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Understanding Infertility, Evaluations, and Treatment Options
Understanding Infertility, Evaluations, and Treatment Options
Understanding Infertility, Evaluations, and Treatment Options
Evaluations,
and Treatment Options
Prof. Medhat E Helmy
Email:medhathelmy@hotmail.com
DEFINITIONS
• Infertility is a unique medical condition
because it involves a couple, rather than a
single individual.
• It is defined as failure of a couple to
conceive
– after 12 months of regular intercourse without
use of contraception in women less than 35
years of age;
– and after six months of regular intercourse
without use of contraception in women 35
years and older [1].
• Some clinicians use the term subfertility
to describe this failure to conceive unless
the couple has been proven to be sterile.
• Fecundability, the probability of achieving
a pregnancy in one menstrual cycle, is a
more accurate descriptor because it
recognizes varying degrees of infertility.
• The large majority (80 to 90 percent) of
apparently normal couples will conceive
within the first year of attempted
conception.
• Five to 15 percent of apparently normal
couples will conceive in the second 12
months of attempted conception so that
after 24 months of trying to become
pregnant, 95 percent of couples will have
conceived.
• Fecundability was 0.25 in the first three
months of observation, and then
• decreased to 0.15 during the next nine
months of observation.
• The fecundability of the cohort decreases
over time and with increasing age of the
female partner. Thus, the possibility of
infertility may be suspected after only six
months of unprotected intercourse
without conception.
• Patients who have not achieved
pregnancy after 12 months have even
lower fecundability.
Prognosis
The best prognosis for treatment-
independent conception [8].
•Under age 30,
•A less than two-year history of infertility,
•A previous pregnancy,
•do not have tubal disease,
– anovulation,
– partners with male factor infertility, or
– endometriosis,
PREVALENCE OF INFERTILITY
• From 1982 to 2002, the percentage of
infertile women fell from 8.5 to 7.4 percent.
This figure is lower than the incidence of
infertility estimated from prospective
studies in the United States, which ranges
from 12 to 18 percent [10].
PREVALENCE OF INFERTILITY
•In the United States, 7.3 million women
(12% of women of reproductive age) had
difficulty or were unable to get pregnant or
carry a baby to term.2 (Based on data from
2002)
•Only half of those couples will actually seek
and receive treatment, but with treatment, 2
of 3 couples will succeed in having a child.
PREVALENCE OF INFERTILITY
• Worldwide, the prevalence of infertility is highest in
Eastern Europe, North Africa/Middle East, Oceania,
and Sub-Saharan Africa [12].
• It is not known whether fecundity varies among racial
and ethnic groups when adjusted for confounders.
• The National Survey of Family Growth found that
married black women had about twice the odds of
infertility as married white women, after adjustment
for education, income, and self-reported history of
pelvic inflammatory disease [9].
• Others have shown that this disparity cannot be
explained by differences in common risk factors for
infertility, such as smoking, obesity, fibroids, or ovarian
volume.
CAUSES OF INFERTILITY
• Some causes of infertility are easily
identifiable, such as azoospermia (no
sperm cells in the ejaculate),longstanding
amenorrhea, or bilateral tubal obstruction.
• However, the situation is less clear in
most couples. It is often difficult to weigh
or prioritize these findings when
counseling infertile couples or planning
treatment programs.
• Adding to the complexity of the situation,
there are few data regarding the predictive
validity of these tests despite their
widespread use. Thus, an abnormal test
result cannot be said to be the cause of
infertility in a particular couple.
• One population-based study reported the
following results [15]:
– Male factor (hypogonadism, post-testicular
defects, seminiferous tubule dysfunction) — 26
percent
– Ovulatory dysfunction — 21 percent
– Tubal damage — 14 percent
– Endometriosis — 6 percent
– Coital problems — 6 percent
– Cervical factor — 3 percent
– Unexplained — 28 percent
• The frequency of these factors in infertility
is similar whether infertility is primary or
secondary, and has not changed
significantly over the past 25 years in
developed countries [16].
CAUSES OF INFERTILITY
• In developed countries (WHO),
– female factor infertility was reported in 37 %
– male factor infertility in 8 %
– both male and female factor infertility in 35 %.
– Five % of couples had unexplained infertility
There Are Multiple Causes of Infertility
Causes of Infertility
Tubal factor
14%
Multiple factors 18%
(male + female)
Ovaluatory dysfunction
6%
7%
Endometriosis
1%
Uterine factor
Unexplained
11%
Male factor
19%
Other causes 6%
Arlene
Centers for Disease Control and Prevention. 2006 Assisted J. Morales,
Reproductive M.D., Success
Technology FACOGRates: National Summary and Fertility Clinic Reports.
