georg griesinger uk-sh, campus luebeck germany. we have a problem…

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√ √