OHSS Prevention and Treatment - an evidence-based approach
Hassan N. Sallam,
MD, FRCOG (England), PhD (London)
Professor and Chair, Obstetrics and Gynaecology, The University of Alexandria, and
Director of the Suzanne Mubarak Regional Center for Women’s Health and Development
2
ndAnnual Congress of the Society for Reproductive
Medicine, 1-4 October 2009, Antalya, Turkey
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)
Ovary Symptoms/signs
Grade 1 Abdominal
distension
Grade 2 5-10 cm Nausea/vomiting Grade 3 >10 cm Ascites
Grade 4 > 12 cm Pleural effusion
Grade 5 Haemoconcentration
oliguria
Mild
Moderate
Severe
Pathophysiology of OHSS
Pathophysiology of OHSS
Pathophysiology of OHSS
OHSS Prevention and Treatment
1. Prediction of OHSS
2. Primary prevention (before starting HMG/FSH)
3. Secondary prevention (after starting HMG/FSH and before HCG
administration)
4. Management of established OHSS
(after 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
OHSS Prevention and Treatment
1. Prediction of OHSS
2. Primary prevention (before starting HMG/FSH)
3. Secondary prevention (after starting HMG/FSH and before HCG
administration)
4. Management of established OHSS
(after 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, 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, 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
Study Patients with OHSS
Controls P value
Smitz et al, 1990 50% (5/10) None (0/1663) <0.0001
MacDougall et al, 1992
63 % (5/8) None (0/1287) <0.0001
Delvigne et al, 1993
37 % (47/128) 15 % (38/256) <0.0001
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
Study Patients with OHSS (Age in years)
Controls (Age in years)
P value
Navot et al, 1988 27.8 ± 3.6 31.5 ± 5.7 <0.05
Lyons et al, 1994 29.7 ± 1.8 33.9 ± 0.15 <0.05
Delvigne et al, 1993
30.2 ± 3.5 32.0 ± 4.5 <0.05
Enskog et al, 1999 30.2 ± 0.7 32.5 ± 0.2 <0.05
Relationship between BMI and OHSS
Study Number of
patients with OHSS
Number of control subjects
P value
Papanikolau et al, 2006
23.13 ± 0.8 23.05 ± 0.1 NS
Delvigne et al, 1993
22.0 ± 3.4 21.9 ± 3.2 NS
Enskog et al, 1999 23.2 ± 0.92 23.0 ± 0.16 NS
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
FSH
Genetic predisposition to predict OHSS
Allelic frequencies Genotypic frequencies
A T AA AT TT
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 value NS NS NS NS NS
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, 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 ± 472 1507 ± 727 NS
Mean dose/BMI
± SD (IU/BMI) 57.7 ± 18.7 54 ± 18 NS
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
AMH to predict OHSS
Lee et al. Hum Reprod 23: 160, 2008
AMH to predict ovarian response
Early follicular Mid-luteal
Cut-off (ng/mL) 2.7 2.7
Sensitivity (%) 83.3 91.7
Specificity (%) 82.4 88.2
PPV (%) 76.9 84.6
NPV (%) 87.2 93.8
Accuracy (%) 82.8 89.6
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, 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 ovary Left ovary
Measuring AFC =Normal response
Total AFC
Sensitivity Specificity PPV Accuracy
<4 0.21 0.99 0.86 0.78
<5 0.28 0.99 089 0.80
<6 0.41 0.95 0.75 0.89
<7 0.69 0.80 0.56 0.77
<8 0.76 0.74 0.51 0.75
AFC to predict poor responders
Kwee et al, RBEJ 5:9, 2007
Measuring AFC = Low (poor) response
Total AFC
Sensitivity Specificity PPV Accuracy
<10 0.94 0.71 0.36 0.76
<12 0.88 0.80 0.44 0.81
<14 0.82 0.89 0.58 0.88
<16 0.47 0.96 0.67 0.88