2008. http://www.cdc.gov/ART/ART2006/508PDF/2006ART.pdf. Accessed April 20, 2009.
Decline in Fertility With Age:
The Fixed Ovarian Pool Becomes
Depleted as Time Passes
Monthly Fertility Rate
1 .2
1 .0
0 .8
0 .6
Relative rate
0 .4
0 .2
20 25 30 35 40 45 50
50
40
30
20
Percent
10
0 <21 22 24 26 28 30 32 34 36 38 40 42 44 46 48 >48
Age (years)
Pregnancy Live birth Singleton live birth
Medications Medications
Previous infertility testing and therapies Previous infertility testing and therapies
Infertility evaluation – history-3
Male Female
– drug therapy,
– surgery, and/or
– procedures such as
• intrauterine insemination or
• in vitro fertilization.
Contraindications to infertility
therapy
• The only absolute contraindications to
infertility therapy are contraindication to
pregnancy and contraindication to use of the
drugs or surgery used to enhance fertility.
• The ethics of restricting infertility therapy for
other reasons, such as parental child-rearing
ability, severe obesity, life-style issues
(tobacco smoking, alcohol consumption), are
controversial
• The parent's marital status, sexual orientation,
and HIV status should not be used to deny
infertility treatment
• Women who use infertility therapies (IVF
or non-IVF) appear to have a small but
statistically significant increase in risk of
some pregnancy complications, such as
preterm birth [34,35].
• Compared to the general population, an
increased risk of adverse pregnancy
outcomes has also been observed among
untreated subfertile women who
conceived naturally.
Treatment Options for Infertile Couples
Condition Treatment Options
Female infertility
Ovulatory failure or dysfunction OI
Tubal factor COS with IVF
Endometriosis IUI (patent tubes), or COS with IVF
Male infertility
Male subfertility IUI with or without OI
Male factor COS with ICSI
Female and/or male infertility
Unexplained IUI, COS with IVF, or ICSI
Messinis. Hum Reprod . 2005;20:2688. Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2008;90
(5 suppl):S7. Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2006;86(5 suppl):S187.
Ovulation Induction: Clomiphene Citrate
• CC is an antiestrogen that binds to estrogen receptors and interferes
with estrogen-negative feedback
– Results in an alteration in pulsatile GnRH secretion
– Leads to increases in gonadotropin secretion and follicular development
• CC is widely used for ovulation induction in women with PCOS and in
couples with unexplained infertility
• CC treatment successfully induces ovulation in about 80% of properly
selected candidates
– Pregnancy rates are much lower (30%-40% per cycle)
– 40%-45% of couples can become pregnant within 6 cycles
– Failure to conceive after successfully induced ovulation is indication for
further evaluation
• Patient characteristics predictive of poor response to CC:
– Hypothalamic disorder
– Low estrogen levels
– Obesity
American Society for Reproductive Medicine. Medications for inducing ovulation: a guide for patients. 2006. http://www.asrm.org/Patients/
patientbooklets/ovulation_drugs.pdf. Accessed April 20, 2009.
Case. Can Fam Physician . 2003;49:1465. Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2006;86:S187.
Limitations and Risks With CC for OI
• CC is generally well tolerated, although some side effects may limit its
efficacy and safety
– Short-term, reversible side effects include: hot flashes, mood swings, visual
disturbances, breast tenderness, pelvic discomfort, and nausea
– The antiestrogenic effects may negatively impact the uterine lining, leading
to lower pregnancy rates
– Risk of multiple pregnancy is increased
– Risk of cancer is increased among women who were treated with CC
• Uterine fibroid risk increases with CC treatment
• Risk of ovarian cancer increases among women treated with prolonged
CC
• Treatment should be limited to no more than 6 cycles or fewer in
consideration of woman’s individual situation
– Age, baseline characteristics, etc
American Society for Reproductive Medicine. Medications for inducing ovulation: a guide for patients. 2006. http://www.asrm.org/Patients/
patientbooklets/ovulation_drugs.pdf. Accessed April 20, 2009.
Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2008;90(5 suppl):S7.
Increased risk of ovarian cancer ?
• While there has been concern about a
possible increased risk of ovarian cancer
with ovulation induction drugs, it appears
that the risk may be due to the infertility
diagnosis rather than the medications
themselves.
