MANAGEMENT OF INFERTILITY CURRENT GUIDELINES

1. MANAGEMENT OFINFERTILITYCURRENT GUIDELINES

2. OBJECTIVES To present the recent concepts in the management of infertility To draw clinically relevant conclusions based on: META-ANALYSIS RANDOMISED CONTROLLED TRIALS GUIDELINES AND PROTOCOLS To discuss the best possible clinical management options with local perspective

3. BACKGROUND INFORMATION At puberty there are 300,000 primordial follicles Dominant follicle produces oestradiol which leads to LH surge Ovulation occurs 24-36 hours later The fertilization life span of the ovum is 24-36 hours The receptivity of the endometrium is days 16-19 of a 28 day cycle

4. BACKGROUND INFORMATION Infertility is rarely absolute so the term sub-fertility may be more appropriate About 84% of couples would conceive within one year of trying for a pregnancy Another 8% would conceive in the next year giving a cumulative pregnancy rate of 92% at the end of two years Subfertility is defined as the inability to conceive within 12-24 months of trying

5. BACKGROUND INFORMATION The single most important determinant of a couple’s fertility is the age of the female partner: At the age of up to 25 years CCR is 60% at six months and 85% at one year At the age of 35 years or more the CCR is 60% at one year and 85% at two years

6. BACKGROUND INFORMATION The other factors influencing the likelihood of a spontaneous pregnancy are: Duration of subfertility Occurrence of a previous pregnancy The effect of age on male fertility, however is less clear Any change in the prevalence of subfertility in recent years is a difficult question to answer but the male fertility is declining

7. CURRENT GUIDELINES The current clinical approach to the investigations and the management of infertility is backed by the evidence-based guidelines issued by: Royal College of Obstetricians and Gynaecologists (RCOG) American Society of Reproductive Medicine (ASRM) European Society of Human Reproduction and Embryology (ESHRE)

8. INVESTIGATIONS The male partner should normally have two semen analyses performed during the initial investigation. Laboratories that perform semen analysis should undertake this according to recognised WHO methodology. Laboratories should also practice internal quality control and belong to an external quality control scheme .

9. INVESTIGATIONS While regular menstruation is strongly suggestive of ovulation, this should be confirmed by the measurement of serum progesterone in the mid-luteal phase There is no value in measuring thyroid function or prolactin in women with a regular menstrual cycle, in the absence of galactorrhoea or symptoms of thyroid disease

10. INVESTIGATIONS Early follicular phase estimation of FSH and LH is only performed if clinically indicated The female partner should normally have a test of tubal patency during the initial investigation of infertility

11. INVESTIGATIONS A hysterosalpingogram may be used as a screening test for tubal patency in low risk couples When an evaluation of the pelvis is required, however, a diagnostic laparoscopy with dye transit is the procedure of choice

12. INVESTIGATIONS Ultrasound scan and hydrotubation has not been widely adopted. The images obtained by falloposcopy are not yet of sufficiently good quality to provide useful clinical information.

13. INVESTIGATIONS Before any uterine instrumentation, consideration should be given either to screening women for Chlamydia trachomatis, using an appropriately sensitive technique, or using appropriate antibiotic prophylaxis .

14. INVESTIGATIONS Endometrial biopsy to evaluate the luteal phase should not be performed as part of the routine investigation of the infertile couple The postcoital test is not recommended in the routine investigation of the infertile couple Sperm function tests are specialised tests and should not be used in the routine investigation of the infertile couple .

15. INVESTIGATIONS Routine testing for antisperm antibodies in semen is not recommended Hysteroscopy should not be considered as a routine investigation in the infertile couple as there is no evidence linking the treatment of uterine abnormalities with enhanced fertility An ultrasound examination of the endometrium is unnecessary in the initial investigation of infertility. However, ultrasound evaluation of the ovaries may be useful

16. DIAGNOSIS OF PCOS The debate was resolved in Rotterdam in May 2003 At PCOS consensus workshop It was agreed that two of the following three criteria were essential to establish diagnosis: OVARIAN DYSFUNCTION CLINICAL OR BIOCHEMICAL EVIDENCE OF HYPERANDROGENISM POLYCYSTIC OVARIAN MORPHOLOGY ON ULTRASOUND

17. DIAGNOSIS OF PCOS Ultrasound is the gold standard for the diagnosis of PCO. The diagnostic criteria is of 10 discrete follicles of <10mm usually peripherally arranged around an enlarged, hyperechogenic central stoma

