Prevention of OHSS
Shahar Kol, IVF Unit Rambam Health Care
Campus, and Macabbi Health Services,
Haifa, Israel. February 2012
Content
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Scope of the problem
Preventive strategies
What really works
Physiology of the agonist trigger
Side benefits
Severe OHSS: is it still a problem?
Maternal deaths and rates per 100,000 ART procedures,
including IVF: United Kingdom: 1997–2005
Number
Rate
95% CI
Number of
treatment
cycles
1997– 1999
20
19.17
12.41–29.61
104,320
2000–2002
8
7.32
3.71–14.44
109,308
2003–2005
12
10.08
5.76–17.61
119,080
Deaths
Year
* Source Human Fertilisation and Embryology Authority
•
“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), all had their embryos frozen
Braat DDM, et al. Hum Reprod 2010;25:1782–1786
Incidence and prediction of OHSS in women
undergoing GnRH antagonist IVF cycles
● 2524 antagonist-based cycles (1801 patients)
● 53 patients (2%) were hospitalized because of OHSS
– Conclusions: clinically significant OHSS is a limitation even in
antagonist cycles
“There is more than ever an urgent need for alternative final
oocyte maturation – triggering medication”
Papanikolaou EG, et al. Fertil Steril 2006;85:112–120
Preventive strategies: coasting
● There was no evidence to suggest any benefit of withholding
gonadotrophins (coasting) after ovulation in IVF for the
prevention of OHSS
D’angelo A, et al. Cochrane Database Syst Rev 2011;(6):CD0028110
Preventive strategies: cryopreservation
● There is not enough evidence to show whether using frozen
embryos …can reduce OHSS in women who are at high risk
D’angelo A and Amso N. Cochrane Database Syst Rev 2007;(3):CD002806
Preventive strategies: intravenous albumin
● Intravenous (iv) colloid fluids … at the time of oocyte retrieval
may be beneficial for women with a high risk of developing
OHSS
● Borderline evidence of benefit with the routine use of human
albumin in the prevention of OHSS (1660 patients)
● Good evidence to support the use of hydroxyethyl starch in the
prevention of OHSS (487 patients)
Youssef MA, et al. Cochrane Database Syst Rev 2011; (2): CD001302
IV albumin for the prevention of severe OHSS: a
systemic review and meta-analysis
● 1199 patients
● IV albumin does not appear to reduce the occurrence of severe OHSS
Venetis CA, et al. Fertil Steril 2011; 95:188–196,196.e1–3
Preventive strategies: recombinant LH
European Recombinant LH Study Group. J Clin Endocrinol Metab
2001;86:2607–2618
Treatment arm
Parameters examined
5000 IU
rhLH
(n=39)
15,000 IU
u-hCG
(n=34)
30,000 IU
15,000 + 10,000 IU
rhLH
(n=39)
u-hCG
(n=41)
rhLH
(n=26)
u-hCG
(n=22)
rhLH
(n=25)
u-hCG
(n=24)
15.17 ± 8.34
15.46 ± 6.75
14.23 ± 5.61