• However, because one study suggested an
increase after 12 cycles of clomiphene
citrate, women should not receive more
than 12 cycles.
Increased risk of Breast cancer ?
• There does not appear to be an increased
risk of breast cancer with ovulation
induction drugs.
Use of IUI in OI Protocol
• Indications
– Unexplained infertility
– Male subfertility—mild
oligozoospermia,
asthenozoospermia, or
teratozoospermia
– Failure to conceive after
ovulation induction treatment
– Ejaculatory failure
– Retrograde ejaculation
• Procedure
– Washed prepared sperm are
deposited in the uterus just
before the release of an egg or Image on file with Schering-Plough/Organon.
eggs in a natural or stimulated
cycle
• Success rate: up to 15% per
cycle
• Significant risk for multiple
pregnancy
American Society for Reproductive Medicine. Assisted reproduction technologies: a guide for patients. 2008. http://www.asrm.org/Patients/
patientbooklets/ART.pdf. Accessed April 20, 2009.
Intracytoplasmic Sperm Injection
Indications Success Rate and
• Very low numbers of motile Complications
sperm • Fertilization rate: 50%-80%
• Severe teratospermia • Live offspring: 20%-40%
• Problems with sperm (40% in younger women;
binding to and penetrating success declines with
the egg maternal age)
• Antisperm antibodies
• Prior or repeated fertilization
failure with standard IVF
methods
• Frozen sperm limited in
number
and quality
• Obstruction of the male
reproductive tract not
amenable to repair
American Society for Reproductive Medicine. Intracytoplasmic sperm injection (ICSI). 2008. http://www.asrm.org/Patients/FactSheets/ICSI-Fact.pdf.
Accessed April 20, 2009. Campbell and Irvine. Br Med Bull. 2000;56(3):616. Palermo et al. Sem Reprod Med. 2000;18(2):161.
Controlled Ovarian Stimulation:
Gonadotropin Treatment
• Starts with higher dose of gonadotropins than for OI (COS: 150-225 IU
of FSH; OI: 50-75 IU of FSH)
• Needs GnRH analog treatment to prevent interference by endogenous
hormones
• COS is followed by oocyte retrieval, IVF, and transfer of embryos
COS
hCG
hCG
Day 2 or 3
of menses
Embryo Transfer
Day 6 of FSH
GnRH antagonist
Cycle day
21-24 rFSH/hMG IVF
Luteal phase
support
or
GnRH agonist
ICSI
rFSH/hMG
Down regulation
Ovarian hyperstimulation
syndrome (OHSS)
• Ovarian enlargement due to multiple ovarian
cysts as a result of multifollicular development.
• an acute fluid shift out of the intravascular
space.
• The most severe manifestations include
massive ovarian enlargement
hemoconcentration and third-space
accumulation of fluid;
• These changes may be complicated by renal
failure, hypovolemic shock, thromboembolic
episodes, acute respiratory distress syndrome,
and death
OHSS
• OHSS occurs after luteinization of a large
number of follicles.
• Such massive follicular luteinization is
usually only observed in exogenous
gonadotropin cycles following
administration of hCG, or after
administration of GnRH agonist;
• It rarely occurs in women treated with CC.
• The clinical symptoms usually appear 5 to
10 days following the first dose of the
ovulatory trigger (hCG, GnRH agonist).
OHSS
• Mild ovarian hyperstimulation also rarely
develops following an endogenous LH
surge
• in a setting of spontaneous multifollicular
development. This has been described in
case reports, particularly in
• women with polycystic ovarian syndrome
or hypothyroidism
OHSS
• Severe, recurrent, spontaneous OHSS during
pregnancy has been described in several reports.
• In these instances, the OHSS was due to a
mutation in the serpentine region of the FSH
receptor that resulted in a broadening of ligand
specificity, thereby allowing stimulation by
endogenous hCG.
• The persistent stimulation of the FSH receptor
during pregnancy resulted in excessive follicular
recruitment and subsequent ovarian
hyperstimulation.
OHSS
• Development of massive ascites and
hypovolemia due to increased capillary
permeability are the cardinal clinical
events in the pathogenesis of OHSS .
• Hypovolemia results in
hemoconcentration, decreased central
venous pressure, low blood pressure, and
tachycardia
OHSS
• Vascular endothelial growth factor (VEGF) of
follicular origin is the main, although possibly not
the only, component responsible for development
of OHSS .
