1. Prevention of ovarian hyperstimulation syndrome in OHSS patients
Georg Griesinger
University Clinic of Schleswig-Holstein, Campus Luebeck
Dept. of Obstetrics and Gynecology
VVOG Post-Universitaire Studiedag
Zemst, 13 Nov 2008

2. What is the OHSS incidence in your center?

3. German IVF registry, 2006

4. Number of OHSS cases per year in Germany?
0,41 (incidence DIR) x
~ IVF cycles with ovarian stimulation per year
= 164 OHSS cases

5. = 1.080 OHSS III cases per year in Germany
Hum Reprod Dec;21(12):

6. OHSS III° incidence: 2,1% 95% CI: 1.6 – 2.8
Fertility and Sterility Vol. 85, No. 1, 2006

7. ........................ OHSS [MeSH] AND fatality [MeSH]
death of a 31-year-old woman …who developed a fatal adult respiratory distress syndrome Fineschi et al., 2006
autopsy case of severe OHSS …..28-year-old Japanese female…… who died of rapid respiratory insufficiency Semba et al., 2000
21 year old woman ……cerebral infarction….complete persistent hemiplegia Hwang et al., 1998

8. Clinically relevant OHSS
OHSS that requires hospitalisation
WHO grade III
Golan,1989 grade IV-V
‚severe‘ ‚critical‘
Navot,1992
Rizk, 1999 grade B,C

9. Prediction
Prevention
Treatment

10. primary prevention: intended to decrease the overall risk in the general population
secondary prevention: detection of patients at risk and preventive measure only in those patients
tertiary prevention: prophylaxis of further damage in patients with a disease

11. Can we reliably predict OHSS?

12. Long GnRH-agonist protocol
De Angelo et al., 2004
E2 = 3,354 pg/ml
Sens + Spec = 85%
GnRH-antagonist protocol
Papanicolaou et al., 2006
18 follicles >10 mm or E2 > 5,000 pg/l
Sens = 83%
Spec = 84%
5/53 CASES OF SEVERE OHSS
STILL MISSED WITH THESE CRITERIA
I d like to show you graphs from two recent studies which are likely to be more representative of what is we are doing nowadays in terms of ovarian stimulation.

13. No reliable test to identify all OHSS risk patients
develop ovarian stimulation routines that are associated with a per se decreased risk of OHSS (primary prevention)
develop measures of OHSS prevention for individual risk patients, which are safe and efficacious, and can therefore be liberally utilized (secondary prevention)
develop better treatment regimen for patients with onset of OHSS to avoid further complications (tertiary prevention)

14. Reduction of follicles Trigger of final oocyte maturation:
OHSS Prevention
Ovarian stimulation
Reduction of follicles
Trigger of final oocyte maturation:
Luteal phase
GnRH-antagonist instead of GnRH-agonist long
Delayed FSH start
Natural cycle IVF
Cycle cancellation
In vitro Maturation
Coasting
early aspiration of small follicles
unilateral follicular aspiration
GnRH-agonist instead of hCG
Reduced dose hCG
Recombinant LH instead of hCG
hCG free luteal phase support
Elective cryopreservation of embryos
Luteal phase GnRH-antagonist administration

15. Ovarian stimulation
OHSS incidence reduction
Natural cycle IVF √
In vitro Maturation √
Cycle cancellation √
efficacy ?
---

16. Number-needed-to-treat-to-harm with a GnRH-agonist long protocol for OHSS III
Kolibianakis et al., Hum Reprod Update 2006
Outcome: severe OHSS associated with hospital admission
EXPECTED OHSS III° INCIDENCE: 3.5%
RR = 0.47, 95% CI 0.27–0.82, P = 0.01
NNT TO HARM = 53 ( )
3,46%

17. GnRH-antagonist vs GnRH-agonist long OHSS III
Crude incidence of OHSS =
1.5%

18. A mild treatment strategy for in-vitro fertilisation:
a randomised non-inferiority trial
Mild stimulation: reduction OHSS, but also not the final solution
Incidence of OHSS =
1.4%
Heijnen et al.,Lancet 2007; 369: 743–49

19. Coasting OHSS II-III in 3-10% Delvigne & Rozenberg, HRupdate, 2002
Still high OHSS incidence, efficacy not clear (especially when coasting >3 days)
Delvigne & Rozenberg, HRupdate, 2002

