Evidence based infertility management

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Our practice should be based on evidence but how to track all evidence: this talk may help in this

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Evidence based infertility management

  1. 1. ‫ا‬ ِ‫ن‬ َٰ‫م‬ْ‫ح‬‫ه‬‫ر‬‫ال‬ ِ ‫ه‬‫اَّلل‬ ِ‫م‬ْ‫س‬ِ‫ب‬ِ‫يم‬ ِ‫ح‬‫ه‬‫لر‬
  2. 2. EVIDENCE BASED INFERTILITY TREATMENT kasr al ainy school of Medicine Cairo University
  3. 3. OUTLINE OF THIS TALK  EBM : Introduction  Model of creating evidence : RCT  Model of creating evidence : Systematic review  Economic evaluation  Prognosis  Others
  4. 4. EBM  Clinical medicine is currently in transition from experience-oriented practice to an evidence-based one which requires the best available evidence that answers our clinical questions
  5. 5. EBM - WHAT IS IT? Clinical Expertise Research Evidence Patient Preferences
  6. 6. EVIDENCE THAT MATTERS  Meaning focusing the efforts to find evidence that is more practical and useful to the patient patient-oriented evidence For infertility : Conception
  7. 7. IS ALL EVIDENCE CREATED EQUAL!!
  8. 8. RCT ANATOMY Participants RandomlyAssigned Intervention Group Control Group Follow-up Follow-up Intervention Group Control Group
  9. 9. 9 PICO Patient woman, 34 years, 2ys 1ry unexplained inf. Intervention IUI Comparison wait Outcome Pregnancy
  10. 10. months to ongoing pregnancy 363024181260 Cumulativeongoingpregnancyrate 1,0 0,8 0,6 0,4 0,2 0,0 IUI-censored exp-censored IUI exp exp=1, IUI=2 -- delayed treatment -- early treatment RR: 1,0 (CI: 0,86-1,2) N= 90 (71%) N= 90 (71%)
  11. 11. OUTLINE OF THIS TALK  EBM : Introduction  Model of creating evidence : RCT  Model of creating evidence : Systematic review  Economic evaluation  Prognosis  Others
  12. 12. MODEL OF RCT : REVERSED HMG/CC PROTOCOL
  13. 13. CURRENT PRACTICE OF O.I IN IUI Clomiphene Citrate hMG or FSH ______________________________________________
  14. 14. EMERGING PROTOCOL: REVERSED HMG/CC Clomiphene Citrate hMG or FSH ______________________________________________
  15. 15. Some cases are CC resistant  about 25% of IUI cycles suffer from premature LH surge cancellation. WHY
  16. 16. RATIONAL its antiestrogenic effect may suppress premature LH rise while maintaining a positive influence on ovarian follicle development if continued till the day of hCG
  17. 17. IF TRUE : DOUBLE BENEFITS The use of hMG at start of cycle for few days will avoid CC resistant cases use of CC till the day of hCG will prevent LH surge
  18. 18. NEW CONCEPT HAS TO BE TESTED To study the effectiveness of Clomiphene citrate (CC) in preventing a premature LH surge in women undergoing IUI
  19. 19. RCT STUDY Setting: Kasr Al-AiniUniversity hospital. Duration: January 2008 to July 2009 Registered : (ACTRN12607000568415)
  20. 20. SAMPLE SIZE CALCULATION  if premature LH surge rate among the hMG only group is 20%.  Assuming CC is effective by reducing it by 15%  Then hMG + CC group will be 5%,  So we will need to study 75 couples in each arm in order to reach a power of 80%.