• This peptide has two actions:
– it is a potent promoter of neovasculogenesis; and
– it may increase permeability of blood vessels walls
(mediated by in part by nitric oxide), thereby disrupting
functional integrity of the vascular bed [10-14].
• In addition, VEGF can induce changes in cellular
actin fibers, which may compromise the integrity of
tight cell junctions.
• VEGF levels correlate with both the presence and
CLASSIFICATION AND
CLINICAL MANIFESTATIONS
• Grade I (mild hyperstimulation)
• Grade II (moderate hyperstimulation)
• Grade III (severe hyperstimulation)
Grade I (mild hyperstimulation)
• It is characterized by bilateral ovarian
enlargement with multiple follicular and
corpus luteum cysts measuring up to 5 by 5
cm.
• Serum estradiol (E2) concentration greater
than 1500 pg/mL (6000 pmol/L) and
progesterone concentration greater than 30
ng/mL (115 nmol/L) in the early part of the
luteal phase.
superovulation" or "controlled
ovarian hyperstimulation
• Mild hyperstimulation has been renamed "
superovulation" or "controlled ovarian
hyperstimulation" to distinguish it from
excessive ovarian stimulation associated
with morbid sequelae.
• However, mild hyperstimulation also
raises the incidence of high-order multiple
pregnancy , which can result in more
spontaneous abortions and perinatal
complications.
Grade II (moderate
hyperstimulation)
• Ovaries enlarged up to 12 by 12 cm,
accompanied by abdominal discomfort
and gastrointestinal symptoms (eg,
nausea, vomiting, and diarrhea).
• A sudden increase in weight of more than
3 kg may be an early sign of moderate
hyperstimulation.
Grade III (severe
hyperstimulation)
• The presence of large ovarian cysts (more
than 12 by 12 cm), ascites, and, in some
patients, pleural and/or pericardial
effusion,
• Electrolyte imbalance (hyponatremia,
hyperkalemia), hypovolemia, and
hypovolemic shock.
• Marked hemoconcentration, increased
blood viscosity, and thrombo-embolic
phenomena, including DIC.
• Spontaneous regression occurs over 10 to
14 days, but may take longer if
implantation occurs.
• The incidences of moderate and severe
ovarian hyperstimulation are 3.1 to 6
percent and 0.25 to 1.8 percent,
respectively.
• In one study, the pregnancy rate in
hyperstimulated cycles was threefold
higher than in nonhyperstimulated cycles
TREATMENT of OHSS
• The best treatment of OHSS is primary
prevention.
• Preventing ovulation by withholding hCG
is an effective method of avoiding
hyperstimulation in overstimulated ovaries.
• Alternatively, aspiration of follicles 36
hours after administration of the ovulatory
dose of hCG may lower the risk of
developing clinical hyperstimulation by
reducing the mass of luteinized granulosa
• Medical therapy suffices for most patients,
• laparotomy reserved for catastrophic
complications, such as ovarian torsion or
rupture and internal hemorrhage.
• Women with severe symptoms often
require intensive medical care.
• Vaginal intercourse is restricted in all
grades of OHSS because of the risk of
cyst rupture.
• Patients should also avoid impact-type
Treatment of mild
hyperstimulation
• Treatment is supportive, as needed.
• However, mild ovarian hyperstimulation can
develop into moderate or severe disease,
especially if conception ensues.
• observed for enlarging abdominal girth, acute
weight gain, and abdominal discomfort on an
ambulatory basis for at least two weeks or until
the appearance of menstrual bleeding.
Treatment of moderate
hyperstimulation
• Observation, bed rest, provision of adequate
fluids, and sonographic monitoring of cyst size.
• Serum electrolytes, hematocrit, and creatinine
should also be evaluated.
• Some clinicians have outpatients keep track of
their fluid intake and output; intake or output less
than 1000 mL/day or a discrepancy in fluid
balance greater than 1000 mL/day would be a
cause for concern
• Initiation of resolution
– the cysts become smaller on two consecutive
ultrasound examinations
– clinical symptoms recede.
• Early detection of
– continuous weight gain (two pounds or more a
day),
– increase in severity of existing symptoms, or
– the appearance of new symptoms, such as
vomiting, diarrhea, and dyspnea.