20. GnRH
-antagonists

21. Novel concepts in Coasting
E2 < 3000 pg/ml ?
4 follicles ≥ 16mm?
Hyper
response?
hCG
FSH
FSH
GnRH-agonist daily
GnRH-antagonist daily
Case control study of gustofson
n= 85, coasting ~ 1.5 days
Ongoing pregnancy rate: ~ 60 %
Severe OHSS: %
Gustofson et al., Hum Reprod 2006
Gustofson et al., Fertil Steril 2006

22. Conventional coasting
Novel concepts in Coasting
RCT: 192 patients
Antagonist
coasting
Conventional coasting
Days of coasting
1.74 ± 0.91
2.82 ± 0.97
No of oocytes
16.5 ± 7.6
14.06 ± 5.2
No of embryos
2.87 ± 1.2
2.21 ± 1.1
Clinical pregnancy
(N.S.)
55.32%
47.92%
No OHSS in both study groups
I think that for those who already use coasting as an OHSS preventive measure, trying antagonist coasting certainly appeas worthwhile
Aboulghar et al., RBMonline 2007

23. Coasting in Antagonist protocols
Bahceci et al., 2006; Farhi et al., 2008

24. Ovarian stimulation Ovarian stimulation
GnRH-antagonist instead of GnRH-agonist long
Delayed FSH start (“mild”)
Natural cycle IVF
Cycle cancellation
In vitro Maturation
Coasting
Reduces OHSS incidence, but is not the final solution
idem
Efficacy questionable
Efficacy zero ?

25. Reduction of follicles Trigger of final oocyte maturation:
OHSS Prevention
Ovarian stimulation
Reduction of follicles
Trigger of final oocyte maturation:
Luteal phase
GnRH-antagonist instead of GnRH-agonist long
Delayed FSH start
Natural cycle IVF
Cycle cancellation
In vitro Maturation
Coasting
early aspiration of small follicles
unilateral follicular aspiration
GnRH-agonist instead of hCG
Reduced dose hCG
Recombinant LH instead of hCG
hCG free luteal phase support
Elective cryopreservation of embryos
Luteal phase GnRH-antagonist administration

26. The final solution to OHSS prevention…..
Abolish hCG as a triggering agent!?

27. GnRH-agonist trigger
Gonen et al., 1990

28. Luteal phase after agonist trigger?
Progesterone serum values with NO
luteal phase supplementation
Day of administration of GnRH-a or hCG
Beckers et al., 2003

29. Drastic luteolysis…
Will it prevent OHSS?
Kol S, Fertil Steril 2004

30. Trigger of final oocyte maturation
Does GnRH-agonist triggering prevent OHSS? ?
RCT
hCG
agonist
Observational study
OHSS risk population
General population
Oocyte donors
Trigger of final oocyte maturation
RCT

31. OHSS I-II: RR with 95% confidence intervals (heterogeneity p = 0.57)
Evidence from RCTs
Mantel-Haenszel
Update of: Griesinger et al., Hum Reprod update 2005

32. Evidence from observational, uncontrolled trials 16 publications total n= 1,091 OHSS risk patients  a single case reported: late-onset OHSS in a pregnant woman
Full publication: Itskovitz-Eldor, 2000; Kol and Muchtar, 2005; Engmann, 2006; Orvieto, 2006; Griesinger, 2007;
Abstract: Bracero, 2001; Meltzer, 2002; Bankowski, 2004; Carone, 2005; Chun, 2005; Erden, 2005; Shapiro, 2005; Bukulmez, 2005; Bar-Hava, 2005; Körösi, 2006; Bodri, 2006
Update of: Griesinger et al., RBMonline 2006

33. 0.2 triptorelin or 0.5 mg buserelin and hCG
No difference between
0.2 triptorelin or 0.5 mg buserelin and hCG
no. of oocytes
no. of MII oocytes
fertilisationrate
embryo Score
BUT:
ongoing PR drastically reduced
Human Reproduction Update, 2006

34. GnRH-antagonist stimulation
OHSS risk?
GnRH-agonist trigger
Elective 2PN freezing
Cryo-ET
Griesinger et al., Hum Reprod 2007

