1. NEW STRATEGIES FOR OHSS PREVENTION Ali Rüştü Ergür, M.D., Assoc.Prof. GATA Haydarpaşa Hospital The 2nd Congress of Current Opinion in Reproductive Medicine and Assisted Reproductive Technologies and 1st Congress of the Society of Reproductive Medicine Çeşme-İzmir, April 20, 2008

2. THE GOOD

3. THE BAD

4. THE UGLY

5. OHSS (OVARIAN HYPERSTIMULATION SYNDROME) SHOULD BE ACCEPTED THE MOST SERIOUS AND DETRIMENTAL COMPLICATION OF OVARIAN STIMULATION

6. OHSS (OVARIAN HYPERSTIMULATION SYNDROME) WHY THE MOST SERIOUS AND DETRIMENTAL ? 1.Marked extravascular exudate, 2.Profound intravascular depletion, 3.Hemoconcentration 4.Increased blood coagulability (Rizk and Aboulghar, 2005)

7. OHSS (OVARIAN HYPERSTIMULATION SYNDROME) Acute fluid shift out of the intravascular space Ascites Hydrothorax Generalized edema Major electrolyte imbalance Reduced renal perfusion Marked hemoconcentration Vascular complications

8. OHSS (OVARIAN HYPERSTIMULATION SYNDROME) End-stage complications; Liver dysfunction Respiratory complications Renal complications Vascular complications Death

9. OHSS (OVARIAN HYPERSTIMULATION SYNDROME) HIGH RESPONDERS

10. PREVENTION OF OHSS Level 1 : Patient identification at risk Level 2 : Organization of ovarian stimulation for a required but less follicular development Level 3 : Proper monitorization Level 4 : Decreasing the developing follicles and rapid estradiol increase Level 5 : Prevention of pregnancy occurrence Level 6 : Medical treatment and hospitalization

11. PREVENTION OF OHSS LEVEL 1: Patient identification at risk Patients with PCOS/Hyperandrogenic chronic anovulation (HCA) Previous OHSS history Oligomenorrhea or amenorrhea High LH/FSH ratio Polycystic appearance of ovaries by sonography Young age < 35 years old Egg donors

12. PREVENTION OF OHSS LEVEL 2: Ovarian stimulation for a required but less follicular development Low doses of gonadotropins (100-150 IU/day) Minimal stimulation protocols (CC/gonadotropin/antagonist) Dual suppression with OCP and GnRH-a Use of GnRH antagonist vs. agonist HCG dose and alternatives Metformin

13. PREVENTION OF OHSS LEVEL 2: Low Dose Gonadotropins Low dose gonadotropin therapy, 75-150 IU/day, is effective for the prevention of OHSS whether gonadotropin is urinary or recombinant El-Sheikh MM, 2001 Golan A, 1988 Homburg R, 2002 VanWely M, 2003 Gorry A, 2006 Low dose gonadotropin therapy (75 IU), Homburg and Howles, 1999

14. PREVENTION OF OHSS LEVEL 2: Low Dose Gonadotropins Marci R, 2001

15. PREVENTION OF OHSS LEVEL 2: Low Dose Gonadotropins Ragni G, 2006

16. PREVENTION OF OHSS LEVEL 2: Low Dose Gonadotropins OHSS risk is lower in low dose regimens Koundouros, 2008

17. PREVENTION OF OHSS LEVEL 2: Minimal Stimulation Protocols Minimal Stimulation Protocol CC/Gonadotropins/Antagonist Advantages 1.Reduced cost 2.Friendlier IVF 3.Acceptable pregnancy rates/transfer 4.Less OHSS Disadvantages 1.High rate of cancellation and lack of transfer 2.Less oocytes 3.No excess of embryos for cryopreservation

18. PREVENTION OF OHSS LEVEL 2: Minimal Stimulation Protocols Minimal Stimulation Protocol CC/Gonadotropins/Antagonist AuthorProtocol Weigert (2002) CC 100 mg days 3-7 Rec FSH-LH (300 IU) on alternate days Williams (2002) CC 100 mg days 3-7 Gonadotropins (150 IU) starting on day 9 Engel (2002) CC 100 mg days 3-7 Gonadotropins (225 IU) starting on day 8 Antagonist starting day 8 Hwang (2003) CC 100 mg days 3-7 Gonadotropins (150 IU) on alternate days Antagonist on follicle 14 mm<

19. PREVENTION OF OHSS LEVEL 2: Minimal Stimulation Protocols Minimal Stimulation Protocol CC/Gonadotropins/Antagonist AuthorOocytesPreg. Rate/Tr. % Weigert (2002)7.7±3.643 Williams (2002)3.9±2.238 Engel (2002)6.4±4.826 Hwang (2003)8.0±3.235

