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OHSS Management in OI/IUI Cycles


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OHSS Management in OI/IUI Cycles

  1. 1. Ovarian Hyperstimulation Syndrome (OHSS) Management in OI/IUI Cycles Sandro Esteves, M.D., Ph.D. Director, ANDROFERT Andrology & Human Reproduction Clinic Campinas, BRAZIL ASPIRE III, Istanbul, September 2013
  2. 2. Esteves, 2 Know the Numbers Aetiopathogenesis Clinical Aspects What is in it for me?
  3. 3. Esteves, 3 Review this Lecture at: ASPIREIII,Istanbul September2013 OHSS: Management in OI/IUI Cycles
  4. 4. Esteves, 4 Singleton live birth at term Maximize Treatment Beneficial Effects Minimize Complications and Risks Cycle Cancellation Multiple Pregnancy OHSS
  5. 5. Esteves, 5 Incidence1: 3-6% moderate OHSS ~2% severe OHSS OHSS 1Aboulghar. Fertil Steril. 2012;97:523-6; 2Confidential Enquiry into Maternal and Child Health, 2007; 3ICMART 1.5 million cycles/year3 ~500 deaths (last 10 years) : 3/100,000 cycles2
  6. 6. Esteves, 6 Lower incidence; Mostly mild!! OI/CC: 13.5% of mild forms1 IUI: 2-8% cycle cancellation2 Delvigne & Rozenberg Hum Reprod Update. 2003;9:77-96; Cantineau et al., Cochrane Database Syst Rev. 2007; 18:CD005356 OHSS
  7. 7. Having Difficulty Conceiving 1Boivin J, et al. Hum Reprod 2007;6:1506; 2ObGyn Research 2003, EMD Serono; 3Domar AD. Fertil Steril 2004;81:271 Treated by Infertility Specialist 20% stop treatment before finishing clomiphene citrate (CC)2 23% complete CC and then stop2 45% never seek the doctor1 100 Treated by ObGyn 55 31 25-40% consult but never start treatment2 60-65% drop out before completing treatment3 20 8
  8. 8. Esteves, 8 Shift of Fluid from Intravascular to Third Space hCG  Vascular Permeability Intravascular Volume Depletion and Haemoconcentration Extravascular Transudate Accumulation No direct vasoactive activity Vasoactive Substances VEGF Aetiopathogenesis Albert et al. Mol Hum Reprod. 2002;8:409; Chen et al. Hum Reprod. 2000;15:1037; Gómez et al. Endocrinology. 2002;143:4339
  9. 9. Esteves, 9 VascularEndothelial GrowthFactor 1Yan et al, J Clin Endocrinol Metab 1993; 77:1723; 2Neulen et al, J Clin Endocrinol Metab 1995; 80:1967; ; 3Wang et al, J Clin Endocrinol Metab 2002; 87:3300; 4Pellicer et al, Fertil Steril 1999; 71:482; Induces endothelial cell proliferation Increases capillary permeability VEGF and OHSS: • VEGF is expressed in human ovaries1 • VEGF mRNA expression increases in granulosa cells after hCG administration2,3 • Elevated VEGF levels in serum, plasma, and peritoneal fluids4
  10. 10. Esteves, 10 Early onset Late onset Lyons CA et al., Hum Reprod 1994, 9:792.; Mathur RS, Fertil Steril 2000, 73:901; Papanikolaou et al.,Hum Reprod. 2005; 20:636. ClinicalAspects Exogenous hCG administered for final oocyte maturation Endogenous hCG produced by implanting blastocyst 3–7 days after hCG 12 -17 days after hCG Predicted by high number of growing follicles and elevated E2 levels Predicted by number of gestacional sacs (multiple pregnancy) Higher risk of preclinical miscarriage More likely to be severe
  11. 11. Esteves, 11 ClinicalAspects Severity of symptoms, signs and laboratory findings Rabal et al., 1967 Schenker and Weinstein, 1978 Golan et al., 1989 Navot et al., 1992 Rizk & Aboughar, 1999