  21. 21. DROP OUT CASES  In order to compensate for discontinuations, we recruited 115 women in each arm  Each couple were included only once in this trial in order to prevent a possible unit-of-analysis error in interpreting the results
  22. 22. 23 RCT ANATOMY Participants RandomlyAssigned Intervention Group Control Group Follow-up Follow-up Intervention Group Control Group
  23. 23. OUTCOME PARAMETERS Primary outcome parameters  Clinical pregnancy rate per women randomised ( i.e. fetal heart pulsations demonstrated by TVS at 6 –7 weeks’ gestation)  Premature LH Secondary outcome parameters  E2 levels,  Number of mature follicles  Endometrial thickness On day of HCG
  24. 24. NOVEL PROTOCOL 75 IU/HMG CD3 CD?7 150 mg CC hCG IUI DF ≥ 18 mm 34-36h DF ≥ 12 mm
  25. 25. CONTROL GROUP 75 IU/HMG CD3 hCG IUI DF ≥ 18 mm CD7 34-36h DF ≥ 12 mm CD?7
  26. 26. RESULTS Variable Group I (n=115) Group II (n=115) P value Age (years) 27.3 ± 4.7 28.4 ± 2.7 NS Duration of infertility (years) 3.1 ± 1.9 2.4 ± 1.6 NS Cause of infertility Mild male factor Unexplained infertility 61 (53%) 54 (47%) 58 (50.4%) 57 (49.6%) NS NS BMI 28.5 ± 1.6 28.1 ± 3.1 NS
  27. 27. RESULTS (CONT.) Variable Group I (n=110) Group II (n=107) P value Number of cancelled cycles Inadequate response Hyper response 5/110 4/5 1/5 8/107 6/8 2/8 NS NS NS Basal LH (mIU/mL) 6.4 ± 2.2 5.8 ± 2.4 NS Basal FSH (mIU/mL) 6.7 ± 2.5 7.2 ± 4.8 NS Days of stimulation 7.2 ± 1.8 8.1 ± 1.3 NS E2 at time of HCG (pg/mL) 360.3 ± 162.9 280 ± 110.0 P <.05*
  28. 28. RESULTS (CONT.) Variable HMG/CC (n=110) HMG (n=107) P value LH on day of hCG (miu/ml) for cases with no premature LH surge 7.3 ± 1.8 7.8 ± 2.2 NS Number of Follicles ≥ 16 mm 2.4 ± 0.97 1.3 ± 1.1 P < 0.05* Number of patients with premature LH surge 6 (5.45%) 17 (15.89%) P<0.001* End. Thickness (mm) 5.9 ± 0.7 4.9 ± 1.9 NS Clinical Pregnancy 11 (10%) 9 (8.41%) NS
  29. 29. FOR WHOM  This protocol is especially suitable for young women, for those with unexplained infertility or mild male factor i.e good responders  it may also be suitable for PCOS women to avoid the risk of severe OHSS
  30. 30. CONCLUSION  This is a novel protocol for O.I in IUI  The protocol is simple, safe and appears to be very cost effective.
  31. 31. JUST A QUESTION  Would u change ur O.I from CC/hMG to hMG/CC ??
  32. 32. OUTLINE OF THIS TALK  EBM : Introduction  Model of creating evidence : RCT  Model of creating evidence : Systematic review  Economic evaluation  prognosis  Others
  33. 33. MODEL OF SR : GN
  34. 34. TYPES OF GONADOTROPIN MARKETED  Human derived gonadotropins – hMG,HP- hMG, HP-FSH  Recombinant human gonadotropins - follitropin alfa and follitropin beta,
  35. 35. THE IDEAL COH PROTOCOL .. ..  Improve pregnancy rate  Reduce complications (OHSS)  Consider the financial status of patients.
  36. 36. Meta-analysis : Al-Inany et al, 2005
  37. 37. hMG was associated with a pooled 4 % increase in live birth rate when compared with rFSH (CI 1-7%)
  38. 38. RECENTLY RELEASED
  39. 39. GN: FINAL WORD Madelon van Wely1, Irene Kwan2, Anna L Burt3, Jane Thomas4, Andy Vail5, Fulco Van der Veen6, Hesham G Al-Inany
  40. 40. TYPES OF STUDIES  RCTs only.
