0
‫ا‬ ِ‫ن‬ َٰ‫م‬ْ‫ح‬‫ه‬‫ر‬‫ال‬ ِ ‫ه‬‫اَّلل‬ ِ‫م‬ْ‫س‬ِ‫ب‬ِ‫يم‬ ِ‫ح‬‫ه‬‫لر‬
GN: FINAL WORD
Madelon van Wely1, Irene Kwan2, Anna L Burt3, Jane
Thomas4, Andy Vail5, Fulco Van der Veen6, Hesham G
Al-In...
3
WHY DO WE NEED THIS TALK
 To update our knowledge and understanding
 To provide evidence for decision-makers
 To prov...
4
BUT
EVIDENCE
IS NOT ALL THE SAME
IBSA
Satel
lite
Sym
posi
um
5
E
VI
D
E
N
C
E
THE EVIDENCE PYRAMID
IBSA
Satel
lite
Sym
posi
um
6
WHY SR ARE ON THE TOP
 Rigorous methodology
 Peer reviewed
 Relatively large sample size
...
IBSA
Satel
lite
Sym
posi
um
7
RCT ANATOMY
Participants
RandomlyAssigned
Intervention Group
Control Group
Follow-up
Follow-...
8
IVF/ICSI CYCLES
 Multifollicular development
is still an integral
component for ovarian
stimulation in IVF / ICSI
cycle...
9
In The Market
VS
rec FSHHuman
derived Gn
10
HOW TO KNOW
 large randomised trial is needed to estimate the
difference between human derived Gn and rFSH
(van Wely e...
11
SAMPLE SIZE CALCULATION FOR SUCH RCT
 For a study to have 80% power to detect a difference of 5% in
ongoing pregnancie...
12
SO THE SOLUTION
 systematic review and meta-analysis of
randomised trials comparing the effectiveness of
hMG versus rF...
HOWEVER,
 Several systematic reviews and one international
Health Technology Assessment report compared
rFSH with urinary...
EXOGENOUS GONADOTROPIN THERAPY
The goal:
EFFECTIVENESS
Meta-analysis :
Al-Inany et al, 2005
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)
L...
RECENTLY RELEASED
ONGOING PREGNANCY/ LIVE-BIRTH RATE
CONFLICTING RESULTS
 Two reviews compared rFSH to urinary FSH and
found higher pregnancy rates per cycle started for
rFSH...
MOREOVER
 Three reviews compared rFSH with hMG and and
reported evidence of a difference in live birth and
clinical pregn...
CONFOUNDING FACTORS
 Firstly, gonadotrophin-releasing hormone (GnRH)
agonists and GnRH antagonist are often used in
conju...
INFLUENCE OF PHARMACEUTICAL COMPANIES
 Secondly many trials have been performed by
pharmaceutical companies and the confl...
CRYO EMBRYOS
 Thirdly, it is now customary to freeze
supernumerary embryos and to transfer
frozen/thawed embryos if trans...
OBJECTIVES
 To compare the effectiveness of recombinant
gonadotrophin (rFSH) with the three main types of
urinary-derived...
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 ...
TYPES OF STUDIES
 Randomised controlled trials only.
 Quasi-randomised controlled trials, in which
allocation was, for e...
TYPES OF PARTICIPANTS
 Normogonadotrophic (defined as having normal
serum concentration of FSH and LH) women
undergoing f...
PRIMARY OUTCOMES
 Effectiveness:
live birth per woman or, if not reported, pregnancy
ongoing beyond 20 weeks per woman
 ...
SECONDARY OUTCOMES
 Effectiveness:
frozen-thawed embryo transfers
 Clinical pregnancy rate
Adverse:
Multiple pregnancy r...
42 RCTS
 including 8 abstracts form congress proceedings)
met all selection criteria and were included in the
review.
 T...
RESULTS
 There was no evidence of a difference in live
birth or pregnancy ongoing beyond 20 weeks (28
trials, N=7339; OR ...
SUBGROUP ANALYSIS: HMG VS RFSH
 There were significantly less live births after rFSH
as compared to hMG (11 trials, N=319...
