Prevention of OHSS Shahar Kol, IVF Unit Rambam Health Care Campus, and Macabbi Health Services,...
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Transcript of Prevention of OHSS Shahar Kol, IVF Unit Rambam Health Care Campus, and Macabbi Health Services,...
Prevention of OHSS
Shahar Kol, IVF Unit Rambam Health Care Campus, and Macabbi Health Services, Haifa, Israel. February 2012
Content
● Scope of the problem● Preventive strategies● What really works● Physiology of the agonist trigger● Side benefits
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
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
Maternal deaths and rates per 100,000 ART procedures, including IVF: United Kingdom: 1997–2005
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
● 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: cryopreservation
Youssef MA, et al. Cochrane Database Syst Rev 2011; (2): CD001302
● 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)
Preventive strategies: intravenous albumin
● 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
IV albumin for the prevention of severe OHSS: a systemic review and meta-analysis
Preventive strategies: recombinant LH
European Recombinant LH Study Group. J Clin Endocrinol Metab 2001;86:2607–2618
● 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 + 10,000 IU
p (linearity)Parameters examinedrhLH (n=39)
u-hCG(n=34)
rhLH (n=39)
u-hCG (n=41)
rhLH (n=26)
u-hCG (n=22)
rhLH (n=25)
u-hCG (n=24)
No. of follicles >10 mm 14.03 ± 5.32 16.44 ± 6.9515.17 ± 8.34 15.46 ± 6.75 14.23 ± 5.61 14.00 ± 4.90
a a 0.3007
No. of oocytes retrieved 10.23 ± 4.70 11.74 ± 6.2711.84 ± 7.53 11.78 ± 6.75 12.62 ± 6.22 10.82 ± 5.70
a a 0.1702
Oocytes in metaphase II 85.5% 77.8%90.8% 88.6% 57.6% 84.5%
a a 0.183
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 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 IUbBecause the numbers were small, no statistical comparison was performed on these data
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
Youssef MA, et al. Human Reprod Update 2010;16:459–466
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
OHSS % (n) nOvulation trigger
Oocyte source
Trial type Reference
0 (0/13)31(4/13)
1513
GnRHahCG
Own RCT, high risk Babayof, et al 2006
0 (0/33)31 (10/32)
3332
GnRHahCG
Own RCT, high risk Engamnn, et al 2008
0 (0/30)17 (5/30)
3030
GnRHahCG
Donors RCT Acevedo, et al 2006
0 (0/1046)1.3 (13/1031)
10461031
GnRHahCG
Donors Retrospective Bodri, et al 2009
0 (0/40) 40GnRHa Own Observational,
High riskGriesinger, et al 2010
0 (0/152)2 (3/150)
152150
GnRHahCG
Own RCT Humaidan, et al 2009
0 (0/23)4 (1/23)
2323
GnRHahCG
Own Retrospective, case-controlled, high risk
Engmann, et al 2006
0 (0/42) 42GnRHahCG - cancelled
Own Retrospective case-control, high risk
Manzanares, et al 2009
0 (0/254)6 (10/175)
254175
GnRHahCG
Donors Retrospective Hernandez, et al 2009
0 (0/82)7 (5/69)
8269
GnRHahCG
Own Retrospective, high risk
Orvieto, et al 2006
0 (0/32)1 (1/42)
3242
GnRHahCG
Donors Retrospective, high risk: agonist arm only
Shapiro, et al 2007
0 (0/44)7 (3/44)
4444
GnRHahCG
Donors RCT Sismanoglu, et al 2009
8 (1/12) 12GnRH, luteal rescue with hCG 1500IU
Own Observational, high risk
Humaidan, et al 2009
0 (0/106)8 (9/106)
106106
GnRHahCG
Donors RCT Galindo, et al 2009
0 (0/50)16(8/50)
5050
GnRHahCG
Donors RCT Melo, et al 2009
0 (0/45)15 (33)
445
GnRHahCG
Own RCT, high risk Shahrokh, et al 2010
• 16 publications
• Agonist: 2005 patients, not a single case of OHSS!
• hCG: 92 cases in 1810 patients, 5.1%
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
Failures?
The physiology of agonist trigger
1. Humaidan P, et al. Reprod Biomed Online 2011; (Epub ahead of print);2. Gonen Y, et al. J Clin Endocrinol Metab 1990;71:918–922
LH surge1 FSH surge2
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+POHSS 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 (%) 0/33 (0) 5/32 (15.6) 0 (0–0.74)a 0.02
OHSS (PP)
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
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) 1.22 (0.4–3.4) 0.45
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
GnRHa/hCG hCG
Patients, n 125 141
Rate of transfer, n (%) 110/125 (88) 116/141 (82)
Embryos transferred, mean 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)
Humaidan P, et al. personal communication
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.
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. Humaidan P, et al. Reprod Biomed Online 2005;11:679–6842. Humaidan P, et al. Human Reprod 2009;24:2389–23943. Imoedemhe DA, et al. Fertil Steril 1991;55:328–3324. Oktay K, et al. Reprod Biomed Online 2010;20:783–788 5. Eppig JJ. Nature 1979;281:483–4846. Strickland and Beers. J Biol Chem 1976;251:5694–57027. Yding Andersen C. Reprod Biomed Online 2002;5:232–2398. Yding Andersen C, et al. Mol Hum Reprod 1999;5:726–7319. Zelinski-Wooten MB, et al. Human Reprod 1995;10:1658–1666
The advantage for the ‘normal responder’
Kol S, et al. Human Reprod 2011;26:2874–2877
FSH/hMG
Antagonist
Agonist trigger
36 hours
OPU
1500 IU hCG
4 days
1500 IU hCG
ET
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?
Thank you
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 Total OHSS elimination
Painful P injections or leaky, messy vaginal P
Patient-friendly luteal phase