18. WHICH INVESTIGATIONS? Diagnostic tests for infertility were classified into following three categories by ESHRE Capri workshop in 2000 Tests which have an established correlation with pregnancy Tests which are not consistently correlated with pregnancy Tests which seem NOT to correlate with pregnancy

19. Tests which have an established correlation with pregnancy Semen analysis Tubal patency test by HSG or Laparoscopy Mid luteal serum progesterone for the diagnosis of ovulation

20. Tests which are not consistently correlated with pregnancy Zona free hamster egg penetration tests Post-coital test Antisperm antibodies assays

21. Tests which seem NOT to correlate with pregnancy Endometrial dating Varicocoel assessment Chlamydial testing MAY HAVE A ROLE IN SPECIAL SITUATIONS

22. MANAGEMENT The management of infertility should take place in a dedicated infertility clinic staffed by an appropriately trained professional team with facilities for investigating and managing problems in both partners.

23. MANAGEMENT Both partners should be seen together Privacy and sufficient clinical time Classical history taking with emphasis on exploring a couple’s anxieties Counseling is very important and essential Routine examination is not necessary unless indicated by the history

24. MANAGEMENT Each stage in the investigation and treatment of infertility should be fully explained to the couple. Written information in a range of languages should be available where appropriate. Environmental factors can affect fertility and therefore an occupational history should be taken.

25. MANAGEMENT The management of the individual couple should always be discussed in the context of their particular clinical situation. Patients should be fully involved in decisions regarding their treatment. Couples should also have access to infertility counselors outside the clinical team, and to patient support groups

26. GENERAL ADVICE TO THE COUPLE Sexual intercourse every 2-3 days Timed intercourse to coincide with ovulation causes stress and not to be recommended Smoking reduces both, women’s fertility as well as semen quality Excessive alcohol is detrimental to semen quality and may cause erectile dysfunction

27. GENERAL ADVICE TO THE COUPLE A body mass index of more than 29 is associated with reduced fertility in both men and women Folic acid supplement prior to conception and up to 12 weeks of conception Rubella immunity should be checked If vaccinated then advise to avoid pregnancy for at least one month after vaccination

28. MALE INFERTILITY In considering the results of semen analysis for the individual couple, it is important to take into account the duration of infertility, the woman’s age and the previous pregnancy history . Further investigations of the male partner should be preceded by a clinical examination including an assessment of secondary sexual characteristics and testicular size .

29. MALE INFERTILITY Further investigations of the male partner may include endocrine tests, microbiological assessment of the semen and imaging of the genital tract but should be initiated in the context of a specialist infertility clinic. Laboratories reporting semen analysis results should establish normal ranges for their own populations and indicate these on report sheets .

30. MALE INFERTILITY Certain in vitro tests of sperm function can be of use in predicting fertility . However, at this stage, their use and interpretation should be restricted to those few centres with relevant expertise. Surgery on the male genital tract should be carried out only in centres where there are appropriate facilities and trained staff.

31. MALE INFERTILITY Testicular biopsy should be performed only in the context of a tertiary service where there are facilities for sperm recovery and cryostorage. Vasectomy reversal is an effective treatment for men who want to reverse their sterilisation. Surgical correction of epididymal blockage can be considered in cases of obstructive azoospermia. Where a diagnosis of hypogonadotrophic hypogonadism is made in the male partner the use of gonadotrophin drugs is an effective fertility treatment.

32. MALE INFERTILITY Bromocriptine is an effective treatment for sexual dysfunction in men with hyperprolactinaemia. Intrauterine insemination is an effective treatment where the man has mild abnormalities of semen quality. Infection of the male genital tract should be treated if present, but there is no evidence that this will improve fertility.

33. MALE INFERTILITY Anti-oestrogens, androgens, bromocriptine and kinin-enhancing drugs have not been shown to be effective in the treatment of Male infertility Antioxidants, mast cell blockers and alpha blockers need further evaluation. The use of systemic corticosteroids for treatment of antisperm antibodies can only be recommended in the context of further research.

34. MALE INFERTILITY There is no evidence that semen quality and pregnancy rates improves in men with normal sperm count after surgical treatment of a clinically apparent varicocele The benefits of the treatment of a varicocele in oligozoospermic men is less certain

35. MALE INFERTILITY IVF and ICSI are effective treatments for men with moderate to severe semen abnormalities ICSI has made it possible for men with only few sperms to become fathers Sperms for ICSI can be obtained by TSA are directly from testicular biopsy as well as aspiration from epididymus

36. TUBAL INFERTILITY Tubal surgery should be carried out only in centres where there are appropriate facilities and trained staff. Where proximal tubal obstruction is suspected this should be confirmed by selective salpingography and a tubal catheterisation procedure may be attempted. Tubal surgery may be appropriate for selected cases of mild distal tubal disease or proximal tubal obstruction. If pregnancy has not occurred within 12 months of tubal surgery, IVF should be discussed .

