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<ul><li>بِسْمِ اللَّهِ الرَّحْمَٰنِ الرَّحِيمِ </li></ul>
PREVENTION OF SEVERE OHSS
16 follicles 12 mature oocytes 14 oocytes Extras frozen if good 2 to 3 transferred 9 fertilize normally 5 divide normally ...
OHSS is a serious complication  of ovulation induction. In its severest forms, it is complicated by  hemoconcentration, ve...
OHSS INCIDENCE <ul><li>Non IVF : mild 8.0  -23% </li></ul><ul><li>moderate 0.005 -7% </li></ul><ul><li>severe 0.008 -10% <...
PATHOGENESIS OF SEVERE OHSS <ul><li>Kidney (JGA)   rorenin  Ovary             </li></ul><ul><li>      ace  </li></ul><ul><...
DIAGNOSIS OF SEVERE OHSS <ul><li>clinic : distended abdomen, diarrhea    dyspnea, weight gain, hypotension,  tachycardia <...
<ul><li>  severe   critical </li></ul><ul><li>ovaries   >12 cm   > 12 cm </li></ul><ul><li>ascites/hydrothorax   massive  ...
How to prevent  OHSS ? <ul><li>Before Start :  Identifying the patients at risk before ovulation induction . </li></ul><ul...
Before Start <ul><li>IDENTIFYING THE PATIENTS AT RISK  </li></ul><ul><li>BEFORE OVULATION INDUCTION : </li></ul><ul><li>Hi...
METFORMIN COCHRANE REVIEW,  TSO  ET AL., 2008
LOW DOSE GONADOTROPİNS <ul><li>OHSS risk is lower in low dose regimens </li></ul><ul><li>Koundouros, 2008 </li></ul>Second...
MILD STIMULATION PROTOCOL  <ul><li>KAK </li></ul>Karimzadah et al., 2010
HOW TO SUSPECT DURING COH  <ul><li>rapidly rising serum E2 levels  </li></ul><ul><li>More than 20 growing follicles </li><...
<ul><li>So what to do!! </li></ul><ul><li>For complete prevention:  withholding hCG and continuing GnRHa  (Navot et al., 1...
<ul><li>ALTERNATIVES TO HCG </li></ul><ul><li>hCG is similar in action to LH however it is not identical.  </li></ul><ul><...
<ul><li>OTHER ALTERNATIVES TO HCG </li></ul><ul><li>Rec hCG </li></ul><ul><li>250 µg is as effective as 10, 000 IU of hCG ...
  COCHRANE REVIEW,  AL-INANY ET AL., 2011
GNRHAGONIST FOR TRIGGERRING OVULATION YOUSSEF ET AL., 2010
<ul><li>Coasting </li></ul><ul><li>It is withholding gonadotropins for few days before giving hCG until E2 drops to a safe...
  COCHRANE REVIEW,  D’ANGELO E.AL. 2010    Coasting vs. no coasting
<ul><li>Coasting   </li></ul><ul><li>CLINICAL AND PRACTICAL ASPECTS </li></ul><ul><li>When to stop gonadotropins? </li></u...
GnRH antagonist In a Cochrane review by Al-Inany  et al (2011) comparing agonist and antagonist, significant difference in...
WHY:  (AL-INANY ET AL, 2010)
CANCELLATION FOR RISK OF OHSS
<ul><li>So we may say confidently that GnRH antagonist is safer than GnRH agonist in IVF/ ICSI cycles  </li></ul>
BUT NOT ALL DOCTORS WOULD GO FOR ANTAGONIST
(GNRH) ANTAGONISTS: OFF LABEL INDICATION  <ul><li>unique Idea </li></ul><ul><li>Administration during GnRH agonist cycle <...
VALUE <ul><li>allow continued stimulation while rapidly decreasing the E2 level to a range that is clinically acceptable. ...
 
OUR RESULTS Parameter Coasting (n = 96) Antagonist (n = 94) P-value Age (years) 30.0 ± 4.9 29.6 ± 4.6 NS Duration of infer...
<ul><li>Intravenous Albumin to Prevent OHSS </li></ul><ul><li>Cochrane review update  (Al-Inany et al., 2011) </li></ul><u...
BACKGROUND <ul><li>Administration of intravenous fluids such as human albumin might result in :- </li></ul><ul><li>A resto...
BACKGROUND <ul><li>Hydroxyethyl starch (HES)  is a plasma expander that has gained recent attention as an alternative to a...
RESULTS OF SEARCH 9/23 10 RCTs (n= 2048) 7 RCTs :  HA vs. P 1 RCT :  HES vs. P 2 RCTs :HA vs. HES vs. P No RCTs compared d...