Medical treatment of severe
hyperstimulation
• Maintaining blood volume while correcting
the disturbed fluid and electrolyte balance
• Relieving secondary complications of
ascites and hydrothorax
• Preventing thromboembolic phenomena
Clinical findings in women with
ovarian hyperstimulation syndrome
• Bloating • Hyponatremia,
• Nausea, vomiting, hyperkalemia
diarrhea • Pleural and
• Lethargy pericardial effusions
• Shortness of breath • Ascites
• Oliguria • Hypercoagulability
• Rapid weight gain and thrombosis
• Hemoconcentration • Adult respiratory
distress syndrome
• Leukocytosis
Laboratory monitoring in
women with grade 3 OHSS
Daily Once, repeat as
• Leukocyte count indicated
• Hemoglobin and • Liver function tests
hematocrit • Prothrombin and
• Electrolytes partial thromboplastin
time
• Chest radiograph (if
respiratory symptoms
are present)
Fluid balance
• net fluid flow (intake/output record),
• weight and girth measurements, and
• hematocrit examinations.
• A central venous pressure catheter may
be required in women who are
hemodynamically unstable
• one to two liters of isotonic fluid is given
to such women in the first hour to rapidly
restore tissue perfusion.
• Further fluids optimally should be given
while monitoring the central venous or
pulmonary capillary wedge pressure.
• Fluid repletion should continue at the
initial rapid rate as long as the cardiac
filling pressures and the systemic blood
pressure remain low.
• Plasma expanders such as dextran, human
albumin (200 mL of 25 percent albumin over
four hours), and plasma (500 to 1000 mL over
24 hours) supplemented with appropriate
electrolytes should be administered early and
repeated as needed
• Oral indomethacin, which blocks prostaglandin
synthesis and reduces capillary permeability.
• Hematocrit should be monitored every four
hours; plasma expanders can be stopped when
the hematocrit is less than 38 percent
Diuretics
• Diuretic agents are not recommended
since
– fluid in the third space is not affected by these
drugs.
– most diuretics act at the distal tubule with
minimal effect on the proximal tubule
• Renal failure may respond to a dopamine
drip (0.18 mg/kg per hour) [27]. Oral
docarpamine administration could be one of the options
in the management of patients with OHSS requiring
dopamine therapy
Ascites
• Sonographically guided Paracentesis
resulted in a marked improvement of renal
function (due to increased venous return),
blood osmolarity, and hemoconcentration,
as well as relief of dyspnea and abdominal
discomfort
• Other authors have reinfused the
withdrawn ascitic fluid (after
microfiltration) and reported relief of
symptoms and improvement of renal
Pleural effusions
• Pleural effusions should be drained to
relieve dyspnea.
• Paracentesis may also be useful in
alleviating breathing difficulties in patients
with ascites and hydrothorax
Thromboembolism
• Thromboembolic events are the most serious,
but rarest, complications of OHSS.
• Thromboses can occur in either the arterial (25
percent) or venous (75 percent) circulations and
may lead to permanent neurologic injury or death.
• Prophylactic anticoagulation with heparin or low
molecular weight heparin, antiembolism
stockings, and or intermittent pneumatic
compression boots should be considered to
minimize the risk of venous thrombosis
• Anticoagulant therapy is usually
unnecessary if above therapies are
promptly employed.
• Blood coagulation may be monitored
because of the danger of disseminated
intravascular clotting.
Resolution
• After a period of several days, third space fluid
begins to re-enter the intravascular space,
hemoconcentration reverses, and natural
diuresis ensues.
• The patient feels better and her appetite and
ability to take oral fluids improve.
• Intravenous fluids are tapered as oral intake
increases. Some clinicians limit oral intake to
1000 mL/day at this time to facilitate diuresis
and maintain euvolemia [2].
• Complete resolution typically takes 10 to 14
days from the onset of initial symptoms.
Risk factors
• Young age
• High serum estradiol concentrations
immediately prior to human chorionic
gonadotropin (hCG) administration
• Polycystic ovary morphology tend to have
the most exuberant response to
exogenous gonadotropins)
Treatment for reducing the
incidence and/or severity of OHSS
in high risk cycles
• Withholding hCG. Exogenous hCG, which mimics
an ovulatory luteinizing hormone (LH) surge, also
contributes to hyperstimulation risk due to the
pharmacologic doses that are used, as well as
its prolonged biologic half-life.
• The GnRH agonists are capable of evoking an LH
surge sufficient for inducing ovulation, but, in
general, not long enough to provoke ovarian
hyperstimulation. However, some risk of ovarian
hyperstimulation remains (Antagonist)
Treatment for reducing the incidence
and/or severity of OHSS
• However, corpus luteum function
following GnRH agonist induced ovulation
may be inadequate to sustain nidation and
continuation of pregnancy,
– Pharmacologic luteal support should be given.
