OHSS Should this be treated or be prevented? When to cancel a

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OHSS
Should this be treated or be prevented?
When to cancel a cycle?
All cycles should be triggered with GnRH
agonist and not by hCG!
Shahar Kol, IVF Unit Rambam Health Care Campus and Macabbi Health Services, Haifa, Israel
November, 2011
Content
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How do we routinely trigger ovulation?
Is it in agreement with physiology?
Do we have other options?
The physiology of agonist trigger.
Agonist trigger main advantage: OHSS-free
clinic. No need to cancel cycles, ever.
• The advantage of agonist trigger for the
“normal responder”.
How do we routinely trigger ovulation ?
• We have only one option: hCG.
Is it in agreement with physiology?
• Adequate final oocyte maturation.
• Early luteal phase over-stimulation – main
reason for luteal phase defect in IVF.*
• No FSH surge.
hCG
*Fauser and Devroey, 2003
Do we have other options?
JCEM 2001
15,000+10,000 IU gave 20% live birth rate but with a 12% OHSS rate.
The physiology of agonist trigger.
LH surge
Humaidan et al, 2011
The physiology of agonist trigger.
FSH surge
Gonen et al, 1990
Does it make a difference? (1)
• Agonist trigger: more MII oocytes compared
with hCG trigger.
Humaidan et al, 2005, 2009
Imoedemhe et al, 1991
Octay et al, 2009
Does it make a difference? (2)
The pregnancy rate in completed cycles and the ongoing pregnancy rate per ET were
significantly higher in the study group (dual trigger) than in the control group (hCG only).
F&S 2008
Is it possible that in some patients FSH surge is needed?
Does it make a difference? (3)
The effect of adding 450 IU of FSH to the
hCG trigger.
Lamb et al, 2011
What happens after agonist trigger?
Complete luteolysis!
Induction of LH surge and oocyte maturation by GnRH analogue (Buserelin) in
women undergoing ovarian stimulation for IVF
“No signs of OHSS were observed in 2 patients who on previous
stimulation developed severe OHSS… GnRHa offers a new means by
which OHSS can be prevented.”
Itskovitz et al, Gynecological Endocrinology 1988, 2:Suppl1, 165.
Luteal phase
Natural cycle day 7-9=
75 pg/ml vs. 18
Natural cycle day 7-9=
750 pg/ml vs. 184
Nevo et al, 2003
“agonist trigger provides a safe and OHSS-free clinical environment”
Agonist trigger main advantage: OHSS-free
clinic. No need to cancel cycles, ever.
“The utilization of GnRH agonist for triggering ovulation in antagonist cycles has
been a breakthrough in the elimination of OHSS.”
16 publications
Ovulation
trigger
n
OHSS % (n)
RCT, high risk
Oocyte
source
own
GnRHa
hCG
Engamnn et al 2008
RCT, high risk
own
GnRHa
hCG
Acevedo et al 2006
RCT
donors
GnRHa
hCG
Bodri et al 2009
Retrospective
donors
GnRHa
hCG
Griesinger et al 2010
Observational,
High risk
RCT
own
GnRHa
15
13
33
32
30
30
1046
1031
40
0 (0/13)
31(4/13)
0 (0/33)
31 (10/32)
0 (0/30)
17 (5/30)
0 (0/1046)
1.3 (13/1031)
0 (0/40)
own
GnRHa
hCG
Engmann et al 2006
Retrospective, casecontrolled, high risk
own
GnRHa
hCG
152
150
23
23
0 (0/152)
2 (3/150)
0 (0/23)
4 (1/23)
Manzanares et al 2009
Retrospective casecontrol, high risk
own
GnRHa
hCG - cancelled
42
0 (0/42)
Hernandez et al 2009
Retrospective
donors
GnRHa
hCG
Orvieto et al 2006
Retrospective, high
risk
Retrospective, high
risk: agonist arm only
own
GnRHa
hCG
donors
GnRHa
hCG
254
175
82
69
32
42
0 (0/254)
6 (10/175)
0 (0/82)
7 (5/69)
0 (0/32)
1 (1/42)
Sismanoglu et al 2009
RCT
donors
GnRHa
hCG
Humaidan et al 2009
Observational, high
risk
own
GnRH, luteal rescue
with hCG 1500IU
44
44
12
0 (0/44)
7 (3/44)
8 (1/12)
Galindo et al 2009
RCT
donors
GnRHa
hCG
Melo at al 2009
RCT
donors
GnRHa
hCG
Shahrokh et al 2010
RCT, high risk
own
GnRHa
hCG
106
106
50
50
4
45
0 (0/106)
8 (9/106)
0 (0/50)
16(8/50)
0 (0/45)
15 (33)
Reference
Trial type
Babayof et al 2006
Humaidan et al 2009
Agonist: 2005 patients,
not a single case of OHSS!
hCG: 92 cases in 1810
patients, 5.1%
Shapiro et al 2007
Severe OHSS: Is it still a problem?
“In 2003-2005, 4 deaths (of the 12) were due to OHSS”.
~3 OHSS-related deaths per 100,000 ART cycles.
Three OHSS-related deaths (3:100,000 ART cycles), all had their embryos frozen.
Braat et al, 2010
Hyper-responder: How to prevent
OHSS + good clinical outcome?
• Trigger with agonist.
• Intensive luteal support.
OHSS high risk patients
Randomization
N=32
N=34
Dual suppression OCP’s & luprolide
OCP’s + Ganirelix
HCG trigger
luprolide trigger
Engmann, et al, 2008
LUTEAL SUPPORT:
E2 patches 0.1 mg X 3, qod
P4 in oil, 50 mg/day;
MONITOR E2+P4 LEVELS!
Engmann et al, 2008
How high can we go?
The advantage for the “normal responder”
antagonist
FSH/hMG
Agonist
trigger
OPU
36h
1,500 IU hCG
ET
4 days
1,500 IU hCG
Kol et al 2011
”The granulosa/luteal cells obtained on the
day of oocyte retrieval after agonist trigger
have the capacity to respond to hCG by
increasing the secretion of steroids.”
Engmann et al, 2011
Crystal ball: where are we heading?
In
Out
Antagonist-based protocols
“long agonist” protocols
Agonist trigger
hCG trigger
LH activity-based luteal support
Progesterone-based luteal support
Total OHSS elimination
~1% severe OHSS
Total OHSS elimination
OHSS-related death rate: 3:100,000
Patient friendly luteal phase
Painful P injections or leaky, messy
vaginal P.
Thank you

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