperms from testis or epidydimus by TESA or
MESA.
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Hereditary disease: Recent advances have introduced preimplantation genetic diagnosis which enables embryo
biopsy in cases with family history of genetic disease like hemophilia and cystic brosis. Hence, donor insemination can
be avoided.
Patients must be properly selected for IUI. It is important that patients are appropriately counseled about success
rates, multiple pregnancy and ovarian hyperstimulation before they are taken up for IUI. Male subfertility has been the
most controversial indication for IUI. Although pregnancy rate in the presence of severe male factor and endometriosis is
low with IUI the procedure should not be rejected outright without considering cost effectiveness when compared with
IVF.
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REFERENCES
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1. Zhao Y, Garcia J, Jarow JP, Wallach EE. Successful management of infertility due to retrograde ejaculation using assisted reproductive
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2. Ohl DA, Denil J, Bennet CJ, Randolf JF, Menge AC, Mc Cabe M. Electroejaculation following retroperitoneal lymphadenectomy. J Urol 1991; 145:
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3. Ohl DA, Wolf LJ, Menge AC, Christman GM, Hurd WW, Ansbacher R, Smith YR, Randolph JF Jr. Electroejaculation and assisted reproductive
technologies: a report of two cases. Arch Androl 2004; 50(6): 391–4.
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technologies in the treatment of anejaculatory infertility. Fertil Steril 2001; 76(6): 1249–55.
4. Esfandiari N, Gotlieb L, Casper RF. Seminal hyperviscosity is associated with poor outcome of controlled ovarian stimulation and intrauterine
insemination: a prospective study. Int J Fertil Womens Med 2006; 51: 21–7.
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5. van Weert JM, Repping S, Van Voorhis BJ, van der Veen F, Bossuyt PM, Mol BW. Performance of the postwash total motile sperm count as a
predictor of pregnancy at the time of intrauterine insemination: a meta-analysis. Fertil Steril 2004; 82(3): 612–20.
6. Zhao Y, Vlahos N, Wyncott D, Petrella C, Garcia J, Zacur H, Wallach EE. Impact of semen characteristics on the success of intrauterine
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insemination. J Assist Reprod Genet 2004; 21(5):143–8.
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7. Bujan L, Pasquier C, Labeyrie E. Lanusse-Crousse P, Morrucci M, Daudin M. Insemination with isolated and virologically tested spermotozoa is a
safe way for human immunode ciency type 1 virus-serodiscordant couples with an infected male partner to have a child. Fertil Steril 2004; 82:
857–62.
8. Savasi V, Ferrazzi E, Lanzani C, Oneta M, Parrilla B, Persico T. Safety of sperm washing and ART outcome in 741 HIV −1 serodiscordant couples.
Hum Reprod 2007; 22: 772–7.
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9. Settlage DSF, Motishima M, Tredway DR. Sperm transport from external cervical os to fallopian tube in women: a time and quantitative study.
Fertil Steril 1973; 24: 55–61.
10. Steures P, van der Steeg JW, Verhoeve HR, van Dop PA, Hompes PG, Bossuyt PM, van der Veen F, Habbema JD, Eijkemans MJ, Mol BW. Does
ovarian hyperstimulation in intrauterine insemination for cervical factor subfertility improve pregnancy rates? Hum Reprod 2004; 19(10): 2263–6.
11. Steures P, van der Steeg JW, Hompes PG, Bossuyt PM, Habbema JD, Eijkemans MJ, Koks CA, Boudrez P, van der Veen F, Mol BW. The additional
value of ovarian hyperstimulation in intrauterine insemination for couples with an abnormal postcoital test and a poor prognosis: a randomized
clinical trial. Fertil Steril 2007; 88: 1357–62.
12. Martinez AR, Bernadus RE, Vermeiden PW, Schoemaker J. Basic questions on intrauterine insemination an update. Obstet Gynecol Surv 1993; 48:
811–23.
13. Werbrouck E, Spiessens C, Meuleman C, D'Hooghe T. No di erence in cycle pregnancy rate and in cumulative live-birth rate between women with
surgically treated minimal to mild endometriosis and women with unexplained infertility after controlled ovarian hyperstimulation and intrauterine
insemination. Fertil Steril 2006; 86(3): 566–71.
14. Ombelet W, Vandeput H, Janssen M, Cox A, Vossen C, Pollet H, Steeno O, Bosmans E. Treatment of male infertility due to sperm surface
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antibodies: IUI or IVF? Hum Reprod 1997; 12(6): 1165–70.
15. Verhulst SM, Cohlen BJ, Hughes E, Te Velde E, Heineman MJ. Intra-uterine insemination for unexplained subfertility. Cochrane Database Syst Rev
2006 Oct 18;(4): CD001838.
16. Guzick DS, Carson SA, Coutifaris C, Overstreet JW, Factor Litvak P, Steinkampf MP, Hill JA, Mastoianni L, Nakajima ST, Vogel DL, Canfeild RE.
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cacy of superovulation and intrauterine insemination in treatment of infertility. National cooperative reproductive Medicine Network N Engl J
Med 1999; 340: 177–83.
17. Randall GW, Gantt PA. Intrauterine insemination results in couples requiring extended semen transport time. Int J Fertil Womens Med 2007; 52:
28–34.
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