Transcript NEW STRATEGIES FOR OHSS PREVENTION

NEW STRATEGIES FOR
OHSS PREVENTION
Ali Rüştü Ergür, M.D., Assoc.Prof.
GATA Haydarpaşa Hospital
The 2nd Congress of Current Opinion in Reproductive
Medicine and Assisted Reproductive Technologies and
1st Congress of the Society of Reproductive Medicine
Çeşme-İzmir, April 20, 2008
THE GOOD
THE BAD
THE UGLY
OHSS (OVARIAN
HYPERSTIMULATION SYNDROME)
SHOULD BE ACCEPTED THE MOST
SERIOUS AND DETRIMENTAL
COMPLICATION OF OVARIAN
STIMULATION
OHSS (OVARIAN
HYPERSTIMULATION SYNDROME)
WHY THE MOST SERIOUS AND
DETRIMENTAL ?
1.
2.
3.
4.
Marked extravascular exudate,
Profound intravascular depletion,
Hemoconcentration
Increased blood coagulability
(Rizk and Aboulghar, 2005)
OHSS (OVARIAN
HYPERSTIMULATION SYNDROME)
Acute fluid shift out of the intravascular space
Ascites
Hydrothorax
Generalized edema
Major electrolyte imbalance
Reduced renal perfusion
Marked hemoconcentration
Vascular complications
OHSS (OVARIAN
HYPERSTIMULATION SYNDROME)
End-stage complications;
•
•
•
•
•
Liver dysfunction
Respiratory complications
Renal complications
Vascular complications
Death
OHSS (OVARIAN
HYPERSTIMULATION SYNDROME)
HIGH RESPONDERS
PREVENTION OF OHSS
• Level 1 :
• Level 2 :
Patient identification at risk
• Level 3 :
• Level 4 :
Proper monitorization
• Level 5 :
• Level 6 :
Prevention of pregnancy occurrence
Organization of ovarian stimulation
for a required but less follicular development
Decreasing the developing follicles
and rapid estradiol increase
Medical treatment and hospitalization
PREVENTION OF OHSS
LEVEL 1: Patient identification at risk
• Patients with PCOS/Hyperandrogenic chronic
anovulation (HCA)
• Previous OHSS history
• Oligomenorrhea or amenorrhea
• High LH/FSH ratio
• Polycystic appearance of ovaries by
sonography
• Young age < 35 years old
• Egg donors
PREVENTION OF OHSS
LEVEL 2: Ovarian stimulation for a
required but less follicular development
• Low doses of gonadotropins (100-150 IU/day)
• Minimal stimulation protocols
(CC/gonadotropin/antagonist)
• Dual suppression with OCP and GnRH-a
• Use of GnRH antagonist vs. agonist
• HCG dose and alternatives
• Metformin
PREVENTION OF OHSS
LEVEL 2: Low Dose Gonadotropins
Low dose gonadotropin therapy (75 IU), Homburg and Howles, 1999
• Low dose gonadotropin therapy, 75-150 IU/day, is
effective for the prevention of OHSS whether
gonadotropin is urinary or recombinant
El-Sheikh MM, 2001
Golan A, 1988
Homburg R, 2002
VanWely M, 2003
Gorry A, 2006
PREVENTION OF OHSS
LEVEL 2: Low Dose Gonadotropins
Marci R, 2001
PREVENTION OF OHSS
LEVEL 2: Low Dose Gonadotropins
Ragni G, 2006
PREVENTION OF OHSS
LEVEL 2: Low Dose Gonadotropins
•
OHSS risk is lower in low dose regimens
Koundouros, 2008
PREVENTION OF OHSS
LEVEL 2: Minimal Stimulation Protocols
Minimal Stimulation Protocol
CC/Gonadotropins/Antagonist
Advantages
1. Reduced cost
2. Friendlier IVF
3. Acceptable pregnancy rates/transfer
4. Less OHSS
Disadvantages
1. High rate of cancellation and lack of transfer
2. Less oocytes
3. No excess of embryos for cryopreservation
PREVENTION OF OHSS
LEVEL 2: Minimal Stimulation Protocols
Minimal Stimulation Protocol
CC/Gonadotropins/Antagonist
Author
Protocol
Weigert (2002)
CC 100 mg days 3-7
Rec FSH-LH (300 IU) on alternate days
Williams (2002)
CC 100 mg days 3-7
Gonadotropins (150 IU) starting on day 9
Engel (2002)
CC 100 mg days 3-7
