Medical managment of ovarian hyperstimulation


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Medical managment of ovarian hyperstimulation

  1. 1. Dr. Sharda Jain Dr. Jyoti Agarwal Dr. Jyoti Bhaskar Dr. Abhishek Parihar OVARIAN HYPERSTIMULATION SYNDROME (OHSS) : Our Experience in 580 IVF Cycles
  2. 2. OHSS in IVF Incidence Pathophysiology Our experience Prevention Management N- 580 cycles
  3. 3. Really a Unique Most Serious iatrogenic problem of OI A Complicated Complication
  4. 4. Associated with increased capillary permeability leading to haemo- concentration, ASCITES, Pleural / pericardial effusions and ovarian enlargement OHSS “Capillary Leakage Syndrome” Increase B/L Ovarian enlargement + Acute shift in body fluids
  5. 5. Incidence Mild – 33% Now Omitted in IVF Cycles Moderate – 3-6% Severe – 2% Critical – 0.1 – 0.2%
  6. 6. No Unanimity CLASSIFICATION OHSS
  7. 7. <10 >10
  8. 8. EARLYEARLY <10<10  Correlated to ovarian response to stimulation.  Acute effect of exogenous hCG administration 1. Occurs within 9 days after oocyte retrieval LATELATE >10>10 1. Poorly correlated to the ovarian response 1. More correlated to the endogenous hCG produced by the implanting embryos 2. Administration of hCG for LPS 3. After the initial 10 days period after oocyte retrieval Types of OHSSTypes of OHSS
  9. 9. Pathogenesis is still unclear
  10. 10. 3 Treatment Facts that influence OHSS • HCG Triggerfor ovulation creates HAVOC • Long protocol of Down regulation With GnRH agonist in IVF is associated ↑ OHSS (No. of days of GT > dose & type ) – Compels IVF experts to use long protocol Supposedly ↑ PR With long protocol We are of the opinion that long protocol parse does not causes OHSS
  11. 11. OHSS does not develop if HCG is not administered Dr Razia S Our Findings also support
  12. 12. HCG Albert et al. Mol Hum Reprod. 2002;8:409; Chen et al. Hum Reprod. 2000;15:1037; Gómez et al. Endocrinology. 2002;143:4339
  13. 13. Moderate Moderate abdominal pain Nausea +/- Vomiting Ultrasound Evidence of ASCITES Ovarian size 8-12 cm Grading (Mild is Deleted in IVF) Severe N & V ++, pain ++ , Clinical ascites (rarely hydrothrorax) Ovarian size > 12 cm, Oliguria heamoconcentration - HEAMATOCRIT <45%
  14. 14. Critical Ovarian size > 12 cm TENSE ASCITES ± HYDROTHORAX WHITE CELL COUNT > 25 000/ ML PCV > 55 gm % OLIGURIA / ANURIA Venous thrombosis ± Thromboembolism Acute respiratory distress syndrome Critical OHSS Needs ICU care
  15. 15. Our Experience with OHSS A. OHSS does not occur without hcg trigger B. IF PREGNANCY OCCURS the condition is likely to worsen progressively over a period of three to five weeks requires very close observation including hospitalization in few cases. C. IF NO PREGNANCY OCCUR the symptoms and sign all disappear spontaneously with in 10 – 12 days of the hcg injection
  16. 16. 16Dr Razia SPrediction Can OHSS be accurately Predicted ?