ACCORDING TO DOWNREGULATION
 There was no evidence of a difference in live birth
between rFSH and urinary gonadotrophins ...
SEVERE OHSS
 There was no evidence of a difference in the
primary safety outcome OHSS
 (32 trials, N=7740; OR 1.18, 95% ...
35
HOW TO INTERPRET THE FIGURES!
 A benefit from recombinant FSH would be
displayed graphically to the left of the centre...
LIVE BIRTH RATE
OHSS
DOWN REGULATION PROTOCOL
FRESH/FROZEN CYCLES
INFLUENCE OF PHARMACEUTICAL COMPANIES
MULTIPLE PREGNANCY
MISCARRIAGE
CONCLUSION
Gonadotrophins
are
Gonadotrophins
are
Gonadotrophins
ECONOMIC ANALYSIS
 IVF/ICSI cycle, there are probabilities
- Pregnancy
- No pregnancy
- Abortion
- Repeat trial (usually ...
EXAMPLE : HMG, 1ST CYCLE
Start Cycle
10,000
Ovum Pickup
No OHSS
Ovum Pickup
OHSS
9810
190
Fertilization
& Transfer
No Oocy...
MARKOV EV ANALYSIS: RFSH
rFSH: By the end of the 3rd cycle, the individual’s probability of ending at re-starting
the cycl...
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 ...
HOW TO MAKE DECISION ABOUT DRUG
THANK YOU
Dr. Hesham Al-Inany MD, PhD
e-mail : kaainih@yahoo.com
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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 final word came from Cochrane mega- systematic review. This talk will illustrate this issue

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

  1. 1. ‫ا‬ ِ‫ن‬ َٰ‫م‬ْ‫ح‬‫ه‬‫ر‬‫ال‬ ِ ‫ه‬‫اَّلل‬ ِ‫م‬ْ‫س‬ِ‫ب‬ِ‫يم‬ ِ‫ح‬‫ه‬‫لر‬
  2. 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. 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. 4 BUT EVIDENCE IS NOT ALL THE SAME
  5. 5. IBSA Satel lite Sym posi um 5 E VI D E N C E THE EVIDENCE PYRAMID
  6. 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. 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. 8 IVF/ICSI CYCLES  Multifollicular development is still an integral component for ovarian stimulation in IVF / ICSI cycles (Keck et al, 2005)
  9. 9. 9 In The Market VS rec FSHHuman derived Gn
  10. 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. 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. 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. 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. 14. EXOGENOUS GONADOTROPIN THERAPY The goal:
  15. 15. EFFECTIVENESS Meta-analysis : Al-Inany et al, 2005
  16. 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. 17. RECENTLY RELEASED
  18. 18. ONGOING PREGNANCY/ LIVE-BIRTH RATE
  19. 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. 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. 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. 22. INFLUENCE OF PHARMACEUTICAL COMPANIES  Secondly many trials have been performed by pharmaceutical companies and the conflict of interest may have introduced bias.
  23. 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. 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. 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. 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. 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. 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. 29. SECONDARY OUTCOMES  Effectiveness: frozen-thawed embryo transfers  Clinical pregnancy rate Adverse: Multiple pregnancy rate Miscarriage rate per woman
  30. 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. 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. 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. 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. 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. 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. 36. LIVE BIRTH RATE
  37. 37. OHSS
  38. 38. DOWN REGULATION PROTOCOL
  39. 39. FRESH/FROZEN CYCLES
  40. 40. INFLUENCE OF PHARMACEUTICAL COMPANIES
  41. 41. MULTIPLE PREGNANCY
  42. 42. MISCARRIAGE
  43. 43. CONCLUSION Gonadotrophins are Gonadotrophins are Gonadotrophins
  44. 44. ECONOMIC ANALYSIS  IVF/ICSI cycle, there are probabilities - Pregnancy - No pregnancy - Abortion - Repeat trial (usually up to 3 cycles) - Stop trial
  45. 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. 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. 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. 48. HOW TO MAKE DECISION ABOUT DRUG
  49. 49. THANK YOU Dr. Hesham Al-Inany MD, PhD e-mail : kaainih@yahoo.com
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