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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