  41. 41. PRIMARY OUTCOMES: PATIENT ORIENTED  Effectiveness: live birth per woman or, if not reported, pregnancy ongoing beyond 20 weeks  Adverse: Rate of severe OHSS
  42. 42. SECONDARY OUTCOMES  Effectiveness: frozen-thawed embryo transfers  Clinical pregnancy rate Patient acceptability/satisfaction Adverse: Multiple pregnancy rate Miscarriage rate per woman
  43. 43. 42 RCTS  The total number of participants was 9606
  44. 44. RESULTS  There was no evidence of a difference in live birth or pregnancy ongoing beyond 20 weeks (28 trials, N=7339; OR 0.97, 95% CI 0.87 - 1.08) for rFSH versus urinary gonadotrophins.  Meaning 25% live birth rate (22-26% in different centers)
  45. 45. SEVERE OHSS  There was no evidence of a difference in the primary safety outcome OHSS  (32 trials, N=7740; OR 1.18, 95% CI 0.86 - 1.61).  Typical rate of 2% OHSS
  46. 46. 47 HOW TO INTERPRET THE FIGURES!  A benefit from recombinant FSH would be displayed graphically to the left of the centre-line.  A benefit from hMG would be displayed graphically to the right of the centre-line
  47. 47. LIVE BIRTH RATE
  48. 48. OHSS
  49. 49. FRESH/FROZEN CYCLES
  50. 50. MULTIPLE PREGNANCY
  51. 51. MISCARRIAGE
  52. 52. CONCLUSION Gonadotrophins are Gonadotrophins are Gonadotrophins
  53. 53. OUTLINE OF THIS TALK  EBM : Introduction  Model of creating evidence : RCT  Model of creating evidence : Systematic review  Economic evaluation  Prognosis  Others
  54. 54. MODEL OF ECONOMIC ANALYSIS : GN
  55. 55. HOW TO MAKE DECISION ABOUT DRUG
  56. 56. ECONOMIC ANALYSIS  IVF/ICSI cycle, there are probabilities - Pregnancy - No pregnancy - Abortion - Repeat trial (usually up to 3 cycles) - Stop trial
  57. 57. EXAMPLE : HMG, 1ST CYCLE Start Cycle 10,000 Ovum Pickup No OHSS Ovum Pickup OHSS 9810 190 Fertilization & Transfer No Oocytes 373+7=380 9437+183=9620 Clinical Pregnancy -ve βHCG 2982 6638 Ongoing Pregnancy Miscarriage 405 2577 3246 3392 Continue Stop Goal! Therefore, for a cohort of 10,000 individuals the expected, mathematically exact, outcome at the end of the 1st cycle is 380+405+3392 = 4177 patients who will restart the cycle, and 2577 who achieved ongoing pregnancy, and 3246 who gave up on IVF from the first trial
  58. 58. MARKOV EV ANALYSIS: RFSH rFSH: By the end of the 3rd cycle, the individual’s probability of ending at re-starting the cycle is 6.6%, in ongoing pregnancy is 35.9%, and in discontinuing IVF is 57.5 % % Start Cycle % Pregnancy % Stop IVF 0 0.2 0.4 0.6 0.8 1 1.2 1 2 3 stop Cycle Probability
  59. 59. MARKOV EV ANALYSIS: HMG % Start Cycle % Pregnancy % Stop IVF 0 0.2 0.4 0.6 0.8 1 1.2 1 2 3 stop Cycle Probability hMG: By the end of the 3rd cycle, the individual’s probability of ending at re-starting the cycle is 6%, in ongoing pregnancy is 40.8%, and in discontinuing IVF is 53.2 %
  60. 60. HOW TO MAKE DECISION ABOUT DRUG
  61. 61. HCG VS. LH MONITORING  If normoovulatory (e.g male factor), LH monitoring is preferred  If ovulatory dysfunction: hCG is preferred Meta-analysis by Kosmos et al, 2007
  62. 62. OUTLINE OF THIS TALK  EBM : Introduction  Model of creating evidence : RCT  Model of creating evidence : Systematic review  Economic evaluation  Prognosis  Others
  63. 63. PROGNOSIS
  64. 64. HOW TO ESTIMATE  Chance to conceive naturally (home conception) (treatment independent pregnancy)  Chance to get pregnant after IVF
  65. 65. http://www.amc.nl/prognosticmodelhttp://www.amc.nl/prognosticmodel
  66. 66. CLINICAL CONSEQUENCES • Couples with prognosis <30% = IVF • Couples with prognosis > 40% = expectant management • Couples with prognosis 30-40% = IUI
  67. 67. Lintsen, A.M.E. et al. Hum. Reprod. 2007
  68. 68. ACCORDINGLY  classified for each woman into one of three groups, i.e.,  (i) predictor of good prognosis  (ii) intermediate prognosis  (iii) predictor of poor prognosis.
  69. 69. OTHERS
  70. 70. CABERGOLINE (CB2) THERAPY IN FACE OF OHSS  VEGF induces VP (vascular permeability)1,2  Effects of Cb2 attributable to VEGF receptor dephosphorylation3  Cb2 prevents VP in a dose dependent manner without affecting angiogenesis and implantation in humans (n = 35 treated in face of OHSS)4  Cb2 reduced the amount of ascites, hemoconcentration and incidence of moderate-severe OHSS5  Cb2 0.5 mg x 8 days (total of 4 mgs) starting day of trigger 1) McClure, et al, Lancet, 1994; 344: 235-236. 2) Bates, et al, Vascul Pharmacol, 2002; 39: 225-237. 3) Gomez, et al, Endocrinology, 2006; 147: 5400-5411. 4) Alvarez, et al, Hum Reprod, 2007; 22: 3210-3214. 5) Alvarez, et al, J Clin Endocrinol Metab, 2007; 92: 2931-2937.
