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Treatment of unexplained infertility

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Title: Treatment of unexplained infertility


1
Treatment of unexplained infertility
  • Dr. Ashraf Fouda
  • Consultant obstetrics gynecology
  • Damietta General Hospital

2
INTRODUCTION
  • It is relatively simple to identify the cause of
    infertility in women with ovulatory disorders or
    tubal disease and in men with semen
    abnormalities.
  • These categories account for the source of
    infertility in approximately 75 of couples.
  • Infertility in the remaining 25 of couples is
    due to endometriosis (8 ) or miscellaneous
    factors (eg, cervical factor, immunological
    factor, uterine synechiae) (2 ) or is
    unexplained (15 ) 1-3.

3
DEFINITION AND DIAGNOSIS
4
Overview
  • Unexplained infertility refers to the absence of
    a definable cause for a couple's failure to
    achieve pregnancy after 12 months of attempting
    conception despite a thorough evaluation 4.
  • Authorities vary in their concept of what
    constitutes a thorough evaluation, the nature of
    which has evolved over time.

5
Thorough evaluation typically includes
documentation of
  • Adequate ovulation
  • using either a mid-luteal phase serum
    progesterone greater than 10 ng/mL or urine
    testing documenting the LH surge.
  • More resource-intensive approaches would be to
    perform serial transvaginal ultrasounds to
    monitor the development and rupture of a dominant
    ovarian follicle or an endometrial biopsy to
    demonstrate secretory changes in the endometrium.

6
Thorough evaluation typically includes
documentation of
  • Tubal patency
    by
    hysterosalpingogram or laparoscopy.
  • Normal uterine cavity
    as documented by
    hysterosalpingogram, hysteroscopy, or
    sonohysterogram.
  • Normal semen analysis
  • 20 million sperm per mL,
  • greater than 50 forward motility, and
  • greater than 40 normal morphology
    (using World Health Organization criteria).

7
Thorough evaluation typically includes
documentation of
  • Adequate ovarian oocyte reserve
  • using either a cycle day 3 follicle stimulating
    hormone (FSH) concentration less than 15 mIU/mL
    5,6 or a clomiphene challenge test (ie,
    clomiphene citrate 100 mg daily is administered
    on cycle days 5 to 9 an FSH level less than
    15 mIU/mL on both cycle days 3 and 10 is normal).
  • However, the upper threshold for a normal FSH
    concentration is laboratory dependent cutoff
    values of 10 to 25 mIU/mL have been reported
    because of use of different FSH assay reference
    standards.

8
Role of laparoscopy
  • Fertility specialists differ on whether
    laparoscopy is an important component of a
    thorough infertility evaluation.
  • In many fertility centers, laparoscopy is not
    performed prior to initiating therapy for
    infertility because it requires general
    anesthesia and is a resource intensive step.

9
Role of laparoscopy
  • However, numerous studies indicate that for
    couples with a normal initial infertility
    work-up, laparoscopy will demonstrate previously
    undetected stage I or II endometriosis or
    periovarian or peritubal adhesions in a
    substantial proportion of women.
  • Detection of these abnormalities may result in
    alternative treatment plans, such as surgery for
    endometriosis or direct referral to an IVF
    program if there are peritubal adhesions 7-9.

10
Role of laparoscopy
  • However, the trend of referring infertile couples
    to IVF relatively quickly has led many
    authorities to note that laparoscopy could
    probably be avoided in women with a normal HSG
    since the presence of endometriosis and adhesions
    does not markedly influence the effectiveness of
    IVF treatment 10.

11
Role of laparoscopy
  • In making a decision, clinicians and couples
    need to weigh
  • the availability of resources,
  • the risk associated with laparoscopy, and
  • the knowledge that laparoscopy demonstrates
    abnormalities not otherwise detected by other
    infertility tests and that
  • laparoscopic treatment of minimal and mild
    endometriosis enhances fecundity.

