Are you treating
subfertile couples: Then must know followings: What is Fecundability? : Ans:-probability of achieving pregnancy within one
menstrual cycle. For a normal couple, this is approximately 25%.Q. What is Fecundity? Ans: : Ability to
achieve a live birth within one menstrual cycle . Prevalence of subfertility?? Data
from the 2006 to 2010 NSFG continued to show that as in the 2002 data, 11.9% of
women of reproductive age reported having received infertility services at some
point in their lives. The What are common causes of subfertility? This
encompasses six principal categories
1)
Male factor &
Coital dysfunction 2) Ovulatory
dysfunction, other endocrine disorders including hypothyroidism, hyperprolactinaemia,
Adrenal disorders , hyperandrogenism, hyperinsulinaemia
3)
Structural
(tubal/peritoneal and uterine)
4)
Endometriosis
& Kochs , Pelvic adhesive disease
5)
Cervical factors 6) Unexplained causes.
History eliciting: What to
ask?? Ans: History and Investigations in a case of subfertility
should aim at the following factors and final
etiological diag rests much on this
tactful enquiry and diligent examination
Complete menstrual history, dysmenorrhea or
menorrhagia, pelvic or abdominal pain, dyspareunia, symptoms of thyroid
disease, galactorrhea, symptoms of hirsutism, exercise habits, diet history is essential
and indices of stress has to be assessed.
The causes infertility encompasses five principal categories
.Q.1:-When to initiate investigation for fertility disorders? Ans: By and large if woman is asymtomatic i,.e.
with no systemic symptoms, she is aged
< 35 yrs without any menst irregularities(cycles are regular) and is of normal BMI then investigations should be initiated one year after marriage. But if the age of F partner
is > 35 yrs then Fertility investigations should commence earlier
Q.2 : How many months after marriage one should
initiate fertility related investigations if she is aged > 35 years? Ans: In such settings
most practitioners will initiate diagnostic evaluation after inability to
conceive for 6 months.
Q.3: What are the list of routine infertility
evaluation? Ans Prior to investigations
some enquiry is relevant. Such are :-1) elicitation of history of any medical/ surgical diseases in
past, any history of miscarriage, previous marriage if any , drug abuse,
addiction, any regular drug intake for chr disease , contraceptive use ,This should
be followed by clinical examination of
both partners. BMI of both partner are important so also any endocrine stigmata.
Duration of infertility, methods of contraception, previous evaluation and
treatment, prior reproductive history, sexual dysfunction, coital frequency
and satisfaction, sexually transmitted infections, tobacco and alcohol use,
caffeine use, family history of mental retardation, and birth defects
’ History elicited from
the female partner should include the following:
Complete menstrual
history, dysmenorrhea or menorrhagia, pelvic or abdominal pain, dyspareunia,
symptoms of thyroid disease, galactorrhea, symptoms of hirsutism, exercise
habits, and indices of stress
• Q. 2B Basic Investigations : 1 semen
analysis, , evaluation of reproductive hormones like PRL and TSH 5)basal scan & , follow up scan in unstimulated cycle. If she
denies to come to clinic frequently for evaluation in natural cycle then
assessment of ovulation can be done by LH kit at home . But in doing that we miss a) lagging of endometrial
thickness, b) speed of growth of DF,c)
No of growing follicles and d)
possible LUF. However a regular
cycling woman means that in all probality she is ovulating. Hysterosalpingogram,
and, laparoscopy are done if indicated. Lap is very informative may be done at an early stage of evaluation
if clinical findings suggest Pelvic
adhesions, or endometriosis . Fixity of
uerus andndrness of POD/ adenexae with ormal Total couny & CRP almost usulay poiny to such diseases which
can onlybe diagnosed by LH procedute Weight and body mass index, thyroid
exam, breast exam, signs of hirsutism, pelvic or abdominal tenderness, uterine
size and mobility, adnexal masses and/or tenderness, cul-de-sac tenderness, or
nodularity
• Baseline studies and labs may include
the following: thyroid-stimulating hormone, prolactin, follicle-stimulating
hormone (FSH), 17-hydroxyprogesterone, serum testosterone, progesterone,
dehydroepiandrosterone (DHEAS), semen analysis, and hysterosalpingogram (HSG).
