Transcript Conclusions - IVF Israel

Prevention of OHSS
S. Kol, May 2006
OHSS – scope of the problem
• Severe form: 0.2-1% of stimulation cycles.
• Mortality: 1:45,00 to 1:50,000 per infertile
women receiving gonadotropins.
WHO 2001
OHSS: incidence, recent data
• Two large trials, 1458 patients, agonistbased protocol, comparing Menopur and
Gonal F (Arce and Sorensen, ASRM 2005)
• Patients at high risk for OHSS - “dropouts”.
• Moderate – severe OHSS: 2%
F&S January 2006
Objective: to determine OHSS incidence in 2,524 antagonist-bas
cycles (1801 patients).
Results: fifty three patients (2%) were hospitalized because of OH
Conclusions: clinically significant OHSS is a limitation even in
antagonist cycles.
“There is more than ever an urgent need for alternative final oocy
maturation – triggering medication”
Morbidity
•
An autopsy case of ovarian hyperstimulation syndrome with massive pulmonary edema and pleural
effusion.
•
Case report: delirium associated with ovarian hyperstimulation syndrome.
•
Cortical vein thrombosis misinterpreted as intracranial haemorrhage in severe ovarian
hyperstimulation syndrome: case report.
•
Subclavian deep vein thrombosis associated with the use of recombinant follicle-stimulating hormone
(Gonal-F) complicating mild ovarian hyperstimulation syndrome.
•
A severe case of ovarian hyperstimulation syndrome: 65 liters of ascites aspirated in an on-going IVFET twin pregnancy.
•
Central retinal artery occlusion associated with severe ovarian hyperstimulation syndrome.
•
A case of forearm amputation after ovarian stimulation for in vitro fertilization-embryo transfer.
•
Stroke in ovarian hyperstimulation syndrome in early pregnancy treated with intra-arterial rt-PA.
•
Internal jugular vein thrombosis: a late complication of ovarian hyperstimulation syndrome despite
mini-dose heparin prophylaxis.
and more and more…
Past predictions of the future
• “We don’t like their sound, and guitar music is on
the way out” Decca Recordings Co. rejecting the
Beatles, 1962.
• “Stocks have reached what looks like a
permanently high plateau”. Irving Fisher, Professor
of Economics. Yale University, 1929.
• “$100 million is way too much to pay for
Microsoft” IBM 1982.
• “Who the hell wants to hear actors talks?” H.M.
Warner, Warner Brothers, 1927.
“Severe OHSS will remain a complication of IVF cycles
despite all attempts of prevention.” R.G. Forman, Human
Reproduction 14:2687, 1999.
“…absolute prevention will not be possible” García-Velasco et al
F&S, March 2006.
Accepted preventive strategies
•
•
•
•
•
•
Canceling the cycle
Coasting
Albumin IV
Cryopreservation
Recombinant LH
Low hCG dose
Coasting
• Most popular choice.
• Open questions: for whom? how many days? Safe value to
give hCG? Magnitude of E2 drop?
• Cochrane database: D'Angelo A, Amso N. Coasting for
preventing ovarian hyperstimulation syndrome. The
Cochrane Database 2002 “There is a lack of randomised
controlled trials…there is insufficient evidence to
determine if coasting is an effective strategy for preventing
OHSS.”
IV albumin
• Conflicting results.
• Cochrane database: Aboulghar M, Evers JH, Al-Inany H.
Intra-venous albumin for preventing severe ovarian
hyperstimulation syndrome. The Cochrane Database of
Systematic Reviews 2002: “Clear benefit from
administration of intra-venous albumin at the time of
oocyte retrieval in prevention of severe OHSS in highrisk cases”.
Intravenous albumin does not prevent moderate-severe ovarian hyperstimulation
syndrome in high-risk IVF patients: a randomized controlled study. Bellver at al 2003
The questionable use of albumin for the prevention of ovarian hyperstimulation syndrome
in an IVF programme: a randomized placebo-controlled trial. Ben-Chetrit et al 2001
Personal communication with Professor Aboulghar: review amendm
albumin is ineffective.
Cryopreservation
• OHSS can be severe until menses.
• Cochrane database: D'Angelo A, Amso N. Embryo
freezing for preventing ovarian hyperstimulation
syndrome. The Cochrane Database of Systematic
Reviews 2002, “insufficient evidence to support
routine cryopreservation and insufficient evidence for
the relative merits of intra-venous albumin versus
cryopreservation“
Recombinant LH
• Not available as trigger.
• No data on OHSS prevention.
• In theory, will not prevent late, pregnancyassociated, OHSS.
Low hCG dose
• Questionable, unreliable.
• “Reducing the dose of hCG does not
eliminate the risk of OHSS in a high risk
group” Schmidt el al, Fertility Sterility October 2004
“Severe OHSS will remain a complication of IVF cycles
despite all attempts of prevention.” R.G. Forman, Human
Reproduction 14:2687, 1999.
Total OHSS prevention can only be achieved
by ovulation triggering with a GnRH agonist.