  17. 17. Young patients Lean women Polycystic Ovarian PCOS Previous OHSS • High number of follicle in both ovaries at the quiescent state before Stimulation (>- 10 follicle of 4-10mm in each ovary) • Raised AMH Easily Recognized WHO are AT HIGH RISK BEFORE OI – IUI & IVF Screen Before IVF PRIMARY RISK FACTORS SENSITIVE OVARIES Picked up by USD before during after OI 25.0 pmol/l for a high response ( >7 ng/ml
  18. 18. Our Experience of OHSS IVF in 580 IVF cycles Profile of Early / Late OHSS Early (N = 6) Late (N = 4) Incidence 1.03 .68 Age 32 yrs 29 yrs BMI 22 - 29 26 Basal FSH Mean 7.4 8.3 Basal LH Mean 8.3 4.2 PCOS on USG 52% 25% E2 on day of HCG Over 4000 Over 2400
  19. 19. Profile of EARLY / LATE OHSS Cases Early (N = 6) Late (N = 4) No of Follicle on day of HCG >16 All None No of Oocyts retrieved 24 - 26 <16 Cancellation of ET 32% (2/6) Nil No of embryo transfer 3 to 4 3 Positive HCG 50% (2/4) 100% Abortion / Ectopic 1 (Abortion) 1 (Ectopic) Clinical Pregnancy 1/4 3/4 Our Experience of OHSS in 580 IVF cycles
  20. 20. Does PCOS Causes Poor Egg / Embryo Quality ?? IN OUR EXPERIENCE - Women with PCOS undergoing IUI to IVF are commonly found to have poor quality eggs with reduce potential with fertilization We do not think it is due to intrinsic deficit in egg quality; it looks related to intra ovarian hormonal changes brought about by OHSS
  21. 21. •Primary •Secondary Prevention of OHSS : Better than Cure “Ten Commandments” Rizk B,1993,ESHRE Symposium
  22. 22. • Avoid hCG trigger in high risk cases (Predicted based on history/ Exam/USG – before & during IVF Cycle) • Reducing Exposure to large doses Gonadotropins in high risk cases. • GnRH Antagonist Protocols in high responders • GnRHa trigger • Avoidance of hCG for LPS • Insulin-Sensitizing Agents Primary Prevention Strategies
  23. 23. • Cryopreservation of embryos & ET in next cycle (our first Priority) • Coasting (Second Priority) • Cycle Cancellation (Last Priority) • Other Possible Strategies for Preventing OHSS - Cabergoline - HES - Antagonist - IV albumin in cases of paracentisis • Nonrecommended Strategies Aromatase Inhibitors Follicular Aspiration Consider - Low dose HCG on OPU Day (1500 IU) If ET is planed Secondary Prevention Strategies GnRH antagonist, instead of a long-protocol Agonist trigger or Reduced Dose of hCG for trigger ????
  24. 24. 1.Decrease Gonadotropin dose and duration – 75-112iu start dose – Frequent monitoring 2. GnRH Antagonist Protocols – Fewer mid-size follicles – Significant reduction in severe OHSS OR 0.43 (0.33-0.57) – Similar Live Birth rates OR 0.86 (0.69-1.08) Al-Inany et al. Cochrane 2011 How to prevent OHSS in High Risk Cases Primary Prevention
  25. 25. 3. Avoidance of hCG for luteal support • High E2 and P levels during IVF suppress pituitary LH production • Need exogenous P or hCG/LH • hCG for luteal support doubles OHSS risk compared How to Prevent OHSS primary Prevention
  26. 26. 4. Metformin* Hyperinsulinaemia in PCOS Co-treatment during IVF Similar Live-Birth rates Significant Reduction in OHSS in PCOS patients OR 0.27 (0.16-0.47) Tso et al. Cochrane 2009 How to prevent OHSS Primary Prevention
  27. 27. Role of Metformin in OHSS Prevention • Metformin has also been used for the prevention of OHSS. • In a meta – analysiss of eight randomized controlled trials of women with PCOS metforming given 2 months before strating COS significantly reduced the risk of severe OHSS (odd ratio(OR))OF 0.21,95% confidence interval (CI)0.11-0.41,p<0.00001) (costello et al 2006)
  28. 28. Role of Metformin in OHSS Prevention • The mechanism of action of metformin is not completely clear, but reduction of Anti – Mullerian Hormone (AMH) values and a reduced insulne dependent VEGE production has been suggested (Tang et al 2006)
  29. 29. • GnRH antagonist, instead of a long-protocol • Agonist trigger or Reduced Dose of hCG for trigger ???? • Cryopreservation of embryos & ET in next cycle • Coasting • Cycle Cancellation • Other Possible Strategies for Preventing OHSS - Cabergoline - HES - Antagonist - IV albumin in cases of paracentisis • Nonrecommended Strategies Aromatase Inhibitors Follicular Aspiration Consider - Low dose HCG on OPU Day (1500 IU) If ET is planed Secondary Prevention Strategies
  30. 30. Proposed Protocol of Zero% OHSS at our centre • The use of the GnRH antagonist protocol for OI instead of long protocol • Ovulation Triggering with GnRH agonist Instead of HCG trigger • Cryopreservation of all oocytes and embryos ↓ ET in frozen – thawed cycle 3 Steps
  31. 31. STEP - 1 Use of GnRH antagonist Protocol for OI • Patients friendly - Fewer injection of OI - Short duration of stimulation - Absence of side effects Uses • ↓↓ OHSS rate • No difference in Term LB Rates Between antagonist & agonist Al- Inany et al 2006- 20011, Kolibisnskis et al 2006 Devroey et al 2009 2011
  32. 32. STEP - II Ovulation Triggering - ↓↓↓↓ OHSS Rate - but can’t eliminate it all together GOLD STANDARD as ovulation triggering agent because of long half life with levels remaining elevated even after six days of administrations NO HCG TRIGGER Antagonist protocol GnRH Agonist trigger For triggering final Oocyte maturation • Effective in preventing OHSS (Segal and Casper ,1992
