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Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
Evidence based infertility management
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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

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

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  • 1. ‫ا‬ ِ‫ن‬ َٰ‫م‬ْ‫ح‬‫ه‬‫ر‬‫ال‬ ِ ‫ه‬‫اَّلل‬ ِ‫م‬ْ‫س‬ِ‫ب‬ِ‫يم‬ ِ‫ح‬‫ه‬‫لر‬
  • 2. EVIDENCE BASED INFERTILITY TREATMENT kasr al ainy school of Medicine Cairo University
  • 3. OUTLINE OF THIS TALK  EBM : Introduction  Model of creating evidence : RCT  Model of creating evidence : Systematic review  Economic evaluation  Prognosis  Others
  • 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. EBM - WHAT IS IT? Clinical Expertise Research Evidence Patient Preferences
  • 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. IS ALL EVIDENCE CREATED EQUAL!!
  • 8. RCT ANATOMY Participants RandomlyAssigned Intervention Group Control Group Follow-up Follow-up Intervention Group Control Group
  • 9. 9 PICO Patient woman, 34 years, 2ys 1ry unexplained inf. Intervention IUI Comparison wait Outcome Pregnancy
  • 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. OUTLINE OF THIS TALK  EBM : Introduction  Model of creating evidence : RCT  Model of creating evidence : Systematic review  Economic evaluation  Prognosis  Others
  • 12. MODEL OF RCT : REVERSED HMG/CC PROTOCOL
  • 13. CURRENT PRACTICE OF O.I IN IUI Clomiphene Citrate hMG or FSH ______________________________________________
  • 14. EMERGING PROTOCOL: REVERSED HMG/CC Clomiphene Citrate hMG or FSH ______________________________________________
  • 15. Some cases are CC resistant  about 25% of IUI cycles suffer from premature LH surge cancellation. WHY
  • 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. 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. 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. RCT STUDY Setting: Kasr Al-AiniUniversity hospital. Duration: January 2008 to July 2009 Registered : (ACTRN12607000568415)
  • 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. 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. 23 RCT ANATOMY Participants RandomlyAssigned Intervention Group Control Group Follow-up Follow-up Intervention Group Control Group
  • 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. NOVEL PROTOCOL 75 IU/HMG CD3 CD?7 150 mg CC hCG IUI DF ≥ 18 mm 34-36h DF ≥ 12 mm
  • 25. CONTROL GROUP 75 IU/HMG CD3 hCG IUI DF ≥ 18 mm CD7 34-36h DF ≥ 12 mm CD?7
  • 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. 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. 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. 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. CONCLUSION  This is a novel protocol for O.I in IUI  The protocol is simple, safe and appears to be very cost effective.
  • 31. JUST A QUESTION  Would u change ur O.I from CC/hMG to hMG/CC ??
  • 32. OUTLINE OF THIS TALK  EBM : Introduction  Model of creating evidence : RCT  Model of creating evidence : Systematic review  Economic evaluation  prognosis  Others
  • 33. MODEL OF SR : GN
  • 34. TYPES OF GONADOTROPIN MARKETED  Human derived gonadotropins – hMG,HP- hMG, HP-FSH  Recombinant human gonadotropins - follitropin alfa and follitropin beta,
  • 35. THE IDEAL COH PROTOCOL .. ..  Improve pregnancy rate  Reduce complications (OHSS)  Consider the financial status of patients.
  • 36. Meta-analysis : Al-Inany et al, 2005
  • 37. hMG was associated with a pooled 4 % increase in live birth rate when compared with rFSH (CI 1-7%)
  • 38. RECENTLY RELEASED
  • 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. TYPES OF STUDIES  RCTs only.
  • 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. SECONDARY OUTCOMES  Effectiveness: frozen-thawed embryo transfers  Clinical pregnancy rate Patient acceptability/satisfaction Adverse: Multiple pregnancy rate Miscarriage rate per woman
  • 43. 42 RCTS  The total number of participants was 9606
  • 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. 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. 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. LIVE BIRTH RATE
  • 48. OHSS
  • 49. FRESH/FROZEN CYCLES
  • 50. MULTIPLE PREGNANCY
  • 51. MISCARRIAGE
  • 52. CONCLUSION Gonadotrophins are Gonadotrophins are Gonadotrophins
  • 53. OUTLINE OF THIS TALK  EBM : Introduction  Model of creating evidence : RCT  Model of creating evidence : Systematic review  Economic evaluation  Prognosis  Others
  • 54. MODEL OF ECONOMIC ANALYSIS : GN
  • 55. HOW TO MAKE DECISION ABOUT DRUG
  • 56. ECONOMIC ANALYSIS  IVF/ICSI cycle, there are probabilities - Pregnancy - No pregnancy - Abortion - Repeat trial (usually up to 3 cycles) - Stop trial
  • 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. 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. 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. HOW TO MAKE DECISION ABOUT DRUG
  • 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. OUTLINE OF THIS TALK  EBM : Introduction  Model of creating evidence : RCT  Model of creating evidence : Systematic review  Economic evaluation  Prognosis  Others
  • 63. PROGNOSIS
  • 64. HOW TO ESTIMATE  Chance to conceive naturally (home conception) (treatment independent pregnancy)  Chance to get pregnant after IVF
  • 65. http://www.amc.nl/prognosticmodelhttp://www.amc.nl/prognosticmodel
  • 66. CLINICAL CONSEQUENCES • Couples with prognosis <30% = IVF • Couples with prognosis > 40% = expectant management • Couples with prognosis 30-40% = IUI
  • 67. Lintsen, A.M.E. et al. Hum. Reprod. 2007
  • 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. OTHERS
  • 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. DESTONIX FOR PREVENTION OF OHSS Favours cabergoline Favours control
  • 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. KARYOTYPE  Only in men with a severe male factor or non- obstructive azoospermia, the man’s karyotype should be investigated
  • 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. OVARIAN DRILLING  The clear benefit and role of surgical therapy in ovulation induction in women with PCOS is uncertain.
  • 76. OVULATION : THE DILEMMA IUI alone IUI + O.I Timed intercourse O.I alone
  • 77. IUI/CC VS IUI/GN
  • 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. 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. TYPE OF CATHETER FOR IUI  Catheter choice is not important and does not affect pregnancy outcome Abousetta et al, 2006
  • 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. 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. PLEASE VOTE IUI + O.I IVF + sET NC IVF
  • 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. HYDROSALPINX  Women with ultrasound visible hydrosalpinges should be offered salpingectomy before IVF because this improves the chance of a live birth
  • 86. ENDOMETRIOSIS  Medical treatment of minimal and mild endometriosis does not enhance fertility in subfertile women and should not be offered
  • 87. ENDOMETRIOMA  Women with ovarian endometriomas should be offered laparoscopic cystectomy because this improves the chance of pregnancy.
  • 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. 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. GROWTH HORMONE
  • 91. ET  Women undergoing in vitro fertilisation treatment should be offered ultrasound-guided embryo transfer because this improves pregnancy rates.
  • 92. ET  Bed rest of more than 20 minutes’ duration following embryo transfer does not improve the outcome of in vitro fertilisation treatment
  • 93. ASSISTED HATCHING  Assisted hatching is not recommended because it has not been shown to improve pregnancy rates
  • 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. 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. CHILDREN  Current research is broadly reassuring about the health and welfare of children born as a result of assisted reproduction
  • 97. THANK YOU Dr. Hesham Al-Inany MD, PhD e-mail : kaainih@yahoo.com

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