The GnRHa-induced LH/FSH surge
• LH and FSH levels rise 4 and 12 hours post
trigger, respectively.
• LH surge lasts for 24 hours.
• Surge amplitude comparable to physiology.
• A single agonist dose reliably triggers
ovulation.
Itskovitz et al 1991
Luteal phase
• Normal early follicular-luteal shift in
ovarian steroidogenesis.
• Short luteal phase: early luteolysis.
Case-control study
(Lewit et al Hum Reprod 11:1399, 1996)
• 16 patients who developed severe OHSS
when hCG was given as trigger (group A).
• Each patient underwent at least 1 cycle
during which GnRH agonist was given as
trigger (triptorelin 0.2 mg, group B).
• In group B – no OHSS!!!
Stimulation variables
Group
hCG
E2 max (pmol/l) No. oocytes No. hMG amp
16,969±8,948
28±11
24±6
GnRH-a 20,816±9,568
36±14
21±4
Lewit et al
Oocyte quality
Group
FZ
Atretic
GV
NVS
PB
hCG
6(3%)
8(4%)
10(5%)
10(5%)
180 (84%)
214
11(4%)
15(6%)
19(7%)
7(3%)
205(80%)
257
GnRH-a
Total
Lewit et al
Limitations
• Prospective study – ethical dilemma?
• Not applicable in agonist-based cycles:
unresponsive pituitary.
Use
antagonists???
Efficacy GnRHa vs hCG for triggering of final
oocyte maturation
Fauser et al, JCEM Feb. 2002, 87:709
•
•
•
•
Objective: Can agonists trigger ovulation as
effective as hCG?
Randomized prospective multi-center study.
Antagonist-based cycles, normal responders.
Outcome measures: number of metaphase II
oocytes
Protocol
Fauser et al, 2002
Clinical outcome (mean±SD)
Triptorelin
(n=17)
Leuprorelin
(n=15)
hCG
(n=15)
Number of oocytes/subject
9.8 ± 5.4
8.7 ± 4.5
8.3 ± 3.3
Proportion of metaphase II oocyte
72 ± 18%
85 ± 17%
86 ± 17%
Fertilization
61 ± 30%
62 ± 23%
56 ± 18%
No. of embryos obtained per
subject, grades 1 and 2 pooled
2.7 ± 34%
3.2 ± 2.6
3.3 ± 2.0
Implantation rate
15 ± 34%
18 ± 37%
7 ± 14%
18%
20%
13%
Ongoing pregnancy rate
Fauser et al, 2002
Serum concentrations of LH (hCG), FSH, E2 and P
Fauser et al, 2002
Can this approach
prevent OHSS?
Human Reproduction, September 2000
Use of a single bolus of GnRH agonist
triptorelin to trigger ovulation after
GnRH antagonist ganirelix treatment in
women undergoing ovarian stimulation
for assisted reproduction, with special
reference to the prevention of ovarian
hyperstimulation syndrome: preliminary
report: Short communication
J. Itskovitz-Eldor et al
Treatment scheme for
high responders
Day 2-3
menses
Day 6
rFSH
High responder triptorelin 0.2mg
Rec FSH
OPU
ganirelix
ET
Progesteron
e
Stimulation characteristics of 8 women with increased
risk for developing OHSS and who received 0.2 mg
triptorelin for triggering ovulation
a
Sub.
rFSH (IU)
Foll11mm
7
1350
22
33
1500
39
E2 pg/ml
Oocytes
%MII
2980
29
100
21
3660
14
100
1950
24
3350
30
90
108a 1875
22
1
100
109
1275
28
7670
52
54
112
1575
34
4050
30
93
126
2175
22
3690
15
67
158
1575
28
3020
16
56
Empty follicle syndrome
6410
No OHSS !!!
Results
• Mean no. of follicles>11mm=25.1±4.5
• Median E2 (pg/ml)=3675 (range 2980–7670)
• Mean number of oocytes=23.4 (±15.4), 83% MII
• Mean number of embryos=15.4±6.6
• 7 ETs from fresh embryos: 1 pregnancy
• 17 ETs from frozen-thawed embryos: 4
pregnancies
Itskovitz et al, 2000
Median values of serum LH and E2
after injection of triptorelin 0.2mg
Time after injection
(n=8)
Serum LH
(IU/l)
Serum estradiol
(pg/ml)
Pre-dose
0.5 h
1h
2.4
12.7
14.3
4775
4630
4505
2h
4h
10-12 h
Day of OPU
73.7
219
71.0
7.9
5080
5540
6000
2375
Day of ET
First week post-ET
0.8
1.0
963
145
Itskovitz et al, 2000
Mechanism
What is the mechanism of OHSS prevention?
Lower levels of inhibin A and pro-alpha C
during the luteal phase after triggering oocyte
maturation with GnRH agonist versus hCG
Nevo et al, Fertil Steril 79:1123, 2003
Clinical characteristics
Nevo et al, 2003
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
Evidence-based medicine
• We need a RCT in the context of OHSS prevention.