20. PREVENTION OF OHSS LEVEL 2: Minimal Stimulation Protocols Minimal Stimulation Protocol CC/Gonadotropins/Antagonist 1.Pregnancy rate per transfer comparable with the long agonist protocol 2.No severe OHSS in all studies 3.This protocol should be considered as an option in patients with OHSS risk

21. PREVENTION OF OHSS LEVEL 2: Dual suppression with OCP and GnRH-a Protocol 1.Low dose OCP (35µg) for 25 days 2.GnRH agonist on day 21 of OCP 3.150 IU of gonadotropins on the 3rd day of menstrual bleeding with GnRH-a Damario, 1997

22. PREVENTION OF OHSS LEVEL 2: Dual suppression with OCP and GnRH-a Damario, 1997

23. PREVENTION OF OHSS LEVEL 2: Dual suppression with OCP and GnRH-ant Rombauts, 2006

24. PREVENTION OF OHSS LEVEL 2: Use of GnRH antagonist vs. agonist Advantages 1.Lower peak E2 levels 2.Reduced number of oocytes 3.GnRH-a use for ovulation triggering as a substitute for hCG Disadvantage 1.Lower pregnancy rate compared to long agonist protocol

25. PREVENTION OF OHSS LEVEL 2: Use of GnRH antagonist vs. agonist Ludwig, 2001

26. PREVENTION OF OHSS LEVEL 2: Use of GnRH antagonist vs. agonist Ragni G, 2005

27. PREVENTION OF OHSS LEVEL 2: Use of GnRH antagonist vs. agonist

28. GnRH antagonist protocol is a short and simple protocol with good clinical outcome, but the lower pregnancy rate compared with the GnRH agonist long protocol and the non-significant difference between both protocols regarding prevention of premature LH surge and prevention of severe ovarian hyperstimulation syndrome Al-Inany, 2002

29. PREVENTION OF OHSS LEVEL 2: Use of GnRH antagonist vs. agonist Data between the GnRH antagonist group (group I) and the GnRH agonist group (group II) Group I (n=73) Group II (n=75) Total recombinant FSH (IU)2052.1±375.052138±407.3 Days of stimulation9.3±1.59.6±1.4 Days of antagonist 1.86±0.73 Estradiol (pg/ml)1900±5622140±730 Oocytes donated13.8±3.214.3±2.7 Fertilization rate (%)7379 Embryos transferred2.34±0.772.36±0.73 Mild hyperstimulation2 (2.73)3 (4) Clinical pregnancy/cycle started29 (39.72)31 (41.33) Implantation (%)23.925.4 Twins3 (10.34)4 (12.9) Triplets1 (3.44)0 (0) Prapas N, 2005

30. PREVENTION OF OHSS LEVEL 2: Use of GnRH antagonist vs. agonist Effects of GnRH antagonist cotreatment on the incidence of ovarian hyperstimulation syndrome remains uncertain, although a trend is present in favour of the GnRH antagonists Tarlatzis, 2006

32. PREVENTION OF OHSS LEVEL 2: Antagonist in GnRH Analog Cycles Retrospective study 87 patients with long agonist protocol or microdose flare protocol Agonists discontinued and ganirelix acetate started and continued till E2 dropped to less than 3000 pg/ml and appropriate of follicles Gustofson, 2006

33. PREVENTION OF OHSS LEVEL 2: Antagonist in GnRH Analog Cycles Gustofson, 2006

34. PREVENTION OF OHSS LEVEL 2: HCG Dose and Alternatives HCG similar to LH Longer half-life than LH SO…. 1.Reduce hCG dose 2.Recombinant hCG ? 3.GnRHa (for gonadotropin only cycles or antagonist cycles)

35. PREVENTION OF OHSS LEVEL 2: HCG Dose and Alternatives Pregnancy outcome in GnRH agonist versus hCG group BuserelinhCGP Patients (n)5567 Rate of ET [n (%)]48 (87)57 (85)NS No. of ET [mean (range)]1.71 (1–2)1.64 (1–2)NS Positive hCG per ET [n (%)]14 (29)25 (44) >0.10 Clinical pregnancy [n (% )]3 (6)24 (36) 0.002 Implantation rate (n)3/8933/97 <0.001 Early pregnancy loss [n (%)]11 (79)1 (4) 0.005 Humaidan, 2005

