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Medical Management of Ovarian Hyperstimulation Syndrome (OHSS) In 1500 IUI Cycles Practical tips


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Medical Management of Ovarian Hyperstimulation Syndrome (OHSS) In 1500 IUI Cycles Practical tips

  1. 1. Dr. Sharda Jain Dr. Jyoti Agarwal Dr. Jyoti Bhaskar Dr. Aruna Saxena Dr Abhishek S. Parihar Medical Management of Ovarian Hyperstimulation Syndrome (OHSS) In 1500 IUI Cycles Practical tips Directors:
  2. 2. Review this Lecture at: Slideshare. net : Medical Management of Ovarian Hyperstimulation Syndrome (OHSS) In 1500 IUI Cycles Practical tips
  3. 3. Goals of Ovulation induction in IUI Minimize RISK Complications AIM Ideal Outcome Singleton live Birth at term Cycle Cancellation Multiple Pregnancy OHSS
  4. 4. IMPORTANCE of OHSS in IUI WHAT IT means to US & to You ? • Totally Iatrogenic problem Induced by clinician – when GT is used for OI • Without HCG Trigger OHSS is extremely rare. • 100% prevention impossible • It has Profound Economical impact & Profound Psychological Impact FATAL CASES In IUI are RARE but Is a REALITY & a possibility !!! (Though not reported)
  5. 5. OHSS in IUI is Not Reported in Literature as it should be In IVF : MORTALITY : 3 / 1,00,000 CYCLES 1 Aboulghar. Fertil Steril. 2012;97:523-6; 2 Confidential Enquiry into Maternal and Child Health, 2007; 1-5 million IVF cycles / year 500 death (last 10 years) Grossly Underreported
  6. 6. CLINICS providing ovarian stimulation with Gonadotrophins for IUI/IVF - Protocol should be in place for preventing, diagnosing and managing OHSS Nice Guideline 2004 80% Gynaecologists in India Practise IUI
  7. 7. Clinical Aspects
  8. 8. Classification
  9. 9. Classification Mathur et al - 2005. • THE EARLY FORM (<10 days after the HCG trigger. • THE LATE FORM (>- 10 days after HCG). • COMBINATION of the early form , followed by pregnancy is SERIOUS AND LONG LASTING (Papnikolaou et al., 2004)
  10. 10. Classification and staging of ovarian hyperstimulation syndrome (Whelan 2000) •Grade 1: Abdominal distension /discomfort •Grade 2: grade 1 plus nausea and vomiting or diarrhea ovaries enlarged 5-12 cm •Grade 3: Sonograding evidence of ascites •Grade 4: clinical evidence of ascites or hydrothorax or difficult breathing •Grade 5 :All of the above puls decrease blood volume nemoconcertration, diminished renal perfusion and function , and coagulation abnormal •From whelan , with permission Followed in Lifecare IVF M I L D S E V E R E MODERATE
  11. 11. Mild Mild abdominal pain Abdominal bloating Ovarian size usually <8 cm Moderate Moderate abdominal pain Nausea +/- Vomiting Ultrasound Evidence of ascites Ovarian size 8-12 cm HCT > 41% , WBC>15,000, Hypoproteinemia GRADING
  12. 12. Mild Mild abdominal pain Abdominal bloating Ovarian size usually <8 cm Moderate Moderate abdominal pain Nausea +/- Vomiting Ultrasound Evidence of ascites Ovarian size 8-12 cm GRADING
  13. 13. Moderate OHSS i.e ultrasound evidence of Ascites on day of IUI warns gynecologist to take action • Infact , Action should be taken on day of trigger itself PCOD Ascites
  14. 14. Severe N & V ++, pain ++ , Clinical ascites (rarely hydrothrorax) Ovarian size > 12 cm, Oliguria heamoconcentration - HEAMATOCRIT > 45% Hypoproteinaemia 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 Very Very Rare
  15. 15. Etiology The Etiology of OHSS is complex, HCG Development of OHSS involves increase vascular permeability and loss of fluid , protein and electrolytes into the peritoneal cavity, which leads to hemoconcentration. Either exogenous or endogenous (from resulting pregnancy is believed to be an early contributing factor).