12
POSSIBLE ETIOLOGIES
  • The exact etiology of unexplained infertility is
    unknown, but several possibilities have been
    proposed.
  • Subtle changes in follicle development,
    ovulation, and the luteal phase have been
    reported in some women with unexplained
    infertility 11,12.
  • In other couples, the male partner's semen
    analysis shows sperm concentration and motility
    at the lower end of the normal range 13.

13
POSSIBLE ETIOLOGIES
  • Many cases of unexplained infertility are
    probably caused by the presence of
    multiple factors (eg, female partner over
    35 years of age, male partner with low normal
    semen parameters), each of which on their own do
    not significantly reduce fertility, but can
    reduce the pregnancy rate when combined.

14
POSSIBLE ETIOLOGIES
  • Couples with unexplained infertility who are
    treated with in vitro fertilization (IVF)
    demonstrate reduced oocyte fertilization and
    embryo cleavage rates compared to couples in whom
    tubal factor is the cause of the infertility,
    although the rates of live birth per transfer are
    equivalent for both groups.
  • This was illustrated in a study that showed that
    the oocyte fertilization and embryo cleavage rate
    for unexplained and tubal factor infertility were
    52 and 60 percent, respectively 14.

15
POSSIBLE ETIOLOGIES
  • Couples with unexplained infertility also had a
    higher rate of complete fertilization failure
    when treated with IVF than couples with tubal
    factor infertility (6 versus 3 percent).
  • These results suggest that couples with
    unexplained infertility probably have
    subtle functional abnormalities in
    oocyte and/or sperm function.

16
CONSERVATIVE MANAGEMENT
  • The management of couples with unexplained
    infertility
  • Usually starts with treatments that consume few
    resources
    (e.g., life style changes,
    tubal flushing, intrauterine insemination IUI,
    clomiphene, clomiphene plus IUI) and
  • Moves sequentially to treatments requiring
    proportionately greater resources
    (e.g., gonadotropin
    injections plus IUI or IVF) .

17
CONSERVATIVE MANAGEMENT
  • Life style changes
  • Expectant management
  • Timed intercourse
  • Tubal flushing

18
Life style changes
  • Epidemiological studies indicate
  • Cigarette smoking,
  • Abnormal body mass index, and
  • Excessive caffeine consumption and
  • Excessive alcohol consumption
    reduce fertility in the
    female partner.
  • Couples with unexplained infertility should be
    informed of a possible relationship between
    cigarette smoking and their infertility and
    advised to stop smoking for this reason, as well
    as for benefits in overall health.

19
Life style changes
  • The female partner should be counseled to try to
    achieve a body mass index between 20 and 27
    kg/m2, reduce caffeine intake to no more than 250
    mg daily (two cups of coffee), and reduce alcohol
    intake to no more than four standardized drinks
    per week .
  • These changes may be useful for enhancing both
    natural and assisted conception .
  • This is also an appropriate time to mention
    life-style changes for health promotion to the
    male partner for his general health benefits.
  • Couples with unexplained infertility and a low
    frequency of coitus should increase coital
    frequency to two to three times per week .

20
Expectant management
  • Approximately 1 to 3 of couples with
    unexplained infertility followed prospectively
    without active treatment become pregnant each
    month 19.
  • Therefore, effective fertility treatment for
    unexplained infertility must demonstrate an
    increase in the pregnancy rate above this
    baseline fecundability.
  • The age of the female partner influences the
    pregnancy rate associated with expectant
    management 20.
  • Women with unexplained infertility older than 37
    years of age have a pregnancy rate of less than 1
    per cycle with expectant management.

21
Expectant management
  • In a randomized trial, six months of expectant
    management for couples with a good prognosis for
    fertility (young age, no bilateral tubal disease,
    no sperm problems) was associated with an ongoing
    pregnancy rate comparable to that achieved with
    intrauterine insemination plus gonadotropin
    injections 21.
  • Thus, expectant management may be an option for a
    couple with unexplained infertility in whom the
    female partner is less 32 years of age and the
    problem of oocyte depletion is not an immediate
    concern.