14.00 ± 4.90
a
a
0.3007
11.84 ± 7.53
11.78 ± 6.75
12.62 ± 6.22
10.82 ± 5.70
a
a
0.1702
a
a
0.183
p (linearity)
No. of follicles >10 mm
14.03 ± 5.32
16.44 ± 6.95
No. of oocytes retrieved
10.23 ± 4.70
11.74 ± 6.27
Oocytes in metaphase II
85.5%
77.8%
No. of oocytes inseminated
9.82 ± 4.74
11.26 ± 5.73
11.63 ± 7.52
11.57 ± 6.57
12.38 ± 6.25
10.55 ± 5.74
a
a
0.1687
No. of embryos
5.42 ± 3.33
7.00 ± 4.68
6.65 ± 5.02
6.36 ± 4.68
7.67 ± 4.34
6.33 ± 5.19
a
a
0.0983
No. of embryos transferred
2.39 ± 0.60
2.48 ± 0.85
2.58 ± 0.6
2.52 ± 0.62
2.78 ± 0.8
2.67 ± 0.73
a
a
0.4310
Implantation rate
6.0 ± 0.16%
15.0 ± 0.31%
6.0 ± 0.19%
9.0 ± 0.24%
11.0 ± 0.26%
3.0 ± 0.09%
19.0 ± 0.33%
17.0 ± 0.33%
0.1373
Pregnancy (total)
15.4% (n=6)
26.5% (n=9)
10.3% (n=4)
24.4% (n=10)
23.1% (n=6)
13.6% (n=3)
32.0% (n=8)
37.5% (n=9)
0.2689
Clinical pregnancy
10.3% (n=4)
23.5% (n=8)
7.7% (n=3)
14.6% (n=6)
15.4% (n=4)
13.6% (n=3)
28.0% (n=7)
25.0% (n=6)
0.1479
Live birth
5.1% (n=2)
17.6% (n=6)
7.7% (n=3)
12.2% (n=5)
15.4% (n=4)
4.5% (n=1)
20.0% (n=5)
16.7% (n=4)
0.0606
Cryopreserved embryos
4.42 ± 2.65
6.81 ± 3.67
7.93 ± 4.18
4.90 ± 3.24
6.27 ± 2.96
4.80 ± 3.19
5.75 ± 2.49
9.89 ± 3.22
0.2645
Cryopreserved embryos
transferred
3.42 ± 1.83
5.67 ± 2.65
3.50 ± 1.84
3.27 ± 1.49
3.00 ± 1.41
2.17 ± 0.98
2.50 ± 0.71
4.75 ± 2.43
0.9092
Pregnancy from
cryopreserved embryos (total)
16.7%
(n=2/12)
0.0%
(n=0/9)
50.0%
(n=5/10)
27.3%
(n=3/11)
62.5%
(n=5/8)
33.3%
(n=2/6)
0.0%
(n=0/2)
0.0%
(n=0/8)
b
Clinical pregnancy from
cryopreserved embryos
8.3%
(n=1/12)
0.0%
(n=0/9)
40.0%
(n=4/10)
27.3%
(n=3/11)
50.0%
(n=4/8)
16.7%
(n=1/6)
0.0%
(n=0/2)
0.0%
(n=0/8)
b
Live birth from cryopreserved
embryos
8.3%
(n=1/12)
0.0%
(n=0/9)
30.0%
(n=3/10)
18.2%
(n=2/11)
12.5%
(n=1/8)
0.0%
(n=0/6)
0.0%
(n=0/2)
0.0%
(n=0/8)
b
aThe
90.8%
88.6%
57.6%
84.5%
IVF data of days u-hCG/rhLH 0–4 of patients from group 15,000 + 10,000 IU were pooled with those from group 15,000 IU
the numbers were small, no statistical comparison was performed on these data
bBecause
● 15,000 + 10,000 IU gave 20% live birth rate but with a 12% OHSS rate
European Recombinant LH Study Group. J Clin Endocrinol Metab
2001;86:2607–2618
Preventive strategies: lowering hCG dose
● Reducing the dose of hCG does not eliminate the risk
of OHSS in a high-risk group
Schmidt DW, et al. Fertil Steril 2004;82(4):841–846
Preventive strategies: dopamine agonists
OHSS incidence
OHSS severity
Youssef MA, et al. Human Reprod Update 2010;16:459–466
What really works:
● GnRH agonist versus hCG for oocyte triggering
in GnRH antagonist ART cycles
Youssef MA, et al. Human Reprod Update 2010;16:459–466
•
16 publications
•
Agonist: 2005
patients, not a single
case of OHSS!
