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Prevention of OHSS

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 P hysiology of the agonist trigger Side benefits. Severe OHSS: is it still a problem?.

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Prevention of OHSS

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  1. Prevention of OHSS ShaharKol, 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 • “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. FertilSteril 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):CD0028110

  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. FertilSteril 2011; 95:188–196,196.e1–3

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

  11. aTheIVF 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 bBecausethe 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 ClinEndocrinolMetab 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. FertilSteril 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. 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 subacuteintraperitoneal hemorrhage” Griesinger G, et al. FertilSteril2011;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 ClinEndocrinolMetab1990;71:918–922

  18. What happens after agonist trigger? Complete luteolysis! Luteal phase Natural cycle Day 7–9 = 75 pg/mL vs18 Natural cycle Day 7–9 =750 pg/mL vs 84 Nevo O, et al. FertilSteril2003;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+POHSS high-risk patients Engmann L, et al. FertilSteril2008;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. FertilSteril2010;93:847–854

  22. 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. 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 Reprod2009;24:2389–2394 Imoedemhe DA, et al. FertilSteril 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 BiolChem1976;251:5694–5702 Yding Andersen C. Reprod Biomed Online 2002;5:232–239 Yding Andersen C, et al. Mol Hum Reprod1999;5:726–731 Zelinski-Wooten MB, et al. Human Reprod1995;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 Reprod2011;26:2874–2877

  25. Kol S, et al. Human Reprod 2011;26:2874–2877

  26. “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? Thank you

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