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Georg GriesingerUK-SH, Campus Luebeck
Germany
OHSSdeath of a 31-year-old woman …who developed a
fatal adult respiratory distress syndromeFineschi 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
........................
We cannot reliably
predict which
patients will
develop OHSS …
We have another problem…
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 OHSS efficacy?natural cycle IVF: no OHSS efficacy?
….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!?
Gonen et al., 1990
antagonist
agonist
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
1 2 3 4 5 6 7 8 9 10 11
200 IU recombinant FSH
cycle days
antagonist 0.25 mg
10.000 IU hCG TRIPTORELIN 0.2 mg
≥ 3 follicles≥ 17 mm
Progesterone 90-600mg vaginallyProgynova 2 x 2 mg orallyLuteal phase support
Kolibianakis et al., 2005; Humaidan et al., 2005
No difference between0.2 triptorelin/0.5 mg buserelin vs. 10.0000 hCGLuteal 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
Progesterone serum values withNOluteal phase supplementation
Beckers et al., 2003
Day of administration of GnRH-a or hCG
Will it prevent OHSS?
Kol S, Fertil Steril 2004
Does GnRH-agonist triggering prevent OHSS?
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
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
Griesinger et al., Hum Reprod 2007
Update of Griesinger et al., Hum Reprod 2007
Update of Griesinger et al., Hum Reprod 2007
0 10 20 30 40 500
10
20
30
40
50
weeks
live
bir
th r
ate
[%
]
0 1 2 3 4 5 60
10
20
30
40
50
transfer cycles
live
bir
th r
ate
[%
]
Cu
mu
lati
ve i
nci
den
ce o
f p
osi
tive
hC
G t
est
lead
ing
to l
ive b
irth
Mean number of ETs:
2.1
Mean number of embryos
transferred
2.1
Mean time-to-conception
21 weeks
(Jan/08)
German multi-centric studyGnRH-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
hCG dose Luteal phase support
Clinical or ongoing
pregnancy rate
Humaidan, 2006
RCTn=13
1500 IU 35h after buserlin
90 mg vag. P + 4mg oral E2
46.0% (6/13)
Humaidan, 2007
RCTn=100
1500 IU 35h after buserlin
90 mg vag. P + 4mg oral E2
40.5% (XX)
Shapiro, 2007
Retrospective
n=45
1000-2500 IU hCG on day of
leuprolide
E2 and P supplement
s
53.3% (24/45)
50 mg IM P in oil daily + 0.3 transdermal E2 every 2nd day, starting the evening after oocyte retrieval, continuing until a positive heart beat
GnRH-agonist hCG
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√ √