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Unexplained infertility means that couple does not conceive after 1year of unprotected vaginal sexual intercourse, with basic infertility evaluation showing no obvious abnormality.

15%to 20% of infertile couples


Publicado en: Salud y medicina


  2. 2. Over 300 ppts are available on ***for use of public/Doctors / Lifecarecentre
  4. 4. DEFINITION • Unexplained infertility means that couple does not conceive after 1year of unprotected vaginal sexual intercourse, with basic infertility evaluation showing no obvious abnormality. • INCIDENCE 15%to 20% of infertile couples UNEXPLAINED IS PRIMARILY A DIAGNOSIS OF EXCLUSION
  5. 5. ESHERE 2000 Categorized investigation of infertility in to 3 *Direct relation with pregnancy rate **Non consistent Relation with PR eg PCT anti- sperm anti-bodies ***No Association with PR eg EB, Varicele
  6. 6. 3 BASIC INVESTIGATIONS FOR DIAGNOSIS OF UNEXPLAINED INFERTILITY • Normal basic semen analysis according to WHO criteria (WHO,2010) + semen culture • Patent fallopian tube confirmed by HSG / SSG Role of Diagnostic Laparoscopy is debated • Ovulation confirmed by mid –luteal serum Progesterone level • +follicle monitoring
  7. 7. *To be abandoned. **Missed diagnosis ( bad investigation , bad interpretation ) MANY OPINIONS about UI
  8. 8. It is essential to understand that though these tests do assist us in planning treatment, but they have their limitations.
  9. 9. • Processed total motile sperm count >10million • 24 h survival >70%,and • Normal sperm morphology of>4%(according to kruger’s criteria) • Predict good pregnancy outcome with (94%sensitivity , 86%specificity) SPERM PARAMETERS & PR
  10. 10. SEMEN ANALYSIS : HAS LIMITATIONS IN TERMS OF PREGNANCY RATE Despite the many advanced tests available for sperm function we still cannot assess the fertilizing ability of the sperm in vivo. Fertilization failures have been observed with semen showing absolutely normal characteristics as defined by WHO standards (1999 & 2010) WHO laboratory manual for the examination of human semen & sperm cervical mucus Interaction, 4th edn. Cambridge university press, cambridge 1999 WHO manual 2010
  11. 11. Tubal Patency / Day 21 Serum Progesterone • Tubal patency does not necessarily indicate normal tubal function ** a rise in progesterone in the luteal phase can occur even if the oocyte remains trapped in the follicle (luteinised un-ruptured follicle). ***In addition couples with no fertility problems may show abnormal results.
  12. 12. CAUSES OF INFERTILITY • Routine infertility assessment reveals that in approximately 30% of couples the reason for infertility lies with the male partner. • In 35% cases female factors are responsible • In 20% couple it is a combination of both • In 15 – 20 % cases the cause of infertility is unexplained.
  13. 13. THE FEMALE FACTOR The female factor includes *ovulatory dysfunction 20 to 30 %, **tubal damage 20 to 30 % , ***endometriosis 5 to 10 % & ****cervical mucus problems 5 %. In another 5% of patients infertility is related to coital problems Br Med j 291:1693-97, 1985
  14. 14. SOME HIDDEN SUBTLE , PUTATIVE ISSUES underlying UI • Poor ovarian reserve • Poor Oocyte quality: chromosomal abnormalities contribute to oocyte disorders & impaired embryonic development. • Increased chromosomal anomalies (Aneuploidies) are also found in the oocytes of older women. • Oocyte maturation arrest ( failure to complete meiosis) : it may be the cause of infertility in some couples previously classified as having unexplained infertility.
  15. 15. POSSIBLE FACTORS FERTILIZATION Problems with fertilization are identified during conventional IVF only like defective sperm – poor zona binding & zona penetration, failure of oocyte activation may result in failure of fertilization.
  16. 16. POSSIBLE ENDOMETRIAL FACTOR • The endometrium has been extensively studied in the implantation phase to try & identify molecular & biochemical marker of implantation key adhesion molecules, certain biochemical marker & gene expression which are Not near normal OR • Endometrial Vascular Changes OR • Genetic Factor
  18. 18. MANAGEMENT OF UI Unexplained subfertility creates some complexity in management mainly because of the lack of a specific , & potentially treatable abnormality. The treatment is generally Empirical.
  19. 19. Management of UI *CONSERVATIVE T T* Technically a couple is said to have UI if they have not conceived within a year of trying & investigations. • It has been observed that about 40 – 65% of couple with UI conceive within three year without active management. • After 39 months the chances of conception fall by 2% every month, a decrease of about 10% for additional year of infertility.
