OHSS prevention: Yes, we can!

1. OHSS prevention: Yes, we can!   ShaharKol, IVF Unit Rambam Health Care Campus, and Faculty of Medicine, Technion, Israel Institute of Technology, February, 2014

2. Faculty Disclosure Off-Label Product Use

3. content • OHSS: is it still a problem? • No OHSS post agonist trigger! • Mechanism? • Failures? • The question of pregnancy rate. • Agonist trigger: back to physiology. • Agonist trigger is not the issue, luteal support is. Meta-analysis should follow. • A revolution in the making.

4. OHSS: Is it still a problem? “We did not have a single case in years.”

5. 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.

6. Three OHSS-related deaths (3:100,000 ART cycles), all had their embryos frozen. Braat et al, 2010

7. Incidence of OHSS Objective:to determine OHSS incidence in 2,524 antagonist-based cycles (1801 patients). Results:fifty three 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” F&S January 2006

8. How to prevent OHSS? • Agonist trigger is the most effective approach.

9. PRE-ANTAGONIST ERA

10. Antagonist era • Use of a single bolus of GnRH agonist triptorelin to trigger ovulation after GnRH antagonist ganirelix treatment in women undergoing ovarian stimulation for assisted reproduction, with special reference to the prevention of ovarian hyperstimulation syndrome: preliminary report: Short communication . Itskovitz-Eldor et al. 2000

11. 16 publications Agonist: 2,005 patients, not a single case of OHSS! hCG: 92 cases in 1,810 patients, 5.1%

12. What really works: • GnRH agonist versus hCG for oocyte triggering in GnRH antagonist ART cycles Total events 0 (GnRH) 21 (hCG) Youssef MA, et al. Human Reprod Update 2010;16:459–466

13. Lower levels of inhibin A and pro-alpha C during the luteal phase after triggering oocyte maturation with GnRH agonist versus hCG Mechanism of OHSS prevention? Nevo et al. 2003

14. Luteal phase Natural cycle day 7-9= 75 pg/ml vs. 18 Natural cycle day 7-9= 750 pg/ml vs. 184 Nevo et al, 2003

15. Summary • The lower levels of luteal steroidal and nonsteroidal hormones reflect luteolysis, and may explain the mechanism of OHSS prevention by GnRH-a. • Pregnancy post agonist trigger does not rescue the CL!!! Nevo et al, 2003

16. A safe and OHSS-free clinical environment

17. 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 • The patient was hospitalized on day of OPU, with abdominal distension, drastically enlarged ovaries (right and left ovarian volume 363 cm2 and 261 cm2, respectively), and lower abdominal pain. • She received low molecular weight heparin, cabergoline (0.5 mg/d), and IV infusion therapy, including albumin. Griesinger G, et al. Fertil Steril 2011;95:2029–2033

18. Failures? (cnt’d) • “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”.

19. Pregnancy rate post agonist trigger • We showed that agonist trigger causes quick and irreversible luteolysis. • Therefore, the right luteal support is crucial. • The evolution of post agonist luteal support.

20. Luteal phase – non-supplemented • Beckers et al (2003) – very low pregnancy rate.

21. Luteal phase – conventional support Not good enough!

22. Luteal phase – modified support We are getting there!

23. LUTEAL PHASE: INTENSIVE E+P OHSS high-risk patients Engmann et al, 2008

26. All freeze advantages • No OHSS • Better endometrium in thaw cycles. • Less ectopic pregnancies in thaw cycles. • Comparable, or even better, clinical outcome in thaw cycles. • Better obstetric outcome? • Fresh transfer post agonist trigger requires daily IM injections of progesterone in oil.

27. …AND WHEN OHSS IS NOT THE MAIN ISSUE?... “… 42% of those who received hCG reported subjective complaints (mostly abdominal discomfort), whereas this percentage was 0% in those who received GnRH agonist to trigger ovulation. Cerrillo et al, 2009

28. hCG does not imitate physiology! LH surge goes together with FSH surge. Is FSH surge redundant? Gonen et al 1990

29. Dual role of hCG trigger • Final oocyte maturation. • Early luteal phase stimulation. • Same dose for both functions? hCG

30. Gonadotropin-releasing hormone agonist versus HCG for oocyte triggering in antagonist assisted reproductive technology cycles. 11/2010 • Totally different approaches to luteal support, no common ground for comparison. • Agonist triggering is not the issue, individualized luteal support is!

31. Plain language summary: “We recommend that GnRH agonist as a final oocyte maturation trigger should be not used”. 1985: In view of the poor reproductive outcomes following IVF we believe there is no indication for further research with IVF for the treatment of infertile couples…

32. Further research • Agonist trigger in “empty follicle syndrome” • Agonist trigger in “egg factor” infertility • Agonist trigger in repeated IVF failure cases. • Immature eggs post hCG in face of adequate follicular size on trigger day. • hCG-based, P-free luteal support post agonist trigger

33. Non OHSS-high-risk patients: 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

34. 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

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

36. What do practitioners say? Among the five most downloaded papers

37. TAKE HOME MESSAGE “The results of this survey indicate that GnRH trigger is widely used worldwide and therefore has become part of the standard of care today. Hence, doctors are entitled to prescribe it just as patients may ask that this option is considered in their case.”

38. “Agonist triggering is viewed as one of the major advances in ovarian stimulation, with the potential to eliminate OHSS…”

39. Revolution in the making

40. Thank you