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Section 6 Infertility and Recurrent Pregnancy Loss
Chapter
36
Artificial Insemination
Ashok Agarwal and Shyam S. R. Allamaneni
INTRODUCTION
Artificial insemination is an assisted conception method that can
be used to alleviate infertility in selected couples. The rationale
behind the use of artificial insemination is to increase the gamete
density near the site of fertilization.1 The effectiveness of artificial
insemination has been clearly established in specific subsets of
infertile patients such as those with idiopathic infertility, infertility
related to a cervical factor, or a mild male factor infertility
(Table 36-1).2,3 An accepted advantage of artificial insemination
is that it is generally less expensive and invasive than other
assisted reproductive technology (ART) procedures.4
This chapter provides a comprehensive description of
indications for artificial insemination, issues to consider before
donor insemination, complications associated with intrauterine
insemination (IUI), factors affecting the success of artificial
insemination, and the current evidence available on effectiveness
of artificial insemination for different indications.
HISTORY
Artificial insemination has been used in clinical medicine for
more than 200 years for the treatment of infertile couples. In
1785 John Hunter, a Scottish surgeon from London, advised a
man with hypospadias to collect his semen and have his wife
inject it into her vagina. This was the first documented case of
successful artificial insemination in a human.
In the second half of the nineteenth century, numerous reports
were published of human artificial insemination in France, England,
Germany, and the United States. In 1909, the first account of
successful donor artificial insemination was published in the
United States. By 1949, improved methods of freezing and
thawing sperm were being reported.
Today, artificial insemination is frequently used in the treatment
of couples with various causes of infertility, including ovulatory
dysfunction, cervical factor infertility, and unexplained infertility
as well as those with infertility caused by endometriosis, male,
and immunologic factors. Artificial insemination with donor semen
has become a well-accepted method of conception.
widely available, the terms homologous artificial insemination
and heterologous artificial insemination were used to differentiate
these two alternative sources. However, the use of these biomedical terms in this manner is at variance with their scientific
meaning, where they denote different species or organisms (as in,
e.g., homologous and heterologous tissue grafts).
In the latter half of the 20th century, the terms artificial
insemination, donor (AID) and artificial insemination, husband
(AIH) found common use. However, the widespread use of the
acronym AIDS for acquired immunodeficiency syndrome resulted
in the replacement of AID with therapeutic donor insemination
(TDI). An analogous alternative term for AIH has not evolved,
probably in part because of the increasingly common situation
where the woman’s partner is not her legal husband. In this chapter,
artificial insemination using these two standard sperm sources
will be designated simply as partner and donor insemination.
Techniques
Several different techniques have been used for artificial
insemination. The original technique used for over a century was
intravaginal insemination, where an unprocessed semen sample
is placed high in the vagina.
In the latter half of the 20th century, the cervical cap was
developed to maintain the highest concentration of semen at the
external os of the cervix. It was soon discovered that placing the
semen sample into the endocervix (intracervical insemination)
resulted in pregnancy rates similar to that obtainable using a cervical
cap and superior to those seen with high vaginal insemination.5
Intrauterine Versus Intracervical Insemination
A major breakthrough came in the 1960s when methods were
developed for extracting enriched samples of motile sperm from
semen. These purified samples were free of proteins and prostaglandins, and thus could be placed within the uterus using a
technique designated intrauterine insemination (IUI). This
Table 36-1
Infertility Disorders with Proven Benefit from
Partner Insemination
GENERAL CONSIDERATIONS
Idiopathic infertility
Semen Sources
The source of semen for artificial insemination can be either
from the woman’s male partner or from a donor, who usually
remains anonymous. When donor insemination first became
Cervical factor infertility
Mild male factor infertility
From Cohlen BJ: Should we continue performing intrauterine inseminations in the year 2004?
Gynecol Obstet Invest 59:3–13, 2004.
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technique was found to result in pregnancy rates 2 to 3 times
those of intracervical insemination. However, intracervical
insemination is still utilized in some practices.5
In an effort to further improve pregnancy rates, techniques
were developed to place washed sperm samples directly into the
tubes via transcerival cannulation (intratubal insemination) or
into the peritoneal cavity via a needle placed through the posterior
cul-de-sac (intraperitoneal insemination). Another technique
developed in Europe, termed fallopian tube sperm perfusion,
involves pressure injection of a large volume (4 mL) of washed
sperm sample while the cervix is sealed to prevent reflux of the
sample.6 This technique appears to have a higher pregnancy rate
than IUI in couples with unexplained infertility. The remainder
of these technically difficult approaches have never been shown
to result in better pregnancy rates than IUI. One prospective,
randomized study found that simultaneous intratubal insemination
actually decreased the pregnancy rates associated with IUI.7
In modern clinical practice in the United States, IUI is the
predominant technique used for artificial insemination.
