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Prediction and prevention of OHSS - an evidence-based approach

Prediction and prevention of OHSS - an evidence-based approach. Hassan N. Sallam, MD, FRCOG, PhD (London) Professor in Obstetrics and Gynaecology The University of Alexandria, and Clinical and Scientific Director, Alexandria Fertility Center, Alexandria, Egypt.

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Prediction and prevention of OHSS - an evidence-based approach

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  1. Prediction and prevention of OHSS -an evidence-based approach Hassan N. Sallam, MD, FRCOG, PhD (London) Professor in Obstetrics and Gynaecology The University of Alexandria, and Clinical and Scientific Director, Alexandria Fertility Center, Alexandria, Egypt 3rd Congress of Society of Reproductive Medicine, 5 – 9 October 2011, Antalya / Turkey

  2. The old Alexandria medical school

  3. The uterus (after Soranos of Ephesus)

  4. Ovarian hyperstimulation syndrome (OHSS) Rabau et al, Am J Obstet Gynecol 98: 92, 1967

  5. Ovarian hyperstimulation syndrome Ovarian hyperstimulation syndrome (OHSS) is a rareiatrogenic complication of ovarian stimulation occurring during the luteal phase or during early pregnancy. It is potentially fatal and is difficult to predict. Fortunately, the reported prevalence of the severe form of OHSS is small, ranging from 0.5 to 5%.

  6. OHSS – a potentially fatal complication Figueroa-Casas. Extraordinary ovarian reaction to gonadotropins: fatal case. Ann Circ (Rosario): 23: 116, 1958 Schenker and Weinstein. Ovarian hyperstimulation syndrome: a current survey. FertilSteril 30: 255, 1978 Fineschi et al. An immunohistochemical study in a fatality due to ovarian hyperstimulation syndrome. Int J Legal Med 120: 293, 2006 Madill et al. Ovarian hyperstimulation syndrome: a potentially fatalcomplication of early pregnancy. J Emerg Med 35: 283, 2008

  7. Early and late OHSS Early onset OHSS 3 to 7 days after HCG Excessive response to stimulation Late onset OHSS 12 to 17 days after HCG Due to pregnancy Lyons et al, Hum Reprod. 9: 792, 1994; Mathur et al, Fertil Steril 73: 901, 2000

  8. Classification (grading) of OHSS Rabau et al, 1967 Schenker and Weinstein, 1978 Golan et al, 1989 Navot et al, 1992 Rizk and Aboulghar, 1999 Rabau et al, Am J Obstet Gynecol 98: 92, 1967; Schenker and Weinstein, Fertil Steril 30: 155, 1978; Golan et al, Obstet Gynecol Surv 44: 430, 1989; Navot et al, Fertil Steril 58: 249, 1992; Rizk and Aboulghar, Textbook of IVF and ART 9: 131, 1999

  9. OHSS grading (Golan et al, 1989) Mild Moderate Severe

  10. Pathophysiology of OHSS Pathophysiology of OHSS Pathophysiology of OHSS

  11. Prevention of OHSS 1. Prediction of OHSS 2. Primary prevention (before starting HMG/FSH) 3. Secondary prevention (after starting HMG/FSH and before HCG administration)

  12. Evidence-based medicine Level A –The recommendation based on good and consistent scientific evidence (RCT) Level B –The recommendation is based on limited or inconsistent scientific evidence (CT, cohort, case control) Level C –The recommendation is based primarily on consensus and expert opinion

  13. Prevention of OHSS 1. Prediction of OHSS 2. Primary prevention (before starting HMG/FSH) 3. Secondary prevention (after starting HMG/FSH and before HCG administration)

  14. Prediction of OHSS (A) Risk factors: PCOS, young patients, low BMI, previous OHSS, pregnancy, genetic predisposition (B) Biochemical indices:Plasma oestradiol peak, insulin resistance, serum VEGF, von Willebrand factor, FSH, AMH (C) Ultrasound indices:PCO pattern, high AFC, ovarian volume, low intra-ovarian vascular resistance

  15. Prediction of OHSS (A) Risk factors: PCOS, young patients, low BMI, previous OHSS, pregnancy, genetic predisposition (B) Biochemical indices: Plasma oestradiol peak, insulin resistance, serum VEGF, von Willebrand factor, FSH, AMH (C) Ultrasound indices: PCO pattern, high AFC, ovarian volume, low intra-ovarian vascular resistance

  16. Polycystic ovary syndrome(Chereau, 1844; Stein and Leventhal, 1934) Read at a meeting of the Central Association of Obstetricians and Gynecologists, November 1 to 3, 1934, New Orleans, La

  17. Relationship between PCOS and OHSS Smitz et al, Hum Reprod 5: 933, 1990; MacDougall et al, Hum Reprod 7: 597, 1992; Delvigne et al, Hum Reprod 8: 1361, 1993

  18. Relationship between age and OHSS

  19. Relationship between BMI and OHSS Papnikolau et al, Fertil Steril 85: 112, 2006; Delvigne et al, Hum Reprod 9: 1361, 1993; Enskog et al, Fertil Steril 71: 808, 1999

