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

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.

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)

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.

Indications for IUI - oligospermia 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.

IUI : Step by Step Patient’s 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.

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 < 43 years ? (Day 3 FSH < 10-15 mIU/Ml, if age > 37 yrs)

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 & > 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.

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

Synchronization of the menstrual cycle Brown 1978 Intercycle FSH  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

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.

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)

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.

Monitoring ovarian stimulation Transvaginal ultrasound scanning : . No. & size of follicles . Pattern & thickness of endometrium  Estrogen blood level

Endometrial thickness & Monitoring ovarian stimulation After Zeev Shoham Correlation between E2 and endometrial thickness

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.

Sperm processing Rationale 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.

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) ??

Sperm processing Samples with an acceptable number of motile sperm ( > 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

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

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

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

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

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.

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.

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.

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.

Continued IUI beyond four trials 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

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.

Measures to minimize risk of OHSS 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 > 14 mm) does not reduce the PRs and reduce multiple pregnancy rate.

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.

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

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.

e-mail : ramoamman@yahoo.co.uk Thank You For Your Attention Dr. J.Yousef FICS,FRCOG e-mail : ramoamman@yahoo.co.uk