Transcript OHSS Prevention and Treatment

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)
Ovary
Symptoms/signs
Grade 2
5-10 cm
Abdominal
distension
Nausea/vomiting
Moderate Grade 3
>10 cm
Ascites
Grade 4
> 12 cm
Pleural effusion
Grade 1
Mild
Severe
Grade 5
Haemoconcentration
oliguria
Pathophysiology
of
OHSS
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
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
FSH
FSH
receptor
Genetic predisposition to predict OHSS
Allelic frequencies
Genotypic frequencies
A
T
AA
AT
TT
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
Caucasian
controls
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
Normoinsulinaemic
(n = 21)
Hyperinsulinaemic
(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
Late onset OHSS
Ludwig et al, Hum Reprod 13:
30, 1998
Von Willebrand factor to predict OHSS
Todorow et al, Hum Reprod 8: 2039, 1993
Day 3 FSH to predict OHSS
Pregnant
Non-pregnant
P value
4.4+/-1.3
mIU/ml
6.1+/-2.9
mIU/ml
0.001
OHSS
No OHSS
P value
4.5+/-1.2
mIU/ml
5.9+/-2.8
mIU/ml
0.003
Cut-off point = 5.25 mIU/ml
Onagawa et al, Gynecol Endocrinol 18:335-40, 2004
AMH to predict OHSS
Cut-off value
3.36 ng/ml
AMH
Cut-off value
33 years
Age
BMI
Lee et al. Hum Reprod 23: 160, 2008
Cut-off value
18.44 Kg/m2
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, 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 ovary
Left ovary
AFC to predict ovarian
response
Kwee et al, RBEJ 5:9, 2007
AFC to predict poor responders
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
Kwee et al, RBEJ 5:9, 2007
AFC to predict hyper responders
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
Kwee et al, RBEJ 5:9, 2007
AFC versus AMH to predict poor response
AMH
AFC
Hendricks Broer
et al,etFertil
Steril
83(2):
291, 2005
al, Fertil
Steril 91:
705, 2009
AFC v/s AMH to predict hyper-response
AFC
AMH
Broer et al, Hum Reprod Update 17: 46, 2011
Predictors of OHSS (Sallam et al, 2011)
OHSS
No OHSS
P value
No. of cycles
11
22
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)
34.66 (9.00)
0.33
Day 3 leptin (ng/ml)
40.27 (28.06)
44.77 (25.71)
0.324
Day 3 VEGF (pg/ml)
438.00 (178.08)
448.27 (216.81)
0.446
Day 3 AFC
21.64 (3.20)
14.32 (3.81)
< 0.0002*
Day 3 AMH (ng/ml)
4.50 (2.87)
2.17 (1.55)
< 0.005*
E2 on HCG day (pg/ml) 5965.82 (1191.99) 2207.27 (659.32) < 0.0001*
Sallam et al, Predictors of OHSS, submitted for publication
ROC curves comparing AMH and AFC
ROC Curve
1.00
AFC
.75
Cut-off
value
=>14
Source of the Curve
.50
AMH
Reference Line
Sensitivity
Basal AMH
Cut-off
value
3.36
ng/ml
.25
E2 at HCG admin.
Antral follicle coun
0.00
t
0.00
.25
.50
.75
1.00
1 - Specificity
Diagonal segments are produced by ties.
Sallam et al, Predictors of OHSS, submitted for publication
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
Ovarian volume
Ivarsson et al, Arch Dis Child 58, 352, 1983
3-D U/S in obstetrics and gynaecology
Ovarian volume to predict OHSS
OHSS
Controls
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
P value
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:
PPV = 78.5 %; FNR = 18.1%
Delvigne et al, Hum Reprod 8: 1353, 1993
Conclusion 1 - Prediction
Good predictors
Bad predictors
Further
evaluation
PCOS
Genetic
predisposition
PCO pattern
Young age
Serum VEGF
BMI
AFC
Von 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
FSH versus 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
Chronic low-dose step-up protocol
Homburg et al, Fertil Steril 63: 729, 1995
Low dose step-up protocol (RCT)
Conventional
Step-up
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
P value
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)
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
Step-up versus step-down protocol (RCT)
Step-up (n=18)
Step down (n=17)p
Santbrink and Fauser, J Clin Endocrinol Metab 82: 3597, 1997
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
Chronic low-dose step-up versus stepdown protocol (RCT)
Low dose step-up
Step down
No. of patients
85
72
Duration of
treatment (days)
15.2 ± 7
9.7 ± 3.1
< 0.001
Total dose of
rec-FSH (IU)
951 ± 586
967 ± 458
NS
Mono-follicular
growth
68.2%
32%
< 0.0001
Ovulation rate
70.3%
61.7%
0.02
Pregnancies/cycle
18.7%
15.8%
NS
OHSS
2.25%
11%
<0.001
Christian-Maitre et al, Hum Reprod 18:1626, 2003
P value
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
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
P value
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 (0.0020.608) *
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
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 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
• 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
Coasting to prevent OHSS (Cochrane)
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 = -3.92 (95% CI -4.47 to -3.37) *
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. 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
• 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)
No of
No patients
Patients
patients
Reference with agonist
with OHSS
with hCG
trigger
post agonist
trigger
Babayof et
al, 2006
15
13
0/15
(RCT)
Engmann et
al, 2008
33
32
0/33
(RCT)
Acevedo et
al, 2006
30
30
0/30
(RCT)
TOTAL
78
75
0/78
Kol and Solt, JARG 25: 63, 2008
Patients
with OHSS
post hCG
(%)
P value
4/13 (31%)
<0.05
10/32 (31%)
<0.001
5/30 (17%)
<0.05
19/75 (25%)
<0.001
GnRH agonists to trigger ovulation
Griesinger et al, Human Reprod Update 12: 159, 2006
GnRH agonists to trigger ovulation
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) *
Youssef et al, Cochrane Database Syst Rev 10;(11):CD008046, 2010
GnRH agonists to trigger ovulation with
modified luteal support (OS)
No OHSS after GnRHa triggering
5% risk difference (with 95% CI: -0.07 to 0.02)
Delivery rate after modified luteal support
6% risk difference (95% CI: -0.14 to 0.2)
Delivery rate after conventional luteal support
18% risk difference (95% CI: -0.36 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
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
Costello et al. Hum Reprod 21:1387, 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
• 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)
HES
Control group
No. of patients
100
82
No. of
pregnancies
28
24
NS
Moderate OHSS
10
32
<0.00001
Severe OHSS
2
7
NS
Graf et al, Hum Reprod 12: 2599, 1997
P value
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
• 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
Cabergoline inactivates the VEGF
receptor 2 (VEGFR-2)
A = Vascular permeability
B = Serum prolactin
C = Plasma progesterone
Gomez et al, Endocrinol 147: 5400, 2006
Cabergoline to prevent OHSS (RCT)
Albumin +
Cabergoline
Albumin only
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
P value
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. Calcium
Control group
No. of patients
84
371
OHSS
3 (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
P value
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/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
• 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)
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
• 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
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 %)
Rimington et al, Hum Reprod 12: 1443, 1997
0.765
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)
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 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
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