Q.3:-How to carry on “ A complete workup of
unexplained infertility” . If not doe earlier
then one should insist on following tests like A) AMH, AFC estimation,
Day3 basal FSH are tests for ovarian reserve and B) laparoscopy-hysteroscopy
even if HSG or SIS were normal at
initial stages of fertility evaluation before reporting to you.
Q What are the
benefits of Hysteroscopy??
initial hysteroscopy. Findings on hysterescopy (%)
Submucosal myoma
Single large polyp
Polypoid endometrium
Endometrial hyperplasia
Uterine cavity hypoplasia
Adhesions
Endocervical polyp
Multiple lesions
Without any finding
According to the results of any studies abnormal
hysteroscopic findings were observed
in about 60% of
the cases with repeated IVF failures which
are higher than
the result of previous studies due to the
exclusion of the
other possible reasons of repeated ET
failures. It is
said that sonography
as specific, but not
sensitive method compared to the hysteroscopy. The sensitivity
and specificity of sonography in comparison with hysteroscopy were 91% and 83%
with the false
positive rate of 9.2%, and false negative rate of
5.1%
in Ragni study.
We treated the structural abnormalities
at the time of hysteroscopy, and we had no early,
late,
major, or even minor complications in our series.
The
pathological reports confirmed the observed lesions
in
94.7%, with nonspecific endometritis in 13.2 % (n=
7)
of cases.
It has been shown that in elderly women, age-
related uterine
pathology such as submucous myoma,
endometrial
hyperplasia, and polyps were more
prominent, other
than in younger patients, other uterine
lesions such as
adhesions, and tubal ostia occlusion
were more
common. In our experiences, we have seen
single polyp and endometrial hyperplasia more (but
not
significant) in the patients with ≤30 years old
rather
than the younger group (p-value= 0.78). Also
there
were more (but not significant) abnormalities
especially
single polyp,
polypoid endometrium, and hyperplasia
in group of the
patient with more than 8 years infertility
(p=0.08, p=0.06, and p=0.12).
This communication, emphasis the need of
hysteroscopy in patients with unexplained repeated
IVF/ICSI-ET failure According to our experience, it
seems legitimate
to perform hysteroscopy in women
who had 2 IVF-ET
failures before trying any other
procedure after
excluding all other possible etiological
or accompanying
factors. The results were significant in
the group with
longer duration of the infertility. Our
study showed
that the direct view of the uterine cavity
by hysteroscopy
was more sensitive and specific, and more accurate in the
evaluation of intracavity pathology
in comparison with sonography in patients with
unexplained repeated IVF failures.
Also,
hysteroscopy proved to be a very useful, accurate and safe method of assessing
uterine and endometrial functional status
in patients with repeated IVF/ICSI-ET failures
after excluding other possible reason for implantation failure, although it couldn’t
evaluate uterine and endometrial
functional status.
Pont 1: Early assessment
of Ovarian reserve; if not on first visit disregarding her age. The overall
incidence of infertility has remained stable over the decades but investigative
schedules , as I have witnessed for six decades, has changed considerably. Many
a experienced dedicated practitioner have of late have included the evaluation
of ovarian reserve as first-line workup for infertility. May be environmental pollution , increased prevalence of poor lifestyle, diet, drug abuse and auto
immune diosrder might have collectively forced the ART specialists to carryout Ov reserve test
at an early date .
Q.2 : Prevalence of Unexplained infertility:-Approximately
15% to 30% of couples will be diagnosed with unexplained infertility after
their diagnostic workup which however do not
include Hysterolaproscopy bu does
include Folicular monitoring , HSG/SIS and basal frertlity hormonres (FSH,LH,
PRL ) and some sytemic hormes like TSH .
Q. Ovulatory
defects are present in 40% of infertile women and in approximately 15% of
couples with infertility anovulatory levels of serum progesterone (< 3
ng/mL) are found in only a very small minority of eumenorrheic patients. We recommend that couples have a semen
analysis, testing for detection of ovulation (mid luteal progesterone, LH kit),
assessment of ovarian reserve, transvaginal ultrasound, and HSG. With this
expanded testing, fewer than 15% to 30% of couples will have unexplained infertility.