IV FLUIDS VERSUS PLACEBO, SEVERE OHSS  18/23
AFTER OPU : DOPAMINE AGONIST : YOUSSEF ET AL., 2010
YOUSSEF ET AL., 2010
<ul><li>Postponing the Embryo Transfer </li></ul><ul><li>Cryopreservation of all embryos </li></ul><ul><li>Several studies...
Conclusion OHSS   is a preventable disease that  should not be allowed to happen
CONCLUSION <ul><li>Absolute prevention : no hCG or cycle cancellation </li></ul><ul><li>Relative prevention : coasting, al...
THANK YOU Dr. Hesham Al-Inany  MD, PhD e-mail : hesham@khosoba.com
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Infertility- A CASE DISCUSSION
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  1. 1. <ul><li>بِسْمِ اللَّهِ الرَّحْمَٰنِ الرَّحِيمِ </li></ul>
  2. 2. PREVENTION OF SEVERE OHSS
  3. 3. 16 follicles 12 mature oocytes 14 oocytes Extras frozen if good 2 to 3 transferred 9 fertilize normally 5 divide normally 30-40% of couples 4 stop dividing & sperm Typical progression
  4. 4. OHSS is a serious complication of ovulation induction. In its severest forms, it is complicated by hemoconcentration, venous thrombosis, electrolyte imbalance and renal and hepatic failure. Shenker and Weinstein, 1978; Navot et al., 1992; Aboulghar et al., 1993
  5. 5. OHSS INCIDENCE <ul><li>Non IVF : mild 8.0 -23% </li></ul><ul><li>moderate 0.005 -7% </li></ul><ul><li>severe 0.008 -10% </li></ul><ul><li>IVF : mild 100% </li></ul><ul><li>moderate 21- 44% </li></ul><ul><li>severe 1- 10% </li></ul><ul><li>estimated mortality 1/45.000-1/500.000 </li></ul><ul><li>estimated morbidity 0.1-0.5% </li></ul>
  6. 6. PATHOGENESIS OF SEVERE OHSS <ul><li>Kidney (JGA) rorenin Ovary </li></ul><ul><li> ace </li></ul><ul><li>PG Angiotensin II A-tensin I A-tensinogen </li></ul><ul><li>histamin (liver) </li></ul><ul><li>inflam. cytokines ANGIOGENESIS </li></ul><ul><li>(IL-1,IL-6,TNF) IL-2 (FF) </li></ul><ul><li> Capillary permeability </li></ul><ul><li>VEGF(ovary) </li></ul><ul><li> </li></ul><ul><ul><ul><ul><ul><li> fluid shift </li></ul></ul></ul></ul></ul>hCG (LH) E 2
  7. 7. DIAGNOSIS OF SEVERE OHSS <ul><li>clinic : distended abdomen, diarrhea dyspnea, weight gain, hypotension, tachycardia </li></ul><ul><li>U/S: enlarged ovaries (>12 cm) + ascites </li></ul><ul><li>X-ray: pleural effusion </li></ul><ul><li>lab: Hct > 45% </li></ul><ul><li>total proteins/albumine </li></ul><ul><li>trombocytes </li></ul><ul><li>ureum/creatinine ; creat.clear. </li></ul><ul><li>electrolyte imbalance ( K , acidosis) </li></ul><ul><li>liver enzyms </li></ul><ul><li> -hCG </li></ul>
  8. 8. <ul><li> severe critical </li></ul><ul><li>ovaries >12 cm > 12 cm </li></ul><ul><li>ascites/hydrothorax massive tense </li></ul><ul><li>hct >45% >55% </li></ul><ul><li>WBC >15.000 >25.000 </li></ul><ul><li>oliguria yes extreme </li></ul><ul><li>creatinin 1.0 - 1.5 >1.6 </li></ul><ul><li>creat. clearence >50 ml/min <50 ml/min </li></ul><ul><li>renal failure not yet yes </li></ul><ul><li>liver disfunction yes yes </li></ul><ul><li>complications nasarca thrombo-emb. </li></ul><ul><li> ARDS </li></ul>
  9. 9. How to prevent OHSS ? <ul><li>Before Start : Identifying the patients at risk before ovulation induction . </li></ul><ul><li>Before Start : Metformin & Proper ovulation induction protocol </li></ul><ul><li>During Cycle : Careful monitoring of ovarian response: </li></ul><ul><ul><ul><li>US </li></ul></ul></ul><ul><ul><ul><li>E2 </li></ul></ul></ul><ul><li>Before OPU during ovulation induction: </li></ul><ul><ul><ul><li>Cancel the cycle </li></ul></ul></ul><ul><ul><ul><li>hCG dose and alternatives </li></ul></ul></ul><ul><ul><ul><li>Coasting </li></ul></ul></ul><ul><ul><ul><li>Antagonist </li></ul></ul></ul><ul><li>After OPU Cryopreservation of all embryo </li></ul><ul><li> Dopamine agonist </li></ul><ul><li>Luteal phase support </li></ul>