EVALUATION
Male Evaluation
Semen Analysis
The male partner is initially evaluated by obtaining a complete
semen analysis and screen for sperm antibodies. A minimum of
two samples provided over 1 to 2 months is analyzed. A third
sample may be required if there is a discrepancy between
the initial samples. All samples should be provided after 48 to
72 hours of sexual abstinence. Samples should be analyzed within
2 hours of collection.
Antisperm Antibodies
540
Male antisperm antibodies are found in approximately 10% of
semen samples from infertile couples. Men with antisperm antibodies attached to their sperm are classified as having immunologic
infertility. These antibodies are believed to decrease fertility by
inducing agglutination or immobilization of the sperm. Studies
have identified multiple antisperm antibodies that correspond to
a variety of sperm components.
There are multiple known risk factors for the development of
male antisperm antibodies.8 Vasectomy results in the development
of antisperm antibodies in the majority of men. After successful
vasovasostomy, more than half of these men will have detectable
sperm-bound antibodies. The pregnancy rates will depend on
many factors, including the titer and quantity of gross agglutination.
Obstructive azospermia from any cause (e.g., congenital absence
of the vas deferens, cystic fibrosis, infant hernia repair) increases
the risk of antisperm antibodies. Reproductive infections (e.g.,
epididymitis, prostatitis, or orchitis) are also associated with
antisperm antibodies.
Antisperm antibody tests are performed as a routine part of
a complete semen analysis during the initial infertility evaluation.
The most commonly used test in clinical practice is probably the
immunobead assay.8 This quantitative assay evaluates live sperm
and indicates percent bound, antibody isotype, and binding
location. For routine screening, some andrology laboratories
use a commercially available mixed antiglobulin reaction assay
(SpermMar).
Male subfertility is significantly increased when the antisperm
antibody level is greater than 50%.9,10 Antisperm antibodies
interfere with sperm–zona pellucida binding and prevent embryo
cleavage and early development.
Complete Evaluation
In the presence of persistently abnormal results on semen
analysis, a complete history, physical examination, and laboratory
evaluation is performed to find and treat any potentially reversible
abnormalities (see Chapter 35).
Female Evaluation
The female partner should undergo a basic infertility evaluation
so that any correctable factors can be identified and treated
before artificial insemination (see Chapter 34). In addition to a
detailed history and physical examination, each woman considering partner or donor insemination should be evaluated with
an imaging technique, usually a hysterosalpingogram, to document
patent tubes. Unless oral or injectable medications are used to
induce superovulation, ovulatory function should be evaluated
with a urinary luteinizing hormone (LH) detection kit and midluteal serum progesterone level. Further evaluation is required
in the event of detection of any clinical or laboratory abnormalities.
In the past, a great deal of time was spent investigating the
possibility of cervical factor infertility by evaluating the character
and sperm survivability in periovulatory cervical mucus, using
what is termed a postcoital test. This test had many false-positive
results, because it depended more on timing in the cycle and
hormonal status than on static cervical characteristics. Except
for exclusion of cervicitis during pelvic examination, timed
evaluation of cervical mucus and sperm interaction is infrequently
included in a fertility examination. This is because partner IUI
is used as a basic fertility enhancement method for the majority
of couples who have otherwise been unable to conceive regardless
of diagnosis.
INDICATIONS
Partner Insemination
Partner insemination was originally developed as a treatment for
male factor infertility. With the advent of IUI, partner insemination
has been found to be an excellent treatment for a range of diagnoses, including cervical factor infertility, unexplained infertility,
and subfertility, on the basis of other diagnoses or therapeutic
measures (Table 36-2). This ability of partner insemination to
increase pregnancy rates regardless of diagnosis has made this
technique one of the fundamental approaches to infertility
treatment today.
Male Factor Infertility
Partner insemination appears to be of clear benefit when the
couple’s infertility is the result of any condition that makes it
difficult to place semen high in the vagina during coitus. Male
conditions resulting in this situation are termed ejaculatory failure.
The most common causes of ejaculatory failure are impotence,
severe hypospadias, and retrograde ejaculation. A unique condition
that has been found to be treatable with artificial insemination
is impotence secondary to spinal cord injury.11
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Table 36-2
Indications and Contraindications for Partner Insemination
Indications
Contraindications
Male Factor Infertility
Absolute Contraindications
Disorders of semen density, motility,
and morphology (mild oligospermia,
asthenozoospermia,
teratozoospermia)
Immunologic factors
Ejaculatory failure
Mechanical factors (malformed
urethra, hypospadias)
Rh blood factor incompatibility
Medical conditions that could endanger
the patient’s life
A partner with hereditable disease
Cervical neoplasia
Blocked tubes
Active genital tract infection in either
partner
Female Factor Infertility
Relative Contraindications
Cervical factor
Vaginismus
Mild endometriosis
Ovulatory dysfunction
Severely abnormal semen parameters
Multiple failures at previous partner
insemination attempts
Recent chemotherapy or radiotherapy
Coexisting multiple infertility etiologies
Pelvic surgery
Older age woman
Unexplained Fertility
An Adjunct to Other Infertility Treatments
Partner IUI appears to be of value for increasing per cycle fecundity
when inducing ovulation in women with ovulatory dysfunction.13
After ovulation induction with clomiphene citrate, partner IUI
might work by overcoming the decreased cervical mucus
associated with the use of clomiphene.14 With gonadotropins,
partner IUI might compensate for subtle changes in sperm transport within the uterus or tubes related to marked alterations
in circulating estrogen and progesterone levels associated with
their use.