ovulation kit and measure the progesterone levels 7 to
8 days after the LH surge is detected. Whereas
laparoscopy used to be part of the basic infertility workup, it is now reserved
for selected cases
Serum progesterone levels
higher than 3 ng/mL suggest that ovulation has occurred and levels higher than
10 ng/mL are optimum. According to the guidelines of the ASRM, laparoscopy
should be performed in women with unexplained infertility or signs and symptoms
of endometriosis or in whom reversible adhesive tubal disease is suspected. The
principal treatments for unexplained infertility include expectant observation
with timed intercourse and lifestyle changes, clomiphene citrate and
intrauterine insemination (IUI), controlled ovarian hyperstimulation (COH) with
IUI, and IVF. fecundity were 4.7 and 2.4 per 100 person-months (rate ratio,
1.9; 95% confidence interval, 1.2–3.1). The authors concluded “laparoscopic
resection or ablation of minimal and mild endometriosis enhances fecundity in
infertile women. Reproduction and Embryology (ESHRE) Multicentre Trial reported
in 1991 that pregnancy rates per cycle were 15.2% in gonadotropin-only cycles,
27.4% in gonadotropin and IUI cycles, and 25.7% in IVF cycles. The pregnancy
rate for IVF cycles has since increased with availability of improved and sequential media, embryo micromanipulation,
and extended embryo culture. The ASRM Practice Committee published an
analysis on the appropriate roles and the cost-effectiveness of the various
procedures in the management of unexplained infertility by analysis of
previously published data.2,14 There
is limited information on the cost-effectiveness of various treatments;
however, it appears that there is a correlation between the cost of a treatment
modality and its pregnancy rates. Therefore, depending on the individual couple
and their particular clinical situation, COH
with IUI may be attempted first, with transition to IVF/ICSI if pregnancy
is not achieved in a timely manner.
Fast Track and Standard Treatment [FASTT] Trial) :--Clomiphene citrate/IUI versus IVF (Fast Track and
Standard Treatment [FASTT] Trial) has recently been completed. In this trial,
Reindollar and colleagues27 studied
503 couples assigned to conventional infertility treatment or an accelerated track to IVF. All
couples had unexplained infertility and underwent infertility treatment for the
first time. Patients were randomized to receive either a conventional treatment
regimen of 3 cycles of clomiphene/IUI, 3 cycles of FSH/IUI, and up to 6 cycles
of IVF or to receive an accelerated treatment course of 3 cycles of clomiphene
citrate/IUI and then up to 6 cycles of IVF. In the conventional arm, 247
couples underwent 646 clomiphene citrate/IUI, 439 FSH/IUI, and 261 IVF
treatment cycles; in the accelerated arm, 256 couples received 642 clomiphene
citrate and 357 IVF cycles.
Outcome of Conventional arm As of April 2007, 43/232 (18.5%) of the women in the
conventional arm became clinically pregnant after clomiphene citrate/IUI,
43/170 (25.3%) after FSH/IUI cycle, and 71/111 (64%) after IVF.
Outcome
of the accelerated arm, 50/242
(20.7%) became pregnant after clomiphene citrate/IUI and 117/171 (68.4%) in an
IVF cycle. The median time to pregnancy in the accelerated arm was shorter than
the conventional arm. The complete study has not yet been published.
Rev
Obstet Gynecol. 2008 Spring; 1(2): 69–76.
PMCID: PMC2505167
Diagnosis and Treatment of Unexplained Infertility
Abstract
Significant advances have
occurred in the diagnosis and, more importantly, in the treatment of
reproductive disorders over the past decade. The overall incidence of
infertility has remained stable1;
however, the success rates have markedly improved with the widespread use of
assisted reproductive technologies. Treatment options and success vary with the
cause of infertility. Approximately 15%
to 30% of couples will be diagnosed with unexplained infertility after their
diagnostic workup.2
In this review, we
specifically discuss the routine testing performed to diagnose unexplained
infertility. We also discuss additional testing, such as assessment of ovarian
reserve, and the potential role of laparoscopy in the complete workup of unexplained infertility. Finally, we outline the
available therapeutic options and discuss the efficacy and the
cost-effectiveness of the existing treatment modalities.
Diagnosis
of Unexplained Infertility: The Basic Infertility Evaluation
Infertility is customarily
defined as the inability to conceive after 1 year of regular unprotected
intercourse. The infertility evaluation is typically initiated after 1 year of
trying to conceive, but in couples with advanced female age (> 35 years),
most practitioners initiate diagnostic evaluation after an inability to
conceive for 6 months.
