AIH

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Intrauterine insemination
In the Management of Subfertile Couples
Dr. JEHAD YOUSEF FICS, FRCOG ALHAYAT ART CENTER
AMMAN JORDAN
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Objectives of the Presentation

• To examine the current indications, clinical and
  laboratory methodologies used in IUI and the
  impact of female and male factors on success.
• Emphasis is centered in questioning the
  following - The value of IUI against
  timed intercourse. - IUI
  application with or without COH.
  -
  Timing and frequency of IUI.
• - Impact of various parameters on success.

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Artificial Insemination (A.I.H)

• Intra-vaginal insemination (IVI)
• Intra-cervical insemination (ICI)
• Intrauterine insemination (IUI)
• Fallopian tube sperm perfusion (FSP)
• Sperm Intra-fallopian insemination (SIFI)
• Direct Intra-peritoneal insemination (DIPI)
• Intra-follicular insemination (IFI)

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Intrauterine Insemination

• The rationale is that increasing the density of
  both eggs and sperm near the site of
  fertilization will increase the likelihood of
  pregnancy.

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Indications for IUI

• The impossibility of vaginal ejaculation
• - psychogenic or organic impotence
• - severe hypospadias, retrograde ejaculation
• - cry preservation of sperm in cases of cancer
  treatment.

• Abnormal male factor
• - oligospermia
• - asthenospermia
• - teratospermia
• Unexplained infertility
• Cervical factor infertility
• Husband is away from wife for long time (work
  abroad)
• HIV negative women with processed semen of HIV
  ve husband.

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IUI Step by Step

• Patients selection
• Natural cycle or
• Controlled Ovarian stimulation.
• Monitoring of treatment, to measure the growth of
  follicles, individualize drug doses, and prevent
  hyper stimulation.
• Sperm preparation
• Insemination
• Luteal support.

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Selection of patients

• A Valid indication for IUI
• Normal or mildly abnormal semen parameters (Semen
  analysis within 3 months of the planned IUI)
• No evidence of intrauterine disease and patent
  tubes (at least one) as
  shown in a Recent HSG or (laparoscopy /
  hysteroscopy)
• Female age lt 43 years ?
  (Day 3 FSH
  lt 10-15 mIU/Ml, if age gt 37 yrs)

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Protocol of natural cycle IUI

• Monitoring begins 16 days before expected menses
  by TVS for follicular maturation.
• Once a mature sized follicle of 18-24 mm gt 9mm
  trilaminar endometrium are obtained the woman
  will monitor urinary LH every 4-5 hours.
• Intrauterine insemination is timed 36-40 hours
  from the LH surge and will be repeated within 12
  hours if the oocyte had not released as yet.

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Controlled ovarian hyperstimulation before IUI
The rationale
? Number of oocytes available ( ? chance
of fertilization ) ? Steroid production
( ? chance of implantation ) It may correct
subtle ovulatory disorders, such as luteinized
unruptured follicle syndrome, not detected with
routine diagnostic studies More exact time to
ovulation and insemination can be determined
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Synchronization of the menstrual cycle
Brown 1978
ovulation

• Menses is the marker for onset of
  uterine/endometrial cycle.
• inter-cycle ?FSH is the marker for functional
  onset of ovarian cycle.
• Only those antral follicles which coincide with
  the inter-cycle rise in
• FSH can enter the final stages of follicular
  growth

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Synchronization of the menstrual cycle

• Controlling the timing of occurrence of
  inter-cycle increase in FSH
• Timely use of E2 (2 mg estradiol valerate, PO
  BID starting 3 days before the onset of menses of
  the previous cycle.
• Short-term use of the OC pill for 7 to 21 days in
  the cycle preceding stimulation cycle.

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Ovarian Stimulation Protocols

• Clomiphene citrate or similar drugs
• u-hMG or highly purified u-hMG
• Purified u-FSH or highly purified u-FSH
• Recombinant (r-FSH)
• Combinations
• --------------------------------------------------
  --------------------
• GnRH agonists in combination with hMG and/or FSH
  (long, short or ultra short protocol)
• GnRH antagonists in combination with hMG and/or
  FSH (fixed or variable protocol)

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Which ovarian stimulation to chose before
intra-uterine insemination?