  20. 20. *EXPERTS…..PLEA FOR CONSERVATIVE TREATMENT IF YOUNG* It has been suggested that treatment should be deferred for 3 years if the woman’s age is below 35 years.
  21. 21. Age & duration of infertility are the two most important prognostic factor The rate at which treatment progresses, depends on the *Age of the patient, **The duration of infertility & ***The level of anxiety of the couple the couple can become TOP spoiling game
  22. 22. PREGNANCY RATES IN UNEXPLAINED INFERTILITY Method Pregnancy rate (%) INTERCOURSE (TIMED) 4 (follicular monitoring) Iui 6 ----------do--------- Cc 6 ----------do--------- CC+IUI 8 FSH / HMG 7.7 CC/FSH/IUI 9-12 FSH / HMG / IUI 17-20% IN-VITRO- FERTILIZATION 20 to maximum 30
  23. 23. UNEXPLAINED INFERTILITY CONCLUSIONS : In stimulated cycles PR was higher with IUI compared to timed intercourse. & COH + IUI is far better than IUI alone
  24. 24. THE TREATMENT CARRIED OUT for UI ARE AS FOLLOWS: • Ovulation induction • Ovulation induction with intrauterine insemination (IUI) • IVF ( in-vitro fertilization) & IVF / ICSI
  25. 25. Ovulation induction The rationale behind using ovulation induction as a treatment for UI is , that it A. increases the number of oocytes available for fertilization B. Allow correction of luteal phase defect ,& C. Corrects subtle defects on ovarian function Drugs used for ovulation induction include *Clomiphene citrate (CC), *Letrozole & *Gonadotrophins
  26. 26. CLOMIPHENE CITRATE (CC) although the absolute treatment effect is small, given the low cost & ease of administration … clomiphene citrate appears to be a sensible first choice treatment for women with unexplained infertility. Treatment with CC should not be extended beyond six cycles because of endometrial receptor depletion , concern about risk of ovarian cancer & multiple pregnancy
  27. 27. GONADOTROPINS Controlled ovarian stimulation (COS) with gonadotropins +IUI has shown to increase the pregnancy rate significantly in women with more that 3 years of UI. The therapy also resulted in a significant increase in multiple pregnancy rate 18% Good pregnancy rates of approximately 20% have been reported with this regime + IUI
  28. 28. Atahulla et al 2002 Last word on which agent for OI is far away conducted a study to assess the efficacy of oral versus injectable ovulation induction agents for unexplained sub- fertility. They concluded that there was insufficient evidence to suggest that oral agents were either inferior or superior to injectable agents in the treatment of unexplained sub- fertility & recommended larger trials. COCHRANE.. Data base 2002
  29. 29. PREGNANCY RATES IN UNEXPLAINED INFERTILITY Method Pregnancy rate (%) INTERCOURSE (TIMED) 4 (follicular monitoring) Iui 6 ----------do--------- Cc 6 ----------do--------- CC+IUI 8 FSH / HMG 7.7 CC/FSH/IUI 9-12 FSH / HMG / IUI 17-20% IN-VITRO- FERTILIZATION 20 to maximum 30
  30. 30. INTRAUTERINE INSEMINATION Intrauterine Insemination (IUI) is used both in stimulation & un-stimulation cycles. The rationale of IUI being that an enhanced preparation of motile sperms is deposited as close to the oocyte as possible. The cervical mucus barrier is bypassed & there is an additional psychological benefits that the infertility is being treated.
  32. 32. •Factors related to couples • Factors related to therapy FAVOURABLE PREDICTORS OF IUI OUTCOME
  33. 33. A. COUPLE : • Female age < 35y , Male < 40 yrs • Shorter duration of infertility (< 5 yrs) **************************************** • Type of Infertility Pregnancy Rate • Primary inf. 7.9% • Secondary 21.4
  34. 34. Higher PR with : • Unexplained infertility (12%-22%) • Ovulatory dysfunction (19-20%) *************************************************** Modest PR- cervical factor (16.4%) ********************************** Poor PR: • Endometriosis(11.9%) • Immunological infertility (10%) • with ejaculatory disorders (13.3%) (bourn hall clinic.1999:tay et al 2007: Wang al 2oo8) Cause of infertility & Pregnancy Rate/cycle :
  35. 35. Effectiveness of IUI in treatment of unexplained infertility 12..22%
  36. 36. GONADOTROPIN THERAPY WITH IUI No doubt that Gonadotropin therapy with IUI is superior to no treatment in UI But has so far not been proven to be superior to CC + IUI in UI
  37. 37. UNEXPLAINED INFERTILITY & INTRAUTERINE INSEMINATION Ovarian Stimulation + IUI has “grade A evidence to confirm its effective use in UI.