Partner IUI also appears to be of some benefit when women
with mild and minimal endometriosis are trying to achieve pregnancy. After appropriate surgical treatment, the monthly improvement in fecundity with partner IUI appears to be similar to that
seen in patients with idiopathic infertility.15
Women with severe endometriosis or tubal disease have a far
lower fecundity rate and often an increased rate of ectopic pregnancies. For this reason, these patients appear to benefit more
from IVF than from partner IUI combined with superovulation.
Unexplained Infertility
Partner insemination is also commonly used as a treatment
for male factor infertility documented by repeated abnormal
results on semen analysis. In couples where there is mild male
factor infertility, defined as a progressive sperm motility of at
least 20% to 30%, the prognosis appears to be good with partner
insemination. Theoretically, increasing the number of motile
sperm reaching the egg should improve fertility whenever
decreased numbers and motility of normally functioning sperm
is the primary problem.
Unfortunately, the pregnancy rates after partner IUI for the
treatment of severe male factor infertility have been disappointing.12 This is probably because markedly abnormal
parameters on routine semen analysis often reflect a sperm defect
that decreases the ability to fertilize eggs. This type of defect is
unlikely to be overcome by increasing the number of sperm to
which the egg is exposed at the site of fertilization. In patients
with severely abnormal parameters on semen analysis and those
with male factor infertility not amenable to partner insemination,
more effective treatment will be either donor insemination or
in vitro fertilization (IVF) with intracytoplasmic sperm injection
(ICSI).
Female Factor Infertility
Female reproductive conditions can also make it difficult to
place semen high in the vagina during coitus. Such conditions that
can benefit from partner insemination include severe vaginismus
and other psychological problems, and less common anatomic
conditions. Little data exists documenting the success of partner
insemination for these conditions.
Women with cervical factor infertility will benefit from IUI,
because this approach bypasses the cervical abnormalities that
decrease fertility. This includes women with abnormal cervical
mucus secondary to noninfectious chronic cervicitis and women
with scant mucus or cervical stenosis, usually the result of
cervical surgery. However, even women with a normal cervix
and mucus appear to benefit from IUI, because the cervix
appears to be the limiting factor in sperm reaching the site of
fertilization in the tube.
Unexplained (i.e., idiopathic) infertility is diagnosed after all
known etiologies of infertility have been excluded. In these cases,
semen analyses are normal and there is no evidence of any female
causes of infertility, such as ovulation defects, tubal factor,
endometriosis, and cervical factor. The average incidence of
unexplained infertility is approximately 15% among infertile
couples.
In couples with unexplained infertility, partner IUI has been
demonstrated to improve pregnancy rates when used in conjunction with superovulation.13 In a meta-analysis of almost
1000 superovulation cycles for unexplained infertility, partner
IUI was found to almost double pregnancy rates (20%) compared
to timed intercourse alone (11%).
Partner IUI appears to overcome one or more unknown fertility
deficiencies that we cannot currently detect. Theoretically, this
might be decreased sperm transport from the vagina to the tube
secondary to either a sperm defect or an abnormality in sperm
transport mechanisms in the female reproductive tract. In other
cases, a subtle sperm fertilization defect might exist that is surmounted by increasing the absolute number of sperm reaching
the egg.
Donor Insemination
In the past, the only available options for couples with severe male
factor infertility (e.g., severe oligospermia, or failure to conceive
using partner insemination) desiring children were either donor
insemination or adoption. Since the widespread availability of
IVF using ICSI, many couples with severe male factor infertility
have chosen to procreate their own genetic children using these
techniques. However, donor insemination remains an option
when IVF/ICSI has been unsuccessful. Alternatively, many
candidates for IVF/ICSI initially choose donor insemination
because it is less invasive and ultimately more likely to achieve
pregnancy for couples with limited resources.
Some women choose donor insemination because they are
not candidates for IVF/ICSI. Perhaps the most obvious situation
is women without male partners who seek pregnancy. The use
of donor insemination is also indicated when the male partner
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has no viable sperm (i.e., azoospermia) or when IVF/ICSI fails
to achieve fertilization. Finally, men with a known genetic
disorder often choose donor insemination to avoid transmission
to their children.
timing strategies are based on either detection of a urinary LH
surge or administration of an ultrasound-timed dose of human
chorionic gonadotropin (hCG ) to trigger ovulation.
