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NEW STRATEGIES FOR OHSS PREVENTION

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. THE GOOD.

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NEW STRATEGIES FOR OHSS PREVENTION

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  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 ? • Marked extravascular exudate, • Profound intravascular depletion, • Hemoconcentration • 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 OHSSLEVEL 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 OHSSLEVEL 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 OHSSLEVEL 2: Low Dose Gonadotropins Low dose gonadotropin therapy (75 IU), Homburg and Howles, 1999 • 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

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

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

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

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

  18. PREVENTION OF OHSSLEVEL 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 OHSSLEVEL 2: Minimal Stimulation Protocols Minimal Stimulation Protocol CC/Gonadotropins/Antagonist

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

  21. PREVENTION OF OHSSLEVEL 2: Dual suppression with OCP and GnRH-a Protocol • Low dose OCP (35µg) for 25 days • GnRH agonist on day 21 of OCP • 150 IU of gonadotropins on the 3rd day of menstrual bleeding with GnRH-a Damario, 1997

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

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

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

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

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

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

  28. PREVENTION OF OHSSLEVEL 2: Use of GnRH antagonist vs. agonist 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 OHSSLEVEL 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 OHSSLEVEL 2: Use of GnRH antagonist vs. agonist Effects of GnRH antagonist cotreatmenton the incidence of ovarian hyperstimulation syndrome remains uncertain, although a trend is present infavour of the GnRH antagonists Tarlatzis, 2006

  31. PREVENTION OF OHSSLEVEL 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

  32. PREVENTION OF OHSSLEVEL 2: Antagonist in GnRH Analog Cycles Gustofson, 2006

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

  34. PREVENTION OF OHSSLEVEL 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

  35. PREVENTION OF OHSSLEVEL 2: HCG Dose and Alternatives Cycle outcome after agonist and HCG triggering of final oocyte maturation Centre 1Centre 2AgonistHCGAgonistHCG Patients18243430 Patients OPU 18243230 Patients ET 15202928 Positive HCG16.7% (3/18)45.8% (11/24)17.6% (6/34)20.0% (6/30) Ongoing preg. Rate5.6%(1/18)41.7%(10/24)2.9%(1/34)16.7% (5/30) Early pregnancy loss66.7% (2/3)9.1% (1/11)83.3% (5/6)16.7% (1/6) Kolibiniakis, 2005

  36. PREVENTION OF OHSSLEVEL 2: HCG Dose and Alternatives Acevedo, 2006

  37. PREVENTION OF OHSSLEVEL 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

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

  39. PREVENTION OF OHSSLEVEL 3: Proper Monitorization • USG • PCOS patterns • Large number of follicles • E2 • Good predictor to OHSS Aboulghar, 2003

  40. PREVENTION OF OHSSLEVEL 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)

  41. PREVENTION OF OHSSLEVEL 4: Coasting Comparison of criteria used for coasting   ReferenceNo. coastedE2 initially (pg/ml)E2 (pg/ml) at hCG Coasting duration (days) Sher (1995)51>3000<30006.1 (3–11) Benavida(1997)22>3000<30001.9 ± 0.9 Tortoriello(1998)22>3000<30002.6 ± 0.3 Dhont (1998)120>2500<25001.9 ± 0.8 Lee (1998)20>2724Decreasing2.8 ± 1.3 Egbase (1999)15>6000<30004.9 ± 1.6 Wald. (1999)65Variable<27244.3 (3–6) Fluker (1999)63>300025% decline3.4 ± 0.1 Al-Shawaf (2001)50>3595<27243.4 ± 1.6 Ulug. (2002)207>4000<40002.9 ± 0.11 Levinsohn, 2003

  42. PREVENTION OF OHSSLEVEL 4: Coasting ICSI outcome according to the number of coasting days Group I <3 daysGroup II >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 ± 23200.0001 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

  43. PREVENTION OF OHSSLEVEL 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

  44. PREVENTION OF OHSSLEVEL 4: Coasting Uluğ, 2004

  45. PREVENTION OF OHSSLEVEL 4: Coasting Moreno, 2004

  46. PREVENTION OF OHSSLEVEL 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

  47. PREVENTION OF OHSSLEVEL 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

  48. PREVENTION OF OHSSLEVEL 5: Prevention of pregnancy occurrence Aboulghar, 2003

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