  38. 38. Meta – Analysis , Published in ‘Human Reproduction’ In a meta – analysis conducted by Hughes it was concluded that COS or IUI alone increased the possibility of pregnancy two – fold but when both were combined the fecundity increase FIVE – FOLD . Pregnancy rates are around 20% & the risk of multiple pregnancy is also around 20%.
  39. 39. ESHRE CAPRI WORKSHOP GROUP • COH/IUI is indicated as empiric treatment for all categories of unexplained infertility • 20% of couple after initial work –up. • Couple with mild male subfertility (20- 40%) • 50% of those in whom conventional treatments have failed.
  40. 40. NICE GUIDELINE 2013 For people with : •Unexplained infertility, •Mild endometriosis or •Mild male factor infertility , Who are having regular unprotected sexual : Advise them to try to conceive for a total of 2 years before IVF will be considered.
  41. 41. Opinions & Practices • Pregnancy resulting from IUI occur during the first 3-4 treatment cycles (88-95%; respectively) • Aboughar et al 2001 suggested maximum of 3 COH/IUI cycles for treatment of unexplained infertility. • However ,others recommended up to 6 cycles
  43. 43. IUI & IVF FOR UNEXPLAINED INFERTILITY • Starting treatment with IUI rather than IVF was either cheaper or more cost –effective than IVF in unexplained infertility (goverde et al ..2000)
  44. 44. IN- VITRO FERTILIZATION In vitro fertilization is now a widely accepted treatment for unexplained infertility after NICE GUIDELINES 2013 Since live birth rates per cycle is low , varying between 13 & 30% & the cost of treatment very high, one needs to evaluate it in comparison with other treatment in UI
  45. 45. IUI & IVF FOR UNEXPLAINED INFERTILITY Cochrane, 2012 • IVF may be more effective than IUI+COH. (pandian et al 2012) Due to lack of data from RCT s the effectiveness of IVF for unexplained infertility relative to expectant management ,clomiphene citrate and IUI alone remains unproven.
  46. 46. PLACE OF IVF & ICSI IN UI Studies indicate that IVF is superior to FSH & IUI but this benefits is achieved at a considerable cost . IVF being at least 10 times more expensive than OI+IUI (in India) in couples with unexplained infertility a higher fertilization rate was achieved through ICSI compared with conventional IVF fertility steril 77(2):229-32,2002
  47. 47. USE OF BROMOCRIPTINE for UI Bromocriptine improves hyperprolactinaemic amenorrhoea & so could also be helpful in the treatment of unexplained sub-fertility in woman.
  48. 48. TAKE HOME MASSAGES FOR STRATEGY FOR TREATMENT OF UI To plan a strategy one has to balance effectiveness as opposed to invasiveness & cost – effectiveness of the various therapeutic options.
  49. 49. “Proceed from Low – tech to high – tech treatment”, but it is not convincing enough to support a rigid management protocol Hum reprod 18(5) : 907-12,2003 MASSAGE 1
  50. 50. It is essential to give the couple a realistic appraisal of their chances of pregnancy with & without treatment & also to counsel them fully about the risk & side effects of various therapies. MASSAGE 2
  51. 51. In conclusion expectant treatment is the option of choice for young patients with short period of infertility. MASSAGE 3 The spontaneous pregnancy rate is very high in this group of patients.
  52. 52. MASSAGE 4 Evidence suggests that active treatment should be deferred till the couple has tried for THREE YEARS. It is virtually impossible to enforce this in practice when faced with a distressed couple seeking help. THE AGE OF THE FEMALE should be a major factor in decision making & more aggressive treatment may be warranted after the age of 35.
  53. 53. • Evidence shows that treatment with clomiphene is better than no treatment at all. • Gonadotropins & IUI should be used by experts even though it has not proven superior to CC/ IUI. MASSAGE 5
  54. 54. According to the available data , this procedure could be limited to 3 to 4 COH+ IUI. There is evidence that both COH & IUI are important independent positive factor in achieving better pregnancy rate in unexplained infertility. • The treatment effects optimize in 4 IUI cycles & therefore if a couple has not conceived , IVF should be considered next. MASSAGE 6
  55. 55. Whether IVF improve the chances of conception over other treatment has still not been established conclusively but it has an additional advantage of acting as a Diagnostic Tool. MASSAGE 7 Couples with UI may have sperm, oocyte or fertilization defects that will only be discovered during IVF.
  56. 56. IVF/ICSI should be performed in unexplained infertility as it yields a high pregnancy rate as compared to IVF . GIFT is too invasive a procedure & since the results are poorer than IVF it is rarely used Arch gynecol obstet 267(4):177-88,2003, MASSAGE 8
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