LH Surge
Couples choose a donor from profiles of nonidentifiable
information. This information usually includes racial or ethnic
background, blood type, physical characteristics, and certain
social characteristics. Many women who become pregnant as a
result of donor insemination desire to use the same donor for
further pregnancies.
A commonly used method for timing of IUI is based on urinary
LH measurement. Ovulation occurs 40 to 45 hours after the
onset of the LH surge.21 Insemination is thus planned for the
day after detection of a rise in urinary LH. This approach offers
the simplest and most cost-effective of the indirect methods
for predicting ovulation and is just as effective in achieving
pregnancy as more complex ones.22,23
Donor Evaluation
Ultrasound and Human Chorionic Gonadotropin
Thorough evaluation of all potential sperm donors (other than
sexually intimate partners) is necessary to avoid inadvertent
transmission of sexually transmitted diseases or known genetic
syndromes.16 All donors undergo a review of relevant medical
records, personal and family history, and a physical examination.
Determination of normal semen characteristics is extremely
important. In addition, blood grouping and karyotyping is
performed.
Each donor must be screened for risk factors and clinical
evidence of communicable diseases, including:
Transvaginal ultrasonography is widely used to monitor the size
of the follicles and to assess the timing of ovulation. Follicles
become recognizable once they grow to 2 to 3 mm in diameter.
After 8 mm, linear follicular growth occurs at a rate of approximately 2 to 3 mm per day. Ovulation occurs during a natural
cycle when the lead follicle reaches 15 to 24 mm in size.
Injection of hCG can be given to induce predictable ovulation
when at least one follicle diameter is between 17 and 21 mm.
For optimal pregnancy rates, IUI is scheduled 24 to 36 hours
after the injection.
Donor Selection
●
●
●
●
●
●
●
●
human immunodeficiency virus types 1 and 2
human T-lymphotropic virus types I and II
hepatitis B and C
cytomegalovirus
human transmissible spongiform encephalopathy (including
Creutzfeldt-Jakob disease)
Treponema pallidum
Chlamydia trachomatis
Neisseria gonorrheae
If the donor is deemed acceptable and is aware of the ethical
and legal implications, semen can be collected. All donor semen
samples are cryopreserved and quarantined for 6 months. Before
a donor sample is used for insemination, the donor is retested
and determined if eligible.
Success Rate
The actual per cycle fecundity rate with donor IUI is dependent
on multiple factors. A meta-analysis of seven studies demonstrated that IUI yielded a higher pregnancy rate per cycle
than intracervical insemination with donor frozen sperm.17
Overall, the average live birth rate per cycle of donor IUI is
approximately 10%.18
IUI TIMING, COST, AND FREQUENCY
Timing
542
Timing of insemination in relationship to ovulation is one of the
crucial factors in the success of IUI. Although viable sperm
remain in the female reproductive tract for up to 120 hours
after coitus, the best pregnancy rates are obtained when IUI is
performed as close as possible to ovulation.19,20
In the past, IUI was performed on the estimated day of
ovulation based on basal body temperature rises during previous
cycles. However, to optimize fecundity, modern prospective
IUI Cost
The cost-effectiveness of the treatment is an important consideration when deciding on the most appropriate infertility
treatment option.24 The cost of insemination varies from clinic
to clinic, but is presently less than $500 per IUI, including sperm
preparation and injection of the prepared sample. This compares
favorably with the cost of other appropriate ART approaches.
Even when the cost of ovulation induction medication and
monitoring are included, the cost per live birth for IUI after
superovulation has been calculated to be less than half the cost
of IVF treatment.25
IUI Frequency
It is recommended that IUI be performed either one or two
times during each cycle. Performing two inseminations per cycle
is likely to be especially advantageous when timing in relationship to ovulation is less precise. Although it seems intuitive that
fecundity should be increased by two inseminations per cycle, it
remains inconclusive whether the increased fecundity is worth
doubling the patients’ cost and inconvenience compared to one
insemination per cycle.26–30 A recent meta-analysis of more than
1000 IUI cycles revealed a slightly higher but statistically
insignificant difference between the per cycle fecundity rate for
two inseminations (14.9%) compared to one insemination per
cycle (11.4%).31 Accordingly, one well-timed insemination appears
to offer the best balance between efficacy and cost.
