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Which type of Gonadotrophins should we use for ovarian stimulation in IVF?
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Which type of Gonadotrophins should we use for ovarian stimulation in IVF?

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There are many types of gonadotropins: some are recombinant , others are urinary derived. some contain LH like activity , others do not. which to use?? many research with conflicting results but the …

There are many types of gonadotropins: some are recombinant , others are urinary derived. some contain LH like activity , others do not. which to use?? many research with conflicting results but the final word came from Cochrane mega- systematic review. This talk will illustrate this issue

Published in: Health & Medicine

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  • 1. ‫ا‬ ِ‫ن‬ َٰ‫م‬ْ‫ح‬‫ه‬‫ر‬‫ال‬ ِ ‫ه‬‫اَّلل‬ ِ‫م‬ْ‫س‬ِ‫ب‬ِ‫يم‬ ِ‫ح‬‫ه‬‫لر‬
  • 2. GN: FINAL WORD Madelon van Wely1, Irene Kwan2, Anna L Burt3, Jane Thomas4, Andy Vail5, Fulco Van der Veen6, Hesham G Al-Inany
  • 3. 3 WHY DO WE NEED THIS TALK  To update our knowledge and understanding  To provide evidence for decision-makers  To provide our patients with best care based on Evidence
  • 4. 4 BUT EVIDENCE IS NOT ALL THE SAME
  • 5. IBSA Satel lite Sym posi um 5 E VI D E N C E THE EVIDENCE PYRAMID
  • 6. IBSA Satel lite Sym posi um 6 WHY SR ARE ON THE TOP  Rigorous methodology  Peer reviewed  Relatively large sample size  Ensures the highest quality evidence (based on RCT)
  • 7. IBSA Satel lite Sym posi um 7 RCT ANATOMY Participants RandomlyAssigned Intervention Group Control Group Follow-up Follow-up Intervention Group Control Group
  • 8. 8 IVF/ICSI CYCLES  Multifollicular development is still an integral component for ovarian stimulation in IVF / ICSI cycles (Keck et al, 2005)
  • 9. 9 In The Market VS rec FSHHuman derived Gn
  • 10. 10 HOW TO KNOW  large randomised trial is needed to estimate the difference between human derived Gn and rFSH (van Wely et al., 2003).
  • 11. 11 SAMPLE SIZE CALCULATION FOR SUCH RCT  For a study to have 80% power to detect a difference of 5% in ongoing pregnancies (or live births), it will need to randomise over 2400 women (Andersen et al, 2006)  Which is unlikely to happen (huge fund and long duration)
  • 12. 12 SO THE SOLUTION  systematic review and meta-analysis of randomised trials comparing the effectiveness of hMG versus rFSH following a long down-regulation protocol in IVF-ICSI cycles
  • 13. HOWEVER,  Several systematic reviews and one international Health Technology Assessment report compared rFSH with urinary gonadotrophins (hMG, FSH-P, FSH-HP) Daya 1998; Larizgoitia 2000; Agrawal 2000; Daya 2002;Van Wely 2003;NCC-WCH 2004;Al-Inany 2003; Al-Inany 2008;Coomarisamy 2008).
  • 14. EXOGENOUS GONADOTROPIN THERAPY The goal:
  • 15. EFFECTIVENESS Meta-analysis : Al-Inany et al, 2005
  • 16. 16 hMG (363/ 1453) vs. rFSH (324/ 1484) (P < 0.04; O.R = 1.20, 95% CI = 1.01 - 1.42) Al-Inany et al., RBM Online, (2008) Live birth rate
  • 17. RECENTLY RELEASED
  • 18. ONGOING PREGNANCY/ LIVE-BIRTH RATE
  • 19. CONFLICTING RESULTS  Two reviews compared rFSH to urinary FSH and found higher pregnancy rates per cycle started for rFSH (Daya 2002, updated from Daya 1998).  Three reviews compared rFSH versus urinary gonadotrophins (hMG, FSH-P, FSH-HP together) and found no evidence of a difference between these two groups (Larizgoitia 2000;Al-Inany 2003;NCC-WCH 2004).
  • 20. MOREOVER  Three reviews compared rFSH with hMG and and reported evidence of a difference in live birth and clinical pregnancy rate per cycle between rFSH and hMG (Van Wely 2002;Al-Inany 2008;Coomarisamy 2008).