22
Expectant management
  • However, the ovarian oocyte pool declines rapidly
    for women over 37 years of age, inevitably
    causing ovarian aging to become a major component
    of the fertility problem.
  • Thus, expectant management is not recommended for
    these women.

23
Timed intercourse
  • Conception after intercourse is possible from 5
    days before ovulation through the day of
    ovulation 22,23.
  • The highest probability of conception appears to
    be with intercourse 1 to 2 days before ovulation
    23-25.
  • Therefore, attempting to identify the fertile
    period and timing intercourse during this
    interval maximizes the probability of conception.

24
Timed intercourse
  • This can be inferred by comparing the results of
    the following studies
  • The first series consisted of 100 fertile couples
    who conceived without timed intercourse and
    reported pregnancy rates of 50 at 3 months, 75
    at 6 months, and over 90 at
    12 months, whereas
  • The second series of similar couples who used a
    method of fertility awareness with timed
    intercourse observed pregnancy rates of 76 at
    one month and 100 at seven months 26.

25
Identifying the fertile period
  • Measurement of urinary luteinizing hormone is the
    most widely utilized prospective method for
    identifying the fertile period.
  • Better alternatives are methods that have the
    woman examine her vaginal discharge for changes
    suggestive of a preovulatory estrogen effect,
    such as an increased volume of clear, stretchy,
    slippery mucus.
  • Calendar and basal body temperature (BBT) methods
    are not very reliable for identifying the fertile
    period because of normal variation in cycle
    length and because the temperature rise
    associated with ovulation occurs too late to be
    useful in the index cycle 26.

26
Tubal flushing
  • Several studies have reported
    increased pregnancy rates after diagnostic
    hysterosalpingography.
  • The value of this technique was illustrated in a
    Cochrane review of 11 randomized trials 27.

27
Tubal flushing
  • The major findings from this analysis were
  • Tubal flushing with oil-soluble media versus no
    intervention was associated with a significant
    increase in pregnancy rate .
  • Tubal flushing with oil-soluble media was not
    significantly more effective than tubal flushing
    with water-soluble media for achieving pregnancy
    .
  • The addition of oil-soluble media to flushing
    with water-soluble media (water-soluble plus
    oil-soluble media versus water-soluble media
    alone) also did not show a significant benefit
    for achieving pregnancy .

28
Tubal flushing
  • In summary, tubal flushing with oil-soluble media
    at the time of HSG appears to improve
    fecundability in the period of time after the
    procedure.
  • The effect of water-soluble media on pregnancy
    rate and its efficacy compared to oil-soluble
    media are less clear , as randomized trials in
    these areas are either nonexistent (water-soluble
    versus no intervention) or had study design
    variations that preclude reliable comparisons.

29
TREATMENT
  • Intrauterine insemination (IUI)
  • Clomiphene citrate
  • Clomiphene plus IUI
  • Gonadotropin injections with or without IUI
  • In vitro fertilization

30
TREATMENT
  • Couples of all ages often become frustrated with
    their inability to conceive.
  • Active treatment is recommended for these couples
    when expectant management and life style
    modification fail to result in pregnancy.
  • The interventions increase the number of gametes
    available in a given cycle and/or facilitate the
    ability of the gametes to interact.

31
Intrauterine insemination (IUI)
  • The (IUI) procedure consists of
  • Washing an ejaculated semen specimen to remove
    prostaglandins,
  • Concentrating the sperm in a small volume of
    culture media, and
  • Injecting the sperm suspension directly into the
    upper uterine cavity using a small catheter
    threaded through the cervix.