Gonadotropins (225 IU) starting on day 8
Antagonist starting day 8
Hwang (2003)
CC 100 mg days 3-7
Gonadotropins (150 IU) on alternate days
Antagonist on follicle 14 mm<
PREVENTION OF OHSS
LEVEL 2: Minimal Stimulation Protocols
Minimal Stimulation Protocol
CC/Gonadotropins/Antagonist
Author
Oocytes
Preg. Rate/Tr. %
Weigert (2002)
7.7±3.6
43
Williams (2002)
3.9±2.2
38
Engel (2002)
6.4±4.8
26
Hwang (2003)
8.0±3.2
35
PREVENTION OF OHSS
LEVEL 2: Minimal Stimulation Protocols
Minimal Stimulation Protocol
CC/Gonadotropins/Antagonist
1. Pregnancy rate per transfer comparable with
the long agonist protocol
2. No severe OHSS in all studies
3. This protocol should be considered as an
option in patients with OHSS risk
PREVENTION OF OHSS
LEVEL 2: Dual suppression with OCP
and GnRH-a
Protocol
1. Low dose OCP (35µg) for 25 days
2. GnRH agonist on day 21 of OCP
3. 150 IU of gonadotropins on the 3rd day
of menstrual bleeding with GnRH-a
Damario, 1997
PREVENTION OF OHSS
LEVEL 2: Dual suppression with OCP
and GnRH-a
Damario, 1997
PREVENTION OF OHSS
LEVEL 2: Dual suppression with OCP
and GnRH-ant
Rombauts, 2006
PREVENTION OF OHSS
LEVEL 2: Use of GnRH antagonist vs. agonist
Advantages
1. Lower peak E2 levels
2. Reduced number of oocytes
3. GnRH-a use for ovulation triggering as a
substitute for hCG
Disadvantage
1. Lower pregnancy rate compared to long
agonist protocol
PREVENTION OF OHSS
LEVEL 2: Use of GnRH antagonist vs. agonist
Ludwig, 2001
PREVENTION OF OHSS
LEVEL 2: Use of GnRH antagonist vs. agonist
Ragni G, 2005
PREVENTION OF OHSS
LEVEL 2: Use of GnRH antagonist vs. agonist
PREVENTION OF OHSS
LEVEL 2: Use of GnRH antagonist vs. agonist
GnRH antagonist protocol is a short and
simple protocol with good clinical outcome,
but the lower pregnancy rate compared
with the GnRH agonist long protocol and
the non-significant difference between
both protocols regarding prevention of
premature LH surge and prevention of
severe ovarian hyperstimulation syndrome
Al-Inany, 2002
PREVENTION OF OHSS
LEVEL 2: Use of GnRH antagonist vs. agonist
Data between the GnRH antagonist group (group I) and the GnRH agonist
group (group II)
Group I (n=73)
Group II (n=75)
Total recombinant FSH (IU)
2052.1±375.05
2138±407.3
Days of stimulation
9.3±1.5
9.6±1.4
Days of antagonist
1.86±0.73
Estradiol (pg/ml)
1900±562
2140±730
Oocytes donated
13.8±3.2
14.3±2.7
Fertilization rate (%)
73
79
Embryos transferred
2.34±0.77
2.36±0.73
Mild hyperstimulation
2 (2.73)
3 (4)
Clinical pregnancy/cycle started 29 (39.72)
31 (41.33)
Implantation (%)
23.9
25.4
Twins
3 (10.34)
4 (12.9)
Triplets
1 (3.44)
0 (0)
Prapas N, 2005
PREVENTION OF OHSS
LEVEL 2: Use of GnRH antagonist vs. agonist
Effects of GnRH antagonist cotreatment on
the incidence of ovarian hyperstimulation
syndrome remains uncertain, although a
trend is present in favour of the GnRH
antagonists
Tarlatzis, 2006
PREVENTION OF OHSS
LEVEL 2: Antagonist in GnRH Analog Cycles
• Retrospective study
• 87 patients with long agonist protocol or
microdose flare protocol
• Agonists discontinued and ganirelix
acetate started and continued till E2
dropped to less than 3000 pg/ml and
appropriate of follicles
Gustofson, 2006
PREVENTION OF OHSS
LEVEL 2: Antagonist in GnRH Analog Cycles
Gustofson, 2006
PREVENTION OF OHSS
LEVEL 2: HCG Dose and Alternatives
•
•
HCG similar to LH
Longer half-life than LH
SO….
