Georg Griesinger UK-SH, Campus Luebeck Germany

We have a problem…

OHSS 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., year old woman ……cerebral infarction….complete persistent hemiplegia Hwang et al.,

Ovarian stimulation hCG OHSS

We cannot reliably predict which patients will develop OHSS … We have another problem…

OHSS prediction GnRH-antagonist protocol 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! Papanicolaou et al., Fertil Steril 2006 OHSS III

Solutions to our problems … Don‘t do ovarian stimulation! IVM: no OHSSefficacy? natural cycle IVF: no OHSSefficacy? ….or develop ovarian stimulation routines that are associated with a per se decreased risk of OHSS!

OHSS incidence = 1.5% Hospital admission due to OHSS Kolibianakis et al., Hum Reprod Update 2006 Let‘s only use antagonist or ‚mild‘ stimulation!

The final solution to our problem… Abolish hCG as a triggering agent!?

Bolus dose of GnRH-agonist Gonen et al., 1990

antagonist agonist Competition

GnRH-agonist trigger Effect on oocyte competence? Effect on luteal phase? Efficacy of different protocols? Does it prevent OHSS? Protocols for OHSS prevention? Questions we need to ask

Initial protocols IU recombinant FSH cycle days antagonist 0.25 mg IU hCG TRIPTORELIN 0.2 mg ≥ 3 follicles ≥ 17 mm Progesterone mg vaginally Progynova 2 x 2 mg orally Luteal phase support Kolibianakis et al., 2005; Humaidan et al., 2005

No difference between 0.2 triptorelin/0.5 mg buserelin vs hCG Luteal phase: vaginal or i.m. P + oral E2  number of oocytes  number of MII oocytes  fertilisationrate  embryo Score BUT:  ongoing PR massively reduced! Hum Reprod Update 2006

Is the oocyte competence impaired? Good outcome from oocyte donation cycles Acevedo et al., Fertil Steril 2006 Shapiro et al., 2007 Bodri et al., Fertil Steril 2008 Good live birth rates in frozen-thawed cycles Eldar-Geva et al., RBMonline 2006 Griesinger et al., Fertil Steril 2007

How about the luteal phase? Fauser et al., 2002 Luteal phase supplementation with i.m. P

How about the luteal phase? Progesterone serum values with NO luteal phase supplementation Beckers et al., 2003 Day of administration of GnRH-a or hCG

Drastic luteolysis after GnRH-a… Will it prevent OHSS? Kol S, Fertil Steril 2004

Does GnRH-agonist triggering prevent OHSS? Trigger of final oocyte maturation General population OHSS risk population Oocyte donors ?RCThCGagonist Observational study agonist Griesinger et al., RBMonline 2006

OHSS I-II: RR with 95% confidence intervals (heterogeneity p = 0.57) OHSS III Update of : Griesinger et al., Hum Reprod Update 2005

ReferenceTrial typenOHSS Full publication Itskovitz-Eldor, 2000Observational, uncontrolled8No signs or symptoms of OHSS Kol and Muchtar, 2005Observational, uncontrolled6No OHSS leading to hospitalisation Engmann, 2006Retrospective, case-control23No case of OHSS Orvieto, 2006Retrospective, cohort82No case of severe OHSS Griesinger, 2007Prospective, observational20No case of severe OHSS Shapiro, 2007Retrospective, uncontrolled32No case of moderate/severe OHSS Bodri, 2008Retrospective, comparative547No case of moderate/severe OHSS Abstract Bracero, 2001Retrospective, comparative8No signs or symptoms of OHSS Meltzer, 2002Observational, uncontrolled35 1/35 (2.8%) (moderate OHSS requiring hospitalisation) Bankowski, 2004Retrospective, comparative97No case of severe OHSS Carone, 2005Observational, uncontrolled10No signs and symptoms of OHSS Chun, 2005Retrospective, cohort26 1/26 (3.8%) (severe, late-onset in pregnant woman) Erden, 2005Retrospective, cohort97Not reported Shapiro, 2005Retrospective, cohort30 No OHSS requiring aspiration of ascites Bukulmez, 2005Retrospective, comparative10None Bar-Hava, 2005Observational67 1/67 (1.4%) Hospital admission with mild OHSS Körösi, 2006Retrospective comparative25Not reported GnRH-agonist triggering in OHSS risk populations

Evidence from observational, uncontrolled trials 17 publications total n= 1,123 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; Shapiro et al., 2007 (oocyte donation); Bodri et al., 2008 (oocyte donation) Abstract: Bracero, 2001; Meltzer, 2002; Bankowski, 2004; Carone, 2005; Chun, 2005; Erden, 2005; Shapiro, 2005; Bukulmez, 2005; Bar-Hava, 2005; Körösi, 2006; Update of : Griesinger et al., RBMonline 2006

Spatially splitting agonist trigger + ET Oocyte donation √ Acevedo et al., Fertil Steril 2006 Shapiro et al., Fertil Steril 2007 Bodri et al., Fertil Steril 2008 Temporally splitting agonist trigger + ET Griesinger et al., Hum Reprod 2007 Avoiding the luteal phase

GnRH- antagonist stimulation OHSS risk? GnRH-agonist trigger Elective 2PN freezing Cryo-ET 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

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

Cumulative incidence of positive hCG test leading to live birth Mean number of ETs: 2.1 Mean number of embryos transferred 2.1 Mean time-to-conception 21 weeks (Jan/08)

German multi-centric study GnRH-agonist trigger & cryopreservation of 2 PN oocyte for OHSS prevention Study centres: Lübeck, Bonn, Wiesbaden, Würzburg, Erlangen, Köln, Augsburg, Bad Münder

Dual trigger: GnRH-agonist + low dose hCG Humaidan et al., RBMonline 2006 Humaidan et al., ESHRE 2007 Shapiro et al., Fertil Steril 2007 High dose luteal phase support Engmann et al., RBMoline 2006 Engmann et al., Fertil Steril 2008 Modifying the luteal phase

Low dose hCG + GnRH-a hCG doseLuteal phase support Clinical or ongoing pregnancy rate Humaidan, 2006 RCT n= IU 35h after buserlin 90 mg vag. P + 4mg oral E2 46.0% (6/13) Humaidan, 2007 RCT n= IU 35h after buserlin 90 mg vag. P + 4mg oral E2 40.5% (XX) Shapiro, 2007 Retrospective n= IU hCG on day of leuprolide E2 and P supplements 53.3% (24/45)

Prolonged, high dosed Luteal phase support 50 mg IM P in oil daily transdermal E2 every 2 nd day, starting the evening after oocyte retrieval, continuing until a positive heart beat GnRH-agonisthCG Ongoing or Live birth rate Engmann, 2006 (retrospective) 65.2 % (15/23)56.5 (13/23) Engmann, 2008 (RCT) 53.3 (16/30)48.3 (14/29)

Avoiding the luteal phase Modifying the luteal phase Temporally splitting agonist & ET Spatially splitting agonist & ET Dual trigger: low dose hCG High dosed i.m. progesterone + transdermal E2 OHSS risk patients Oocyte donors Feasible, OHSS reduction? Feasible, further studies needed √ √