The Practice Committee of
the American Society for Reproductive Medicine (ASRM) has published guidelines
for a standard infertility evaluation.3 It
includes a semen analysis, assessment of ovulation, a hysterosalpingogram, and,
if indicated,
tests for ovarian reserve and laparoscopy.
When the results of a
standard infertility evaluation are normal, practitioners assign a diagnosis of
unexplained infertility. Although estimates vary, the likelihood that all such
test results for an infertile couple are normal (i.e, that the couple has unexplained infertility) is
approximately 15% to 30%.2
Assessment
of Male Infertility
Male factor infertility is
the only cause of infertility in approximately 30% of couples and a
contributing factor in another 20% to 30%.4
Assessment of the
infertile couple includes evaluation of the male partner by history,
examination, and semen analysis. Important elements of the history include
prior paternity, a history of cryptorchidism, medical and surgical history,
sexual dysfunction, and any use of medications, tobacco, alcohol, or illicit
drugs. On the physical examination, testicular abnormalities such as a
varicocele or absence of the vas deferens can be detected.
If the semen analysis is
abnormal, it should be repeated after at least 1 month by a laboratory that
adheres to World Health Organization (WHO) guidelines, with a quality control
program ensuring accurate testing. Guidelines from WHO regarding the reference
ranges for the number, morphology, and motility in a semen sample have been
published5 and
are shown in Table 1.
A number of commercial
laboratories use a variety of ranges for the different components of the semen
analysis.
Careful attention should be paid to these
ranges and the semen values should be interpreted in the right context.
Although semen analysis is routinely used to evaluate the male partner in
infertile couples, the discriminatory ranges are not clearly defined. A study by
Guzick and colleagues concluded “threshold values for sperm concentration,
motility, and morphology can be used to classify men as subfertile, of
indeterminate fertility, or fertile. None of the measures, however, are
diagnostic of infertility.” Table 2 shows the reference values for fertile,
indeterminate, and subfertile ranges for semen analysis parameters as
identified by regression analysis. Despite its limitations, semen analysis
remains the most important tool in the investigation of male factor
infertility. If any abnormalities are repeatedly detected on a semen analysis,
referral to a urologist may be warranted. The treatment of severe male factor
infertility including azoospermia has been revolutionized with the combination
of in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI).
World Health Organization
Criteria for a Normal Semen Analysis
Fertile, Indeterminate,
and Subfertile Ranges for Semen Analysis Parameters as Identified by Regression
Analysis
Previously, the postcoital test (PCT) assessing the
sperm motility in a sample of postcoital cervical mucus was considered an
integral part of the basic infertility evaluation. However, past investigations
revealed a poor correlation between postcoital sperm motility and pregnancy
outcome.7 In
addition, a 1995 blinded, prospective study demonstrated poor reproducibility
of the test among trained observers, further questioning the validity of the
PCT as a diagnostic tool.8
Today, the PCT has been
largely abandoned and we do not recommend it as a component of the standard
infertility investigation.3
Assessment
of Ovulation
Ovulatory defects are present in 40% of infertile
women and in approximately 15% of
couples with infertility.
Often a defect in
ovulatory function manifests itself in menstrual disturbances and can be
identified by history in the majority of women. A) What
is the history?? A patient with causes of menstrual abnormalities should be
investigated for underlying causes such as 1) polycystic ovarian syndrome,2) thyroid disease, 3) hyperprolactinemia, and 4)
hypothalamic causes secondary to weight changes. Eumenorrhea—normal menstrual cycles by history—is a highly accurate
marker of ovulation and Ovulatory
defects are present in 40% of infertile women and in approximately 15% of
couples with infertility anovulatory levels of serum progesterone (< 3
ng/mL) are found in only a very small minority of eumenorrheic patients.
In addition to a thorough
menstrual history, other methods used to evaluate ovulation include basal body
temperature (BBT) recordings, urinary luteinizing
hormone (LH) ovulation predictor kits, mid
luteal serum progesterone testing, and endometrial biopsy to assess for
secretory endometrial development. B) What about BBT?? Although BBT
recordings are the least costly tool in a reliable patient (Figure 1), they are difficult to interpret and often
frustrating for the patient.
