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

The old Alexandria medical school

The uterus (after Soranos of Ephesus)

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

Ovarian hyperstimulation syndrome Ovarian hyperstimulation syndrome (OHSS) is a rare iatrogenic 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%.

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. Fertil Steril 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 fatal complication of early pregnancy. J Emerg Med 35: 283, 2008

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

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

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

Pathophysiology of OHSS

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)

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

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)

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

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

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

Relationship between PCOS and OHSS StudyPatients with OHSS ControlsP value Smitz et al, % (5/10)None (0/1663)< MacDougall et al, % (5/8)None (0/1287)< Delvigne et al, % (47/128)15 % (38/256)< Smitz et al, Hum Reprod 5: 933, 1990; MacDougall et al, Hum Reprod 7: 597, 1992; Delvigne et al, Hum Reprod 8: 1361, 1993

Relationship between age and OHSS StudyPatients with OHSS (Age in years) Controls (Age in years) P value Navot et al, ± ± 5.7<0.05 Lyons et al, ± ± 0.15<0.05 Delvigne et al, ± ± 4.5<0.05 Enskog et al, ± ± 0.2<0.05

Relationship between BMI and OHSS StudyNumber of patients with OHSS Number of control subjects P value Papanikolau et al, ± ± 0.1NS Delvigne et al, ± ± 3.2NS Enskog et al, ± ± 0.16NS Papnikolau et al, Fertil Steril 85: 112, 2006; Delvigne et al, Hum Reprod 9: 1361, 1993; Enskog et al, Fertil Steril 71: 808, 1999

Genetic predisposition to predict OHSS FSH receptor FSH

Genetic predisposition to predict OHSS Allelic frequenciesGenotypic frequencies ATAAATTT Caucasian controls 40% (78)60 % (118)17 % (17)45 % (44)38 % (37) IVF controls 48 % (121)52 % (131)25 % (31)47 % (59)28 % (36) OHSS patients 55 % (41)45 % (33)30 % (11)51 % (19)19 % (7) P valueNS Daelemans et al, J Clin Endocrinol Metab 89:6310, 2004

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

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

Insulin resistance to predict OHSS in PCOS Normo- insulinaemic (n = 21) Hyper- insulinaemic (n = 31) P value Mean total dose of HMG ± SD (IU) 1395 ± ± 727NS Mean dose/BMI ± SD (IU/BMI) 57.7 ± ± 18NS Ovulation rate (n/cycle) 85.7 % (18/21)83.8% (26/31)NS OHSS rate (n/cycle) 23.8 % (5/21)64.5 % (20/31)<0.05 * Pregnancy rate (n/cycle) 28.5 % (6/21)16% (5/31)NS Abortions (n/pregnancies) 16.6 % (1/6)20% (1/5)NS Felghesu et al. JCEM 82: 644, 1997

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

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

Day 3 FSH to predict OHSS Onagawa et al, Gynecol Endocrinol 18:335-40, 2004 PregnantNon-pregnantP value 4.4+/-1.3 mIU/ml 6.1+/-2.9 mIU/ml OHSSNo OHSSP value 4.5+/-1.2 mIU/ml 5.9+/-2.8 mIU/ml Cut-off point = 5.25 mIU/ml

AMH to predict OHSS Lee et al. Hum Reprod 23: 160, 2008 AMH Age BMI Cut-off value 3.36 ng/ml Cut-off value 33 years Cut-off value Kg/m 2

AMH to predict ovarian response Early follicularMid-luteal Cut-off (ng/mL)2.7 Sensitivity (%) Specificity (%) PPV (%) NPV (%) Accuracy (%) Elgindy et al, Fertil Steril 89:1670, 2008

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

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

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

Trans-vaginal scan showing antral follicles Right ovaryLeft ovary

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

Total AFC SensitivitySpecificityPPVAccuracy < < < < < AFC to predict poor responders Kwee et al, RBEJ 5:9, 2007

Total AFC SensitivitySpecificityPPVAccuracy < < < < < AFC to predict hyper responders Kwee et al, RBEJ 5:9, 2007