35. Cryopreservation
slow cooling
vitrification
°C/min
2 sec.

36. Update of Griesinger et al., Hum Reprod 2007
Patients with GnRH-agonist triggering, n =40
Patients with 2 PN oocytes frozen, n = 39
Patients with at least one embryo transfer, n = 39
Number of (cryo) embryo transfers, n = 81
Update of Griesinger et al., Hum Reprod 2007

37. Cumulative live birth rate (95% confidence interval)
32.5% (13/40)
21.7 – 45.5%
Live birth rate per embryo transfer
16.0% (13/81)
10.4 – 23.9%
Live birth rate per first embryo transfer
17.9% (7/39)
10.0 – 30.1
OHSS incidence: 0% (0.0 – 6.2)
Update of Griesinger et al., Hum Reprod 2007

38. Mean number of embryos transferred
Mean number of ETs:
2.1
Mean number of embryos transferred
Mean time-to-conception
21 weeks
Cumulative incidence positive hCG test leading to live birth

39. Reduced hCG dose? RCT, n= 80 PCOS GnRH-antagonist protocol 10,000 IU
Fertilisation rate
52.8%
65.4%
55.6%
Ongoing pregnancy rate
26.9%
(7 of 26),
30.8%
(8 of 26)
34.8%
(8 of 23),
OHSS III°
3.5%
(1 of 28)
3.8%
(1 of 26) 0%
Kolibianakis et al., 2007

40. low dose hCG & OHSS? Retrospective study, n=94 cycles
> 2, ,000 pg/mL  5000 IU
>4000  3300 IU
5,000 IU
(n=47)
3,300 IU
(n = 47)
Ongoing pregnancy rate
50.0%
43.5%
Moderate OHSS
2.1%
10.6%
Severe OHSS 0%
4.2%
Schmidt et al., 2007

41. Half dose/low dose hCG & OHSS?
Observational pilot study
2.500 vs IU hCG
n = 21 OHSS high-risk patients
62% ongoing pregnancy rate
0 % OHSS
Nargund et al., 2007
Craft, 2007

42. Reduction of follicles Trigger of final oocyte maturation:
OHSS Prevention
Ovarian stimulation
Reduction of follicles
Trigger of final oocyte maturation:
Luteal phase
GnRH-antagonist instead of GnRH-agonist long
Delayed FSH start
Natural cycle IVF
Cycle cancellation
In vitro Maturation
Coasting
early aspiration of small follicles
unilateral follicular aspiration
GnRH-agonist instead of hCG
Reduced dose hCG
Recombinant LH instead of hCG
hCG free luteal phase support
Luteal phase GnRH-antagonist administration
Elective cryopreservation of embryos

44. Clinical pregnancy rate per ET
Griesinger, GebFra 2006

45. Novel concept: Luteal phase antagonist
hCG
3 days later….
early
OHSS
GnRH-antagonist daily
GnRH-antagonist daily
FSH
Works only for early onset OHSS
Report on 3 cases with
early-onset OHSS
Lainas et al., RBMonline 2007

46. Novel concepts: cabergoline
VEGF

47. Novel concepts in treatment: Cabergolin Background:
Vascular fluid leakage
VEGF
VEGF R1
Cabergoline
Dopamine R
agonist
Alvarez et al, JCEM 2007

48. RCT: placebo-controlled Intervention: Cab 0.5 mg, day hCG  hCG+8
Patients: oocyte donors
Inclusion: > 20 oocytes retrieved
cabergoline
n=37
7 (20%)
OHSS II:
OHSS III: 4 (11.4%)
placebo
n=32
OHSS II: 14 (43.5%)
OHSS III: 6 (18.8%)
OHSS is statistically significant, whereas OHSS III is not.
Ongoing-term pregnany rate: 39 and 42%
So it appears as if Cabergoline is able to significantly alleviate the symptoms of OHSS. As Cabergoline is considered a safe drug, even when administered in pregnancy, I think that Cabergoline deserves testing in further trials.
Alvarez et al, JCEM 2007 & Alvarez, Hum Reprod 2007

49. GnRH-antagonist coasting Reduced dose of hCG Luteal phase antagonist
OHSS prevention
Agonist trigger
± freezing
GnRH-antagonist coasting
Reduced dose of hCG
Luteal phase antagonist
+freezing
cabergoline