<18 0.29 0.98 0.71 0.87
AFC to predict hyper responders
Kwee et al, RBEJ 5:9, 2007
Measuring AFC = Hyper-response
AFC versus AMH to predict ovarian response
Hendricks et al, Fertil Steril 83(2): 291, 2005
Broer et al, Fertil Steril 91: 705, 2009 AMHAFC
Ovarian volume
Age Group
Mean Ovarian volume (ml)
SD (ml) 95% Confidence Interval
% Ovaries Imaged
1 day to 3
months 1.06 0.96 0.03-3.56 70
4-12 months 1.05 0.67 0.18-2.71 100
13-24 months 0.67 0.35 0.15-1.68 90
2 -12 years 0.46 - 0.13-0.9 (range) -
13-20 years 4.0 - 1.8-5.7 (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
3-D U/S in obstetrics and gynaecology
Ovarian volume
Ivarsson et al, Arch Dis Child 58, 352, 1983
Ovarian volume to predict OHSS
OHSS Controls P value
No. of patients 8 86
Days of stimulation 10.5 ± 2.5 10.5 ± 1 8 NS
Oestradiol (pg/ml) 2439 ± 1350 937 ± 686 0.0001 No. of follicles 23.3 ± 4.3 13.8 ± 7.5 0.0025
No. of oocytes 164 ± 26 5.9 ± 3 0 0.0001
Cycle length 34.1 ± 5.8 28.7 ± 2 2 0.0001
Body wt before stimulation 55.4 ± 3.8 62.8 ± 11 0.011 Body wt after stimulation 54 3 ± 4.5 62.9 ± 10. 7 0.03
Ovarian volume (ml) 13.2 ± 5 8.9 ± 3.7 0.035
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
OHSS Controls P value
Mean age (years) 32.63 ± 1.77 31.48 ± 3.87 NS Mean duration of
infertility (years)
6.00 ± 2.19 5.29 ± 2.73 NS
Maximal peak systolic velocity
0.15 ± 0.04 0.21 ± 0.10 NS
Mean minimal pulsatility index
0.89 ± 0.30 0.79 ± 0.14 NS
Mean minimal resistance indexes
0.56 ± 0.05 0.53 ± 0.06 NS
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 predictors Bad predictors
PCOS BMI
Young age Genetic predisposition
PCO pattern Serum VEGF
AFC Von Willebrand factor
E2 level on day of HCG Perifollicular blood flow Insulin resistance
Large ovarian volume
AMH
OHSS Prevention and Treatment
1. Prediction of OHSS
2. Primary prevention (before starting HMG/FSH)
3. Secondary prevention (after starting HMG/FSH and before HCG
administration)
4. Management of established OHSS
(after 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)
Conventional Step-up P value
No. of cycles 48 49
Oestradiol on the day of HCG (pg/ml)
1258.6 ± 1003 533.5 ± 525 0.001 No. of pregnancies 7 (14.6%) 7 (14.3%) NS
No. of abortions 1 (14.3%) 1 (14.3%) NS
No. of multiple pregnancies
2 (28.6%) 1(14.3%) NS
No. of OHSS 13 (27.1%) 4 (8.3%) 0.05
Mild OHSS 5 (10.4%) 4 (8.3%) NS
Moderate OHSS 8 (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 versus step-down protocol (RCT)
Low dose step-up Step down P value
No. of patients 19 18
Duration of treatment (days)
18 9 0.003
No. of ampoules 20 14 NS
Monofollicle growth
6 (39%) 17 (100 %) < 0.001
Ovulation rate 84 % 89 % NS
Ongoing pregnancies
2 5 NS
OHSS 0 0 NS
Santbrink and Fauser, J Clin Endocrinol Metab 82: 3597, 1997
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, step-down and conventional protocols (RCT)
Protocol Conventional (n = 19)
Step down (n = 24)
Step up (n = 25)
P value
Small follicles 7.6 ± 1.9 * 6.3 ± 1.0 3.1 ± 0.7 * <0.05
Medium follicles 5.7 ± 1.2 * 5.0 ± 0.8 2.3 ± 0.6 * <0.05
Large follicles 1.5 ± 0.3 1.2 ± 0.2 1.3 ± 0.3 NS
Andoh et al, Fertil Steril 70: 840, 1998
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 cycles 75 75 75
No. of clinical pregnancies (rate)
18 20 33 <0.05
Pregnancy rate 31.0 % 32.2 % 48.5 % NS
No. of multiple pregnancies (rate)
4 (22.2%) 5 (25.0%) 8 (24.0%) NS NS 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)