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

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

Predictors of OHSS (Sallam et al, 2011) OHSSNo OHSSP value No. of cycles1122 Day 3 FSH (mIU/ml)5.97 (2.05) 9.31 (3.01)0.204 Day 3 LH (mIU/ml)6.70 (3.14) 5.74 (3.64)0.230 Day 3 E2 (pg/ml)38.67 (14.41) (9.00)0.33 Day 3 leptin (ng/ml)40.27 (28.06) (25.71)0.324 Day 3 VEGF (pg/ml) (178.08) (216.81)0.446 Day 3 AFC21.64 (3.20) (3.81)< * Day 3 AMH (ng/ml)4.50 (2.87) 2.17 (1.55)< 0.005* E2 on HCG day (pg/ml) ( ) (659.32)< * Sallam et al, Predictors of OHSS, submitted for publication

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

Ovarian volume Age Group Mean Ovarian volume (ml) SD (ml) 95% Confidence Interval % Ovaries Imaged 1 day to 3 months months months years (range) years (range)- 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

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

3-D U/S in obstetrics and gynaecology

Ovarian volume to predict OHSS OHSSControlsP value No. of patients886 Days of stimulation10.5 ± ± 1 8NS Oestradiol (pg/ml)2439 ± ± No. of follicles23.3 ± ± No. of oocytes164 ± ± Cycle length34.1 ± ± Body wt before stimulation55.4 ± ± Body wt after stimulation54 3 ± ± Ovarian volume (ml)13.2 ± 58.9 ± Danninger et al, Hum Reprod 11: 1597, 1996

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

Intrafollicular hemodynamics to predict OHSS OHSSControlsP value Mean age (years)32.63 ± ± 3.87NS Mean duration of infertility (years) 6.00 ± ± 2.73NS Maximal peak systolic velocity 0.15 ± ± 0.10NS Mean minimal pulsatility index 0.89 ± ± 0.14NS Mean minimal resistance indexes 0.56 ± ± 0.06NS Oyesanya, Fertil Steril 65: 874, 1996

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: Delvigne et al, Hum Reprod 8: 1353, 1993 PPV = 78.5 %; FNR = 18.1%

Conclusion 1 - Prediction Good predictorsBad predictorsFurther evaluation PCOSGenetic predisposition PCO pattern Young ageSerum VEGFBMI AFCVon Willebrand factor Day 3 FSH E2 level on day of HCG Perifollicular blood flow Insulin resistance Ovarian volume AMH

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)

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

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

Nugent et al, Cochrane Database: Issue 1, 2009 FSH versus HMG to prevent OHSS

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

Chronic low-dose step-up protocol Homburg et al, Fertil Steril 63: 729, 1995

Low dose step-up protocol (RCT) ConventionalStep-upP value No. of cycles4849 Oestradiol on the day of HCG (pg/ml) ± ± No. of pregnancies7 (14.6%)7 (14.3%)NS No. of abortions1 (14.3%) NS No. of multiple pregnancies 2 (28.6%)1(14.3%)NS No. of OHSS13 (27.1%)4 (8.3%)0.05 Mild OHSS5 (10.4%)4 (8.3%)NS Moderate OHSS8 (16.7%)0 (0%)0.01 Sengoku et al, Hum Reprod 14: 349, 1999

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

Step-down protocol Mizunuma et al, Fertil Steril 55: 1195, 1991

Step-up, step-down and conventional protocols (RCT) ProtocolConventional (n = 19) Step down (n = 24) Step up (n = 25) P value Small follicles7.6 ± 1.9 *6.3 ± ± 0.7 *<0.05 Medium follicles5.7 ± 1.2 *5.0 ± ± 0.6 *<0.05 Large follicles1.5 ± ± ± 0.3NS Andoh et al, Fertil Steril 70: 840, 1998

Santbrink and Fauser, J Clin Endocrinol Metab 82: 3597, 1997 Step-up versus step-down protocol (RCT) Step-up (n=18) Step down (n=17)p