SPERM PREPARATION FOR IUI
Sperm preparation methods are used to process semen samples
such that viable sperm are separated from seminal plasma. This
is necessary before IUI to avoid the consequences of intrauterine injecting of semen plasma proteins and prostaglandins.32
Although seminal plasma protects the spermatozoa from stressful
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Table 36-3
Common Techniques Used for Sperm Preparation Prior to
Intrauterine Insemination
Washing
Swim-up techniques
Swim-up from pellet
Swim-up from ejaculate
Swim-up from ejaculate into hyaluronic acid
Density gradient centrifugation
Glass wool filtration
Mechanical aids
conditions such as oxidative stress,33 it also contains factors that
inhibit the fertilizing ability of the spermatozoa and reduce the
induction of capacitation.34,35 Sperm preparation involves removing
the seminal plasma efficiently and quickly and eliminating dead
sperm, leukocytes, immature germ cells, epithelial cells, and
microbial contamination. Several methods for sperm preparation
are currently used (Table 36-3).
The ideal sperm preparation method recovers highly functional
spermatozoa and enhances sperm quality and function without
inducing damage. It is also cost-effective and allows for the
processing of a large volume of the ejaculate, which in turn
maximizes the number of spermatozoa that are available.36 The
ideal sperm preparation method minimizes the risk of reactive
oxygen species generation, which can adversely affect DNA
integrity and sperm function in vitro.33,37 Several preparation
methods incorporate methylxanthines and pentoxifyllines to
increase sperm motility and improve the fertilization outcome.
The first step in sperm preparation is the performance of a
semen analysis according to the World Health Organization
(WHO) standards to determine the prewash quality of the
sample. Throughout the semen analysis and preparation, it is
important to use sterile technique and media both to minimize
the risk of iatrogenic intrauterine infection and because sperm
can be damaged by bacterial contamination.
Swim-up Techniques
Swim-up techniques are based on active self-migration of motile
spermatozoa into the washing medium. Allowing sperm to swim
up from ejaculate avoids the need for centrifugation, which can
lead to oxidative damage of the sperm. However, this technique
can be used only for ejaculate with a high degree of progressive
motile spermatozoa, because the percentage of motile sperm
recovered depends on sperm motility.
For the swim-up technique, a layer of wash media is gently
layered over the semen sample. The sample is incubated so that
the motile sperm can swim out of the semen sample into the
media. The media is then carefully removed from the semen
fluid and used for IUI. If the initial semen sample has normal
sperm parameters, recovery of reasonable number of sperm with at
least 90% motility is common. The entire procedure takes 2 hours.
Basic Sperm Washing
Sperm washing, the oldest and perhaps the simplest technique,
removes the seminal fluid with little enrichment of motile sperm.
The semen sample is diluted in a sperm wash media containing
antibiotics and protein supplements in a conical centrifuge tube.
The specimen is centrifuged such that all cells congregate in a
pellet, and the supernatant wash solution is carefully removed.
The pellet is resuspended in wash media, and the centrifugation
is repeated. The final pellet, from which all seminal fluid has
been eliminated, is resuspended in a small volume of wash media
for IUI. The entire procedure takes less than an hour.
Density Gradient Centrifugation
The density gradient method is a sperm washing method that
both removes semen fluid and separates living sperm from other
material, including dead sperm cells, white blood cells, and
bacteria. For this method, a density gradient is prepared by
layering suspensions of different concentrations of coated colloidal
silica particles (e.g., Percoll) in a conical centrifuge tube, with
the higher concentrations more superior. The liquefied semen
sample is placed over the upper layer and the tube is centrifuged.
The supernatant is removed from the pellet, and the process is
repeated. The final pellet is resuspended in wash media and used
for IUI. Density gradient sperm washes take approximately 1 hour.
Glass Wool Filtration
The glass wool filtration method is another method for removing
seminal fluid and separating living sperm from other cellular
material after sperm has been washed. For this technique, the
semen samples are first diluted with wash media and centrifuged
in a manner similar to sperm washing. The resulting pellet is
resuspended in wash media and placed on glass wool columns,
created by inserting glass wool into the barrel of a 3-mL syringe.
The washed sperm solution is allowed to filter through the
column by gravity, and the filtrate is collected for IUI.
Which Preparation Method is the Best?
Presently, there is no general consensus as to the best sperm
preparation technique for IUI. In general, swim-up, simple sperm
washing, density gradient centrifugation, and glass wool filtration
methods all effectively produce adequate sperm samples. However, some preparation techniques appear better suited for
particular types of samples; thus, the technique chosen should
be tailored to individual samples.
The preparation techniques most commonly used today are
the double density gradient centrifugation and the glass wool
filtration sperm washing techniques. These techniques have
been shown to improve the number of morphologic normal
spermatozoa with grade A motility and with normal chromatin
condensation in the prepared sample.38–40 In addition, these
techniques best reduce the amount of reactive oxygen species
and leukocytes in the prepared sample and provide spermatozoa
with minimal chromatin and nuclear DNA anomalies and high
nuclear maturity rates.
For semen samples with normal or near-normal sperm parameters, one study has shown that swim-up and density gradient
techniques result in higher pregnancy rates compared to the
washing, swim-down, and refrigeration/heparin techniques.41
For poor samples, the density gradient centrifugation and glass
wool filtration techniques appear to be superior. In cases of very
low sperm counts, simple sperm washing will recover the highest
number of sperm, both motile and nonmotile.