  20. Genetic predisposition to predict OHSS FSH FSH FSH receptor

  21. Genetic predisposition to predict OHSS Daelemans et al, J Clin Endocrinol Metab 89:6310, 2004

  22. Prediction of OHSS (A) Risk factors: PCOS, young patients, low BMI, previous OHSS, pregnancy, genetic predisposition (B) Biochemical indices: Plasma oestradiol peak, insulin resistance, serum VEGF, von Willebrand factor, FSH, AMH (C) Ultrasound indices: PCO pattern, high AFC, ovarian volume, low intra-ovarian vascular resistance

  23. Plasma E2 concentration to predict OHSS Cut-off value For E2 = 2560 ng/L For follicles >12 Papanikolau et al, Fertil Steril 85: 112, 2006

  24. Insulin resistance to predict OHSS in PCOS Felghesu et al. JCEM 82: 644, 1997

  25. Serum VEGF to predict OHSS Early onset OHSS Late onset OHSS Ludwig et al, Hum Reprod 13: 30, 1998

  26. Von Willebrand factor to predict OHSS Todorow et al, Hum Reprod 8: 2039, 1993

  27. Day 3 FSH to predict OHSS Cut-off point = 5.25 mIU/ml Onagawa et al, Gynecol Endocrinol 18:335-40, 2004

  28. AMH to predict OHSS Cut-off value 33 years Cut-off value 3.36 ng/ml AMH Age BMI Cut-off value 18.44 Kg/m2 Lee et al. Hum Reprod 23: 160, 2008

  29. AMH to predict ovarian response Elgindy et al, Fertil Steril 89:1670, 2008

  30. Prediction of OHSS (A) Risk factors: PCOS, young patients, low BMI, previous OHSS, pregnancy, genetic predisposition (B) Biochemical indices: Plasma oestradiol peak, insulin resistance, serum VEGF, von Willebrand factor, FSH, AMH (C) Ultrasound indices: PCO pattern, high AFC, ovarian volume, low intra-ovarian vascular resistance

  31. PCO pattern to predict OHSS Rizk and Smitz, Hum Reprod 7: 320, 1992; Delvigne et al, Hum Reprod 8: 1353, 1993

  32. Antral follicle count(Tomas et al, 1997) Transvaginal ultrasound After ovarian suppression with GnRHa and before starting FSH Follicles 2 to 5 mm in both ovaries Patients with <5 follicles in both ovaries were poor responders Tomas et al, Hum Reprod 12(2):220, 1997

  33. Trans-vaginal scan showing antral follicles Right ovary Left ovary

  34. AFC to predict ovarian response Kwee et al, RBEJ 5:9, 2007

  35. AFC to predict poor responders Kwee et al, RBEJ 5:9, 2007

  36. AFC to predict hyper responders Kwee et al, RBEJ 5:9, 2007

  37. AFC versus AMH to predict poor response AMH AFC Hendricks et al, Fertil Steril 83(2): 291, 2005 Broer et al, Fertil Steril 91: 705, 2009

  38. AFC v/s AMH to predict hyper-response AFC AMH Broer et al, Hum Reprod Update 17: 46, 2011

  39. Predictors of OHSS (Sallam et al, 2011) Sallam et al, Predictors of OHSS, submitted for publication

  40. ROC curves comparing AMH and AFC AFC Cut-off value =>14 AMH Cut-off value 3.36 ng/ml Sallam et al, Predictors of OHSS, submitted for publication

  41. Ovarian volume Cohen et al, AJR 160: 583, 1993; Orsini et al, Radiology 153:113, 1984; Sample et al. Radiology 125:477, 1977; Ivarsson et al, Arch Dis Child 58, 352, 1983

  42. Ovarian volume Ivarsson et al, Arch Dis Child 58, 352, 1983

  43. 3-D U/S in obstetrics and gynaecology

  44. Ovarian volume to predict OHSS Danninger et al, Hum Reprod 11: 1597, 1996

  45. Perifollicular blood flow to predict OHSS Oyesanya, Fertil Steril 65: 874, 1996

  46. Intrafollicular hemodynamics to predict OHSS Oyesanya, Fertil Steril 65: 874, 1996

  47. Combination of indices to predict OHSS Regression analysis showed that the dependent factors were: (1) Log oestradiol, (2) Slope of log oestradiol, (3) HMG dosage, (4) No. of oocytes retrieved and (5) LH/FSH ratio. The following formula was devised: PPV = 78.5 %; FNR = 18.1% Delvigne et al, Hum Reprod 8: 1353, 1993

  48. Conclusion 1 - Prediction

  49. Prevention of OHSS 1. Prediction of OHSS 2. Primary prevention (before starting HMG/FSH) 3. Secondary prevention (after starting HMG/FSH and before HCG administration)

  50. Primary prevention (before starting HMG/FSH) FSH or HMG Low dose step-up protocol Step-down protocol Alternate day HMG/FSH Sequential protocol In-vitro maturation (IVM) GnRH antagonists

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