1. Reduce hCG dose
2. Recombinant hCG ?
3. GnRHa (for gonadotropin only cycles or
antagonist cycles)
PREVENTION OF OHSS
LEVEL 2: HCG Dose and Alternatives
Pregnancy outcome in GnRH agonist versus hCG group
Patients (n)
Rate of ET [n (%)]
No. of ET [mean (range)]
Positive hCG per ET [n (%)]
Clinical pregnancy [n (% )]
Implantation rate (n)
Early pregnancy loss [n (%)]
Buserelin
hCG
P
55
48 (87)
1.71 (1–2)
14 (29)
3 (6)
3/893
11 (79)
67
57 (85)
NS
1.64 (1–2) NS
25 (44)
>0.10
24 (36)
0.002
3/97
<0.001
1 (4)
0.005
Humaidan, 2005
PREVENTION OF OHSS
LEVEL 2: HCG Dose and Alternatives
Cycle outcome after agonist and HCG triggering of final
oocyte maturation
Centre 1
Centre 2
Agonist
HCG
Agonist
HCG
Patients
18
Patients OPU
18
Patients ET
15
Positive HCG
16.7% (3/18)
Ongoing preg. Rate 5.6%(1/18)
Early pregnancy loss 66.7% (2/3)
24
24
20
45.8% (11/24)
41.7%(10/24)
9.1% (1/11)
34
32
29
17.6% (6/34)
2.9%(1/34)
83.3% (5/6)
30
30
28
20.0% (6/30)
16.7% (5/30)
16.7% (1/6)
Kolibiniakis, 2005
PREVENTION OF OHSS
LEVEL 2: HCG Dose and Alternatives
Acevedo, 2006
PREVENTION OF OHSS
LEVEL 2: HCG Dose and Alternatives
• Conclusions
– No differences in the number of MII,
fertilization rate and embryo quality
– Lower pregnancy and implantation rates
– Higher miscarriage rates
For the agonist trigger in IVF patients
PREVENTION OF OHSS
LEVEL 2: Metformin
Comparison of metformin versus placebo or no treatment
in IVF with outcome of OHSS
The risk of OHSS in PCOS women undergoing IVF was
reduced with metformin.