  10. 10. Before Start <ul><li>IDENTIFYING THE PATIENTS AT RISK </li></ul><ul><li>BEFORE OVULATION INDUCTION : </li></ul><ul><li>History of previous OHSS </li></ul><ul><li>PCOD patients . </li></ul><ul><li>AMH > 5 </li></ul>
  11. 11. METFORMIN COCHRANE REVIEW, TSO ET AL., 2008
  12. 12. LOW DOSE GONADOTROPİNS <ul><li>OHSS risk is lower in low dose regimens </li></ul><ul><li>Koundouros, 2008 </li></ul>Second: COH
  13. 13. MILD STIMULATION PROTOCOL <ul><li>KAK </li></ul>Karimzadah et al., 2010
  14. 14. HOW TO SUSPECT DURING COH <ul><li>rapidly rising serum E2 levels </li></ul><ul><li>More than 20 growing follicles </li></ul>
  15. 15. <ul><li>So what to do!! </li></ul><ul><li>For complete prevention: withholding hCG and continuing GnRHa (Navot et al., 1992) </li></ul><ul><li>Delaying hCG = Coasting </li></ul><ul><li>Other alternatives: </li></ul><ul><ul><ul><ul><ul><li>Rec hCG </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Rec LH </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>GnRHa </li></ul></ul></ul></ul></ul>
  16. 16. <ul><li>ALTERNATIVES TO HCG </li></ul><ul><li>hCG is similar in action to LH however it is not identical. </li></ul><ul><li>It has a longer half-time and associated with sustained luteotropic effect. </li></ul><ul><li>(Itskovitz et al., 1991; Haning et al., 1985) </li></ul>
  17. 17. <ul><li>OTHER ALTERNATIVES TO HCG </li></ul><ul><li>Rec hCG </li></ul><ul><li>250 µg is as effective as 10, 000 IU of hCG in terms of PR and implantation rate, however similar incidence of OHSS. </li></ul><ul><li>(The European Rec Human hCG Study Group 2000; Driscoll et al., 2000, Chang et al., 2001) </li></ul><ul><li>Rec LH </li></ul><ul><li>Single rec LH dose significantly reduced OHSS with reduction in PR and implantation rate. </li></ul><ul><li>(Al-Inany, et al, 2005) </li></ul>
  18. 18. COCHRANE REVIEW, AL-INANY ET AL., 2011
  19. 19. GNRHAGONIST FOR TRIGGERRING OVULATION YOUSSEF ET AL., 2010
  20. 20. <ul><li>Coasting </li></ul><ul><li>It is withholding gonadotropins for few days before giving hCG until E2 drops to a safer level. </li></ul><ul><li>Available evidence suggests that such “coasting” does not adversely affect outcome in IVF cycles unless it is prolonged (>2 days) </li></ul>
  21. 21. COCHRANE REVIEW, D’ANGELO E.AL. 2010 Coasting vs. no coasting
  22. 22. <ul><li>Coasting </li></ul><ul><li>CLINICAL AND PRACTICAL ASPECTS </li></ul><ul><li>When to stop gonadotropins? </li></ul><ul><ul><ul><ul><ul><li>When the leading follicles reach 16mm </li></ul></ul></ul></ul></ul><ul><li>how many days? </li></ul><ul><ul><ul><ul><ul><li>Till the E2 drops to < 3000 pg/ml </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>(Sher et al., 1995; Benavida et al., 1997; Tortoriello et al., 1998; </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Egbase et al., 1999; Fluker et al., 2000; Ohata et al., 2000) </li></ul></ul></ul></ul></ul><ul><li>Dose of hCG? </li></ul><ul><ul><ul><ul><ul><li>5000 IU is enough </li></ul></ul></ul></ul></ul><ul><li>Special laboratory aspects? </li></ul><ul><ul><ul><ul><ul><li>Extra time to identify the oocytes from the follicular fluid </li></ul></ul></ul></ul></ul>
  23. 23. GnRH antagonist In a Cochrane review by Al-Inany et al (2011) comparing agonist and antagonist, significant difference in the incidence of OHSS was found.