• Study group: agonist trigger, control group: hCG
trigger.
• The ethical problem of exposing high-responders to
the risk of OHSS.
Prevention of OHSS with the use of GnRH
agonist to trigger final oocyte maturation after
cotreatment with GnRH antagonist in patients
with PCOS or previous high response
undergoing IVF treatment - a prospective
randomized clinical trial.
L. Engmann, A. DiLuigi, D. Schmidt, J. Nulsen,
D. Maier, C. Benadiva
University of Connecticut
ASRM October, 2005
Study Design
•< 40years, FSH < 10 with
•PCOS or PCO Morphology
• Or Previous High Response
Randomization
N=13
N=12
Dual suppression OCP’s & luprolide
OCP’s + Ganirelix
HCG trigger
luprolide trigger
LUTEAL SUPPORT:
E2 patches 0.1 mg X 3, qod
P4 in oil, 50 mg/day;
MONITOR E2+P4 LEVELS!
Engmann et al
Incidence of OHSS
(April 2006 update)
%
50
45
40
35
30
25
20
15
10
5
0
Control N=27
Treatment N=25
P<0.001
OHSS
Mild OHSS
Moderate Severe OHSS
OHSS
Engmann et al
Outcome
(April 2006 update)
80
70
65.4%
60%
51.9%
60.7%
60
48.1%
50
%
56%
37.2%
31.7%
40
Control
Treatment
30
20
10
0
Positive BHCG
Implantation
Clinical
Ongoing
rate
Pregnancy rate Pregnancy rate
Engmann et al
Agonist n=15
hCG n=13
oocytes
19.8±2.5
19.5±1.9
Mature oocytes
17.7±2.9
16.4±2.2
Fertilization rate
57%
51%
E2 trigger day (pmol/l)
9595±996
8081±711
Clinical pregnancy
3/15
4/13
Ovarian volume (day of ET, cm3)
421±100*
846±164
OHSS
0/15*
4/13
*p<0.05
Babayof et al HR May 2006
Agonist trigger in normal responders?
Since there are no ethical problems, we can trigger with agonist, although
there is no reason to look for a substitute to hCG:
• GnRH agonist (buserelin) or hCG for ovulation induction in GnRH
antagonist IVF/ICSI cycles: a prospective randomized study. HR
Humaidan et al, May 2005.
• A lower ongoing pregnancy rate can be expected when GnRH agonist
is used for triggering final oocyte maturation instead of HCG in
patients undergoing IVF with GnRH antagonists. HR Kolibianakis et
al, October 2005.
• GnRH agonist for triggering final oocyte maturation in the GnRH
antagonist ovarian hyperstimulation protocol: a systematic review and
meta-analysis. HR Update Griesinger et al, March 2006.
The importance of luteal support?
reference
E2 trigger
oocytes Clinical
Ongoing
day (pmol/l)
pregnancy pregnancy
Luteal support
Humaidan
et al
7100
8.4
Vag gel prog. 8%,
p.o. estradiol 4
mg, for 12 days
Kolibianakis
et al
7067
10.2
Fauser
et al
4070 (trip)
2590 (leu)
6%
5.6% (Brussels) Vag tab prog 600
2.9% (Lübeck) mg, p.o. estradiol
4 mg. untill 7 W
9.8
8.7
18%
20%
Babayof et al 9595
19.8
20%
Engmann
et al
16
60%
8410
50 mg
progesterone IM
for 2 weeks
Progesterone
50mg IM, p.o.
estradiol 4 mg
56%
0.1mg E2 patches
Progesterone 50
IM until 7 W
IVF Haifa: retrospective data analysis
•
•
•
•
107 high responders, 2004-5
E2 max (pmol/l)=17,268±6305
No. oocytes: 30±7.3
No. embryos: 15.2±6.5
Fresh ET
Thaw ET
n
103
160
Positive βhCG
25 (24%)
75 (47%)
Ongoing/delivery
12 (48%)
45 (60%)
miscarriage
4 (16%)
13 (17%)
biochemical
9 (36%)
17 (23%)
Endometrial effect of high E2 levels
• High serum estradiol concentrations on the day of HCG
injection are detrimental to uterine receptivity without
affecting embryo quality. Simon et al, HR, 1995.
• Implantation rate was significantly higher in normal
(18.5%) as compared with high (0%) responders. Pellicer et
al FS, 1996
Summary
• Agonist trigger is an effective alternative to hCG. Its use is associated with
dramatic and irreversible luteolysis.
• This remarkable phenomenon can be utilized to completely and reliably
prevent OHSS, even in extreme ovarian response.
• Aggressive luteal support is necessary.
• Agonist trigger in high responders is associated with low fresh cycle
pregnancy rate, probably due to the extremely high E2 levels.
• Thaw cycles with embryos obtained after agonist trigger yield good
pregnancy rate.
• Agonist trigger offers no advantage in normal responders.
• Agonist trigger is the perfect patient-tailored safe-gate if a patient hyperresponds.
[email protected]
Thank you