Step-up versus step-down protocol (RCT) Low dose step-upStep downP value No. of patients1918 Duration of treatment (days) No. of ampoules2014NS Monofollicle growth 6 (39%)17 (100 %)< Ovulation rate84 %89 %NS Ongoing pregnancies 25NS OHSS00NS Santbrink and Fauser, J Clin Endocrinol Metab 82: 3597, 1997

Chronic low-dose step-up versus step- down protocol (RCT) Low dose step-upStep downP value No. of patients8572 Duration of treatment (days) 15.2 ± 79.7 ± 3.1< Total dose of rec-FSH (IU) 951 ± ± 458NS Mono-follicular growth 68.2%32%< Ovulation rate70.3%61.7%0.02 Pregnancies/cycle18.7%15.8%NS OHSS2.25%11%<0.001 Christian-Maitre et al, Hum Reprod 18:1626, 2003

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

Alternate day HMG to prevent OHSS Nugent et al, Cochrane Database: Issue 1, 2009

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

Sequential FSH regimen to prevent OHSS (RCT) Step-up protocol step-down protocol Sequential protocol P value No. of cycles75 No. of clinical pregnancies (rate) <0.05 Pregnancy rate31.0 %32.2 %48.5 %NS No. of multiple pregnancies (rate) 4 (22.2%)5 (25.0%)8 (24.0%) NSNS Rate of hyperstimulation 5.2 %13 % *5.9 %<0.05 Koundouros, Fertil Steril 90: 569, 2009

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

In-vitro maturation to prevent OHSS (CCT) IVMIVFOR (95% CI) No. of cycles107 Implantation rate (%) (0.31, 0.84) * Clinical pregnancy [n (%)]23 (21.5)36 (33.7)0.54 (0.28, 1.04) Live birth [n (%)]17 (15.9)28 (26.2)0.53 (0.26, 1.10) Multiple live births [n (% of total live births)] 7 (41.2)10 (37.0)1.26 (0.30, 5.11) Moderate or severe OHSS012 (11.2%)0.036 ( ) * Child et al, Obstet Gynecol 100: 665, 2002

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

GnRHa v/s antagonists to prevent OHSS, 2009 Al-Inany et al, Cochrane Database: Issue 1, 2009

LBR in GnRH agonists v/s antagonists, 2009 Al-Inany et al, Cochrane Database: Issue 1, 2009

GnR a v/s antagonists to prevent OHSS, 2011 Al-Inany et al, Cochrane Database Syst Rev 11;(5):CD001750, 2011

LBR in GnRH agonists v/s antagonists, 2011 Al-Inany et al, Cochrane Database Syst Rev 11;(5):CD001750, 2011

Conclusion 2 – Primary prevention The following approaches are associated with a lower incidence of OHSS: FSH compared to HMG (without GnRHa) (A) Step-up compared to conventional protocol (A) GnRH antagonists compared to agonists (A) IVM compared to IVF but with a lower LBR (B) Sequential compared to step down protocol (A)

Conclusion 2 – Primary prevention (cont…) The following approaches are equivocal in the primary prevention of OHSS: Alternate days compared to conventional protocol (A) Sequential compared to step-up protocol (A) The following approaches need further evaluation: Step-up compared to step down protocol

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)

Late prevention (after starting HMG/FSH and before HCG) Cancellation of the cycle Coasting Diminish HCG dose GnRHa to trigger ovulation Metformin Albumin Cabergoline I.V. Calcium Cryopreservation of embryos GnRH agonists + embryo freezing Unilateral follicle aspiration before HCG Laparoscopic ovarian electro-cautery

Late prevention (after starting HMG/FSH and before HCG) Cancellation of the cycle Coasting Diminish HCG dose GnRHa to trigger ovulation Metformin Albumin Cabergoline I.V. Calcium Cryopreservation of embryos GnRH agonists + embryo freezing Unilateral follicle aspiration before HCG Laparoscopic ovarian electro-cautery

Cancellation of the cycle - attitude of 141 physicians High risk patient Moderate risk patient Low risk patient P value Proceed with IVF8 %22 %38 %<0.001 Cancel cycle14 % 7 %NS Take some preventive measures 78 %64 %55 %<0.01 Delvigne and Rozenberg, Hum Reprod 16: 2491, 2001