Costello, 2006
PREVENTION OF OHSS
LEVEL 3: Proper Monitorization
• USG
– PCOS patterns
– Large number of follicles
• E2
• Good predictor to OHSS
Aboulghar, 2003
PREVENTION OF OHSS
LEVEL 4: Decreasing the developing follicles
and rapid estradiol increase
• Coasting
– Withholding gonadotropin administration for
one or more days
– GnRH agonist is continued
– hCG is given when the estradiol levels drop to
a safe level (generally <3000 pg/ml)
PREVENTION OF OHSS
LEVEL 4: Coasting
Comparison of criteria used for coasting
Reference
Sher (1995)
Benavida (1997)
Tortoriello(1998)
Dhont (1998)
Lee (1998)
Egbase (1999)
Wald. (1999)
Fluker (1999)
Al-Shawaf (2001)
Ulug. (2002)
No. coasted E2 initially (pg/ml) E2 (pg/ml) at hCG
51
22
22
120
20
15
65
63
50
207
>3000
>3000
>3000
>2500
>2724
>6000
Variable
>3000
>3595
>4000
<3000
<3000
<3000
<2500
Decreasing
<3000
<2724
25% decline
<2724
<4000
Coasting duration (days)
6.1 (3–11)
1.9 ± 0.9
2.6 ± 0.3
1.9 ± 0.8
2.8 ± 1.3
4.9 ± 1.6
4.3 (3–6)
3.4 ± 0.1
3.4 ± 1.6
2.9 ± 0.11
Levinsohn, 2003
PREVENTION OF OHSS
LEVEL 4: Coasting
ICSI outcome according to the number of coasting days
Group I <3 days
No. of cycles
983
Age (years)
30.16 ± 4.55
Infertility period (years)
6.59 ± 4.16
HMG amp. per cycle
31.76 ± 9.97
E2 coasting level (pg/ml) 6150 ± 1760
E2 HCG level (pg/ml)
2674 ± 789
Oocytes retrieved
16.45 ± 6.26
MII oocytes
12.94 ± 5.58
2 PN oocytes
8.16 ± 4.39
Embryos per transfer
2.99 ± 0.69
Fertilization rate (%)
62.67
Implantation rate (%)
26.32
Clinical pregnancy rate (%)51.96
Group II >4 days
P
240
29.89 ± 4.91
6.56 ± 3.86
30.38 ± 9.03
7473 ± 2320
2801 ± 930
14.93 ± 6.01
11.60 ± 5.6
7.53 ± 4.59
3.03 ± 0.66
64.92
18.16
35.88
NS
NS
NS
0.0001
NS
0.002
0.003
NS
NS
NS
0.0001
0.0002
Mansour, 2005
PREVENTION OF OHSS
LEVEL 4: Coasting
ICSI outcome of patients who developed severe OHSS
No. of cycles
Age (years)
Infertility (years)
HMG amp.per cycle
E2 level-coasting (pg/ml)
E2 level-HCG (pg/ml)
Oocytes retrieved
Metaphase II oocytes
Two-pronuclear oocytes
Embryos per transfer
Fertilization rate (%)
Implantation rate (%)
Clinical pregnancy rate (%)
16
29.06 ± 9.08
6.23 ± 5.29
28.94 ± 9.15
6412 ± 3327
4916 ± 2704
20.06 ± 7.91
15.40 ± 7.16
9.25 ± 4.99
3.07 ± 0.47
42.37
58.87
80.00
Mansour, 2005
PREVENTION OF OHSS
LEVEL 4: Coasting
Uluğ, 2004
PREVENTION OF OHSS
LEVEL 4: Coasting
Moreno, 2004
PREVENTION OF OHSS
LEVEL 4: Coasting
• Conclusions
– Effective for the prevention of OHSS
– Start coasting when the leading follicles 14-16
mm and estradiol levels 3000-4000 pg/ml
– Less than 4 days
– Till E2 drops to < 3000 pg/ml
– Prolonged coasting ( > 4 days ) can be
detrimental
PREVENTION OF OHSS
LEVEL 5: Prevention of pregnancy occurrence
• Cryopreservation of all embryos, no ET
– Significant decrease in the incidence of OHSS
if the ET cancelled
Wada, 1993
Ferraretti, 1999
Amso, 1990
Salat-Baroux, 1990
– Insufficient evidence to support routine
cryopreservation
Cochrane Review, 2002
PREVENTION OF OHSS
LEVEL 5: Prevention of pregnancy occurrence