IVM IVF OR (95% CI)
No. of cycles 107 107
Implantation rate (%) 9.5 17.1 0.51 (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 OHSS 0 12 (11.2%) 0.036 (0.002-
0.608) *
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
GnRH agonists v/s antagonists to prevent OHSS
Al-Inany et al, Cochrane Database: Issue 1, 2009
LBR in GnRH agonists v/s antagonists
Al-Inany et al, Cochrane Database: Issue 1, 2009
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 but with a lower LBR (A)
• IVM compared to IVF (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
OHSS Prevention and Treatment
1. Prediction of OHSS
2. Primary prevention (before starting HMG/FSH)
3. Secondary prevention (after starting HMG/FSH and before HCG
administration)
4. Management of established OHSS
(after 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
• 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
• 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 IVF 8 % 22 % 38 % <0.001
Cancel cycle 14 % 14 % 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
• Cryopreservation of embryos
• GnRH agonists + embryo freezing
• Unilateral follicle aspiration before HCG
• Laparoscopic ovarian electro-cautery
Coasting to prevent OHSS (OS)
Egbase et al, Hum Reprod 15: 2082, 2000
Coasting to prevent OHSS (OS)
Characteristic Outcome
No. of patients 15
Mean age (years ) ± SD 33.5 ± 2.8
Body mass index ± SD 34.8 ± 5.2
No. of ampoules ± SD 50.2 ± 16.5
Moderate OHSS (%) 3 (20 %)
Severe OHSS 3 (20 %)
Clinical pregnancy rate 5/15 (33.3 %)
Egbase et al, Hum Reprod 15: 2082, 2000
Coasting to prevent OHSS - Guidelines
1. Start at
• Serum E2 >4,500 pg/mL
• E2 production >150 pg/follicle 16–18 mm
• >15 and <30 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
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 ± 1.1 2.87 ± 1.2 <0.0001
Mean number of oocytes (SD)
14.06 ± 5.20 16.5 ± 7.60 <0.02
Clinical pregnancy rate 47.9 % 55.3 % NS
Severe OHSS None None NS
Aboulghar et al, RBMOnline 15: 271, 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
• 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. 2500 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
• 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)
15 13 0/15 4/13 (31%) <0.05
Engmann et al, 2008
(RCT)
33 32 0/33 10/32 (31%) <0.001
Acevedo et al, 2006
(RCT)
30 30 0/30 5/30 (17%) <0.05
TOTAL 78 75 0/78 19/75 (25%) <0.001
Kol and Solt, JARG 25: 63, 2008
GnRH agonists to trigger ovulation
Griesinger et al, Human Reprod Update 12: 159, 2006
Late prevention (after starting HMG/FSH and before HCG)
• Cancellation of the cycle
• Coasting
• Diminish HCG dose
• GnRHa to trigger ovulation
• Metformin
• Albumin
• Cabergoline
• 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 < 0.00001
Late prevention (after starting HMG/FSH and before HCG)
• Cancellation of the cycle
• Coasting
• Diminish HCG dose
• GnRHa to trigger ovulation
• Metformin
• Albumin
• Cabergoline
• 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)
HES Control group P value
No. of patients 100 82
No. of pregnancies
28 24 NS
Moderate OHSS 10 32 <0.00001
Sever OHSS 2 7 NS
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 OHSS 0 0 4 (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
• 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 only P value
No. of patients 83 83
Early OHSS 0 12 (15.0 %) < 0.001