Late prevention (after starting HMG/FSH and before HCG) Cancellation of the cycle Coasting Diminish HCG dose GnRHa to trigger ovulation Metformin Albumin Cabergoline I.V. Calcium Cryopreservation of embryos GnRH agonists + embryo freezing Unilateral follicle aspiration before HCG Laparoscopic ovarian electro-cautery

Coasting to prevent OHSS - Guidelines 1. Start at Serum E2 >4,500 pg/mL E2 production >150 pg/follicle 16–18 mm >15 mature follicles 2. Measure E2 on a daily basis 3. Give hCG when E2 level falls to <3,500 pg/mL 4. Abandon if E2 level rises to >6,500 pg/mL >30 mature follicles Coasting takes >4 days Garcia-Velasco et al, Fertil Steril 85: 547, 2006

Incidence of OHSS OR = 0.53 (95% CI = 0.23 to 1.23) Live birth rate OR = 0.48 (95% CI = 0.14 to 1.62) Clinical pregnancy rate OR = 0.69 (95% CI = 0.44 to 1.08) Oocytes retrieved OR = (95% CI to -3.37) * Coasting to prevent OHSS (Cochrane) D’Angelo et al, Cochrane Database Syst Rev 15;(6):CD002811, 2011

Late prevention (after starting HMG/FSH and before HCG) Cancellation of the cycle Coasting Diminish HCG dose GnRHa to trigger ovulation Metformin Albumin Cabergoline I.V. Calcium Cryopreservation of embryos GnRH agonists + embryo freezing Unilateral follicle aspiration before HCG Laparoscopic ovarian electro-cautery

Diminish HCG dose (OS) 21 infertile patients at risk of OHSS Low dose of HCG (i.e IU) No moderate or severe OHSS 13 women (61.9%) conceived Three twin pregnancies Nargund et al. RBMOnline 14: 682, 2007

Late prevention (after starting HMG/FSH and before HCG) Cancellation of the cycle Coasting Diminish HCG dose GnRHa to trigger ovulation Metformin Albumin Cabergoline I.V. Calcium Cryopreservation of embryos GnRH agonists + embryo freezing Unilateral follicle aspiration before HCG Laparoscopic ovarian electro-cautery

Incidence of OHSS after GnRH agonists to trigger ovulation (MA) Reference No patients with agonist trigger No of patients with hCG trigger Patients with OHSS post agonist Patients with OHSS post hCG (%) P value Babayof et al, 2006 (RCT) 15130/154/13 (31%)<0.05 Engmann et al, 2008 (RCT) 33320/3310/32 (31%)<0.001 Acevedo et al, 2006 (RCT) 30 0/305/30 (17%)<0.05 TOTAL78750/7819/75 (25%)<0.001 Kol and Solt, JARG 25: 63, 2008

GnRH agonists to trigger ovulation Griesinger et al, Human Reprod Update 12: 159, 2006

GnRH agonists to trigger ovulation Youssef et al, Cochrane Database Syst Rev 10;(11):CD008046, 2010 OHSS incidence per randomised woman OR = 0.10 (95% CI = 0.01 to 0.82) * GnRH agonist versus HCG (LBR) OR = 0.44 (95% CI = 0.29 to 0.68) * GnRH agonist versus HCG (OPR) OR = 0.45 (95% CI = 0.31 to 0.65) *

GnRH agonists to trigger ovulation with modified luteal support (OS) No OHSS after GnRHa triggering 5% risk difference (with 95% CI: to 0.02) Delivery rate after modified luteal support 6% risk difference (95% CI: to 0.2) Delivery rate after conventional luteal support 18% risk difference (95% CI: to 0.01) Humaidan, Hum Reprod Update 17(4):510-24, 2011

Late prevention (after starting HMG/FSH and before HCG) Cancellation of the cycle Coasting Diminish HCG dose GnRHa to trigger ovulation Metformin Albumin Cabergoline I.V. Calcium Cryopreservation of embryos GnRH agonists + embryo freezing Unilateral follicle aspiration before HCG Laparoscopic ovarian electro-cautery