  16. 16. 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
  17. 17. OHSS INCIDENCE in IUI Clomiphene + IUI Very Low Incidence Mostly mild !! Upto 13.5% of mild form of OHSS In OI with Clomiphene LITERATURE : Very few reports Inspite of 90% Gynaecologists doing it Delvigne & Rozenberg Hum Reprod Update. 2003;9:77-96; Cantineau et al., Cochrane database Syst.Rev 2007;18:CD005356
  18. 18. Mild OHSS around 10% Cycle Cancellation due to moderate OHSS in IUI : 2 - 10% Database Syst Rev. 2007; 18:CD005356 OHSS OHSS INCIDENCE in IUI (Clomiphene+ GT) LITERATURE : Scant •Lower Incidence • Mild to Moderate only
  19. 19. Lifecare IVF EXPERIENCE on INCIDENCE of OHSS in OI with Clomiphine + IUI N 1000 Cases • Lower Incidence • Mostly mild form !! Mild – 3% Moderate Severe Not Seen OHSS (Pain , > ovarian size)
  20. 20. Mild – became Moderate : 4.8% (N =15) LIFECARE IVF EXPERIENCE With CC + GT + IUI N-320 Lower Incidence Mostly mild to Moderate Mild – 5.5 % (N=17) Severe : Nil OHSS After trigger
  21. 21. Lifecare IVF Experience CC+GT+ IUI (N-320 cases) MODERATE OHSS (after trigger) in 4.8% (N-15) A)Cycle Cancellation 11 cases , 1 pregnancy Advice given in all cases - for no intercourse bcz. of risk Multiple pregnancy & late OHSS B) Converted to IVF i.e. OPU + Freezing of embryo : 4 cases , Pregnancy : Nil (Cabergoline + antagonist for 3 days) No freezing was possible in 3 due to poor quality embryos
  22. 22. Mild : 6% (N-11) Mild become Moderate after trigger = 4.4% (N- 8) A Cycle cancellation = 6, Preg. : Nil (Cabergoline + antagonist2 days) B Converted to IVF 2 cases, Preg : 1 (Caberboline +antagonist 2 days) Lifecare IVF INCIDENCE of OHSS in OI with Pure Gonadotrophins + IUI (N-180)
  23. 23. The Truth is that OHSS MUST BE PREVENTED RATHER than treated
  24. 24. OHSS prevention during stimulation in IUI - Our practice at
  25. 25. HOW TO PREVENT ? • Steps Before stimulation • Step During Stimulation • Step on Impending severe OHSS
  26. 26. 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 over 25.0 pmol/l for a high response NICE Guidelines or >7 ng/ml Easily Recognized WHO are AT HIGH RISK BEFORE OI – IUI & IVF PRIMARY RISK FACTORS SENSITIVE OVARIES
  27. 27. Monitoring for OHSS should be • Easy • Reliable • Patient friendly • Not Expensive • Can be done by Gynaecologist herself doing ovulation Induction + IUI
  28. 28. MONITORING ASSESSING THE FOLLICULAR MATURITY • The follicles normally grow at a rate of 2- 3 mm / day in a stimulated cycle. • Definitive size of the follicle which confirms the maturity of oocytes is still controversial. • A follicle measuring 18—20 mm has been found to contain a mature oocyte.
  29. 29. MONITORING CORELATION WITH SERUM OESTRADIOL LEVELS • Plasma estradiol levels correlates closely with the stage of development of the dominant follicle • Serum estradiol levels >200 pg / ml on day 8 of stimulation indicates adequate dose of gonadotropins. Ultrasound monitoring has totally replaced estradiol monitoring in most centers.
  30. 30. TREATMENT options in Moderate OHSS case in IUI cycle for Gynaecologists • Cancel IUI and reinitiate with lower dose GT next time (give cabergoline + antagonist for 2 days in this cycle) • Convert to IVF i.e. * GnRH trigger, * OPU (Cabergoline + antagonist + HES) * Freezing of all embryos
  31. 31. Low dose step up protocol - Ideal in PCOS First Line Next time start with lower dose of Gonadotropins Starting dose of Gonadopropins Varies between 37.5-75 iu, followed by step – wise increase in dose. • Monofollicular development is aimed • Increase pregnancy rates • Lower risk of OHSS and multiple pregnancies (Homberg et al 1995)
  32. 32. STEP DOWN protocol in PCOS (Second line) • Mimics hormonal pattern in natural cycle. • Starting dose - once dominant follicle of around 10 mm is seen on ultrasound • Then reduce dose by 37.5iu sequentially • NOT PREFFERED
  33. 33. Options for trigger at Lifecare IVF In Mild to Moderate OHSS In cases at high risk of OHSS we usually give GnRH agonist trigger . If we convert to IVF + freeze all embryos and then transfer embryos in next cycle (as cases with very high estradiol levels are not only at high risk for OHSS but also lead to “out of phase endometrium” with lower implantation rates).