  12. 12. Esteves, 12 Abdominal distension/ discomfort Mild nausea, vomiting Diarrhea Enlarged ovaries No relevant laboratorial alteration Lacking clinical significance Fiedler & Ezcurra. Reprod Biol Endocrinol 2012, 10:32 OHSS-Classification Similar to Mild + Ascites Hct >41% WBC >15,000 Hypoproteinemia Require careful monitoring Intractable nausea/vomiting Severe dyspnea; Hydrothorax Oliguria/anuria; Tense ascites Low central venous pressure Rapid weight gain; syncope Severe abdominal pain Venous thrombosis Hct >55%; WBC >25,000 Creatinine >1.6 Creat. Clearance <50 mL/min Hyponatremia: <135 mEq/L Hyperpotassemia: >5 mEq/L Elevated liver enzymes Hospitalization; Intensive care unit Mild Moderate Severe
  13. 13. Esteves, 13 Papanikolaou et al.,Hum Reprod. 2005; ;20:636-41; Humaidan et al., Fertil Steril. 2010; 94: 389-400. Psychological burden High cycle cancellation rates Higher risk of miscarriage Severe Cases May Get Even Worse Acute renal failure Arrhythmia Thromboembolism Pericardial effusion Massive hydrothorax Arterial thrombosis Sepsis Adult respiratory distress syndrome Complications
  14. 14. Esteves, 14 The TRUTH is that OHSS must be PREVENTED rather than treated
  15. 15. Esteves, 15 Identify patients at risk Mild ovarian stimulation Cycle cancellation GnRH-agonist for LH trigger Intravenous colloids Dopamine agonist Antagonist in the luteal phase Primary Prevention Secondary Prevention OHSSManagement
  16. 16. Esteves, 16 Young patients Low BMI Polycystic ovaries PCOS Previous OHSS Easily Recognized Fiedler & Ezcurra. Reprod Biol and Endocrinol 2012, 10:32; Humaidan et al., Fertil Steril. 2010; 94:389-400. BIOMARKERS of Ovarian Response Sensitive ovaries OHSSManagement
  17. 17. Esteves, 17 The Rotterdam Consensus Polycystic ovary: Ultrasound showing ≥12 follicles (2-9 mm) AND/OR ovarian volume >10 cm3 Polycystic Ovary Syndrome: 2 out of 3 Oligo‐ and/or anovulation Clinical and/or biochemical hyperandrogenism Polycystic Ovary OHSS Risk: PCOS > isolated PCOS characteristics Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group. Hum Reprod. 2004; 19:41-7.; Humaidan et al., Fertil Steril. 2010; 94:389-400 OHSSManagement
  18. 18. Esteves, 18 Which are the Biomarkers? ●Hormonal Biomarkers: FSH, Clomiphene citrate challenge test, Inhibin-B, Anti-Mullerian Hormone (AMH); ●Functional Biomarkers: Antral Follicle Count (AFC); ●Genetic Biomarkers: Single Nucleotide Polymorphisms for FSH-R; LH/LH-R; E2-R; AMH-R. OHSSManagement
  19. 19. Esteves, 19 La Marca et, Hum Reprod 2009;24:2264; Fleming et al, Fertil Steril 2012;98:1097. Dimeric glycoprotein; ~140KDa Product of GCs of early follicles Pre-antral and small antral (≤4-8mm) AMH
  20. 20. Esteves, 20 AMH Inter-cycle Intra-cycle ICC: 0.89; 95% IC: 0.83–0.94 Max. Variation: 17.4% Max. Variation: 108% ICC: 0.55; 95% IC: 0.39–0.71 Fanchin et al, Hum Reprod 2005;20:923 Hehenkamp et al. JCEM 2006;91:4057
  21. 21. Esteves, 21 AMH Fleming et al. RBM online 2013;26:130; Rustamov et al. Hum Reprod. 2012; 27:3085; Nelson & La Marca. RBM online 2011;23:411; Assays have different performances DSL and Immunotech Beckman-Couter generation II Fully automated ELISA (to be released) Lack of international standardization and EQC Sample instability Collection in EDTA Storage at room temperature (up to 40% increase) No separation of serum from blood before postage Shortcomings and Pitfalls
  22. 22. Esteves, 22 Broekmans et al. Fertil Steril, 2010; 94:1044-51; Scheffer et al. Hum Reprod 2003;18:700 Sum of antral follicles in both ovaries by TVUS at early follicular phase (D2-D4): 2-10 mm (mean diameter) Greatest 2D-plane AFC Reflect No. AF at a given time that can be stimulated by medication