) What
about Ovulation predictor kits ? Ovulation
predictor kits are useful for women who do not have very long menstrual
cycles and can be used by couples to appropriately time intercourse.
) What about Mid luteal progesterone levels?? Ans:- Mid luteal
progesterone levels are measured around day 21 in women with regular (∼ 28 day) cycles.
However, they are often poorly timed if they are drawn on cycle day 21 in women
with irregular menses. In such women it is better to use an ovulation kit and measure the progesterone
levels 7 to 8 days after the LH surge is detected.
Serum progesterone levels higher than 3 ng/mL suggest that ovulation
has occurred and levels higher than 10 ng/mL are optimum. Although
endometrial biopsy results were previously used to diagnose luteal phase
defect, they do not correlate with fertility status and hence are no longer
recommended.10
An example of a basal body
temperature recording chart. Reprinted with permission from Hyde and DeLamater,
Understanding Human Sexuality, 6th ed. Copyright ©1997 The McGraw-Hill
Companies, Inc. All rights reserved.
Assessment
of Ovarian Reserve
Another test added to the
workup of couples with infertility includes assessment of ovarian reserve. Women with advanced age or history of prior
ovarian surgery are at risk for diminished ovarian function or reserve. Given
the relatively noninvasive nature of the testing, several practitioners are including the evaluation of ovarian
reserve as first-line workup for infertility.
The testing includes a
cycle day 3 serum follicle-stimulating
hormone (FSH) and estradiol level, clomiphene citrate challenge test,
and/or an ultrasonographic ovarian antral follicle count.3 The
results of these tests are not absolute indicators of infertility but abnormal
levels correlate with decreased response to ovulation induction medications and
lowered live birth rates after IVF.
Assessment
of Uterus and Fallopian Tubes
Assessment of the uterine
contour and the tubal patency is an integral part of the basic infertility evaluation.3This may be achieved by
hysterosalpingography (HSG) (Figure 2). An HSG consists of radiographic evaluation of the
uterine cavity and fallopian tubes after injection of a radio-opaque medium
through the cervical canal. Along with laparoscopic dye pertubation, it can
best assess tubal patency: the concordance of HSG with laparoscopic dye
pertubation is estimated as close to 90%.11 However,
patent fallopian tubes on HSG do not confirm that ovum pickup will occur. For
example, women with severe endometriosis may have adherent ovaries in the cul
de sac with normal fallopian tubes.
Normal
hysterosalpingogram. Reprinted from Fertility and Sterility, Volume 83, Baramki
TA, Hysterosalpingography, pages 1595–1606, Copyright 2005, with permission
from Elsevier.
Ultrasound evaluation in
the follicular phase is used to identify uterine fibroids, polyps, and
congenital cavitary anomalies such as a septate uterus. At the same time,
information on ovarian volume and antral follicle counts can be obtained,
making pelvic ultrasound part of the initial workup for infertility. A complete
cavitary assessment, however, necessitates either sonohysterography for
conditions such as uterine polyps, submucus leiomyomas, or Asherman’s syndrome
(uterine synechiae).12
Sonohysterography, an office procedure, involves assessing the uterine cavity with
ultrasound with concurrent instillation of sterile water. Some practitioners
prefer diagnostic office hysteroscopy as
it allows direct visualization of the uterine cavity.
The
Role of Laparoscopy in the Infertility Evaluation
The role of laparoscopy in
the investigation of infertility has changed over the past decade. Whereas
laparoscopy used to be part of the basic infertility workup, it is now reserved
for selected cases. Given that it allows direct visual examination of the
pelvic reproductive anatomy, it is the test of choice to identify otherwise
unrecognized peritoneal factors that influence fertility, specifically
endometriosis and pelvic adhesions. According to the guidelines of the ASRM,
laparoscopy should be performed in women with unexplained infertility or signs
and symptoms of endometriosis or in whom reversible adhesive tubal disease is
suspected.
Recommendations
for the Basic Infertility Evaluation
We recommend that couples
have a semen analysis, testing for detection of ovulation (mid luteal
progesterone, LH kit), assessment of ovarian reserve, transvaginal ultrasound,
and HSG. With this expanded testing, fewer than 15% to 30% of couples will have
unexplained infertility.