32
Intrauterine insemination
  • Soft and firm catheters are both effective,
    ---the soft catheter is a little more
    difficult to use because of bending,
    -the
    firm catheter is a little more uncomfortable for
    the patient 28.
  • In natural cycle IUI, the insemination is timed
    to take place just prior to spontanteous
    ovulation, typically determined by using home
    urine luteinizing hormone (LH) measurement.

33
Intrauterine insemination
  • IUI is also frequently employed in combination
    with ovulation induction.
  • Pregnancy rates are highest when the male
    abstains from ejaculation for 48 to 72 hours
    prior to producing a specimen for IUI 29.
  • A systematic review reported that there is
    insufficient evidence to recommend one sperm
    preparation technique over another 30.

34
Intrauterine insemination
  • Thresholds for sperm count and percent normal
    morphology have also not been determined.
  • One large study of 889 couples who underwent 2564
    IUI cycles suggested IVF should be recommended
    unless at least 5 million motile spermatozoa
    could be inseminated when there was lt30 percent
    normal morphology after sperm preparation 31.
  • Others have suggested a lower threshold of 10
    million 32

35
Intrauterine insemination
  • In couples diagnosed with male infertility,
    IUI more than doubles the pregnancy rate
    compared to intracervical insemination or timed
    natural cycles 33.
  • As an example, one study of couples with mild
    male infertility reported the pregnancy rates per
    cycle for IUI versus intracervical insemination
    or timed natural intercourse were 6.5 and 3.1
    percent, respectively 34.

36
Intrauterine insemination
  • IUI also appears to be effective for couples with
    unexplained infertility.
  • In a large clinical trial sponsored by the
    National Institutes of Health (NIH), 932
    infertile couples were randomly assigned to one
    of four treatment groups 13
  • Intracervical insemination of sperm (ICI)
  • Intrauterine insemination of sperm (IUI)
  • FSH injections plus ICI
  • FSH injections plus IUI

37
Intrauterine insemination
  • The purpose of the ICI was to act as a control
    treatment mimicking natural intercourse the
    purpose of IUI was to place a large number of
    sperm high in the reproductive tract and the
    purpose of FSH injections was to stimulate
    multiple follicular development and ovulation,
    thereby increasing the number of oocytes
    available for fertilization in a single cycle.
  • Most of the women in this study had either
    unexplained infertility or early stage
    endometriosis.

38
Intrauterine insemination
  • The investigators found that the per cycle
    pregnancy rate in the group that received the
    control ICI treatment was 2 per cycle, which is
    a pregnancy rate similar to that achieved with
    expectant management.
  • IUI treatment was associated with a 5 per cycle
    pregnancy rate.
  • Therefore, IUI was clearly effective for the
    treatment of unexplained infertility.

39
Clomiphene citrate
  • Clomiphene has been demonstrated to be effective
    in the treatment of infertility due to
    oligoanovulation or anovulation.
  • A meta-analysis of 11 prospective trials of
    clomiphene treatment for women with unexplained
    infertility demonstrated clomiphene was superior
    to placebo or no treatment 35.
  • In one trial, 118 female partners from couples
    with unexplained infertility were randomly
    assigned to treatment with placebo or clomiphene
    citrate (100 mg daily, cycle days 2 to 6) 36.
  • The per cycle pregnancy rates were 5 and 7
    respectively .
  • Although the absolute treatment effect is modest,
    the low cost and low side effects of clomiphene
    make it a useful initial treatment for
    unexplained infertility.

40
Clomiphene citrate
  • The main complication of clomiphene is an
    increase in the incidence of multiple gestation.
  • In one study of 2369 clomiphene induced
    pregnancies, the incidence of twins, triplets,
    quadruplets, and quintuplets was 7, 0.5, 0.3, and
    0.13 percent, respectively 37.
  • The risk of high-order multiple pregnancies with
    clomiphene treatment is low, but the high volume
    of clomiphene cycles makes this intervention an
    important contributor to the total number of
    high-order pregnancies 38.