Late OHSS 9 (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
• 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
• 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/patient 5.3 % (1/19) 0.9 % – 24.6 % Ongoing PR/patient 36.8 % (7/19) 19.1 % – 59.0 % Ongoing PR/first ET 31.6 % (6/19) 15.4 % – 54.0 %
Cumulative ongoing PR/ET
29.2 % (7/24) 14.9 % – 49.2 %
OHSS 0 % (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
• 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)
15 982 ± 827 16 243 ± 593 NS
Mild OHSS 1 3 NS
Moderate OHSS 1 1 NS
Severe OHSS 2 1 NS
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
• 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 5 0 0.025 *
Moderate OHSS 4 1 0.174
Mean number of oocytes 7.37 10.28
Mean embryos transferred 2.5 2.6
Pregnancy rate/cycle 8/25 (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
• 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
• Coasting
• Diminishing the dose of HCG
• Embryo freezing
• Triggering with GnRHa + embryo freezing
Bibliotheca Alexandrina
OHSS Prevention and Treatment
1. Prediction of OHSS
2. Primary prevention (before starting HMG/FSH)
3. Secondary prevention (after starting HMG/FSH and before HCG
administration)
4. Management of established OHSS
(after HCG administration)
Clinical problems in OHSS
• Electrolyte imbalance
• Haemodynamic changes
• Pulmonary manifestations
• Liver dysfunction
• Hypo-globulinaemia
• Febrile morbidity
• Thromboembolic phenomena
• Neurologic manifestations
Delvigne and Rozenberg, Hum Reprod Update 9: 77, 2003
Management of established OHSS
1. Hospitalization
2. Aspiration of ascitic fluid 3. Circulatory volume correction
4. Electrolyte replacement 5. Corticosteroids
6. Heparinization 7. GnRH antagonists
8. Docarpamine
9. The role of surgery
Management of established OHSS
1. Hospitalization
2. Aspiration of ascitic fluid 3. Circulatory volume correction
4. Electrolyte replacement 5. Corticosteroids
6. Heparinization 7. GnRH antagonists
8. Docarpamine
9. The role of surgery
Hospitalization in severe OHSS
• Severe abdominal pain or peritoneal signs
• Intractable nausea and vomiting
• Severe oliguria or anuria
• Tense ascites
• Hypotension, dizziness or syncope
• Severe electrolyte imbalance
Rizk and Aboulghar, Textbook of IVF & ART, Parthenon 9: 131, 1999
Management of established OHSS
1. Hospitalization
2. Aspiration of ascitic fluid 3. Circulatory volume correction
4. Electrolyte replacement 5. Corticosteroids
6. Heparinization 7. GnRH antagonists
8. Docarpamine
9. The role of surgery
Aspiration of ascitic fluid (OS)
Technique Study
Abdominal paracentesis Rabau et al, 1967 Trans-vaginal aspiration Aboulghar et al, 1990
Indwelling catheter Al-Ramahi et al, 1997 Double pig-tail catheter Abuzeid et al, 2003
Auto-transfusion of ascitic fluid Aboulghar et al, 1992; Fukaya et al, 1994;
Splendiani et al, 1994; Beck et al, 1995 Peritoneo-venous shunting Splendiani et al, 1994; Beck et al, 1995;
Koike et al, 2000
Aspiration of ascitic fluid (OS)
• Hematocrit decreased by 22%
• Creatinine clearance increased by 79.3%
• Urine output increased by 220.7%
• Average volume of aspirated fluid 3900 ml
•Average duration of hospital stay 3.8 days (11 days in the control group)
Aboulghar et al, Fertil Steril 53: 933, 1990;
Aboulghar et al, Obstet Gynecol 81: 108, 1993
Continuous auto-transfusion system for ascitis (CATSA)