•
hCG: 92 cases in
1810 patients, 5.1%
Ovulation
trigger
RCT, high risk
Oocyte
source
Own
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
Own
Retrospective, case- Own
controlled, high risk
Reference
Trial type
Babayof, et al 2006
Humaidan, et al 2009
Engmann, et al 2006
Manzanares, et al 2009 Retrospective case- Own
control, high risk
n
OHSS % (n)
15
13
33
32
30
30
1046
1031
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)
40
0 (0/40)
GnRHa
hCG
152
150
0 (0/152)
2 (3/150)
GnRHa
hCG
23
23
0 (0/23)
4 (1/23)
42
0 (0/42)
254
175
82
69
0 (0/254)
6 (10/175)
0 (0/82)
7 (5/69)
32
42
0 (0/32)
1 (1/42)
44
44
0 (0/44)
7 (3/44)
12
8 (1/12)
106
106
50
50
4
45
0 (0/106)
8 (9/106)
0 (0/50)
16(8/50)
0 (0/45)
15 (33)
GnRHa
hCG
GnRHa
hCG - cancelled
Hernandez, et al 2009
Retrospective
Donors
GnRHa
hCG
Orvieto, et al 2006
Retrospective, high
risk
Retrospective, high
risk: agonist arm
only
RCT
Own
GnRHa
hCG
Donors
GnRHa
hCG
Donors
GnRHa
hCG
Humaidan, et al 2009
Observational, high
risk
Own
Galindo, et al 2009
RCT
Donors
GnRH, luteal
rescue with hCG
1500IU
GnRHa
hCG
Melo, et al 2009
RCT
Donors
GnRHa
hCG
Shahrokh, et al 2010
RCT, high risk
Own
GnRHa
hCG
Shapiro, et al 2007
Sismanoglu, et al 2009
Failures?
OHSS prevention by GnRH agonist triggering of final oocyte maturation in
a GnRH antagonist protocol in combination with freeze-all strategy: a
prospective multicenter study
● Conclusions: “…a single case of a severe early onset OHSS occurred”
– E2 trigger day=47,877 pmol/L
– 13 oocytes
– “drastic decrease of hemoglobin levels to 4.9 mmol/L” (8 grams/dL)
patient received blood transfusion 2 days post OPU
– Hematocrit: 41 trigger day, 37 OPU day, ‘,<35’ post blood transfusion
– 3–4 days post trigger 3.9 litres of “blood-stained ascites which was
indicative of a subacute intraperitoneal hemorrhage”
Griesinger G, et al. Fertil Steril 2011;95:2029–2033
The physiology of agonist trigger
LH surge1
1.
2.
FSH surge2
Humaidan P, et al. Reprod Biomed Online 2011; (Epub ahead of print);
Gonen Y, et al. J Clin Endocrinol Metab 1990;71:918–922
What happens after agonist trigger?
Complete luteolysis!
Luteal phase
Natural cycle
Day 7–9 = 75 pg/mL vs 18
Natural cycle
Day 7–9 = 750 pg/mL vs 84
Nevo O, et al. Fertil Steril 2003;79:1123–1128
How to secure good clinical outcome post
agonist trigger?
● High risk fresh transfer: intensive E2+P luteal support
● High risk: ‘freeze-all’
● Low risk: luteal rescue based on LH activity
Luteal phase: intensive E+P
OHSS high-risk patients
Study group
Control group
Odds ratio (95%CI)
p value
Total, n (%)
0/33 (0)
10/32 (31.3)
0 (0–0.26)a
<0.01
Moderate/severe, n (%)
0/33 (0)
5/32 (15.6)
0 (0–0.74)a
0.02
Total, n (%)
0/30 (0)
10/2 (34.5)
0 (0–0.26)a
<0.01
Moderate/severe, n (%)
0/30 (0)
5/29 (17.2)
0 (0–0.73)a
0.02
22/61 (36)
20/64 (31)
1.18 (0.52–2.65)
0.69
Positive pregnancy, n (%)
19/30 (63.3)
18/29 (62.1)
1.06 (0.37–3.0)
0.92
Clinical pregnancy rate, n (%)
17/30 (56.7)
15/29 (51.7)
1.22 (0.4–3.4)
0.45
Ongoing pregnancy rate, n (%)
16/30 (53.3)
14/29 (48.3)
1.22 (0.4–3.4)
0.45
Primary end points
OHSS (ITT)
OHSS (PP)
Secondary end point (PP)
Implantation rate, n (%)
Other end points (PP)
aThe
estimates of these odds ratios are zero, because no patient developed OHSS in the study group; ITT=intention to treat;
PP=per protocol
Engmann L, et al. Fertil Steril 2008;89:84–91
Modified luteal support post agonist trigger
1500 IU hCG administered at oocyte retrieval rescues the luteal
phase when GnRH agonist is used for ovulation induction: a
prospective, randomized, controlled study
● 305 patients
● No significant differences were seen regarding:
–
–
–
–
–
Positive hCG/ET rate (48 and 48%)
Ongoing pregnancy rate (26 and 33%)
Delivery rate (24 and 31%)
Rate of early pregnancy loss (21 and 17%)
Between the GnRHa and 10,000 intrauterine hCG groups,
respectively
Humaidan P, et al. Fertil Steril 2010;93:847–854
Tailored luteal phase support
Patients with ≤14 follicles ≥12 mm on day of trigger GnRHa + 1500 IU hCG x 2,
versus 5000 IU hCG, both groups E2+P luteal support.