• Drug Cost Drug availability and Patient
  acceptability
• CC is an effective alternative for young women
  with good prognosis, whereas in the remaining
  cases hMG or FSH would be the preferable drug.
• rFSH Vs Urinary preparations No difference in
  clinical pregnancy rate.
• There is no advantage in routinely using GRh-a in
  conjunction with gonadotrophins for ovulation
  stimulation
• At the moment one should use the least expensive
  medication.

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Monitoring ovarian stimulation
?Transvaginal ultrasound scanning . No.
size of follicles . Pattern thickness of
endometrium ? Estrogen blood level
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Endometrial thickness Monitoring ovarian
stimulation
n 183
After Zeev Shoham
Correlation between E2 and endometrial thickness
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Optimum ovarian stimulation For IUI

• 2 - 4 follicules with Ø 18 19 mm.
• Estradiol blood level
• 150-250 pgm / ml per ? 15 mm follicle.
• Endometrium ? 9 mm thick trilaminar.
• IUI between Cycle D13 and D16.
• Cancellation
• ? 6 follicles ? 15 mm irrespective of E2 level
• Estradiol ? 1500 pg/ml.

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Sperm processingRationale

• Concentration of progressively motile and
  morphologically normal spermatozoa into a small
  volume of culture fluid.
• Elemination of seminal PG, lymphokines, cytokines
  and infectious agents
• Reduce the number of free oxygen radicals.

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Sperm processing

• Simple Sperm wash
• Swim-up following sperm wash once or twice.
• Density gradient column separation (filtration in
  Percoll gradients, PureSperm or Isolate).
• Adding chemicals to the washed sperms (caffeine ,
  pentoxyfylline, 2-deoxyadenosine, kallikrien,
  bicarbonate, platelet activating factor) ??

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Sperm processing

• Samples with an acceptable number of motile sperm
  ( gt 20 millions / ml ) can be processed
  efficiently by sperm wash twice and swim-up.
• Poor quality semen samples should be processed
  using density gradient centrifugation DGC.

Morshedi M et al, 2003
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Timing and Frequency of IUI
Fixed protocol Single insemination 36
40 hrs post hCG double insemination
within 12 48 hrs post - hCG Variable
protocol TVS 36 h post hCG- Ovulated ?
single IUI - Not Ovulated? IUI at
once ? IUI 24
hrs later
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IUI technical aspects

• Partially filled urinary bladder lithotomy
  position abdominal US
• Gently and atrumatically clean the cervix with
  saline soaked swab ?
• introduce IUI catheter through cervix no
  touch to fundus
• Slowly inject 0.3-.05 ml of processed semen
• Slowly withdraw catheter

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Management following IUI

• Bed rest
  
  A 10 minutes bed rest after IUI has a positive
  effect on PR.
• Intercourse within 12-18 hours of IUI.
• Luteal phase support, OPTIONS
• - hCG 1.500 IU hCG 3 6 days after 1st hCG
• - Duphastone 10 mg PO / 8 hourly after IUI x
  14 days
• - Cyclogest 400 mg supp. PV or PR once
  daily after IUI x 14 days
• - Utrogestan 100 mg PV / 8 hourly after IUI
  x 14 days

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Evidence based recommendations for practicing IUI
Grade A recommendations
NICE Guidance Feb. 2004

• Couples with mild male factor fertility problems,
  unexplained fertility problems or minimal to mild
  endometriosis should be offered up to six cycles
  of intra-uterine insemination because this
  increases the chance of pregnancy.

Grade A based on randomised controlled trials
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Evidence based recommendations for practicing IUI
Grade A recommendations
NICE Guidance Feb. 2004

• Where intra-uterine insemination is used to
  manage male factor fertility problems, ovarian
  stimulation should not be offered because it is
  no more clinically effective than unstimulated
  intra-uterine insemination and it carries a risk
  of multiple pregnancy.