  33. 33. ZERO % OHSS (Severe / Critical) is achieved • Incidence of Severe OHSS is GnRH antagonist cycles is 0% when triggered with a GnRH agonist. • This was tested in OOCYTE DONORS (Melo et al ,2009) Major Disadvantages in self cycles ↑ Luteal phase defect & significant ↓ Pregnancy Rate
  34. 34. It is EASIER Said Than Done to cancel a cycle !! ↓ GnRH AGONIST as a triggering agent Luteal phase defect - ↓ PR Negative effect on corpus luteum function Negative effect on function of endometrium BY GIVING HCG1500 units on O.P.U. day – P.R. ↑ (NORMALISED) ↑ Cryo Preservation ↑
  35. 35. Step III CRYO PRESERVATION of oocytes & embryo A valuable modality… But Skill - is the key Oocyte / embryo vitrification – ↑ P.R. (40% - 80%) ↓ Severe OHSS to 0% Results better than COASTING Ethical Issue of freezing embryo
  36. 36. • Prevents OHSS as No endogenous hCG • An additional benefit of postponing ET * Avoiding embryo exposure to extremely elevated steroid concentrations. * Supraphysiological hormone levels -detrimental to endometrial receptivity, as well as embryotoxic Valbuena D, Martin J et alFertilSteril2001;76:962–8 Shapiro B et al .FertilSteril2011;96:344–8 ShapiroB, DaneshmandS,GarnerF et alFertilSteril2011;96:516–8 Crypreservation of Embryo & Postponing ET
  37. 37. CDC Report 2008 Pregnancy Rate same in FRESH / FROZEN – thawed cycles
  38. 38. • Withholding Gonadotropins for few days before giving hCG until E2 drops to a safer level (below 3000) • Available evidence suggests that such “coasting” does not adversely affect outcome in IVF cycles unless it is prolonged (>2 days) Coasting
  39. 39. Coasting diminishes the granulosa cell cohort • Follicular growth will continue with the same rate. • E2 will continue to rise then will plateau and then decline.
  40. 40. 1. When to stop gonadotropins? • When the leading follicles reach 16mm 2. how many days? • Till the E2 drops to < 3000 pg/ml Ragaa Mansour et al Human Reproduction Vol.20, 2005 Raziel a et al HumanReproduction,Vol .18 ,2003 3. How ever Pregnancy rates appear to decrease while coasting during prolonged gonadotropin-free periods Practical TipsPractical Tips (Ulug et al, 2004)
  41. 41. duration cycle IR % PR % 1 or 2 100 (48.2%) 41.0 55.7 3 days 49 (23.6%) 18.4 27.9 4 days 58 (28.2%) 10.5 26.7 IR : implantation rate; PR pregnancy rate FR was unaffected Ulug HumReprod 2002
  42. 42. Our impression on coasting At present clinicians should employ strategies which appear to result in a lower incidence of severe OHSS rather than coasting until further evidence has accumulated. cochrane 2011 • Coasting is a useful protocol for prevention of OHSS based on multiple retrospective studies and one randomized controlled trial. We are slowly giving up in Favour of Embryo freezing & ET next cycle
  43. 43. • In our Experience OHSS does not develop if hCG is not administered. • Even if hCG dose is decrease OHSS is really possible. • OHSS is more frequent when hCG is used for luteal support rather than progesterone. • OHSS is more frequent and severe in conception cycles and particularly multiple pregnancies trigger
  44. 44. • IVF outcome unaffected • No significant difference in the incidence of OHSS
  45. 45. Big alert is flagged • If >20 growing follicles(>/=12mm); • Serum E2 >3,000pg/mL the day of hCG admin - istration • Be obsessed for Presence of incipient Ascitis on OPU day • Previous OHSS even with less evident signs of a strong ovarian response Practical Tips to avoid OHSS
  46. 46. Most Important Tips Is important to know that symptoms and signs of OHSS are severely aggravated by rising hcg levels. Thus women with OHSS - should not receive additional; hcg injection as luteal phase support
  47. 47. 6.6. Non recommended strategies:Non recommended strategies: * Follicular Aspiration * Aromatase Inhibitors o * Glucocorticoids - Does not eliminate the risk of OHSS We do not give Further studies are needed
  48. 48. Management of OHSS
  49. 49. * Treatment for women with mild OHSS and many with moderate OHSS can be managed on an Outpatient basis. * Conventional management of OHSS is focused on Supportive Care until the spontaneous resolution of the condition
  50. 50. • Pain relief -paracetamol /oral or parenteral opiates. NSAID should not be given • Antiemetic drugs - those appropriate for the possibility of early pregnancy
  51. 51. • Women should be encouraged to drink to thirst, rather than to excess.this is the most physiological approach to replace fluids. • STRENUOUS EXERCISE and SEXUAL INTERCOURSE should be avoided for fear of injury or torsion of hyper-stimulated ovaries. • Women should continue progesterone luteal support but hCG luteal support is inappropriate & not to be given
  52. 52. • Hospital admission should be recommended to women with severe OHSS. • Multidisciplinary care • If Features of critical OHSS – ICU Care.