36. PREVENTION OF OHSS LEVEL 2: HCG Dose and Alternatives Cycle outcome after agonist and HCG triggering of final oocyte maturation Centre 1 Centre 2 Agonist HCG Agonist HCG Patients 18243430 Patients OPU 18243230 Patients ET 15202928 Positive HCG 16.7% (3/18) 45.8% (11/24) 17.6% (6/34) 20.0% (6/30) Ongoing preg. Rate 5.6%(1/18) 41.7%(10/24) 2.9%(1/34) 16.7% (5/30) Early pregnancy loss 66.7% (2/3) 9.1% (1/11) 83.3% (5/6) 16.7% (1/6) Kolibiniakis, 2005

37. PREVENTION OF OHSS LEVEL 2: HCG Dose and Alternatives Acevedo, 2006

38. PREVENTION OF OHSS LEVEL 2: HCG Dose and Alternatives Conclusions –No differences in the number of MII, fertilization rate and embryo quality –Lower pregnancy and implantation rates –Higher miscarriage rates For the agonist trigger in IVF patients

39. PREVENTION OF OHSS LEVEL 2: Metformin Comparison of metformin versus placebo or no treatment in IVF with outcome of OHSS The risk of OHSS in PCOS women undergoing IVF was reduced with metformin. Costello, 2006

40. PREVENTION OF OHSS LEVEL 3: Proper Monitorization USG –PCOS patterns –Large number of follicles E2 Good predictor to OHSS Aboulghar, 2003

42. PREVENTION OF OHSS LEVEL 4: Decreasing the developing follicles and rapid estradiol increase Coasting –Withholding gonadotropin administration for one or more days –GnRH agonist is continued –hCG is given when the estradiol levels drop to a safe level (generally <3000 pg/ml)

43. PREVENTION OF OHSS LEVEL 4: Coasting Comparison of criteria used for coasting Reference No. coasted E2 initially (pg/ml) E2 (pg/ml) at hCG Coasting duration (days) Sher (1995) 51 >3000 <3000 6.1 (3–11) Benavida (1997) 22 >3000 <3000 1.9 ± 0.9 Tortoriello(1998) 22 >3000 <3000 2.6 ± 0.3 Dhont (1998) 120 >2500 <2500 1.9 ± 0.8 Lee (1998) 20 >2724 Decreasing 2.8 ± 1.3 Egbase (1999) 15 >6000 <3000 4.9 ± 1.6 Wald. (1999) 65 Variable <2724 4.3 (3–6) Fluker (1999) 63 >3000 25% decline 3.4 ± 0.1 Al-Shawaf (2001) 50 >3595 <2724 3.4 ± 1.6 Ulug. (2002) 207 >4000 <4000 2.9 ± 0.11 Levinsohn, 2003

44. PREVENTION OF OHSS LEVEL 4: Coasting ICSI outcome according to the number of coasting days Group I 4 daysP No. of cycles983240 Age (years)30.16 ± 4.5529.89 ± 4.91NS Infertility period (years)6.59 ± 4.166.56 ± 3.86NS HMG amp. per cycle31.76 ± 9.9730.38 ± 9.03NS E2 coasting level (pg/ml)6150 ± 17607473 ± 2320 0.0001 E2 HCG level (pg/ml)2674 ± 7892801 ± 930NS Oocytes retrieved16.45 ± 6.2614.93 ± 6.010.002 MII oocytes12.94 ± 5.5811.60 ± 5.60.003 2 PN oocytes8.16 ± 4.397.53 ± 4.59NS Embryos per transfer2.99 ± 0.693.03 ± 0.66NS Fertilization rate (%)62.6764.92NS Implantation rate (%)26.3218.160.0001 Clinical pregnancy rate (%)51.9635.880.0002 Mansour, 2005

45. PREVENTION OF OHSS LEVEL 4: Coasting ICSI outcome of patients who developed severe OHSS No. of cycles16 Age (years)29.06 ± 9.08 Infertility (years)6.23 ± 5.29 HMG amp.per cycle28.94 ± 9.15 E2 level-coasting (pg/ml)6412 ± 3327 E2 level-HCG (pg/ml)4916 ± 2704 Oocytes retrieved20.06 ± 7.91 Metaphase II oocytes15.40 ± 7.16 Two-pronuclear oocytes9.25 ± 4.99 Embryos per transfer3.07 ± 0.47 Fertilization rate (%)42.37 Implantation rate (%)58.87 Clinical pregnancy rate (%)80.00 Mansour, 2005