Treatment
of Unexplained Infertility
A diagnosis of unexplained
infertility is made after the above-recommended testing fails to reveal any
abnormality. The treatment for
unexplained infertility is therefore, by definition, empiric because it does
not address a specific defect or functional impairment.
The principal treatments
for unexplained infertility include expectant observation with timed
intercourse and lifestyle changes, clomiphene citrate and intrauterine
insemination (IUI), controlled ovarian hyperstimulation (COH) with IUI, and
IVF.
We present the different
treatment options and discuss the advantages and disadvantages of various
treatment strategies.
Expectant
Management and Lifestyle Changes
Epidemiological studies
indicate cigarette smoking, abnormal body mass index (BMI), and excessive
caffeine and alcohol consumption reduce fertility in the female partner. The
female partner should be counseled to achieve a normal BMI, reduce caffeine
intake to no more than 250 mg daily (2
cups of coffee), and reduce alcohol intake to no more than 4 standardized
drinks per week.13
The likelihood of pregnancy without treatment among couples with
unexplained infertility is less than that of fertile couples but greater than
zero.
It is possible that unexplained infertility
represents the lower extreme of the normal distribution of fertility with no
defect present. However, it could also be imagined that the routine infertility
evaluation misses subtle defects because of imperfect or incomplete testing
methods.
Studies of couples with
unexplained infertility who are followed without any treatment report a broad
variation in cumulative pregnancy rates. A retrospective review of 45 studies
by Guzick and colleagues found an
average cycle fecundity of 1.3% to 4.1% in the untreated groups, which was
lower than most treatment interventions.14
Outcome of expectant management ?? In a recent study, couples with unexplained
infertility on a waiting list for IVF in the Netherlands had a 10% to 15%
cumulative chance of pregnancy over a 12-month period. As expected, the age of
the female partner influenced the pregnancy rate associated with expectant
management.15 The
currently available evidence suggests that methods prospectively identifying the
window of fertility are likely to be more effective for optimally timing
intercourse than calendar calculations or BBT.
Although expectant management is associated with
the lowest cost, it results in the
lowest cycle fecundity rates, and is therefore inferior to the commonly
available reproductive techniques outlined below. It may provide an option for
a couple with unexplained infertility in whom the female partner is young and
the problem of oocyte depletion is not an immediate concern.
Laparoscopy
as a Treatment
Whether operative
laparoscopy improves pregnancy outcomes in a subject with unexplained or
minimal/mild endometriosis is of debate. In 1997, Marcoux and colleagues
reported the results of a randomized, controlled trial (RCT) in a population of
341 infertile women 20 to 39 years of age with minimal or mild endometriosis.16During
diagnostic laparoscopy the women were randomly assigned to undergo resection or
ablation of visible endometriosis or diagnostic laparoscopy only. They were
followed for 36 weeks after the laparoscopy or, for those who became pregnant
during that interval, for up to 20 weeks of pregnancy.
In the intervention group,
50 of the 170 women became pregnant in the follow-up period, compared with only
29 of 169 in the diagnostic laparoscopy group. The corresponding rates of
fecundity were 4.7 and 2.4 per 100 person-months (rate ratio, 1.9; 95%
confidence interval, 1.2–3.1). The authors concluded “laparoscopic resection or
ablation of minimal and mild endometriosis enhances fecundity in infertile
women.”16 Interestingly,
a smaller RCT from Italy with a similar study design could not confirm these
results. In the study reported by Parazzini,17 the
1-year birth rate in the resection/ablation group was 10 out of 51 women
(19.6%), compared with 10 out of 45 women (22.2%) in the no-treatment group. A
Cochrane review on the topic published in 2002 concluded that laparoscopic
surgery in the treatment of minimal and mild endometriosis may improve
pregnancy success rates, but that the “relevant trials have some methodological
problems and further research in this area is needed.”18If
laparoscopy is performed in a patient with unexplained infertility and
minimal/mild endometriosis is identified, we recommend ablation of
endometriosis. However, the current literature does not support performing a
diagnostic laparoscopy in all patients with unexplained infertility.