  • 21. CONFOUNDING FACTORS  Firstly, gonadotrophin-releasing hormone (GnRH) agonists and GnRH antagonist are often used in conjunction with gonadotrophins to facilitate cycle control and achieve pituitary down-regulation in ovarian stimulation during assisted reproductive treatment cycles.
  • 22. INFLUENCE OF PHARMACEUTICAL COMPANIES  Secondly many trials have been performed by pharmaceutical companies and the conflict of interest may have introduced bias.
  • 23. CRYO EMBRYOS  Thirdly, it is now customary to freeze supernumerary embryos and to transfer frozen/thawed embryos if transfer of fresh embryos has failed.
  • 24. OBJECTIVES  To compare the effectiveness of recombinant gonadotrophin (rFSH) with the three main types of urinary-derived gonadotrophins (i.e. hMG, FSH-P and FSH-HP) for ovarian stimulation in women undergoing IVF or ICSI treatment cycles.
  • 25. 25 HP-FSH HP-hMG hMG recFSH It fills in a gap in evidence as recombinant FSH was compared to hMG and to HP-hMG but no one compared hMG to HP-hMG
  • 26. TYPES OF STUDIES  Randomised controlled trials only.  Quasi-randomised controlled trials, in which allocation was, for example, by alternation or reference to case record number or to dates of birth, were excluded.  Crossover trials were excluded since the design is not appropriate in this context (Vail 2003)
  • 27. TYPES OF PARTICIPANTS  Normogonadotrophic (defined as having normal serum concentration of FSH and LH) women undergoing fresh and/or frozen-thawed IVF or ICSI treatment cycles
  • 28. PRIMARY OUTCOMES  Effectiveness: live birth per woman or, if not reported, pregnancy ongoing beyond 20 weeks per woman  Adverse: Rate of severe OHSS per woman
  • 29. SECONDARY OUTCOMES  Effectiveness: frozen-thawed embryo transfers  Clinical pregnancy rate Adverse: Multiple pregnancy rate Miscarriage rate per woman
  • 30. 42 RCTS  including 8 abstracts form congress proceedings) met all selection criteria and were included in the review.  The total number of participants was 9606
  • 31. 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)
  • 32. SUBGROUP ANALYSIS: HMG VS RFSH  There were significantly less live births after rFSH as compared to hMG (11 trials, N=3197; OR 0.84, 95% CI 0.72 - 0.99).  This means that for a live birth rate of 25%, use of rFSH instead would be expected to result in a live birth rate between 19% and 25%.
  • 33. ACCORDING TO DOWNREGULATION  There was no evidence of a difference in live birth between rFSH and urinary gonadotrophins for any of the downregulation protocols  (antagonist protocol, N=280; OR 0.88, 95% CI 0.53 - 1.45),  (long GnRHa protocol, N=6437; OR 0.98, 95% CI 0.87 - 1.10),  (short GnRHa protocol, N=402; OR 0.84, 95% CI 0.54 - 1.31),  (no downregulation, N=220; OR 1.17, 95% CI 0.62 - 2.20)
  • 34. 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
  • 35. 35 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
  • 36. LIVE BIRTH RATE
  • 37. OHSS
  • 38. DOWN REGULATION PROTOCOL
  • 39. FRESH/FROZEN CYCLES
  • 40. INFLUENCE OF PHARMACEUTICAL COMPANIES
  • 41. MULTIPLE PREGNANCY
  • 42. MISCARRIAGE
  • 43. CONCLUSION Gonadotrophins are Gonadotrophins are Gonadotrophins
  • 44. ECONOMIC ANALYSIS  IVF/ICSI cycle, there are probabilities - Pregnancy - No pregnancy - Abortion - Repeat trial (usually up to 3 cycles) - Stop trial
  • 45. 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
  • 46. 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
  • 47. 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 %
  • 48. HOW TO MAKE DECISION ABOUT DRUG
  • 49. THANK YOU Dr. Hesham Al-Inany MD, PhD e-mail : kaainih@yahoo.com