41
Clomiphene plus IUI
  • The combination of clomiphene (to increase the
    rate of double ovulation) plus IUI (to place a
    large number of motile sperm high in the female
    reproductive tract) may simultaneously treat mild
    abnormalities of ovulation, oocyte function, and
    sperm function.
  • In one randomized study, 67 couples were assigned
    to treatment with clomiphene plus IUI or placebo
    39.
  • The pregnancy rate per cycle was 9.5 percent for
    clomiphene plus IUI and 3.3 percent for placebo.

42
Clomiphene plus IUI
  • The optimal method for timing IUI is to use a
    commercial kit to determine daily urinary LH
    levels starting on day 10 of the cycle.
  • IUI is performed when urinary LH is detected.
  • This method is as effective, but less expensive,
    than timing based on ultrasound monitoring of
    folliculogenesis with hCG injection and IUI upon
    development of a leading follicle 40-42.
  • Clinical trials have demonstrated that when
    ovarian stimulation with clomiphene or FSH is
    combined with IUI, one IUI per cycle is as
    effective as two 43.

43
Gonadotropin injections with or without IUI
  • Gonadotropin injection can be effective in
    patients who do not conceive with clomiphene
    therapy.
  • As discussed above, a large clinical trial
    sponsored by the NIH randomly assigned 932
    infertile couples with unexplained infertility or
    early stage endometriosis to one of four
    treatment groups ICI, IUI, FSH injections plus
    ICI, or FSH injections plus IUI 13.

44
Gonadotropin injections with or without IUI
  • The pregnancy rate in the control ICI group was 2
    per cycle, while in the FSH plus ICI and the
    FSH plus IUI groups the pregnancy rate per cycle
    was 4 and 9 respectively 13.
  • Therefore, FSH plus ICI and FSH plus IUI were
    clearly effective for the treatment of
    unexplained infertility.
  • One IUI per FSH cycle is as effective as two 43.

45
Gonadotropin injections with or without IUI
  • In another study of gonadotropin injections with
    or without IUI, 62 couples with unexplained
    infertility were randomly assigned to receive IUI
    alone, gonadotropin injections alone, or
    gonadotropin injections plus IUI 44.
  • The per cycle pregnancy rate was 2.2 for IUI
    alone, 6.1 for gonadotropin injections alone,
    and 26 for gonadotropin injections plus IUI.
  • Similar results have been reported by other
    investigators, confirming the higher efficacy of
    a combined approach using both gonadotropin
    injection and IUI 45,46.

46
Gonadotropin injections with or without IUI
  • There is no convincing evidence that the addition
    of a GnRH agonist or antagonist to a
    gonadotropin/IUI cycle improves pregnancy
    outcome.
  • In one study of 91 couples randomly assigned to
    treatment with gonadotropin/IUI or a GnRH agonist
    plus gonadotropin/IUI, the pregnancy rate per
    cycle was similar in both groups (11 and 13
    percent, respectively) 47.
  • Use of a GnRH antagonist with a gonadotropin/IUI
    regimen also does not appear to improve pregnancy
    rates.

47
Gonadotropin injections with or without IUI
  • Many authorities believe that the use of
    gonadotropin injections plus IUI should be
    limited to no more than three cycles because most
    pregnancies with this treatment will occur in
    the first three cycles 49.

48
Gonadotropin injections with or without IUI
  • The main complication of the use of FSH
    injections in the treatment of infertility in
    women with unexplained infertility is an increase
    in the rates of multiple gestation and ovarian
    hyperstimulation.
  • As an example, the type and rate of multiple
    gestation in ongoing pregnancies from this study
    were quadruplets (3 ), triplets (5 ), and twins
    (20 ) 37.
  • Triplet and quadruplet pregnancy are associated
    with major maternal and fetal complications.
  • Some authorities believe that gonadotropin
    injections with or without IUI should not be
    widely used in the treatment of unexplained
    infertility because of the risk of multiple
    gestation 50.