Koike et al, Hum Reprod 15: 113, 2000
Effects of repeated paracenteses (OS)
N = 41 aspirations in 7 women
Before After P value
Uterine artery P.I. 1.27 ± 0.38a 1.19 ± 0.39 < 0.05 Uterine artery MPSV 0.33 ± 0.08 0.34 ± 0.07 NS
Intra-ovarian P.I. 0.70 ± 0.12 0.69 ± 0.11 NS Intra-ovarian MPSV 0.30 ± 0.07 0.29 ± 0.09 NS
P.I. = Pulsatility index
MPSV = Maximum peak systolic velocity
Chen et al, Hum Reprod 13: 2077, 1998
Management of established OHSS
1. Hospitalization
2. Aspiration of ascitic fluid 3. Circulatory volume correction
4. Electrolyte replacement 5. Corticosteroids
6. Heparinization 7. GnRH antagonists
8. Docarpamine
9. The role of surgery
Hydroxyethyl starch (HES) versus albumin for treating OHSS (CCT)
Human albumin (n = 10)
Hydroxyethyl starch group
(n = 6)
P value
Daily urine output (mL) 2,557 ± 1,032 3,582 ± 1,780 <0.05 Abdominal paracentesis (%) 8 (80%) 2 (33%) <0.05 Fluid aspirated per patient (mL) 2,300 ± 230 1,930 NS
Pleurocentesis (%) 2 (20%) 0 <0.05
Hospital stay (d) 19.0 ± 8.2 15.7 ± 5.7 <0.05
Conception (%) 7 (70%) 4 (67%) NS
Abramov et al, Fertil Steril 75: 1228, 2001
Low molecular weight Dextran for the treatment of OHSS (CCT)
Dextran (n=25)
Albumin
(n=25) P value
Amount of HMG (IU) 1854 ± 407 1866 ± 548 NS
Serum E2 (pg/mL) 5072.0 ± 3956.1 4650.1 ± 2053.1 NS Recovery from
hemoconcentration (days)
2.2±1.1 4.4±1.0 0.001
Recovery from leukocytosis (days)
4.0±0.7 7.0±1.7 0.001
Pregnancies 13 10 NS
Miscarriages 2 2 NS
Endo et al, Fertil Steril 82: 1449, 2004
Management of established OHSS
1. Hospitalization
2. Aspiration of ascitic fluid 3. Circulatory volume correction
4. Electrolyte replacement 5. Corticosteroids
6. Heparinization 7. GnRH antagonists
8. Docarpamine
9. The role of surgery
Electrolyte disorders in OHSS (OS)
Type of disorder No. (%)
Haemo-concentration 91 (71.1 %)
Electrolytic 70 (54.6 %)
K 31 (24.2 %)
Na 29 (22.7 %)
Cl 5 (3.9 %)
HCO3 5 (3.9 %)
Elevated transaminases 33 (25.8 %)
Delvigne et al. Hum Rperod 8: 1353, 1993
Management of established OHSS
1. Hospitalization
2. Aspiration of ascitic fluid 3. Circulatory volume correction
4. Electrolyte replacement 5. Corticosteroids
6. Heparinization 7. GnRH antagonists
8. Docarpamine
9. The role of surgery
Glucocorticoids for OHSS (CCT)
Methylprednisolone Controls P value
No. of patients 50 41
No. of oocytes 28.7 ± 8.6 24.0 ± 9.9 <0.01 * E2 concentration 4,848 ± 1,482 3,727 ± 1,329 <0.01 *
Dose of HMG (IU) 2,458 ± 931 2,489 ± 997 NS
OHSS 10 % (5/50) 43.9 % (18/41) <0.01 *
Lainas et al, Fertil Steril 78: 529, 2002
Glucocorticoids for OHSS (RCT)
Glucocorticoids Controls P value
No. of patients 17 14
No. of follicles 26.76 ± 2.49 25.93 ± 1.44 NS
E2 concentration 13404 ± 710 13915 ± 901 NS
Pregnancy rate 41.18 % 35.71 % NS
OHSS 41.2 % (7/17) 42.9 % (6/14) NS
Tan et al, Fertil Steril 58: 378, 1992
Management of established OHSS
1. Hospitalization
2. Aspiration of ascitic fluid 3. Circulatory volume correction
4. Electrolyte replacement 5. Corticosteroids
6. Heparinization 7. GnRH antagonists
8. Docarpamine
9. The role of surgery
Thromboembolism with OHSS
1. Femoral vein (Todros et al 1999; Attia et al, 2007)
2. Internal jugular vein (Hignett et al, 1995; Horstkamp et al, 1996; Ellis et al, 1998; Balaen et al, 2001; Ulug et al,
2003; Ergas et al, 2006; Alasiri and Case, 2008) 3. Subclavian vein (Mills et al, 1992; Rao et al, 2005)