  23. 23. Esteves, 23 Lee et al., Hum Reprod 2008, 23:160–167 Cut-off: 3.36 ng/mL Sensitivity : 90.5% Specificity: 70% in IVF AMH Cut-off: 16 AF Sensitivity: 100% Specificity: 93% AFC AFC Checa et al. Fertil Steril. 2010; 94:1105-7 Prediction of excessive response in IUI with 75 IU/d rec-hFSH
  24. 24. Esteves, 24 Low dose step-up gonadotropin protocol Starting dose: 37.5 – 75 IU Adjustments according to ovarian response Sengoku et al. Hum Reprod. 1999; 14:349-53; Cantineau et al., Cochrane Database Syst Rev. 2007; 18:CD005356., Humaidan et al., Fertil Steril. 2010; 94:389-400 Pen devices: Precise dose delivery Adjustments by small increments Self-administration OHSSManagement
  25. 25. Esteves, 25 2 RCT (n= 297) Low dose step-up in IUI Cantineau et al., Cochrane Database Syst Rev. 2007; 18(2):CD005356 OHSS 13% 2.7% 5.52 (95% CI: 1.85 to 16.52) Pregnancy 31.1% 28.2% 1.15 (95% CI: 0.69 to 1.92) OHSSManagement
  26. 26. Esteves, 26 GnRH-agonist rather than hCG for LH trigger Patient frustration Waste of time and money Risk ovulation and intercourse Risk of multiple pregnancy and late OHSS onset Cantineau et al., Cochrane Database Syst Rev. 2007;18:CD005356; Delvigne & Rozenberg Hum Reprod Update. 2003;9:77-96 OHSSManagement
  27. 27. Esteves, 27 LH/FSH Unload Which and How: Triptorelin 0.2 mg Leuprolide acetate 1 mg Buserelin 0.2-0.5 mg Griesinger et al. Hum Reprod Update. 2006;12:159-68. When: Same criterion of hCG 14 h 20 h 14 h 48 h 20 h 4 h GnRHa LH surge vs natural cycle OHSSManagement
  28. 28. Risk for OHSS markedly reduced: 3%  0% to 2.6% Esteves, 28 GnRH-agonist vs hCG: 11 RCT – 1,055 women Fresh autologous cycles (8 RCT) Live birth Pregnancy Moderate/ severe OHSS OR 0.44 (0.29 - 0.68) OR 0.45 (0.31 - 0.65) OR 0.10, (0.01 to 0.82) Youssef et al. Cochrane Database Syst Rev. 2011 Chance of Pregnancy also reduced: 30%  12% to 22% OHSSManagement
  29. 29. Esteves, 29 Aboulghar & Mansour. Hum Reprod Update 2003;9:275; Humaidan et al. Fertil Steril 2012 ;97:529; Engmann & Benadiva Fertil Steril 2012;97:531 Modified Luteal Support in IVF: hCG bolus OPU day (1,500 UI) or 3x 500 UI boluses; recLH; intense progesterone + estradiol; combined Risk Difference for Pregnancy: 18% (Before) vs 6% (After Modified LP Support) IVF: luteal phase insufficiency LH suppressed due to  Estrogen Management
  30. 30. Study N Trigger Luteal support Findings Romeu 1997 761 hCG X 1.5 mg Leuprolide Acetate (2 doses 12/12h) 1,000- 2,500 IU hCG D0, D2, D4 luteal phase 99% ovulation rate; Similar E2 and P4 levels, miscarriage rates Pregnancy Rates LA (27.3%) vs hCG (17.3%; p=0.0007); No OHSS in LA group Romeu et al. J Assist Reprod Genet. 1997; 14:518; Pirard et al. Hum Reprod. 2005; 20:1798; Diaz et al. J Reprod Med. 2008; 53:33. LHTriggerwithGnRHa inIUI Esteves, 30 Pirard 2005 24 hCG X 0.2 mg Buserelin 0.1 mg Buserelin different schemes Higher P4 levels at D14 with every day buserelin Diaz, 2008 48 hCG X 0.2 mg Triptorelin ----- Higher FSH and LH rise 24h after triptorelin; Higher P4 levels 48h after hCG, albeit suboptimal
  31. 31. Esteves, 31 Primary Prevention: Identify patients at risk Mild ovarian stimulation Cycle cancellation GnRH-agonist for LH trigger Secondary Prevention: Intravenous colloids Dopamine agonist GnRH Antagonist Management