37. TUBAL INFERTILITY When distal tubal surgery is performed, a microsurgical approach using magnification should be used. A laparoscopic approach can be used for adhesiolysis but the use of this approach for salpingostomy needs more evaluation . IVF should be considered as the first line treatment for moderate to severe distal tubal disease .

38. TUBAL INFERTILITY The presence of hydrosalpinges is associated with reduced pregnancy rates following IVF. Tubal reanastomosis is an effective treatment for women who want to reverse their sterilisation. High success rates can be achieved when reversing mechanical tubal occlusion using a microsurgical approach .

39. TUBAL INFERTILITY IVF should be considered first line treatment for moderate to severe tubal disease Both surgery and IVF should be discussed without bias There is no randomised comparison between IVF and tubal surgery

40. OVULATION DISORDERS Before ovulation induction is considered, further investigations will be necessary and these should be carried out only in a specialist clinic . In undertaking ovulation induction, centres should adopt protocols which minimise the risk of multiple pregnancy and ovarian hyperstimulation .

41. OVULATION DISORDERS Patients undergoing ovulation induction must be given information about the risks of multiple pregnancy, ovarian hyperstimulation and the possibility of fetal reduction.

42. OVULATION DISORDERS Clomiphene is an effective treatment for anovulation in appropriately selected women Cumulative Pregnancy Rate continues to rise until ten cycles of treatment. RCOG recommends that up to 12 cycles of treatment should be considered Ovulation induction with clomiphene should only be performed in circumstances which allow access to ovarian ultrasound monitoring.

43. OVULATION DISORDERS With clomiphene ovulation occurs in 70-80% and the cumulative rate over six months is 60% Seventy percent achieve pregnancy at doses of 100 mgs or less Most evidence point towards less pregnancy rate above 100 mgs.

44. OVULATION DISORDERS FSH and hMG are both effective for ovulation induction in women With clomiphene-resistant polycystic ovarian syndrome (PCOS). There is no advantage in routinely using gonadotrophin-releasing hormone analogues in conjunction with gonadotrophins for ovulation induction in women with clomiphene-resistant PCOS. Furthermore, their use may be associated with an increased risk of ovarian hyperstimulation .

45. OVULATION DISORDERS Laparoscopic ovarian drilling with either diathermy or laser is an effective treatment for anovulation in women with clomiphene-resistant PCOS. However, more research is needed into the sequelae of causing ovarian damage in this way. The pulsatile administration of gonadotrophin-releasing hormone is an effective treatment for women with anovulation due to hypothalamic factors.

46. OVULATION DISORDERS Dopamine agonists are effective treatment for women with anovulation due to hyperprolactinaemia Ovulation induction with gonadotrophins should only be performed in circumstances which permit daily monitoring of ovarian response . The criteria for abandoning ovulation induction cycles must be carefully defined in each specialist centre.

47. OVULATION DISORDERS The association between ovarian cancer risk and gonadotrophins or prolonged clomiphene use remains uncertain. There is no evidence to suggest an increased risk of ovarian cancer when clomiphene is used for less than 12 cycles. Patients should be counseled about the putative risks of ovarian cancer associated with ovulation induction therapy. Practitioners should confine the use of gonadotrophins to the lowest effective dose and duration of use .

48. ENDOMETRIOSIS ASSOCIATED INFERTILITY Endometriosis should be classified using the revised AFS system of classification, until such time as a proven functional classification is approved . Surgical ablation of minimal and mild endometriosis improves fertility in subfertile women. Medical treatment of minimal and mild endometriosis does not enhance fertility in subfertile women

49. ENDOMETRIOSIS ASSOCIATED INFERTILITY Ovarian stimulation with intrauterine insemination is more effective than either no treatment or lUl alone in subfertile women with minimal or mild endometriosis. There is no evidence that medical treatment of moderate and severe endometriosis either alone or as an adjunct to surgery improves fertility. Surgical treatment of moderate and severe endometriosis may improve fertility but controlled studies and comparisons with assisted reproduction techniques are required.

50. ENDOMETRIOSIS ASSOCIATED INFERTILITY In cases of moderate and severe endometriosis, assisted reproduction techniques should be considered as an alternative to, or following unsuccessful surgery. Where large ovarian endometriotic cysts are detected, consideration should be given to their surgical treatment because this may enhance spontaneous pregnancy rates and improve access if IVF is considered.