49
In vitro fertilization
  • IVF appears useful for treatment of unexplained
    infertility.
  • A randomized clinical trial of women with
    subfertility (unexplained in 38 percent) and
    tubal patency compared IVF to expectant
    management and found a significantly increased
    pregnancy rate in couples assigned to IVF (20/68
    versus 1/71) 51.
  • A cohort study of couples with unexplained
    infertility initially treated the woman with
    gonadotropin injections plus IUI for up to three
    cycles and then used IVF to treat those who did
    not conceive 52.

50
In vitro fertilization
  • The per cycle pregnancy rate was more than twice
    as high in couples treated with IVF compared to
    those treated with gonadotropin injections plus
    IUI (37 and 16 percent, respectively).
  • Cohort studies of treatment of unexplained
    infertility with IVF with no control group have
    reported per cycle pregnancy rates of 20 to 40
    percent 53.
  • Large, comparative trials using different
    treatment modalities in couples with unexplained
    infertility are warranted 54.

51
INEFFECTIVE TREATMENTS
  • Clinical trials of the treatment of unexplained
    infertility have shown that administration of
    either bromocriptine or danazol was not effective
    55,56.

52
ECONOMIC ISSUES
  • The economic impact of medical treatments are of
    great concern in a resource limited environment.
  • One study of the cost per live birth for various
    treatments of unexplained infertility reported
    the following costs
  • clomiphene plus IUI - 10,000 per pregnancy,
  • FSH plus IUI - 17,000 per pregnancy, and
  • IVF - 50,000 per pregnancy 57.
  • This analysis supports the use of low resource
    intensive treatments prior to initiation of high
    resource intensive procedures in the treatment of
    unexplained infertility.

53
SUMMARY AND RECOMMENDATIONS
  • Unexplained infertility is a source of anxiety
    for couples desiring pregnancy.
  • One to 3 percent of these couples will become
    pregnant per cycle with no intervention.
  • Lifestyle changes may increase the pregnancy rate
    slightly, but IVF increases the per cycle
    pregnancy rate from 20 to 40 percent.
  • Useful treatments include IUI, clomiphene
    citrate, clomiphene plus IUI, gonadotropin
    injections, gonadotropin injections plus IUI, and
    IVF.
  • However, efficacy is not the only consideration
    in choosing therapy.

54
SUMMARY AND RECOMMENDATIONS
  • The approach to the treatment of unexplained
    infertility should balance the efficacy, cost,
    safety, and risks of various treatment
    alternatives and begin with low cost
    interventions and escalate over time to more
    resource intensive interventions.
  • Individual treatment steps should be recommended
    for no more than three to six months.
  • Unexplained infertility cannot be diagnosed until
    an infertile couple completes a thorough
    fertility evaluation that includes evaluation of
    ovarian oocyte reserve (day 3 FSH or clomiphene
    challenge test) and laparoscopy.

55
SUMMARY AND RECOMMENDATIONS
  • Expectant management is associated with a per
    cycle pregnancy rate of about 2 percent.
  • 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, the ovarian
    follicular pool can become depleted during
    expectant management, resulting in untreatable
    infertility.
  • Lifestyle changes, such as discontinuing
    cigarette smoking, may increase fertility in
    women with unexplained infertility.

56
SUMMARY AND RECOMMENDATIONS
  • The approach to the treatment of unexplained
    infertility should balance the efficacy, cost,
    safety, and risks of various treatment
    alternatives.
  • Treatment should begin with low cost
    interventions (lifestyle changes, IUI alone,
    clomiphene alone, and clomiphene plus IUI) and
    escalate over time to more resource intensive
    interventions (gonadotropin injections plus IUI,
    IVF).

57
SUMMARY AND RECOMMENDATIONS
  • Individual treatment steps should be recommended
    for no more than three to six months.
  • 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 58.

58
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