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curved tip is directed in a new course and re-advanced. This
procedure is continued until the catheter can be advanced
without resistance approximately 5 to 6 cm into the uterine
cavity. Rarely, a cervical tenaculum is required to apply downward traction on the cervix to “straighten” an exceptionally
tortuous canal.
A second method for navigation of the endocervical canal for
IUI is by using a semirigid yet flexible catheter that has no
memory.42 Pressure is used to force the catheter to follow the
course of the canal. This technique often requires the use of a
cervical tenaculum to apply countertraction. Because the diameter
of some of these types of catheters is usually larger in caliber
(greater than 3 mm), dilatation is sometimes required in the
presence of cervical stenosis.
A
FACTORS THAT PREDICT PREGNANCY RATES
The highest pregnancy rates with IUI are seen within three to
four cycles.43 The average live birth rate per cycle is approximately 10%.18 Cumulative pregnancy rates depend on the characteristics of the couples being treated. In most reports, the
cumulative pregnancy rate reaches plateau after three to six cycles.
It is difficult to predict with certainty whether pregnancy will
occur. Several models have been proposed but have not been
validated.44,45
B
Figure 36-1 Intrauterine insemination catheters: A, Tefcat catheter
attached to a syringe (Cook Group, Bloomington, Ind.); B, CryoBioSystem
catheter (CryoBioSystem, Paris).
IUI TECHNIQUE
544
IUI is performed using one of several commercially available
intrauterine insemination catheters connected to a 2-mL syringe
(Fig. 36-1). With the fully awake patient in a dorsal lithotomy
position, the cervix is visualized with a bivalve vaginal speculum.
After excess vaginal secretions are wiped from the external
cervical os, the tip of a thin flexible catheter is passed into the
uterine cavity, and the sperm sample, suspended in less than 1 mL
of wash media, is gently expelled high in the uterine cavity.
Increased resistance during injection suggests that the catheter
is kinked or the tip might be inadvertently lodged in the endometrium or tubal ostia. In this situation, the catheter should be
withdrawn 1 cm, and injection reattempted. After IUI, the
catheter is slowly removed and the patient allowed to remain
supine for 10 minutes after insemination in case she experiences
a vasovagal reaction.
Occasionally, there is difficulty navigating the often tortuous
course of the endocervical canal with the tip of the insemination
catheter. There are two common approaches to this blind
procedure. Most commonly, a thin catheter (external diameter
less than 2 mm) with a “memory” is used so that the tip can be
bent 20 to 90 degrees, thus allowing angular navigation in
any direction by carefully twisting the catheter as it is gently
advanced. Resistance in any direction requires that the catheter
tip be withdrawn a matter of millimeters, twisted such that the
Male Factors That Predict IUI Success
Men who have normal seminal characteristics have a higher
chance of initiating a successful pregnancy as a result of IUI than
those with abnormal results on semen analysis. This association
is probably related to two associated factors. First, an abnormal
semen analysis is often associated with an impaired fertilization
capacity. Secondly, pregnancy rates positively correlate with the
total number of motile sperm recovered for IUI, and this number
is often lower in men with abnormal results on semen analysis.
Semen Analysis Characteristics
Semen characteristics clearly affect IUI outcome.46 IUI is a
successful treatment for mild male factor infertility, defined as a
total motile sperm count of more than 5 million and Kruger
morphology of more than 5%.47 In a study in patients with mild
male factor infertility, a live birth rate of 19% per cycle was
reported.47
When prepreparation semen analyses characteristics are
evaluated, the chances of pregnancy after IUI correlate best with
morphology. A meta-analysis of six studies using strict morphology
criteria (Kruger) showed that when the prewashed semen
specimen had more than 4% normal sperm morphology, the
chances of pregnancy after IUI were significantly increased.48
If the WHO standards were used to evaluate sperm morphology,
the presence of more than 30% abnormal sperm in the ejaculate
adversely influenced the pregnancy rate.49
Total Motile Sperm Count
The sperm variable most clearly associated with pregnancy rates
after IUI is the total motile sperm count after sperm wash or
swim-up. In a retrospective study of 9963 IUI cycles, the likelihood of subsequent pregnancy was maximized when the IUI
sample contained more than 4 million motile sperm numbers
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and sperm motility was greater than 60%.50 Total motile sperm
count was reported to affect IUI outcome in 1115 cycles in 332
infertile couples.51 No pregnancy occurred in cases where the
total motile sperm count before semen preparation was less
than 1 × 106.
Sperm DNA Damage Tests
Efforts have been made to find objective assessments of sperm
quality that will predict pregnancy outcomes in men with abnormal
results on semen analysis. Three experimental assessments are
the sperm chromatin structure assay, DNA fragmentation index,
and terminal deoxynuceotidyl transferase-mediated deoxyuridine
triphosphate-nick end labeling (TUNEL).
