Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic condition caused by fertility treatments. It can range from mild to life-threatening. Steps to prevent OHSS include identifying at-risk patients, using low gonadotropin doses, coasting by withholding gonadotropins to lower estrogen levels safely, using GnRH antagonists, and administering metformin. If OHSS occurs, management focuses on investigations, fluid monitoring, and paracentesis if needed.

1. Ovarian Hyperstimulation Syndrome How to Prevent

2. What is it It is an iatrogenic condition Induced by the clinician

3. Exact Pathogenesis is not clear High E2 is the underlying factor

4. Severity In its severest forms, it is complicated by hemoconcentration, venous thrombosis, electrolyte imbalance and renal and hepatic failure

5. Classification of OHSS Study Mild Moderate Severe Rabau et al . (1967) grade 1: estrogen > 150  g and grade 2 : + enlarged ovaries grade 3 : grade 2 + palpable cysts grade 4 : grade 3 + vomiting grade 5 : grade 4 + Ascites grade 6 : grade 5 + changes in blood Volume Golan et al. (1989) grade 1 : distension and discomfort grade 2 : grade 1 + nausea, vomiting, enlarged ovaries grade 3 : grade 2 + US evidence of ascites grade 4 : grade 3 + clinical evidence of ascites and/or breathing difficulties grade 5 : grade 4 + haemoconcentration,

6. Mild form of ovarian hyperstimulation is almost always with ovulation induction

7. Life Threatining Severe OHSS is a serious complication of ovulation induction

9. How to prevent Steps before stimulation Steps during stimulation Steps on impending severe OHSS

10. Steps before stimulation Identifying the patients at risk before ovulation PCOD patients History of previous severe OHSS

11. Before stimulation

12. After Stimulation

13. Steps during Stimulation Be aware of Large number of developing follicles ( more than 20 ) Be aware of High E2 level ( more than 3000 ) on approaching day of hCG If any or both, then what to do!!!!!

14. Steps during Stimulation Gonadotrophin dose according to age and body weight Young age <25 ys : 2 amp Thin woman < 60 kg 2 amp

15. Low Gonadotropin doses Starting with 150 IU for all patients at risk is recommended Type of gonadotropins : urinary vs recombinant No significant difference in the occurrence of OHSS

16. Stop hMG and continue down regulation. This is the only complete prevention. (Aboulghar and Mansour, 2003) Not a preferred choice for both doctors or patients Active Steps

17. Cryopreservation of Embryos Is not a guarantee against developing severe OHSS Still occurs in oocyte donors Risk of embryo degeneration on Thawing Not a preferred choice

18. Coasting 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)

19. Mature follicles can survive for a few days without exogenous FSH/hMG while small follicles will undergo apoptosis / necrosis 33

20. In the absence of gonadotropin stimulation, dominant follicles will continue their growth, while intermediate and small ones will undergo atresia. Coasting diminishes the granulosa cell cohort E2

21. The granulosa cells aspirated from coasted patients showed a ratio in favor of apoptosis, especially in smaller follicles. VEGF protein secretion and gene expression in granulosa cells especially in small and medium follicles were reduced in coasting 24

22. What happens when you start coasting? Follicular growth will continue with the same rate. E2 will continue to rise then will platform and then decline.

23. Clinical and practical Tips The Egyptian IVF-ET Center Experience When to stop gonadotropins? When the leading follicles reach 16mm how many days? Till the E2 drops to < 3000 pg/ml Fluker et al., 2000; Ohata et al., 2000)

24. The number of days of coasting IS NOT the key issue The focus should be on the E 2 level We should wait until it drops to 3000 pg/mL

25. Dose of hCG? 5000 IU is enough Special laboratory aspects? Extra time to identify the oocytes from the follicular fluid

26. The Egyptian IVF-ET Center (May 2001 – May 2003) No. of Cycles 4969 No. of Coasting 560 Mean E 2 on hCG day 3742 + 1074 Days of Coasting 2 – 6 No. of Oocytes 18 + 7 No. of Cancelled ET (cryopreservation of all embryos) 3 OHSS (%) 6 (1.2 per 1000) Clinical Pregnancy (%) 265 (47.32%)

27. Problems with coasting Occasionally E2 drops markedly to very low levels and cycle is canceled. Difficulty in identification of oocytes in aspirated follicular fluid after prolonged coasting.

28. However Pregnancy rates appear to decrease while coasting during prolonged gonadotropin-free periods (Ulug et al, 2004)

29. Why perhaps because suspending gonadotropins may starve the granulosa cells at a critical time of oocyte development when LH is necessary

30. The role of GnRH antagonist in the prevention of OHSS

31. GnRH antagonist In a Cochrane review by Al-Inany et al (2006) comparing agonist and antagonist, significant difference in the incidence of OHSS was found

32. (GnRH) antagonists A unique Idea Administration when follicle reach 16 mm Continue hMG (step down protocol) Monitor by E2 Not more than 3 days

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

34. serum E2 decreased by 49.5% and 41.0% of pretreatment values (long luteal and microdose flare, respectively) after initiation of ganirelix, and 68.1% of the patients became pregnant. ( Gustofson , 2006)

35. GnRH antagonist vs GnRH agonist In patients at high risk of OHSS Multicenter prospective comparative study Ragni et al., 2005 Hum Reprod GnRH agonist GnRH antagonist cycles cancelled cycles severe OHSS E 2 on day of hCG pregnancy (%) per ET 87 49 (56.3%) 6 4322 87 28 (32.2%) 1 2538 18 (31.6%) P<0.001 P=0.006 P<0.001

36. Metformin positively modulates the reproductive axis (namely GnRH-LH episodic release) (Genazzani et al, 2004).

37. Evidence E2 was significantly higher in cycles treated with FSH alone than in those treated with FSH and metformin. (De Leo et al, 1999).

38. Metformin & OHSS Metformin was found to decrease significantly the incidence of severe OHSS (ESHRE award, 2005)

39. It is now our routine to give metformin with the start of down regulation till the day of hCG

40. possible Mechanisms lower intraovarian androgen levels. (Visnova et al; 2003).

41. Improves endothelial function. (J.De Jager et al; 2005, Orio et al; 2005).

42. The use of metformin for women with PCOS Prospective randomized placebo-controlled double-blind study Tang et al., 2006 Hum Reprod Metformin Group control Group Patients Mean total FSH Occytes retrieval Fertilization rate Clinical PR per ET Clinical PR>12 weeks Severe OHSS 52 u 17.2 52.9% 44.4% 38.5% 3.8% 49 u 16.2 54.9% 19% 16.3% 20.4% P=0.022 P=0.023 P=023

43. A systematic review and meta-analysis of randomized controlled trials on metformin co-administration during gonadotropins ovulation induction in PCOS patients Significant reduction in OHSS (OR=0.21; 95% CI = 0.11-0.41 P<0.00001) Does not significantly improve the pregnancy rate Costello et al., 2006 Hum Reprod

44. Luteal support Avoid hCG Progesterone only Close observation

45. .) OHSS is a preventable disease

46. What if it Happens How to Manage

47. Always remember Investigations Haematocrite Liver functions Creatinine Fluid monitoring

48. Always remember ICU Job

49. May do paracentesis : if dyspnoea massive ascitis (>3 liters) Hydrothorax