– Clinical pregnancy rate was lower.
• Another prevention strategy is
administration of recombinant human LH
(rhLH) as the ovulatory trigger rather than
hCG. There were no episodes of OHSS in
those receiving a single dose of up to 30,
Treatment for reducing the
incidence and/or severity of
OHSS
• hCG may be given with a low risk of OHSS
to women with estradiol levels less than
1500 pg/mL in the presence of no more
than two follicles above 17 mm and less
than four smaller follicles.
Reducing the incidence and/or
severity of OHSS
• Coasting [22-24]
• Transforming
• Replacing hCG with a GnRH agonist [25-27]
• Replacing hCG with recombinant LH [17]
• Performing follicular reduction [21]
• Intravenous albumin [28-33]
• Dopamine agonist administration
Intravenous albumin for the
prevention of OHSS
• human albumin administration proximate
to oocyte retrieval reduced the risk of
severe OHSS in high risk women.
• Absolute risk reduction was 5.5 percent
and 18 women would need to be treated to
prevent one case of severe OHSS
• data on the efficacy of intravenous
albumin for the prevention of OHSS are
conflicting.
Hydroxyethyl starch
• The possible efficacy of hydroxyethyl
starch in prevention of OHSS was reported
in two prospective,randomized, placebo-
controlled trials including over 350
patients; the magnitude of benefit was
similar to that noted in the meta-analysis
of intravenous albumin trials
• There is insufficient data to recommend
use of corticosteroid prophylaxis at this
time.
• Cabergoline (0.5 mg daily) or placebo until
the day of hCG administration prevented
the increase in vascular permeability and
reduced the rate of moderate OHSS
Intrauterine insemination (IUI)
• IUI alone is a useful technique for
achieving pregnancy in couples with
severe sexual dysfunction, but can also be
useful in patients with cervical factor
infertility as long as at least one fallopian
tube is patent.
• When IUI is performed during an
unstimulated (natural cycle) or a
clomiphene stimulated cycle, we suggest
use of an over-the-counter ovulation
predictor kit to schedule the optimum time
IUI
• For patients with mild male factor, early
stage endometriosis, or unexplained
infertility, we suggest controlled ovarian
hyperstimulation with IUI rather than
natural cycle IUI (Grade 2B). Ovarian
stimulation may employ clomiphene or
gonadotropins.
• Semen processing for IUI is not difficult to
learn and can be adapted to use in clinical
offices, but care must be taken to ensure
The management of couples
with unexplained infertility
• Unexplained infertility refers to the
absence of a definable cause for a
couple's failure to achieve pregnancy after
12 months of attempting conception (six
months in women 35 years and older)
despite a thorough evaluation.
• The infertility is probably due to subtle
functional abnormalities in oocyte, sperm
or endometrial function.
The management of couples
with unexplained infertility
• It usually starts with treatments that consume
few resources and are low risk and patient
directed (eg, lifestyle changes), and
• then moves sequentially to treatments requiring
proportionately greater resources and risks
(intrauterine insemination, clomiphene,
clomiphene plus intrauterine insemination), and
• finally to higher risk and high resource intensive
interventions (gonadotropin injections plus
intrauterine insemination, IVF)
The management of couples with
unexplained infertility
• Lifestyle changes, such as discontinuing
cigarette smoking and achieving a normal
weight may increase fertility in women with
unexplained infertility.
• Approximately 1 percent of these couples will
become pregnant per cycle with no intervention.
• Expectant management may be an appropriate
therapy for couples where the female partner is
less than 32 years of age.
• For women over 37 years of age, however, the
ovarian follicular pool can become depleted
during expectant management, resulting in
untreatable infertility. Typically women 37 years
Empiric treatment of
unexplained infertility
• Three to four cycles of clomiphene citrate
and intrauterine insemination (IUI) (Grade
2C).
• The second step is either
– one to three cycles of gonadotropin and IUI
– or
– in vitro fertilization, depending on patient
specific factors (eg, personal costs and
insurance coverage, convenience and
availability of treatment).
Empiric treatment of
unexplained infertility
• IVF is the intervention that will result in the
highest per cycle pregnancy rate in the
shortest time interval.
• It is also the most costly intervention and
has a high rate of high order multiple
pregnancy.