The sperm chromatin structure assay provides an objective
assessment of sperm chromatin integrity and can be useful as a
fertility marker.52 In a recent study, DNA damage as measured
using this test was found to predict the outcome of IUI.
The DNA fragmentation index (DFI) has been shown to be
negatively correlated with the overall pregnancy rate in women
undergoing IUI, IVF, or ICSI.53 The chances of achieving pregnancy are significantly lower when the sperm DFI is greater than
27% after IUI processing.54
TUNEL evaluates the degree of sperm DNA fragmentation
and stability.55 In one study, lower degrees of DNA
fragmentation after IUI sperm preparation correlated with
higher pregnancy rates, and no pregnancy occurred when
more than 12% of sperm in an IUI specimen were TUNELpositive.
Hypo-osmotic Swelling Test
The hypo-osmotic swelling test evaluates the membrane integrity
of the sperm tail, detects the differences on the sperm surface,
and detects subtle damage in membrane properties, which
reduces the ability of spermatozoa to induce a viable embryo.56
A sample “passes” the hypo-osmotic swelling test when at least
50% of sperm in an IUI sample swell.57 Sperm specimens that
fail the hypo-osmotic swelling test appear to have decreased
fertilizing ability, and thus pregnancy rates after IUI are lower.
The miscarriage rate was also higher when result of hypo-osmotic
swelling test was less than 50%.
Antisperm Antibodies
Both IUI and IVF appear to be effective in treating subfertility
in men with antisperm antibodies, although IVF/ICSI appears
to have higher pregnancy rates per cycle than IUI.58 However,
to date no large prospective, randomized, controlled trial has
compared IUI to IVF/ICSI in men with antisperm antibodies.
In severe cases of antisperm antibodies, especially when the
sperm head is involved, IVF/ICSI will often be required to
achieve pregnancy.59,60
Female Factors That Predict IUI Success
Many studies have examined the different variables affecting
pregnancy rates after IUI.25,61–64 The influence of lifestyle habits
(e.g., smoking, caffeine consumption, and weight) is unclear but
is most probably significant. There appear to be several important
female factors that are useful in predicting pregnancy rates after
IUI. These factors are maternal age, duration of infertility, and
fenale infertility factors.65
Maternal Age
A woman’s age is an indirect indicator for oocyte quality, and it
has a significant effect on the pregnancy rates. An age-related
decline in female fecundity has been documented in women
undergoing IUI.43,64 Successful pregnancy rates decrease after
age 35 and reduce dramatically after age 40. However, pregnancies can occur at relatively advanced maternal ages, and satisfactory pregnancy rates can be obtained with IUI among women
age 40 to 42.66,67
Duration of Infertility
The longer the duration of infertility, the lower the pregnancy
rates are after IUI.25,43,65 Although the precise limits of infertility
duration for recommending IUI have not been clearly established,
the pregnancy rate may be seriously compromised when infertility
has lasted 3 or more years.
Female Fertility Factors
The success of artificial insemination depends not only on the
quality of oocytes and spermatozoa, but also on the receptivity
of the endometrium. In a retrospective study, the presence of
uterine anomalies negatively affected the success of IUI.65
Endometrial thickness and pattern is also predictive of IUI
success. In a study on women undergoing controlled ovarian
hyperstimulation and IUI, a trilaminar endometrium on the day
of IUI provided a favorable prediction of pregnancy. However,
endometrial thickness and Doppler surveys of the spiral and
uterine arteries and dominant follicle gave no useful predictive
value.68 A study evaluated the role of endometrial volume
measurement in predicting the pregnancy rate in women receiving
controlled ovarian hyperstimulation and IUI.69 An endometrial
volume of less than 2 mL on three-dimensional ultrasound on
the day of insemination was associated with a poor likelihood of
pregnancy.
Pregnancy rates after IUI are dependent on ovum pickup and
transport. It follows that pregnancy rates after IUI are decreased
by other causes of female infertility, including tubal factor and
endometriosis.
RISKS AND COMPLICATIONS
Complications associated with IUI are extremely uncommon.
Most of the complications that occur are related to the
medications used to recruit multiple follicles before IUI.
Pelvic Infections
Limited cramping during or after an IUI procedure from the
catheter or cervical tenaculum is common. These symptoms are
self-limiting and should resolve within hours of the procedure.
Continued discomfort can be an indication of a developing pelvic
infection, which has been estimated to occur in less than 2 per
1000 IUI procedures.63 Early diagnosis and treatment are
essential in these rare cases to minimize the risk to the patient,
particularly that of subsequent decreased fertility.