4. Cerebrovascular (Aboulghar et al 1998) 5. Superior vena cava (Lamon et al, 2000) 6. Central retinal artery (Turkistani et al, 2001)
7. Acute myocardial infarction (Akdemir et al, 2002)
8. Superior saggital sinus (Ou et al, 2003)
Thrombophilia markers in OHSS
Thrombophilia marker Study group (n = 20)
Control group
(n = 41) P value
Factor V Leiden mutation 1 1 NS
MTHFR 677T 7 4 0.03 *
Decreased protein S levels 8 3 0.004 *
Decreased antithrombin
levels 6 0 <0.001 *
Decreased protein C
levels 0 0 -
Antiphospholipid
antibodies 5 3 0.1
No. of women with
thrombophilia 17 11 <.0001 *
Dulitzky et al, Fertil Steril,77: 463, 2002
Concentration of some thrombophilia markers in OHSS
Thrombophilia marker Study group (n = 20)
Control group (n = 41)
P value
Antithrombin III level
(U/dL) 83.1 ± 10.1 102.0 ± 11.0 <0.001 * Protein S level (U/dL) 63.7 ± 15.5 83.3 ± 22.9 0.002 * Protein C level (U/dL) 95.2 ± 13.1 97.4 ± 17.6 NS
Dulitzky et al, Fertil Steril 77: 463, 2002
Heparinization for high risk patients
• Hyperoestrogenaemia
• Immobilization
• Compression of pelvic vessels by ovaries
• Personal history of thrombophilia
• Family history of thrombophilia _______________________________
N.B.1. No RCTs
N.B.2. Thromboembolism occurred despite
heparinization (Horstkamp et al, 1996; Todros et al,
1999; Cil et al, 2000)
Management of established OHSS
1. Hospitalization
2. Aspiration of ascitic fluid 3. Circulatory volume correction
4. Electrolyte replacement 5. Corticosteroids
6. Heparinization 7. GnRH antagonists
8. Docarpamine
9. The role of surgery
GnRH antagonists to treat OHSS (OS)
• 3 women using the long protocol for IVF
• Severe early OHSS after 6 days of oocyte retrieval
• GnRH antagonist was started and continued for 7 days
• The blastocysts were cryopreserved
• OHSS was inhibited in all 3 patients: Haematocrit, WBC, ascitis, E2, progesterone and ovarian volume decreased
• No patient required hospitalization
• GnRH antagonist may have a luteolytic effect
Lainas et al, Reprod Biomed Online 18: 15, 2009
Management of established OHSS
1. Hospitalization
2. Aspiration of ascitic fluid 3. Circulatory volume correction
4. Electrolyte replacement 5. Corticosteroids
6. Heparinization 7. GnRH antagonists
8. Docarpamine
9. The role of surgery
Docarpamine to treat OHSS (OS)
• Docarpamine is converted to Dopamine in the GIT
• Causes renal and mesenteric vasodilatation as well as diuretic and positive inotropic actions
• One tablet (750 mg) taken every 8 h by 22 patients
• The daily urinary output increased from 839 +/- 424 ml to 1133 +/- 509 ml in 4 days (p < 0.05)
• Ascites improved in 19 (86.4%) of 22
• Plasma free dopamine concentration rose to as high as 55.9 +/- 33.2 mg/ml during the first hour
• No major adverse effects of docarpamine in this study
Tsunoda et al, Gynecol Endocrinol 17: 281, 2003
Management of established OHSS
1. Hospitalization
2. Aspiration of ascitic fluid 3. Circulatory volume correction
4. Electrolyte replacement 5. Corticosteroids
6. Heparinization 7. GnRH antagonists
8. Docarpamine
9. The role of surgery
The role of surgery
Surgery should be avoided unless:
• Intra-peritoneal haemorrhage
• Torsion of the ovary
• Thromboarterectomy
• Inferior vena cava clipping
• Amputation for gangrene
• TOP in intractable cases
Serum albumin levels after partial oophor- ectomy in 2 cases with intractable OHSS
Amarin, Hum Reprod 18: 659, 2003