Costello et al. Hum Reprod 21:1387, 2006 Metformin versus placebo or no treatment in IVF for to prevent OHSS in PCOS patients OR = 0.21; 95% CI = 0.11–0.41, P <

Late prevention (after starting HMG/FSH and before HCG) Cancellation of the cycle Coasting Diminish HCG dose GnRHa to trigger ovulation Metformin Albumin Cabergoline I.V. Calcium Cryopreservation of embryos GnRH agonists + embryo freezing Unilateral follicle aspiration before HCG Laparoscopic ovarian electro-cautery

Albumin for the prevention of OHSS Aboulghar et al, Cochrane Database: Issue 1, 2009

Hydroxyethyl starch (HES) to prevent OHSS (CCT) HESControl groupP value No. of patients10082 No. of pregnancies 2824NS Moderate OHSS1032< Severe OHSS27NS Graf et al, Hum Reprod 12: 2599, 1997

HES versus albumin to prevent OHSS (RCT) HES (n = 85) Albumin (n =82) Control group (n = 83) P value Moderate OHSS 5 (5.9 %)4 (4.9 %)12 (14.5 %)<0.05 Severe OHSS004 (4.8 %)<0.05 Overall cases of OHSS 5 (5.9 %)4 (4.89 %)16 (19.2 %)<0.01 Gokmen et al, Eur J Obstet Gyn Reprod Biol 96: 187, 2001

Late prevention (after starting HMG/FSH and before HCG) Cancellation of the cycle Coasting Diminish HCG dose GnRHa to trigger ovulation Metformin Albumin Cabergoline I.V. Calcium Cryopreservation of embryos GnRH agonists + embryo freezing Unilateral follicle aspiration before HCG Laparoscopic ovarian electro-cautery

Effect of cabergoline on rats with OHSS A = Vascular permeability B = Serum prolactin C = Plasma progesterone Gomez et al, Endocrinol 147: 5400, 2006 Cabergoline inactivates the VEGF receptor 2 (VEGFR-2)

Cabergoline to prevent OHSS (RCT) Albumin + Cabergoline Albumin onlyP value No. of patients83 Early OHSS012 (15.0 %)< Late OHSS9 (10/8 %)93(3.8 %)NS Carizza et al, RBMOnline 17: 751, 2008

Late prevention (after starting HMG/FSH and before HCG) Cancellation of the cycle Coasting Diminish HCG dose GnRHa to trigger ovulation Metformin Albumin Cabergoline I.V. Calcium Cryopreservation of embryos GnRH agonists + embryo freezing Unilateral follicle aspiration before HCG Laparoscopic ovarian electro-cautery

I.V. Calcium to prevent OHSS (CCT) I.V. CalciumControl groupP value No. of patients84371 OHSS3 (3.6%)60 (16.2%)<0.01 Pregnancies (CPR)34 (40.5%)107 (28.8%)<0.05 Deliveries (LBR)32 (38.1%)92 (24.8%)<0.02 Gurgan et al, Fertil Steril 96: 53-7, 2011

Late prevention (after starting HMG/FSH and before HCG) Cancellation of the cycle Coasting Diminish HCG dose GnRHa to trigger ovulation Metformin Albumin Cabergoline I.V. Calcium Cryopreservation of embryos GnRH agonists + embryo freezing Unilateral follicle aspiration before HCG Laparoscopic ovarian electro-cautery

Embryo freezing to prevent OHSS D’Angelo and Amso, Cochrane Database: Issue 2, 2002

Late prevention (after starting HMG/FSH and before HCG) Cancellation of the cycle Coasting Diminish HCG dose GnRHa to trigger ovulation Metformin Albumin Cabergoline I.V. Calcium Cryopreservation of embryos GnRH agonists + embryo freezing Unilateral follicle aspiration before HCG Laparoscopic ovarian electro-cautery