Vasovagal Reaction
Vasovagal reactions can occur as a result of manipulation of the
cervix. The resulting vasodilation and decreased heart rate can
lead to hypotension, most commonly manifest by diaphoresis in
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a supine patient. Sitting or standing increases the risk of syncope,
which is unlikely to occur supine. Persistent symptomatic vasovagal reactions in a supine patient will often respond to the
patient crossing her legs.70 More severe cases might require
treatment with intramuscular atropine injection (0.5 mg).
Allergic Reaction
Allergic reactions, including anaphylaxis, can occur after IUI in
response to potential allergens in the wash media. Reactions
have been reported to both the bovine serum albumin and
antibiotics (penicillin and streptomycin) commonly used in the
wash media.71,72 Of these, penicillin allergies are the most
common in the general population. Allergic reactions after IUI
can range from a mild skin rash to life-threatening anaphylaxis
with laryngeal edema, bronchospasm, and hypotension. For the
rare patient experiencing an allergic reaction after IUI, the use
of wash media free of albumin and antibiotics is advised.
Antisperm Antibodies
When IUI was first introduced, there was a concern that the
procedure could result in the development of serum antisperm
antibodies. Fortunately, after 40 years of experience, it appears
that exposure of the upper reproductive tract to washed
spermatozoa during IUI does not stimulate the appearance of
clinically significant female antisperm antibodies.73
Pregnancy-Related Complications
Multiple Pregnancies
The risk of multiple pregnancies is not increased by IUI.
However, medications used to recruit multiple follicles before
IUI do increase this risk. Clomiphene citrate is associated with
a twin risk of 5% to 10% and rare higher-order multiples.
Injectable gonadotropins are associated with multiple pregnancy
rates of 14% to 39%.74–76 Careful monitoring of the number of
periovulatory follicles and peak estradiol levels might decrease
the rate of multiple pregnancies.61,74,77 In general, women are at
high risk if they are younger than age 30, have more than six
preovulatory follicles, and a peak serum estradiol level greater
than 1000 pg/mL.
need to start a family, the alternatives that the male partner has
to procreate his own genetic children, and financial factors.
It is recommended that the couple undergo counseling before
the procedure so that they can both face their feelings concerning infertility, donor insemination, and other concerns. The
male partner may experience a loss of self-esteem and fear
losing his partner because of infertility. Both partners may feel
guilty or angry toward each other for having an infertility problem.
Infertility tends to separate the couple, especially when one side
is uncooperative. Support groups or professional counseling can
be helpful.
Offspring
There are expert opinions both for and against disclosing to the
child that he or she is the product of donor insemination. Before
undergoing donor IUI, the couple should decide if they plan to
disclose the nature of the procedure and the biologic implications to their friends, relatives and, ultimately, their child. If
knowledge of the procedure is shared with friends and relatives,
there is always the risk that the truth will be disclosed to the
child by someone other than the parents. These sometimesunderappreciated issues can cause unnecessary grief if not
adequately addressed prior to therapy.
Legal Issues
It is imperative that both partners understand the legal issues
concerning donor insemination. Before donor insemination, both
partners should sign an informed consent that clearly states the
rights and obligations of the parties involved and those of the
child. Although laws vary from state to state, when sperm is
obtained from a sperm bank, the donor universally has no legal
access to the couple’s identity. In cases where couples elect to
use a donor known to them, an attorney should be obtained to
draft the appropriate papers to terminate any parental rights of
the donor and give the couple full custody of any subsequent
child. In some states, the child conceived from donor sperm
may have the right to obtain identifying information about the
donor once they reach adulthood.
PEARLS
Spontaneous Abortion and Ectopic Pregnancy
The risk of spontaneous abortion appears to be increased after
IUI compared to the fertile population and is in the range of
20% to 25%.1,78 The increased risk is probably not directly
attributed to IUI but is most likely due to the underlying infertility
problem. Likewise, ectopic pregnancy rates depend largely on
the presence of predisposing factors such as tubal disease and do
not appear to be attributed to the IUI procedure.79
PSYCHOLOGICAL, ETHICAL, AND LEGAL
ISSUES OF DONOR INSEMINATION
●
●
●
●
●
Parents
●
Donor insemination has more psychological implications than
partner insemination. Before donor insemination, several issues
should be discussed in detail, including the couple’s desire or
546
●
Artificial insemination is a useful and cost-effective treatment
option in selected groups of infertile couples.
Infertility due to cervical factor and mild male factor (without
any associated female factor) can be treated with intrauterine
insemination without ovarian stimulation.
Artificial insemination appears to be more cost-effective and
simple compared to the IVF/ICSI if the couples are selected
appropriately.
In spite of extensive research, we are still not able to predict
the success of artificial insemination in a specific couple.
Duration of the infertility negatively impacts the artificial
insemination success.
Couples with unexplained infertility have better success with
artificial insemination than natural intercourse.
Couples with unexplained infertility should use controlled
ovarian hyperstimulation along with the artificial insemination.
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