Which type of Gonadotrophins should we use for ovarian stimulation in IVF?
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The document discusses the comparison of recombinant gonadotrophin (rfsh) and urinary-derived gonadotrophins (hmg, fsh-p, fsh-hp) in ovarian stimulation for IVF or ICSI cycles. It highlights that systematic reviews indicate no significant difference in live birth rates between rfsh and urinary gonadotrophins, although some studies suggest lower live birth rates with rfsh compared to hmg. The analysis emphasizes the need for large randomized trials to further investigate these differences and examines the methodology and outcomes of existing studies.
Which type of Gonadotrophins should we use for ovarian stimulation in IVF?
- 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
- 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
- 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
- 40. INFLUENCE OF PHARMACEUTICAL COMPANIES
- 42. MISCARRIAGE
- 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