GnRH agonists + embryo freezing to prevent OHSS (OS) % (n)95% CI Biochemical PR/patient5.3 % (1/19)0.9 % – 24.6 % Ongoing PR/patient36.8 % (7/19)19.1 % – 59.0 % Ongoing PR/first ET31.6 % (6/19)15.4 % – 54.0 % Cumulative ongoing PR/ET 29.2 % (7/24)14.9 % – 49.2 % OHSS0 % (0/24) Griesinger et al, Human Reprod 22: 1348, 2007

Late prevention (after starting HMG/FSH and before HCG) Cancellation of the cycle Coasting Diminish HCG dose GnRHa to trigger ovulation Metformin Albumin Cabergoline I.V. Calcium Cryopreservation of embryos GnRH agonists + embryo freezing Unilateral follicle aspiration before HCG Laparoscopic ovarian electro-cautery

Unilateral follicle aspiration before HCG (RCT) Unilateral follicle aspiration (n = 16) Controls (n = 15) P value Oestradiol (pmol/l) ± ± 593NS Mild OHSS13NS Moderate OHSS11NS Severe OHSS21NS Clinical pregnancy rate 6/16 (37.5%)7/15 (46.6%)NS Egbase et al, Hum Reprod 12: 2603, 1997

Late prevention (after starting HMG/FSH and before HCG) Cancellation of the cycle Coasting Diminish HCG dose GnRHa to trigger ovulation Metformin Albumin Cabergoline I.V. Calcium Cryopreservation of embryos GnRH agonists + embryo freezing Unilateral follicle aspiration before HCG Laparoscopic ovarian electro-cautery

Laparoscopic ovarian electro-cautery (RCT) Conventional IVF (n = 25) LOE + IVF (n = 25) P value Cancellations due to OHSS risk * Moderate OHSS Mean number of oocytes Mean embryos transferred Pregnancy rate/cycle8/25 (32.0 %)9/25 (36.0 %)0.765 Rimington et al, Hum Reprod 12: 1443, 1997

Conclusion 3 – Secondary prevention The following approaches prevent OHSS: Triggering ovulation with GnRH agonists (A) Metformin administration (A) Intravenous albumin (A) Hydroxyethyl starch (A) Cabergoline for early OHSS (A) Laparoscopic ovarian electrocautery (A) The following approaches do not prevent OHSS Coasting (A) Cabergoline for late OHSS (A)

Conclusion 3 – Secondary prevention (cont…) The following approaches are equivocal in preventing OHSS: Coasting versus unilateral oocyte aspiration (A) GnRH antagonists versus coasting (A) The following approaches await further evaluation: Cancellation of the cycle Diminishing the dose of HCG Embryo freezing Triggering with GnRHa + embryo freezing

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

Coasting to prevent OHSS (OS) Egbase et al, Hum Reprod 15: 2082, 2000

Coasting to prevent OHSS (OS) CharacteristicOutcome No. of patients15 Mean age (years ) ± SD 33.5 ± 2.8 Body mass index ± SD34.8 ± 5.2 No. of ampoules ± SD50.2 ± 16.5 Moderate OHSS (%)3 (20 %) Severe OHSS3 (20 %) Clinical pregnancy rate5/15 (33.3 %) Egbase et al, Hum Reprod 15: 2082, 2000

Coasting versus early unilateral follicular aspiration to prevent OHSS D’Angelo and Amso, Cochrane Database Issue 1, 2009

GnRH antagonists versus coasting to prevent OHSS (RCT) Coasting (n = 96) GnRH antagonist (n = 94) P value No. of high quality embryos (SD) 2.21 ± ± 1.2< Mean number of oocytes (SD) ± ± 7.60<0.02 Clinical pregnancy rate47.9 %55.3 %NS Severe OHSSNone NS Aboulghar et al, RBMOnline 15: 271, 2007

Conclusion 1 - Prediction Good predictorsBad predictors PCOSBMI Young ageGenetic predisposition PCO patternSerum VEGF AFCVon Willebrand factor E2 level on day of HCGPerifollicular blood flow Insulin resistance Large ovarian volume AMH