IUI
Intrauterine insemination
involves the placement of washed sperm into the uterine cavity around the time
of ovulation. It can be performed in conjunction with natural ovulation timed
with LH kit, ovulation induction using clomiphene citrate, or injectable
gonadotropins. Few data exist on the use of IUI without ovarian
hyperstimulation (OH). In 1991, Kirby and colleagues reported a RCT of 73
couples with unexplained infertility who were either randomized to IUI or timed
intercourse.19 Conceptions
occurred in 6 of 145 (4.1%) of the IUI cycles and 3 of 123 (2.4%) of the timed
intercourse cycles. A large RCT showed that intracervical insemination alone
had lower pregnancy rates per couple compared with IUI alone.20 It
has been estimated that 37 cycles of IUI without additional ovarian stimulation
would be needed to obtain an additional pregnancy compared with control cycles.2 A
recent Cochrane review on this topic confirmed that IUI with ovulation
induction increased the live birth rate compared with IUI alone.21 Therefore,
IUI without additional treatment with clomiphene citrate or gonadotropins is
not routinely performed in couples with unexplained infertility.
COH
and IUI
Over the past decades,
there has been a marked increase in the use of COH, with or without IUI, in the
treatment of unexplained infertility. Both clomiphene citrate and gonadotropins
have been used for COH, in combination with IUI or alone. The theoretical
rationale for COH in women with a normal ovulatory assessment is that subtle
ovulatory defects missed by standard testing may be overcome, and that an
increased number of eggs available for fertilization may increase the
likelihood of pregnancy. In a similar fashion, introducing washed sperm into
the uterine cavity using IUI may increase the density of motile sperm available
to ovulated oocytes, which should maximize the chance of fertilization.
Use of clomiphene citrate with timed
intercourse in patients with unexplained infertility has been shown to have a
small effect on pregnancy rates: combined analysis of the available evidence
revealed that 40 cycles with empiric clomiphene citrate therapy were necessary
to achieve 1 additional pregnancy.2 Gonadotropin
therapy is superior to clomiphene citrate therapy, and both are most effective
when combined with IUI. A meta-analysis of 27 studies involving 2939 cycles
revealed that the pregnancy rate per cycle was 8% with gonadotropin treatment
alone and 18% with gonadotropin treatment combined with IUI.14 The
cumulative pregnancy rate rises with the number of attempted COH/IUI cycles;
however, there is some evidence suggesting that the number of COH/IUI cycles
prior to treatment with IVF should be limited to 3.22
Aboulghar and colleagues
performed an observational prospective study on 594 couples with unexplained
infertility to determine the optimum number of COH/IUI cycles. They found that
1 to 3 cycles of COH/IUI resulted in 182 pregnancies, with a cycle fecundity of
16.4% and a cumulative pregnancy rate (PR) of 39.2% (total of 1112 cycles with
a mean of 1.9 cycles/patient).22
Up to 3 further trials of
COH/IUI in 91 of these women resulted in only 9 more pregnancies, with a cycle
fecundity of 5.6%, significantly lower than that in the first 3 attempts
(additional 161 cycles with a mean of 1.8 cycles/patient). The cumulative PR
rose to 48.5% by cycle 6, a further increase of only 9.3%.
A historical comparison
group with 131 patients with 3 failed cycles of COH/IUI who underwent 1 cycle
of IVF at the same center resulted in 48 pregnancies, with a cycle fecundity of
36.6% per cycle, suggesting that patients should be offered IVF if they fail to
conceive after 3 trials of COH and IUI.
There are several studies
addressing the effect of IUI on 2
consecutive days over single IUI.23–25 Available
trials on this issue are difficult to interpret because they are not restricted
to patients with unexplained infertility, but also included subjects with other
types of infertility, such as male factor and cervical factor. Although some
studies suggested marginal benefits of
double IUI over single, the most recent randomized trial concluded that
among patients undergoing COH/IUI, results of single and double IUI do not
statistically differ.23 Therefore,
double IUI is not routinely offered.
IVF/ICSI
The most expensive, but
also most successful treatment of unexplained infertility consists of the
spectrum of assisted reproductive technology including IVF, with or without
ICSI. IVF is the treatment of choice for unexplained infertility when the less
costly, but also less successful treatment modalities outlined above have
failed. In the 2006 SART data for unexplained infertility, there were 126,726
completed cycles with 40.4% live birth rate for women younger than 35 years of
age and 38.9% for women 35 to 37 years of age.
In addition to offering
the highest success rate, IVF also explains infertility in some of these
couples. In some IVF programs ICSI is performed in all couples with unexplained
infertility (for an undetected fertilization problem), whereas other programs
may perform ICSI in 50% of the retrieved oocytes.