  24. 24. WHY: (AL-INANY ET AL, 2010)
  25. 25. CANCELLATION FOR RISK OF OHSS
  26. 26. <ul><li>So we may say confidently that GnRH antagonist is safer than GnRH agonist in IVF/ ICSI cycles </li></ul>
  27. 27. BUT NOT ALL DOCTORS WOULD GO FOR ANTAGONIST
  28. 28. (GNRH) ANTAGONISTS: OFF LABEL INDICATION <ul><li>unique Idea </li></ul><ul><li>Administration during GnRH agonist cycle </li></ul><ul><li>when follicle reach ~16mm and E2 level > 4000pmol </li></ul><ul><li>Decrease but Continue hMG (step down protocol) </li></ul><ul><li>Monitor by E2 </li></ul><ul><li>Not more than 3 days </li></ul>
  29. 29. VALUE <ul><li>allow continued stimulation while rapidly decreasing the E2 level to a range that is clinically acceptable. </li></ul>
  30. 31. OUR RESULTS Parameter Coasting (n = 96) Antagonist (n = 94) P-value Age (years) 30.0 ± 4.9 29.6 ± 4.6 NS Duration of infertility (years) 6.64 ± 4.45 7.07 ± 4.3 NS No. of HMG injections 30.52 ± 8.9 29.94 ± 8.8 NS Days of stimulation 1 9.1 ± 1.5 9.4 ± 1.5 NS Peak oestradiol (pg/ml) 5087 ± 1589 5305 ± 1680 NS Oestradiol on day of HCG (pg/ml) 2605 ± 790 2721 ± 699 NS Range of oestradiol on day of HCG (pg/ml) 1110–4136 1223–4093 NS Day of intervention 2.82 ± 0.97 1.74 ± 0.91 <0.0001 No. of oocytes 14.06 ± 5.20 16.5 ± 7.60 0.02 No. of MII oocytes 11.13 ± 4.60 13.14 ± 6.60 NS No. of fertilized oocytes   7.97 ± 3.80   9.14 ± 4.70 NS No. of high quality embryos   2.21 ± 1.10   2.87 ± 1.20 0.0001 No. of embryos transferred   2.83 ± 0.50   2.79 ± 0.40 NS No. of cryopreserved embryos   4.50 ± 3.93   5.77 ± 4.87 NS Clinical pregnancy (%) 46/96 (47.9) 52/94 (55.3) NS Multiple pregnancy (%) 15/46 (32.6) 17/52 (32.7) NS
  31. 32. <ul><li>Intravenous Albumin to Prevent OHSS </li></ul><ul><li>Cochrane review update (Al-Inany et al., 2011) </li></ul><ul><li>7 randomized controlled trials </li></ul><ul><li>Clear evidence of beneficial effect </li></ul>
  32. 33. BACKGROUND <ul><li>Administration of intravenous fluids such as human albumin might result in :- </li></ul><ul><li>A restoration of intravascular volume </li></ul><ul><li>Inactivation of the vasoactive intermediates responsible for the pathogenesis of OHSS </li></ul>5/23
  33. 34. BACKGROUND <ul><li>Hydroxyethyl starch (HES) is a plasma expander that has gained recent attention as an alternative to albumin in reducing the incidence of severe OHSS </li></ul><ul><li>HES is a non-biological substance, it avoids any potential concern about viral transmission that may be present with albumin </li></ul>7/23
  34. 35. RESULTS OF SEARCH 9/23 10 RCTs (n= 2048) 7 RCTs : HA vs. P 1 RCT : HES vs. P 2 RCTs :HA vs. HES vs. P No RCTs compared dextran or haemaccel vs placebo
  35. 36. IV FLUIDS VERSUS PLACEBO, SEVERE OHSS 18/23
  36. 37. AFTER OPU : DOPAMINE AGONIST : YOUSSEF ET AL., 2010
  37. 38. YOUSSEF ET AL., 2010
  38. 39. <ul><li>Postponing the Embryo Transfer </li></ul><ul><li>Cryopreservation of all embryos </li></ul><ul><li>Several studies showed significant decrease in the incidence of OHSS if the ET was cancelled and all the embryos were cryopreserved. </li></ul><ul><li>(Amso et al., 1990; Salat-Baroux et al., 1990; Wada et al., 1993; </li></ul><ul><li>Tiitinen et al.,1995; Ferraretti et al., 1999) </li></ul><ul><li>Cochrane review (D’Angelo and Amso, 2002) </li></ul><ul><ul><li>There is insufficient evidence to support routine cryopreservation. </li></ul></ul>
  39. 40. Conclusion OHSS is a preventable disease that should not be allowed to happen
  40. 41. CONCLUSION <ul><li>Absolute prevention : no hCG or cycle cancellation </li></ul><ul><li>Relative prevention : coasting, albumin or HAES, cryopreservation of all embryos, ovulation trigger by lower hCG dose or GnRHa </li></ul><ul><li>Most promising is : GnRHantagonist till E2<4000pmol </li></ul>
  41. 42. THANK YOU Dr. Hesham Al-Inany MD, PhD e-mail : hesham@khosoba.com
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