46. PREVENTION OF OHSS LEVEL 4: Coasting Uluğ, 2004

47. PREVENTION OF OHSS LEVEL 4: Coasting Moreno, 2004

48. PREVENTION OF OHSS LEVEL 4: Coasting Conclusions –Effective for the prevention of OHSS –Start coasting when the leading follicles 14-16 mm and estradiol levels 3000-4000 pg/ml –Less than 4 days –Till E2 drops to < 3000 pg/ml –Prolonged coasting ( > 4 days ) can be detrimental

49. PREVENTION OF OHSS LEVEL 5: Prevention of pregnancy occurrence Cryopreservation of all embryos, no ET –Significant decrease in the incidence of OHSS if the ET cancelled –Insufficient evidence to support routine cryopreservation Wada, 1993 Ferraretti, 1999 Amso, 1990 Salat-Baroux, 1990 Cochrane Review, 2002

50. PREVENTION OF OHSS LEVEL 5: Prevention of pregnancy occurrence Aboulghar, 2003

51. PREVENTION OF OHSS Intravenous Albumin Having osmotic and transport functions 50 gr. IV at the OPU time Osmotic function only lasts < 36 h Cochrane Review-2002 –Significant reduction in OHSS

52. PREVENTION OF OHSS Intravenous Albumin Coasting is as effective as i.v. albumin in preventing OHSS in high- risk patients but yields inferior pregnancy rates Chen, 2002

53. PREVENTION OF OHSS Intravenous Albumin AlbuminPlaceboP value No. of cycles3837NA Age 29.3 ± 3.929.1 ± 4.1.87aa PCOS15/38 (39.5%)8/37 (21.6%).09bb History of severe OHSS4/38 (10.5%)4/37 (10.8%).96bb No. of follicles ≥14 mm 20.5 ± 5.219.3 ± 3.6.30aa Severe OHSS8/38 (21.1%)6/37 (16.2%).59b Early severe OHSS3 (7.9%)1 (2.7%).61dd Late severe OHSS2 (5.3%)2 (5.4%)1.0dd Combined severe OHSS3 (7.9%)3 (8.1%)1.0dd Clinical pregnancy/ embryo transfer21/38 (55.3%)23/37 (62.2%).54bb Multiple pregnancy rate7/21 (33.3%)7/23 (30.4%).90bb First trimester miscarriage rate1/20 (5%)4/23 (17.3%).35dd Not effective for OHSS prevention Isikoglu, 2007

54. PREVENTION OF OHSS Hydroxyethyl Starch Alternative to albumin Increases the oncotic pressure 1000 ml of hydroxyethyl starch at the time of OPU Cheap and safer alternative to albumin Graf, 1997 König, 1998 Gokmen, 2001

55. PREVENTION OF OHSS Hydroxyethyl Starch HES and albumin are effective for OHSS prevention Gokmen, 2001

56. PREVENTION OF OHSS Corticosteroids Effective »Lainas, 2002 Not Effective »Tan, 1992

57. PREVENTION OF OHSS Ketoconazole NOT EFFECTIVE Parsanezhad, 2003

58. PREVENTION OF OHSS R enin-Angiotensin Blockage and Embryo Cryopreservation Cancellation of ET and dual RAS blockage with an angiotensin receptor blocker and an angiotensin- converting enzyme inhibitor starting from day 1 after oocyte retrieval. Embryos were cryopreserved and transferred in subsequent cycles. Complete elimination of the syndrome is not possible with this treatment. Subsequent pregnancy rates with the transfer of frozen-thawed embryos are high. Ata, 2008

59. PREVENTION OF OHSS CABERGOLİNE Low dose cabergoline Reduced VEGFR2 Reduced OHSS 0.5 mg for eight days after the day of OPU Does not affect ART outcome, prevent OHSS (In Animals) Gomez, 2006 Alvarez, 2006

60. PREVENTION OF OHSS Bone morphogenetic protein 15 (BMP15) alleles OHSS (Francisco, 2006) Elective cryopreservation of all pronuclear oocytes (Griesinger, 2007) Coasting vs. GnRH Antagonist (Aboulghar, 2007) Low dose hCG (2500 IU) (Nargund, 2007)

61. PREVENTION OF OHSS CONCLUSIONS Patient and risk identification Avoid flare protocols Start low doses of gonadotropins During ovarian stimulation –Coasting –GnRH antagonist –Low doses of hCG –Agonist as hCG trigger –Dual suppression (OC + Agonist)

62. PREVENTION OF OHSS CONCLUSIONS Stop gonadotropins and continue GnRH agonist or antagonist Cryopreservation of all embryos or pronuclear oocytes IV albumin or starch Corticosteroids Cycle cancellation and supportive follicular aspiration

63. PREVENTION OF OHSS CONCLUSIONS