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? 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

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

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 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 15.46 ± 6.75 14.23 ± 5.61 14.00 ± 4.90 a 0.3007 No. of oocytes retrieved 10.23 ± 4.70 11.74 ± 6.27 11.84 ± 7.53 11.78 ± 6.75 12.62 ± 6.22 10.82 ± 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 11.63 ± 7.52 11.57 ± 6.57 12.38 ± 6.25 10.55 ± 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 + 10,000 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 + 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

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%

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 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 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

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 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

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

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

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 “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? 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