Comparison
of Different Treatments for Unexplained Infertility
A randomized trial
comparing each of these treatment alternatives against one another and a nontreated
control group has not been performed. The European Society for Human
Reproduction and Embryology (ESHRE) Multicentre Trial reported in 1991 that
pregnancy rates per cycle were 15.2% in gonadotropin-only cycles, 27.4% in
gonadotropin and IUI cycles, and 25.7% in IVF cycles.26 The
pregnancy rate for IVF cycles has since increased with availability of improved
and sequential media, embryo
micromanipulation, and extended embryo culture. The ASRM Practice Committee
published an analysis on the appropriate roles and the cost-effectiveness of
the various procedures in the management of unexplained infertility by analysis
of previously published data.2,14 There
is limited information on the cost-effectiveness of various treatments;
however, it appears that there is a correlation between the cost of a treatment
modality and its pregnancy rates. Therefore, depending on the individual couple
and their particular clinical situation, COH with IUI may be attempted first,
with transition to IVF/ICSI if pregnancy is not achieved in a timely manner.
A RCT of clomiphene
citrate/IUI versus IVF (Fast Track and Standard Treatment [FASTT] Trial) has
recently been completed. In this trial, Reindollar and colleagues27 studied
503 couples assigned to conventional infertility treatment or an accelerated
track to IVF. All couples had unexplained infertility and underwent infertility
treatment for the first time. Patients were randomized to receive either a
conventional treatment regimen of 3 cycles of clomiphene/IUI, 3 cycles of
FSH/IUI, and up to 6 cycles of IVF or to receive an accelerated treatment
course of 3 cycles of clomiphene citrate/IUI and then up to 6 cycles of IVF. In
the conventional arm, 247 couples underwent 646 clomiphene citrate/IUI, 439
FSH/IUI, and 261 IVF treatment cycles; in the accelerated arm, 256 couples
received 642 clomiphene citrate and 357 IVF cycles. As of April 2007, 43/232
(18.5%) of the women in the conventional arm became clinically pregnant after
clomiphene citrate/IUI, 43/170 (25.3%) after FSH/IUI cycle, and 71/111 (64%)
after IVF. In the accelerated arm, 50/242 (20.7%) became pregnant after
clomiphene citrate/IUI and 117/171 (68.4%) in an IVF cycle. The median time to
pregnancy in the accelerated arm was shorter than the conventional arm. The
complete study has not yet been published.
Summary
and Conclusions
A thorough but
time-efficient investigation of the infertile couple is required prior to a
diagnosis of unexplained infertility. Couples should undergo a semen analysis,
ovulation testing, assessment of ovarian reserve, and imaging to assess for
tubal and uterine factors before a diagnosis of unexplained infertility is
made. This workup can be completed within 1 menstrual cycle. In the couples
with unexplained infertility, various treatment modalities are available,
including expectant management with lifestyle changes, operative laparoscopy,
COH (clomiphene citrate or gonadotropins) with IUI, and IVF (with or without
ICSI). The optimal treatment strategy needs to be based on individual patient
characteristics such as age, treatment efficacy, side-effect profile such as
multiple pregnancy, and cost considerations.
Main
Points
Couples should undergo a
semen analysis, ovulation testing, assessment of ovarian reserve, and imaging
to assess for tubal and uterine factors before a diagnosis of unexplained
infertility is made.
The principal treatments
for unexplained infertility include expectant observation with timed
intercourse and lifestyle changes, clomiphene citrate and intrauterine
insemination (IUI), controlled ovarian hyperstimulation with IUI, and in vitro
fertilization (IVF).
Although expectant
management is associated with the lowest cost, it results in the lowest cycle
fecundity rates. It may provide an option for a couple with unexplained
infertility in whom the female partner is young and the problem of oocyte
depletion is not an immediate concern.
The most expensive, but
also most successful treatment of unexplained infertility consists of the
spectrum of assisted reproductive technology including IVF, with or without
intracytoplasmic sperm injection. IVF is the treatment of choice for unexplained
infertility when the less costly, but also less successful treatment modalities
have failed.
The optimal treatment
strategy needs to be based on individual patient characteristics such as age,
treatment efficacy, side-effect profile such as multiple pregnancy, and cost
considerations.
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