OHSS FREE CLINIC
Prof Dr P Devroey
The Era of a OHSS Free Clinic

By understanding biology

By using drugs differently

By innovative strategic thinking
Definition
Definition of OHSS

Iatrogenic complication (!) of
“controlled” (?) ovarian stimulation

Potentially fatal (!)

Risk factor (PCOS)

Triggering mechanism of hCG ( ! )
Intriguing
Intriguing

Iatrogenic
Who is responsible?

Ovarian stimulation
How to stimulate?

HCG is the trigger
HCG to be replaced?
OHSS
Ovarian hyperstimulation syndrome

01 09 2011

PubMed n : 2 275 citations
Severe OHSS
Severe OHSS
IV fluid
 Respiratory distress (intensive care
admission)
 Electrolyte imbalance
 Dopamine to improve diuresis
 Heparin to prevent thrombosis
 Vaginal aspiration of ascitis fluid

Aboulghar SRM 2010
Form
Form of OHSS

Early onset (early OHSS) up to 9
days after oocyte retrieval related to
excessive ovarian response

Late onset (late OHSS) 10 days after
oocyte retrieval induced by
endogenously produced hCG after
implantation
Papanikolaou HR 2005
Incidence
Incidence of OHSS (hospitalized)

2 524 IVF/ICSI cycles

53 patients
2.1 % (95 % CI : 1.6 - 2.8)

Early OHSS (n : 31)
1.2 % (95 % CI : 0.9 - 1.8)

Late OHSS (n : 22)
0.0 % (95 % CI : 0.5 - 1.31)
Papanikolaou FS 2006
Fatal
Fatal OHSS

25 years old Japanese lady

Bilateral chest pain - dyspnoea

Pleural effusion

Fatal after respiratory insufficiency

Autopsy massive pulmonary edema
Semba Patol Int 2000
Fatal
Fatality due to OHSS

31 years old woman

Ovarian stimulation (Gonal F)

Fatal adult respiratory distress
syndrome
Fineschi Int J Legal Med 2006
Maternal death
Maternal death
In IVF in the Netherlands (1984 – 2008)

Death to OHSS : 3 / 100 000 IVF cycles

Respiratory distress (n : 2)

Cerebrovascular thrombosis (n : 1)
Braat HR 2010
Does it mean 30 / 1 000 000 ?
At random citations

OHSS is difficult to predict, but
multiple preventive strategies and
protocols are being developed that
may limit it
Patchava Minerva Ginecol 2009

Ovarian stimulation carries a marked
risk for … ovarian hyperstimulation
syndrome
Kallen Best Pract Res Clin Obstet Gynaecol 2008
At random citations
(continued)

Low dose hCG at the end of the
follicular phase
Nargund RBO 2007

Preventive administration of IV fluid
Youssef Cochrane Database Syst Rev 2011

Continuous vaginal and thoracic fluid
drainage for management of severe
ovarian hyperstimulation syndrome
Ceyhan Gynecol Endocrinol 2008
At random citations
(continued)

Severe ovarian hyperstimulation
syndrome : an intensive care disease
Humeeus Rev Med Chil 1998

Coasting no benefit
D’Angelo Cochrane Database Syst Rev 2011

Dopamine antagonist significant
reduction
Sherwal J Human Reprod Sci 2010
Obstetrical outcome
Obstetrical outcome of IVF
pregnancies in OHSS syndrome
Occurrence
40/3 504
cycles (1.4 %)
Control
(80)
P
Duration of hospitalization
10 Days
0
Early OHSS
22.5 %
0
Late OHSS
75.5 %
0
Thrombo-embolic complications
10.0 %
0
Pregnancy induced
hypertension
21.0 %
9%
S
Preterm labor
36.0 %
11 %
S
Courbiere FS 2011
Iatrogenic ?
The question : Is iatrogenic OHSS
avoidable and erasable ?
Understanding different biological
mechanisms
using different drugs
using different treatment strategies
Devroey et al HR 2011
Is GnRH agonist triggering an
option ?

PubMed 01.03.2011 n : 83 publications

Gonadotrophin-releasing hormone agonist
triggering : the way to eliminate ovarian
hyperstimulation syndrome - a 20 years
experience
Kol Sem Reprod Med 2010
GnRH agonist triggering
Age (years)
GnRH-a
hCG
n : 84
n : 95
33
34
Eggs (mean)
5.9
5.2
Embryos transferred
2.5
2.3
20 %
19 %
Pregnancy rates
Segal FS 1992
Reflexion
Reflexion
It is possible that down regulation
of pituitary receptors and reduced
LH support for the corpus luteum
may occur even after a single
administration of GnRH agonist
Segal FS 1992
Cycle outcome
Brussels
Agonist
hCG
Stimulation (in
patients)
18
24
OPU (n)
18
24
ET (n)
15
20
Ongoing pregnancy
rate / started cycle
1/18 (5.6 %)
Odds ratio (95 % CI) 0.11 (0.02 – 0.52)
P level = 0.005
10/24 (41.7 %)
Kolibianakis HR 2005
GnRH agonist triggering in a GnRH
antagonist cycle
Triggering
GnRH agonist 0.2 mg hCG 10 000
Triptorelin
Vaginal
progesterone
+
+
Estradiol valerate
+
+
Discontinuation
-
-
Pregnancy rate
5.6 %
41.7 %
Kolibianakis HR 2005
GnRH agonist triggering in GnRH
antagonist cycles in OHSS risk