Aboulghar, 2003
PREVENTION OF OHSS
Intravenous Albumin
• Having osmotic and transport functions
• 50 gr. IV at the OPU time
• Osmotic function only lasts < 36 h
• Cochrane Review-2002
– Significant reduction in OHSS
PREVENTION OF OHSS
Intravenous Albumin
Coasting is as effective as i.v. albumin in preventing OHSS in highrisk patients but yields inferior pregnancy rates
Chen, 2002
PREVENTION OF OHSS
Intravenous Albumin
No. of cycles
Age
PCOS
History of
severe OHSS
No. of
follicles ≥14 mm
Severe OHSS
Early severe OHSS
Late severe OHSS
Combined
severe OHSS
Clinical pregnancy/
embryo transfer
Multiple
pregnancy rate
First trimester
miscarriage rate
Albumin
Placebo
P value
38
29.3 ± 3.9
15/38 (39.5%)
37
29.1 ± 4.1
8/37 (21.6%)
NA
.87a
.09b
4/38 (10.5%)
4/37 (10.8%)
.96b
20.5 ± 5.2
8/38 (21.1%)
3 (7.9%)
2 (5.3%)
19.3 ± 3.6
6/37 (16.2%)
1 (2.7%)
2 (5.4%)
.30a
.59b
.61d
1.0d
3 (7.9%)
3 (8.1%)
1.0d
21/38 (55.3%)
23/37 (62.2%)
.54b
7/21 (33.3%)
7/23 (30.4%)
.90b
1/20 (5%)
4/23 (17.3%)
.35d
Not effective for OHSS prevention
Isikoglu, 2007
PREVENTION OF OHSS
Hydroxyethyl Starch
• Alternative to albumin
• Increases the oncotic pressure
• 1000 ml of hydroxyethyl starch at the time
of OPU
• Cheap and safer alternative to albumin
Graf, 1997
König, 1998
Gokmen, 2001
PREVENTION OF OHSS
Hydroxyethyl Starch
HES and albumin are effective for OHSS prevention
Gokmen, 2001
PREVENTION OF OHSS
Corticosteroids
• Effective
» Lainas, 2002
• Not Effective
» Tan, 1992
PREVENTION OF OHSS
Ketoconazole
NOT EFFECTIVE
Parsanezhad, 2003
PREVENTION OF OHSS
Renin-Angiotensin Blockage and Embryo Cryopreservation
• Cancellation of ET and dual RAS blockage with an
angiotensin receptor blocker and an angiotensinconverting enzyme inhibitor starting from day 1 after
oocyte retrieval. Embryos were cryopreserved and
transferred in subsequent cycles.
• Complete elimination of the syndrome is not possible
with this treatment.
• Subsequent pregnancy rates with the transfer of
frozen-thawed embryos are high.
Ata, 2008
PREVENTION OF OHSS
CABERGOLİNE
• Low dose cabergoline
• Reduced VEGFR2
• Reduced OHSS
(In Animals)
Gomez, 2006
• 0.5 mg for eight days after the day of OPU
• Does not affect ART outcome, prevent OHSS
Alvarez, 2006
PREVENTION OF OHSS
• Bone morphogenetic protein 15 (BMP15)
alleles
OHSS
(Francisco, 2006)
• Elective cryopreservation of all pronuclear
oocytes
(Griesinger, 2007)
• Coasting vs. GnRH Antagonist
(Aboulghar, 2007)
• Low dose hCG (2500 IU)
(Nargund, 2007)
PREVENTION OF OHSS
CONCLUSIONS
•
•
•
•
Patient and risk identification
Avoid flare protocols
Start low doses of gonadotropins
During ovarian stimulation
– Coasting
– GnRH antagonist
– Low doses of hCG
– Agonist as hCG trigger
– Dual suppression (OC + Agonist)
PREVENTION OF OHSS
CONCLUSIONS
• Stop gonadotropins and continue GnRH
agonist or antagonist
• Cryopreservation of all embryos or
pronuclear oocytes
• IV albumin or starch
• Corticosteroids
• Cycle cancellation and supportive follicular
aspiration
PREVENTION OF OHSS
CONCLUSIONS