  53. 53. • Women admitted to hospital with OHSS should be assessed at least daily, with more frequent assessment of those with critical OHSS. Standard care involves • Monitoring of appropriate clinical parameters • Fluid balance management • Thromboprophylaxis and • Ascites treatment
  54. 54. Inpatient monitoring of patients with OHSS
  55. 55. • Routine screening for thrombophilia in all women undergoing assisted conception is not warranted. • Thromboprophylaxis should be provided for all women admitted to ICU with OHSS.
  56. 56. • Dopamine agonists and GnRH antagonists , when given together at the time of diagnosis of OHSS, appear to work rapidly and effectively to diminish the clinical symptoms of the disease Rollene et al ,Fertil Steril 2009
  57. 57. Role of Cabergoline in OHSS prevention • Cabergoline appears to reduce that risk of OHSS in high – risk women especially in moderate OHSS. • But there is no evidence that it reduces the chances of severe OHSS. • The use of cabergoline does not affect the pregnancy outcome risk of adverse. Events (Chocrane reviews 2012)
  58. 58. Role of Cabergoline in OHSS Prevention • Cabergoline 0.5 mg tablet daily starting on the day of hcg (just before) injection and continued for total of 8 days have been shown to reduce the risk of OHSS
  59. 59. • Successful management of severe early OHSS by reinitiating GnRH antagonist 3 days after oocyte retrieval incombination with embryo cryopreservation LainasTG et al ReprodBiomedOnline2007
  60. 60. Consider A. Hydroxyethyl starch on OPU Day Nonbiological Potentially safer, cheaperand more effective . B. IV Albumin if paracentesis is needed
  61. 61. • Recently, there has been a trend toward the use of outpatient management with early paracentesis for moderate to severeOHSS.
  62. 62. • Need forsymptomatic pain relief/resp difficulty • Tense ascites • Oliguria with impaired renal function • Hemoconcentration unresponsive to medical treatment
  63. 63. Our Experience Consider Early paracentesis If raising headend does not help patients & patients symptoms become severe & lot of fluid is there in abdominal cavity --- can be safely drained by trans abdominal of trans vaginal route by sterile needle aspiration once or twice. The problem usually correct itself within 10 to 12 days of the hcg shot if pregnancy does not occure, or by the eighth week of pregnancy
  64. 64. SPECIAL TIPS for Donor stimulation • Always use GnRH ANTAGONIST PROTOCOL • Give GnRH AGONIST TRIGGER for ovulation • If Suspicious of Moderate OHSS * Give cabergoline before trigger * After OPU give antagonist inj. for 2-3 days * Give progesterone withdrawl inj MPA Before discharge or Tablets. * Follow - up is must
  65. 65. Women should be reassured that pregnancy may continue normally despite OHSS, and there is no evidence of an increased risk of congenital abnormalities. Mathur RS,Jenkins JM et al BJOG 2000 Raziel A et al Hum Reprod 2002 Wiser A et al Hum Reprod 2005
  66. 66. Key : Take Home Messages • SAFETY OF PATIENT in IVF is public & doctors TOP PRIORITY Concept has to be accepted sooner than later by FOGSI / ICMR Strict guidelines to follow OHSS FREE IVF CLINIC Can be reality ? Yes ofcourse Hospitalization / ICU care can be prevented!!
  67. 67. Slowly Replace Long protocol of GnRH agonist with short antagonist protocol + Agonist ovulation trigger + Oocyte & embryo freezing + ET in Natural cycle Or Artificially prepared Endometrium Key Take Home Messages
  68. 68. OHSS : an IATROGENIC problem must never hold you back if you face it. Instead - these problems can help you shine brighter in the next take off – of your PROFESSIONAL MATURITY & support OHSS Free Clinic
  69. 69. Future Strategy for Safe IVF Practice • 100% antagonist cycle • 100 % Agonist trirger for ovulation • 100% freezing of embryos • 100% frozen-thawed IVF cycles Zero % OHSS Free Clinic
  70. 70. IS A REALITY
  71. 71. Thank You