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Evidence based recommendations for practicing IUI
Grade A recommendations
NICE Guidance Feb. 2004

• Where intra-uterine insemination is used to
  manage unexplained fertility problems, both
  stimulated and unstimulated intra-uterine
  insemination are more effective than no
  treatment. However, ovarian stimulation should
  not be offered, even though it is associated with
  higher pregnancy rates than unstimulated
  intra-uterine insemination, because it carries a
  risk of multiple pregnancy.

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Evidence based recommendations for practicing IUI
Grade A recommendations
NICE Guidance Feb. 2004

• Where intra-uterine insemination is used to
  manage minimal or mild endometriosis, couples
  should be informed that ovarian stimulation
  increases pregnancy rates compared with no
  treatment, but that the effectiveness of
  unstimulated intra-uterine insemination is
  uncertain.

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Evidence based recommendations for practicing IUI
Grade A recommendations
NICE Guidance Feb. 2004

• Where intra-uterine insemination is undertaken,
  single rather than double insemination should be
  offered.
• Where intra-uterine insemination is used to
  manage unexplained fertility problems, fallopian
  sperm perfusion for insemination (a large-volume
  solution, 4 ml) should be offered because it
  improves pregnancy rates compared with standard
  insemination techniques.

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Number of trials of IUI ?

• Pregnancies resulting from IUI occur during early
  treatment cycles.
• Eighty-eight percent of pregnancies occur in
  the first three cycles of IUI and 95.5 within
  the first four cycles (Morshedi M et al, 2003).
• Continued IUI beyond four trials
• is not recommended

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Measures to improve results

• Use of Aspirin in IUI Cycles Hsieh YY et al, 2000
  RCT
  Higher pregnancy rate and better
  endometrial pattern were achieved in patients
  with thin endometrium after aspirin
  administration.
• Type of catheter Smith et al, 2002, RCT
• No difference in PR when using softer
  Wallace catheter or the less pliable Tomcat
  catheter
• Vaginal misoprostol at the time IUI Brown et al.
  2001 RCT
• 200 - 400 µg of misoprostol vaginal
  insertion at the time
• of insemination is associated with higher
  PR.

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Measures to minimize risk ofOHSS

• Shalev E, et al, 1995 RCT
  
  s.c. injection of 0.1 mg GnRHa
  (decapeptyl) instead of hCG in IUI treatment
  cycles at high risk of OHSS.
• De Geyter, et al 1996 RCT
  
  Transvaginal aspiration of supernumerary
  follicles (more than three follicles sized gt 14
  mm) does not reduce the PRs and reduce multiple
  pregnancy rate.

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What is the upper age limit for IUI ?

• Most studies have suggested that it is an
  effective treatment option for women under the
  age of 40 yrs

Success of intrauterine insemination, in women
aged 40-42 years, Hawbe, et al, Fertility and
Sterility, Vol 78, No 1, July 2002

• These researchers found in their review that it
  may be
• a reasonable approach for women under the age of
  43.

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Where IUI should be done?

• Although IUI can be performed in an optimized
  office but Patients need to run from gynecologist
  to the lab. ? Fragmented care because of poor
  coordination.
• Ideally in an optimized clinic in cooperation
  with an IVF unit
• - IVF choice Freezing any extra embryos in
  case of over-response
• - ? Selective follicular reduction in case
  of over-response

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SUMMARY

• IUI is relatively simple, non-invasive, cheap
  easily repeatable.
• Careful selection of patient is important.
• There is good evidence in the literature in favor
  of IUI as a cost-effective treatment for
  unexplained and mild, moderate male factor sub
  fertility.
• Although it may take relatively more treatment
  cycles to achieve pregnancy, there are
  considerable advantages to the patient in terms
  of risk / benefit ratio and financial cost as
  compared with other ARTs.
• Failure of 4 - 6 trials of Gn. stimulated IUI in
  unexplained or mild male infertility, is an
  indication for IVF.

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Thank You For Your Attention
Dr. J.Yousef FICS,FRCOG e-mail
ramoamman_at_yahoo.co.uk