  34. 34. What Luteal support Modified Luteal phase if we are saving the cycle? A. INTENSIVE ESTRADIOL AND PROGESTERONE SUPPORT B. IF WE ARE CONVERTING TO IVF 1. One bolus of 1500 iu hcg administered on the day of OPU if the total number of follicle (12-14 mm) are <16 2. OR, a total of three boluses of hcg (250-500 iu) during the luteal phase 3. OR, recombinant luteinising hormone 300 iu administered every second day until a positive pregnancy test (chen et al 2012)
  35. 35. How would you counsel patient for IVF ? What is the extra cost? • In one mathematical model, the cost - effectiveness ratios for IVF alone Unstimulated IUI followed by IVF and stimulated IUI followed by IVF were £ 12600, £ 13100 and £15100 per live birth , respectively. • the authors concluded that for couple with unexplained infertility and mild male factor, a primary offer of an IVF cycle was cheaper and more cost effective that starting with IUI stimulated IUI followed by IVF (Pashayan et al 2006) We had only pregnancy in our 6 IVF converted cycles – in rest embryo work poor quality
  36. 36. PRIMARY PREVENTION * Identify patients at risk * Close Monitoring * Mild ovarian stimulation (CC+ GT) * Low dose step up GT protocol * With hold HCG trigger * GnRH- agonist for ovulation trigger only in mild cases where we want to save the cycle + MODIFIED LUTEAL PHASE SUPPORT or * Cycle cancellation (if Mod- OHSS on IUI day is detected) No intercourse + cabergoline (5 days) + antagonist 2 day SECONDARY PREVENTION * Dopamine agonist - Cabgoline * Antagonist in the luteal phase *Plasma Expanders – HES, IV albumin 7 3
  37. 37. Withholding HCG trigger is the KEY as only this creates HAVOC !
  38. 38. 38Dr Razia S If This picture on day of trigger should warn - not to give HCG Biggest
  39. 39. Give GnRH – agonist Trigger if Wish to Save Cycle WHICH Drug AND HOW: Triptorelin 0.2 mg Leuprolide acetate 1 mg Buserelin 0.2-0.5 mg When : Same criterion of hCG
  40. 40. • GnRH – agonist rather than hCG trigger ± Cabergoline (A) Cycle cancellation Daily Monitoring 2-3 days • No intercourse • Cabergoline 0.5 mg x 5 days • HES 6% slow • Luteal phase GnRH Antagonists Moderate Cases on day of IUI Mild Cases (B) Convert to IVF Pateint frustation/ waste of Money is addressed • Agonist trigger for ovulation • Cabergoline 0.5 mg X 5 days • Antagonist after OPU for 2-3 days • FREEZING OF EMBRYOS •EMBRYOS Management of OHSS Our
  41. 41. Close Monitoring in MODERATE CASES by IVF unit staff • Abdominal girth daily • Strict I/O chart • Hb, PCV, s. electrolytes • Keep Eye for venous thrombosis Critical Values PCV > 45 Hb >15 gm% Our In MODERATE OHSS
  42. 42. 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)
  43. 43. 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
  44. 44. 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)
  45. 45. 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)
  46. 46. Key Take home Messages Ten Commandments to prevent & treat MODERATE OHSS in IUI cycles 1. Identify cases with primary risk factor for OHSS 2. Gradual and Low dose HMG protocol 3. Ovarian drilling for PCOS 4. Withholding HCG trigger if S/S of mild OHSS 5. Use of GNRH Agonist – to trigger ovulation (to save the cycle) in mild OHSS 6. Modified Luteal phase support
  47. 47. Key Take home Messages 7.Cabergoline 0.5 mg daily Bromocriptine 2.5 mg daily from the day of hcg for 8 days 8.HES 6% slow 9.Luteal phase GnRH Antagonists 2-5 days 10 Close Close monitoring of the patients stimulated with GT is must
  48. 48. ADDRESS 11 Gagan Vihar, Near Karkari Morh Flyover, Delhi - 51 CONTACT US 9650588339, 011-22414049, WEBSITE : E-MAIL ID &
  49. 49. Thank You