GnRHa/hCG
Patients, n
hCG
125
141
110/125 (88)
116/141 (82)
1.3
1.3
IR
49/158 (36)
43/145 (30)
Pos hCG per ET, n (%)
47/110 (43)
41/116 (35)
Clinical pregnancy per patient, n (%)
43/125 (34)
40/141 (28)
Ongoing pregnancy per patient, n (%)
37/125 (30)
36/141 (26)
Rate of transfer, n (%)
Embryos transferred, mean
Humaidan P, et al. personal communication
Side benefits
● Agonist trigger: more MII oocytes compared with hCG trigger1-4
● Potential benefit of FSH surge:5-9
– Promotes LH receptor formation in luteinizing granulosa cells
– Promotes nuclear maturation (i.e. resumption of meiosis)
– Promotes cumulus expansion
1.
2.
3.
4.
5.
6.
7.
8.
9.
Humaidan P, et al. Reprod Biomed Online 2005;11:679–684
Humaidan P, et al. Human Reprod 2009;24:2389–2394
Imoedemhe DA, et al. Fertil Steril 1991;55:328–332
Oktay K, et al. Reprod Biomed Online 2010;20:783–788
Eppig JJ. Nature 1979;281:483–484
Strickland and Beers. J Biol Chem 1976;251:5694–5702
Yding Andersen C. Reprod Biomed Online 2002;5:232–239
Yding Andersen C, et al. Mol Hum Reprod 1999;5:726–731
Zelinski-Wooten MB, et al. Human Reprod 1995;10:1658–1666
The advantage for the ‘normal responder’
Antagonist
FSH/hMG
Agonist
trigger
OPU
36 hours
ET
4 days
1500 IU hCG
Kol S, et al. Human Reprod 2011;26:2874–2877
1500 IU hCG
Stimulation characteristics and embryology data
Stimulation (days)
9.3 ± 2.0
GnRH antagonist (days)
3.8 ± 0.9
FSH (units)
2443 ± 925
E2 day of trigger (pmol/L)
3764 ± 1227
P day of trigger (nmol/L)
2.4 ± 1.65
LH day of trigger (IU/L)
1.9 ± 1.3
Oocytes retrieved
6.7 ± 2.5
Embryos obtained
3.6 ± 1.7
Embryos transferred
2.9 ± 0.9
Embryos frozen
0.8 ± 1.5
Beta hCG (IU/L)
152 ± 86
E2 (day of pregnancy test, pmol/L)
6607 ± 3789
P (day of pregnancy test, nmol/L)
182 ± 50
Values are mean ± SD
Reproductive outcomes
Positive hCG/cycle, n (%)
11/15 (73)
Clinical ongoing pregnancy, n (%)
7/15 (47)
Early pregnancy loss, n (%)
4/11 (36)
Kol S, et al. Human Reprod 2011;26:2874–2877
“The concept of an OHSS-Free Clinic has become a reality. This
approach should include pituitary down-regulation using a GnRH
antagonist, ovulation triggering with a GnRH agonist and vitrification
of oocytes or embryos”
“…luteal phase supplementation with low-dose hCG has to be fine
tuned.”
Devroey P, et al. Human Reprod 2011; 26: 2593–2597
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
1–2% 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