AIM : avoiding OHSS

Patients (n : 12)

> 25 follicles

GnRH agonist triggering and 1 500 hCG 35
hours later

COC (n : 20)

Ongoing pregnancies 50 % (6/12)

No OHSS
Humaidan RBMO 2009
GnRH agonist triggering in GnRH
antagonist cycles (RCT)
GnRH agonist
+ 1 500 hCG
hCG 10 000
152
150
Transfer rate (%)
86
92
Delivery rate / patient
36 / 152 (24 %)
47 / 150 (31 %)
Patients (n)
Humaidan FS 2010
Oocyte donors (GnRHa donors)
Triggering
GnRHa
hCG
P
Subjects (n)
50
50
Age (y)
25
25
2 300
2 300
17
19
rFSH dose (U)
Eggs retrieved (mean)
OHSS rate
0 / 50
8 / 50
0.03
Melo RBMO 2009
Elective vitrification of all zygotes
after GnRH agonist triggering
Days of stimulation (mean)
FSH (U)
COC (mean)
Ongoing pregnancy / patient
10
1 900
16
7 / 19 (37 %)
Griesinger HR 2007
Oocyte donation using egg
cryobanking

153
eggs

117
fertilized

47


blastocysts transferred
2.3 per ET
26
implanted (55 %)
Nagy FS 2009
Oocyte banking (vitrification)
RCT
P
Frozen
Fresh
Ongoing pregnancy
rate / ET
43.7 %
41.7 %
NS
Clinical pregnancy
rate / ET
55.0 %
56.0 %
NS
Implantation rate
40.0 %
41.0 %
NS
Similar results
95 % CI : 0.7 – 1.3
Cobo HR 2010
Oocyte vitrification : closed carrier
Patients
N : 20
Survival rate
111 / 123 (90 %)
Fertilization rate
86 / 111 (75.5 %)
Cleavage rate (day 3)
80 / 86 (93 %)
Clinical pregnancy rate per patient
10 / 20
Ongoing pregnancy rate
9 / 20
Frozen embryo replacement
1/
Cumulative
Ongoing pregnancy rate per patient
Implantation per warmed oocyte
3
10 / 20 (50 %)
14 / 123 (11.4 %)
Personal communication
Oocyte vitrification after GnRH agonist
triggering versus coasting

Observational study

Oocyte vitrification after GnRH agonist
triggering (n : 152)

Classical coasting (n : 96)

Egg vitrification
(pregnancy rate 50 %)

Clinical coasting
(pregnancy rate 30 %)
Herrero FS 2010
Endometrial biopsy on the day of
ovulation, natural cycle
No secretory features
Endometrial biopsy on the day of
oocyte retrieval, GnRH agonist and
gonadotrophin stimulation cycle
Clear secretory features
Endometrium histology at OPU and the
probability of pregnancy
Author
Stimulation
Endometrial
advancement
≤ 3 days
Odds ratio
95% CI
P
0.22
0.06-0.89
0.03
0.23
0.05-0.98
0.05
> 3 days
Clinical pregnancy rate
Ubaldi (1997)
hMG/agonist
10/32
0/7
Kolibianakis
(2002)
RecFSH/antagonist
11/49
0/6
21/81
0/13
Ongoing pregnancy rate
Ubaldi (1997)
hMG/agonist
Kolibianakis
(2002)
RecFSH/antagonist
10/32
0/7
8/49
0/6
18/81
0/13
Kolibianakis FS 2002
Advanced endometrial maturation
- no pregnancies

Upregulated genes

SERPINB6

FOXO3A

SOX17

CDC42
Van Vaerenbergh I HR 2009
CONCLUSION
Past
Today

Down regulation with
GnRH agonist

For first cycle always
GnRH antagonist

HCG for final egg
maturation

GnRH agonist triggering if
at risk for OHSS

Freeze all

ET of fresh embryo
adding low dose hCG in
luteal phase

OHSS ≈ 2 %

OHSS 0 %
CODA
OHSS FREE CLINIC
AFR segmentation strategy
(A)
Optimization of
(A)
stimulation
(B)
Optimization of
GnRH agonist to trigger
(F)
embryology
(C)
Optimization of
GnRH antagonist and
Freeze all
oocytes/embryos
(R)
Replacement in receptive
endometrial
endometrium
implantation potential
(spontaneous or artificial)