This document discusses strategies for preventing severe ovarian hyperstimulation syndrome (OHSS) during in vitro fertilization treatment. It describes the pathogenesis of OHSS and risk factors. Methods for prevention discussed include using a mild stimulation protocol, metformin treatment, coasting by withholding gonadotropins before triggering ovulation, using a GnRH antagonist protocol instead of agonist, cryopreserving all embryos, and administering intravenous albumin or hydroxyethyl starch after oocyte retrieval to reduce risk. The document concludes that OHSS is a preventable complication through various medical interventions and protocols.

1. بِسْمِ اللَّهِ الرَّحْمَٰنِ الرَّحِيمِ

2. PREVENTION OF SEVERE OHSS

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. 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. OHSS INCIDENCE Non IVF : mild 8.0 -23% moderate 0.005 -7% severe 0.008 -10% IVF : mild 100% moderate 21- 44% severe 1- 10% estimated mortality 1/45.000-1/500.000 estimated morbidity 0.1-0.5%

6. PATHOGENESIS OF SEVERE OHSS Kidney (JGA) rorenin Ovary ace PG Angiotensin II A-tensin I A-tensinogen histamin (liver) inflam. cytokines ANGIOGENESIS (IL-1,IL-6,TNF) IL-2 (FF) Capillary permeability VEGF(ovary) fluid shift hCG (LH) E 2

7. DIAGNOSIS OF SEVERE OHSS clinic : distended abdomen, diarrhea dyspnea, weight gain, hypotension, tachycardia U/S: enlarged ovaries (>12 cm) + ascites X-ray: pleural effusion lab: Hct > 45% total proteins/albumine trombocytes ureum/creatinine ; creat.clear. electrolyte imbalance ( K , acidosis) liver enzyms  -hCG

8. severe critical ovaries >12 cm > 12 cm ascites/hydrothorax massive tense hct >45% >55% WBC >15.000 >25.000 oliguria yes extreme creatinin 1.0 - 1.5 >1.6 creat. clearence >50 ml/min <50 ml/min renal failure not yet yes liver disfunction yes yes complications nasarca thrombo-emb. ARDS

9. How to prevent OHSS ? Before Start : Identifying the patients at risk before ovulation induction . Before Start : Metformin & Proper ovulation induction protocol During Cycle : Careful monitoring of ovarian response: US E2 Before OPU during ovulation induction: Cancel the cycle hCG dose and alternatives Coasting Antagonist After OPU Cryopreservation of all embryo Dopamine agonist Luteal phase support

10. Before Start IDENTIFYING THE PATIENTS AT RISK BEFORE OVULATION INDUCTION : History of previous OHSS PCOD patients . AMH > 5

11. METFORMIN COCHRANE REVIEW, TSO ET AL., 2008

12. LOW DOSE GONADOTROPİNS OHSS risk is lower in low dose regimens Koundouros, 2008 Second: COH

13. MILD STIMULATION PROTOCOL KAK Karimzadah et al., 2010

14. HOW TO SUSPECT DURING COH rapidly rising serum E2 levels More than 20 growing follicles

15. So what to do!! For complete prevention: withholding hCG and continuing GnRHa (Navot et al., 1992) Delaying hCG = Coasting Other alternatives: Rec hCG Rec LH GnRHa

16. ALTERNATIVES TO HCG hCG is similar in action to LH however it is not identical. It has a longer half-time and associated with sustained luteotropic effect. (Itskovitz et al., 1991; Haning et al., 1985)

17. OTHER ALTERNATIVES TO HCG Rec hCG 250 µg is as effective as 10, 000 IU of hCG in terms of PR and implantation rate, however similar incidence of OHSS. (The European Rec Human hCG Study Group 2000; Driscoll et al., 2000, Chang et al., 2001) Rec LH Single rec LH dose significantly reduced OHSS with reduction in PR and implantation rate. (Al-Inany, et al, 2005)

18. COCHRANE REVIEW, AL-INANY ET AL., 2011

19. GNRHAGONIST FOR TRIGGERRING OVULATION YOUSSEF ET AL., 2010

20. Coasting It is withholding gonadotropins for few days before giving hCG until E2 drops to a safer level. Available evidence suggests that such “coasting” does not adversely affect outcome in IVF cycles unless it is prolonged (>2 days)

21. COCHRANE REVIEW, D’ANGELO E.AL. 2010 Coasting vs. no coasting

22. Coasting CLINICAL AND PRACTICAL ASPECTS When to stop gonadotropins? When the leading follicles reach 16mm how many days? Till the E2 drops to < 3000 pg/ml (Sher et al., 1995; Benavida et al., 1997; Tortoriello et al., 1998; Egbase et al., 1999; Fluker et al., 2000; Ohata et al., 2000) Dose of hCG? 5000 IU is enough Special laboratory aspects? Extra time to identify the oocytes from the follicular fluid

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. WHY: (AL-INANY ET AL, 2010)

25. CANCELLATION FOR RISK OF OHSS

26. So we may say confidently that GnRH antagonist is safer than GnRH agonist in IVF/ ICSI cycles

27. BUT NOT ALL DOCTORS WOULD GO FOR ANTAGONIST

28. (GNRH) ANTAGONISTS: OFF LABEL INDICATION unique Idea Administration during GnRH agonist cycle when follicle reach ~16mm and E2 level > 4000pmol Decrease but Continue hMG (step down protocol) Monitor by E2 Not more than 3 days

29. VALUE allow continued stimulation while rapidly decreasing the E2 level to a range that is clinically acceptable.

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

32. Intravenous Albumin to Prevent OHSS Cochrane review update (Al-Inany et al., 2011) 7 randomized controlled trials Clear evidence of beneficial effect

33. BACKGROUND Administration of intravenous fluids such as human albumin might result in :- A restoration of intravascular volume Inactivation of the vasoactive intermediates responsible for the pathogenesis of OHSS 5/23

34. BACKGROUND Hydroxyethyl starch (HES) is a plasma expander that has gained recent attention as an alternative to albumin in reducing the incidence of severe OHSS HES is a non-biological substance, it avoids any potential concern about viral transmission that may be present with albumin 7/23

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

36. IV FLUIDS VERSUS PLACEBO, SEVERE OHSS 18/23

37. AFTER OPU : DOPAMINE AGONIST : YOUSSEF ET AL., 2010

38. YOUSSEF ET AL., 2010

39. Postponing the Embryo Transfer Cryopreservation of all embryos Several studies showed significant decrease in the incidence of OHSS if the ET was cancelled and all the embryos were cryopreserved. (Amso et al., 1990; Salat-Baroux et al., 1990; Wada et al., 1993; Tiitinen et al.,1995; Ferraretti et al., 1999) Cochrane review (D’Angelo and Amso, 2002) There is insufficient evidence to support routine cryopreservation.

40. Conclusion OHSS is a preventable disease that should not be allowed to happen

41. CONCLUSION Absolute prevention : no hCG or cycle cancellation Relative prevention : coasting, albumin or HAES, cryopreservation of all embryos, ovulation trigger by lower hCG dose or GnRHa Most promising is : GnRHantagonist till E2<4000pmol

42. THANK YOU Dr. Hesham Al-Inany MD, PhD e-mail : hesham@khosoba.com