  32. 32. Esteves, 32 Youssef et al. Cochrane Database Syst Rev. 2011;16:CD001302. IVF 20% Human Albumin (50 mL) 6% Hydroxyethyl starch (HES); 1L No. Studies (patients) 8 RCT (n=1,660) 3 RCT (n=487) Severe OHSS OR: 0.67 (95% CI: 0.45-0.99) OR: 0.12 (0.04-0.40) CPR OR: 0.76 (0.48-1.21) OR: 1.2 (0.49-2.95) OI and IUI: Data Not Available HowtoAvoidOHSS Increase oncotic pressure and reverse leakage of fluid Bind mediators of ovarian origin
  33. 33. Esteves, 33 Youssef et al., Hum Reprod Update. 2010;16:459-66; Tang et al. Cochrane Database Syst Rev. 2012; 15;2:CD008605. IVF Youssef, 2010 4 RCT (n=570) Tang, 2010 2 RCT (n=230) OHSS OR = 0.41 (95% CI: 0.25-0.66) OR 0.40 (95% CI: 0.20-0.77) Severe OHSS OR 0.50 (0.20-1.26) OR 0.77 (0.24-2.45) CPR OR 1.07 (0.70-1.62) OR 0.94 (0.56-.59) Miscarriage Rate OR 0.31 (0.03-3.07) OR 0.31 (0.03-3.07) HowtoAvoidOHSS Decrease incidence of early-onset OHSS
  34. 34. Esteves, 34 Cabergoline, Quinagolide, Bromocriptine dopamine agonists Basu et al. Nat Med 2001;7:569–74; Gomez et al. Endocrinology 2006; 147:5400–11.; Soares. Fertil Steril. 2012; 97:517-22. HowtoAvoidOHSS In vitro studies: Activation of dopamine receptor-2 (Dpr2) promote internalization of VEGFR-2 (become unreachable for VEGF); Cabergoline in rats: Phosphorylation of VEGFR-2 reduced by 42%; Inhibition of VEGF production in cultured granulosa cells exposed to hCG.
  35. 35. Esteves, 35 Most effective regimen: 0.5 mg daily for 8 days Start on the day of hCG administration; Ideally a few hours before hCG is given Soares. Fertil Steril. 2012; 97(3):517-22. HowtoAvoidOHSS No major complications
  36. 36. Esteves, 36 1Minaretzis et al. J Clin Endocrinol Metab. 1995;80:430; 2Fridén & Nilsson. Acta Obstet Gynecol Scand. 2005;84:812; 3Asimakopoulos et al. Fertil Steril. 2006;86:636; 4Taylor et al. J Endocrinol. 2004;183:1; 5Lainas et al. Reprod Biol Endocrinol. 2012;10:69; 6Lainas et al. Hum Reprod. 2013; April 26. HowtoAvoidOHSS Supress endogenous LH secretion (luteolytic effect) Decrease vasoactive cytokines producted by corpus luteum1 Direct effect on the ovary reducing VEGF production2,3,4 Lainas et al., 20125 40 pts.; early-onset severe OHSS Ganirelix (0.25 mg) daily from D5-D8 after oocyte retrieval + embryo freezing NO HOSPITALIZATION; Rapid resolution of OHSS Lainas et al., 20136 22 pts.; early-onset severe OHSS Ganirelix (0.25 mg) daily from D5-D7 after OPU + embryo transfer; 172 controls at risk of OHSS NO HOSPITALIZATION; Rapid resolution of OHSS; No late-onset OHSS; LBR: 41% (Antag.) vs 43% (controls)
  37. 37. Esteves, 37 OHSS has a dramatic psychological effect in patients’ life; those who suffer from it are unwilling to continue treatment. OHSS must be PREVENTED rather than treated. Improving patients’ welfare starts at identifying who are at risk for OHSS, and continues by individualization of the ovulation induction protocol. KeyMessages OHSS: Management in OI/IUI Cycles
  38. 38. Esteves, 38 Improving patients’ welfare starts at identifying who are at risk for OHSS, and continues by individualization of the ovulation induction protocol. KeyMessages GnRH-agonists LH trigger virtually eliminates OHSS; luteal phase support is required. OHSS: Management in OI/IUI Cycles
  39. 39. Esteves, 39 Secondary prevention by albumin, HES and carbegoline are useful but not fully eliminate the risk. GnRH Antagonists during luteal phase holds promise to treat OHSS in early stages. KeyMessages OHSS: Management in OI/IUI Cycles