  71. 71. DESTONIX FOR PREVENTION OF OHSS Favours cabergoline Favours control
  72. 72. MALE INFERTILITY  A Cochrane review of eight randomized studies comparing varicocelectomy versus no varicocelectomy showed no benefit of varicocele treatment over expectant treatment or 1.10 (95% C.I 0.73-1.68) (Evers and Collins 2004).
  73. 73. KARYOTYPE  Only in men with a severe male factor or non- obstructive azoospermia, the man’s karyotype should be investigated
  74. 74. PCOS  Metformin is not an effective addition to clomifene citrate as the primary method of inducing ovulation in women with PCOS  It can be added in cases with CC resistant women
  75. 75. OVARIAN DRILLING  The clear benefit and role of surgical therapy in ovulation induction in women with PCOS is uncertain.
  76. 76. OVULATION : THE DILEMMA IUI alone IUI + O.I Timed intercourse O.I alone
  77. 77. IUI/CC VS IUI/GN
  78. 78. 299 COUPLES (UNEXPLAINED INFERTILITY OR MALE SUBFERTILITY Received daily 50 IU rec FSH from day 3 When follicles are 13-14 mm Randomized 0.25 mg antagonist no antagonist Clinical PR 12.2% Clinical PR 12.6% NS GnRH antagonists in IUI (Crosignani et al 2007) 148 151
  79. 79. HCG ADMINISTRATION VS. LUTEINIZING H MONITORING FOR IUI TIMING (KOSMAS ET AL 2007). 2623 patients 1461 received hCG 1162 spontaneous LH surges Significantly lower PR Significantly higher PR (OR, 0.74; 95% CI 0.57-0.96)
  80. 80. TYPE OF CATHETER FOR IUI  Catheter choice is not important and does not affect pregnancy outcome Abousetta et al, 2006
  81. 81. REST AFTER IUI  15 minutes' immobilisation after insemination is an effective modification.  Immobilisation for 15 minutes should be offered to all women treated with intrauterine insemination. Custer et al, 2009
  82. 82. THE FUTURE OF IUI IUI + O.I 10% success rate Cost 100$ IVF + sET 25% success rate Cost 1000$ NC IVF 20% success rate Cost 350$
  83. 83. PLEASE VOTE IUI + O.I IVF + sET NC IVF
  84. 84. TUBAL SURGERY  For women with mild tubal disease, tubal surgery may be more effective than no treatment in centres where appropriate expertise is available.
  85. 85. HYDROSALPINX  Women with ultrasound visible hydrosalpinges should be offered salpingectomy before IVF because this improves the chance of a live birth
  86. 86. ENDOMETRIOSIS  Medical treatment of minimal and mild endometriosis does not enhance fertility in subfertile women and should not be offered
  87. 87. ENDOMETRIOMA  Women with ovarian endometriomas should be offered laparoscopic cystectomy because this improves the chance of pregnancy.
  88. 88. LIVE BIRTH RATE AFTER IVF FOR UNEXPLAINED INFERTILITY: COCHRANE REVIEW (PANDIAN ET AL 2005) IVF vs. Expectant TT 2 trials OR 3.24; 95% CI 1.07-9.8 IVF vs. IUI 1 trial OR 1.96; 95% CI 0.88-4.4 IVF vs. COH/IUI 2 trials OR 1.15; 95% CI 0.55-2.4 IVF vs. GIFT 3 trials OR 2.57; 95% CI 0.93-7.08
  89. 89. ICSI VS IVF  ICSI improves fertilisation rates compared to IVF, but once fertilisation is achieved the pregnancy rate is no better than with in vitro fertilisation
  90. 90. GROWTH HORMONE
  91. 91. ET  Women undergoing in vitro fertilisation treatment should be offered ultrasound-guided embryo transfer because this improves pregnancy rates.
  92. 92. ET  Bed rest of more than 20 minutes’ duration following embryo transfer does not improve the outcome of in vitro fertilisation treatment
  93. 93. ASSISTED HATCHING  Assisted hatching is not recommended because it has not been shown to improve pregnancy rates
  94. 94. LUTEAL PHASE SUPPORT  Women who are undergoing in vitro fertilisation treatment using GnRHa for pituitary down- regulation should be informed that luteal support using progesterone improves pregnancy rates
  95. 95. RISK  a possible association between ovulation induction therapy and ovarian cancer remains uncertain .  Practitioners should confine the use of ovulation induction agents to the lowest effective dose and duration of use
  96. 96. CHILDREN  Current research is broadly reassuring about the health and welfare of children born as a result of assisted reproduction
  97. 97. THANK YOU Dr. Hesham Al-Inany MD, PhD e-mail : kaainih@yahoo.com

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