1. Prevention of OHSS
Shahar Kol, IVF Unit Rambam Health Care Campus, and Macabbi Health Services, Haifa, Israel. February 2012

2. Content Scope of the problem Preventive strategies What really works
Physiology of the agonist trigger
Side benefits

3. Severe OHSS: is it still a problem?
Maternal deaths and rates per 100,000 ART procedures, including IVF: United Kingdom: 1997–2005
Year
Deaths
95% CI
Number of treatment cycles
Number
Rate
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
* 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

4. Three OHSS-related deaths (3:100,000), all had their embryos frozen
Braat DDM, et al. Hum Reprod 2010;25:1782–1786

5. 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

6. 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):CD

7. 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

8. 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

9. 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

10. Preventive strategies: recombinant LH
European Recombinant LH Study Group. J Clin Endocrinol Metab 2001;86:2607–2618

11. 15,000 + 10,000 IU gave 20% live birth rate but with a 12% OHSS rate
Treatment arm
5000 IU
15,000 IU
30,000 IU
15, ,000 IU
p (linearity)
Parameters examined
rhLH
(n=39)
u-hCG
(n=34)
(n=41)
(n=26)
(n=22)
(n=25)
(n=24)
No. of follicles >10 mm
14.03 ± 5.32
16.44 ± 6.95
15.17 ± 8.34
± 6.75
± 5.61
± 4.90 a
0.3007
No. of oocytes retrieved
10.23 ± 4.70
11.74 ± 6.27
± 7.53
± 6.75
± 6.22
± 5.70
0.1702
Oocytes in metaphase II
85.5%
77.8%
90.8%
88.6%
57.6%
84.5%
0.183
No. of oocytes inseminated
9.82 ± 4.74
11.26 ± 5.73
± 7.52
± 6.57
± 6.25
± 5.74
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
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
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
23.5% (n=8)
7.7% (n=3)
14.6% (n=6)
15.4% (n=4)
28.0% (n=7)
25.0% (n=6)
0.1479
Live birth
5.1% (n=2)
17.6% (n=6)
12.2% (n=5)
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)
(n=0/8) b
Clinical pregnancy from cryopreserved embryos
8.3%
(n=1/12)
40.0% (n=4/10)
50.0%
(n=4/8)
16.7%
(n=1/6)
Live birth from cryopreserved embryos
(n=0/9)
30.0% (n=3/10)
18.2% (n=2/11)
12.5%
(n=1/8)
(n=0/6)
aThe IVF data of days u-hCG/rhLH 0–4 of patients from group 15, ,000 IU were pooled with those from group 15,000 IU
bBecause the numbers were small, no statistical comparison was performed on these data
15, ,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

12. 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

13. Preventive strategies: dopamine agonists
OHSS incidence
OHSS severity
Youssef MA, et al. Human Reprod Update 2010;16:459–466

14. 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

15. Agonist: 2005 patients, not a single case of OHSS!
OHSS % (n) n
Ovulation
trigger
Oocyte source
Trial type
Reference
0 (0/13)
31(4/13) 15 13
GnRHa
hCG
Own
RCT, high risk
Babayof, et al 2006
0 (0/33)
31 (10/32) 33 32
Engamnn, et al 2008
0 (0/30)
17 (5/30) 30
Donors
RCT
Acevedo, et al 2006
0 (0/1046)
1.3 (13/1031)
1046
1031
Retrospective
Bodri, et al 2009
0 (0/40) 40
Observational,
High risk
Griesinger, et al 2010
0 (0/152)
2 (3/150)
152
150
Humaidan, et al 2009
0 (0/23)
4 (1/23) 23
Retrospective, case-controlled, high risk
Engmann, et al 2006
0 (0/42) 42
hCG - cancelled
Retrospective case-control, high risk
Manzanares, et al 2009
0 (0/254)
6 (10/175)
254
175
Hernandez, et al 2009
0 (0/82)
7 (5/69) 82 69
Retrospective, high risk
Orvieto, et al 2006
0 (0/32)
1 (1/42)
Retrospective, high risk: agonist arm only
Shapiro, et al 2007
0 (0/44)
7 (3/44) 44
Sismanoglu, et al 2009
8 (1/12) 12
GnRH, luteal rescue with hCG 1500IU
Observational, high risk
0 (0/106)
8 (9/106)
106
Galindo, et al 2009
0 (0/50)
16(8/50) 50
Melo, et al 2009
0 (0/45)
15 (33) 4 45
Shahrokh, et al 2010
16 publications
Agonist: 2005 patients, not a single case of OHSS!
hCG: 92 cases in 1810 patients, 5.1%

16. 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

17. The physiology of agonist trigger
LH surge1
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

18. 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

19. 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

20. Luteal phase: intensive E+P OHSS high-risk patients
Study group
Control group
Odds ratio (95%CI)
p value
Primary end points
OHSS (ITT)
Total, n (%)
0/33 (0)
10/32 (31.3)
0 (0–0.26)a
<0.01
Moderate/severe, n (%)
5/32 (15.6)
0 (0–0.74)a
0.02
OHSS (PP)
0/30 (0)
10/2 (34.5)
5/29 (17.2)
0 (0–0.73)a
Secondary end point (PP)
Implantation rate, n (%)
22/61 (36)
20/64 (31)
1.18 (0.52–2.65)
0.69
Other end points (PP)
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)
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

21. 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

22. Tailored luteal phase support
Patients with ≤14 follicles ≥12 mm on day of trigger GnRHa IU hCG x 2, versus 5000 IU hCG, both groups E2+P luteal support.
GnRHa/hCG
hCG
Patients, n
125
141
Rate of transfer, n (%)
110/125 (88)
116/141 (82)
Embryos transferred, mean
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)
Humaidan P, et al. personal communication

23. 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
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

24. The advantage for the ‘normal responder’
Agonist
trigger
OPU ET
Antagonist
36 hours
4 days
FSH/hMG
1500 IU hCG
1500 IU hCG
Kol S, et al. Human Reprod 2011;26:2874–2877

25. 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

26. “The concept of an OHSS-Free Clinic has become a reality
“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

27. Crystal ball: where are we heading?
Out In
‘Long agonist’ protocols
Antagonist-based protocols
hCG trigger
Agonist trigger
Progesterone-based luteal support
LH activity-based luteal support
1–2% severe OHSS
Total OHSS elimination
OHSS-related death rate: 3:100,000
Painful P injections or leaky, messy vaginal P
Patient-friendly luteal phase
Thank you