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

What is the OHSS incidence in your center?

German IVF registry, 2006

Number of OHSS cases per year in Germany? 0,41 (incidence DIR) x ~40.000 IVF cycles with ovarian stimulation per year = 164 OHSS cases

= 1.080 OHSS III cases per year in Germany Hum Reprod. 2006 Dec;21(12):3235-40

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

........................ 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 ........................

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

Prediction Prevention Treatment

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

Can we reliably predict OHSS?

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.

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)

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

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

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 (39 - 159) 3,46%

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

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

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

GnRH -antagonists

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: 1.5 - 7.5 % Gustofson et al., Hum Reprod 2006 Gustofson et al., Fertil Steril 2006

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

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

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 ?

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

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

GnRH-agonist trigger Gonen et al., 1990

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

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

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

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

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

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

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

Cryopreservation slow cooling vitrification - 50.000°C/min 2 sec.

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

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

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

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

low dose hCG & OHSS? Retrospective study, n=94 cycles > 2,500 - 4,000 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

Half dose/low dose hCG & OHSS? Observational pilot study 2.500 vs. 5.000 IU hCG n = 21 OHSS high-risk patients 62% ongoing pregnancy rate 0 % OHSS Nargund et al., 2007 Craft, 2007

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

Clinical pregnancy rate per ET Griesinger, GebFra 2006

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

Novel concepts: cabergoline VEGF

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

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

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