Transcript Ovarian Hyperstimulation Syndrome (OHSS)

Prof. Luc O. Delbeke
Centrum voor Reproductieve Geneeskunde
Universitair Ziekenhuis Antwerpen
Ovarieel Hyperstimulatie Syndroom (OHSS)
Antwerpen 23/10/2003
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23 oktober 2003
Ovarieel Hyperstimulatie
Syndroom (OHSS)
Prof. Luc O. Delbeke
Centrum voor Reproductieve Geneeskunde
Universitair Ziekenhuis Antwerpen
Casus 1
32 j., G0
T. Spinder Fertiliteit in de praktijk september 2003
idiopatische infert.
6 x cc/IUI
IVF
superovulatie :
Ovul. inductie :
ovum aspirat. :
Fertilisation
:
GnRHa kort + 200 IE rec FSH/d 7 d
10.000 IU hCG bij 12 foll.  18 mm
E2 niet bepaald
35 h na hCG : 14 eicellen
13 x 2PN
2 ER + 6 CRYO
Luteale fase
:
1500 IE hCG op dag OPU + 5, +7, +9
Casus 1 : follow up
OPU + 7
: misselijk, braken, geen pijn, nl. diurese
OPU + 8
: opname via HA : apathie + verward spreken
helder bewustzijn, afasie, hemianopsie, facialis parese
en mot. uitval rechter hand
CT hersenen: vers infarct links temporo-parietaal
Echocardio: ruimte innemend proces linker ventrikel
labo
: Hb: 10.5 nmol/l; Hct 0.48; WBC 24.5.103; tromb 227.103
CRP 17 ng/l; hypo-albuminaemie
behandeling
: open hart chirurgie: resectie trombus linker ventr.
pleura- en ascites drainage; fraxiparine; P4 vag.
evolutie
: oplopend hCG tot dag 29 na OPU, waarna miskraam
Case 2
(Levy ea, Hum Reprod, 1995)
26 y G1P1 , surgical removal of craniopharyngioma :
panhypopituarism (Hypogon. Hypogonadism - WHO I)
G1 after hMG: severe OHSS
pre treatment
superovulation
ovul. ind.
: PCO -like ovaries; low gonadotrop. and TSH
: FSH 1 amp/d 5d, 2 amp/d 5d, 3amp/d 13d
: 10.000 IU hCG
E2 475 pg/ml
foll.: 2 > 18; 5 < 15; 10 < 9mm
luteal phase
:?
Case 2
follow up
day hCG + 11 : abdominal pain , swelling
nausea, vomiting
on admission
: distended abdomen,
treatment
: paracentesis (3 l)
evolution
: hCG < 5IU/L
admission
ovaries palpaple above the umbilicus
no edema nor pleural effusion
on U/S multip. ovarian cysts (8-10 cm)
colloid and crytalloid iv infusions
full recovery , no further complications
OHSS
Definition
A SERIOUS IATROGENIC COMPLICATION
of ovulation induction with a severe impact on the patients
health
(morbidity and mortality).
OHSS rarely occurs spontaneous during pregnancy
OHSS: signs and symptoms
Mild
Gr I
Gr II
Gr III
nausea, vomiting,
diarrhea
+
U/S ascites / weight
+
ovaries > 12 cm
Severe
abd. distension
+
ovaries 5 - 12 cm
Moderate
(Golan, 1989)
Gr IV clin. ascites/hydrothorax
ovaries > 12 cm
+
Gr V
hypovol., hemoconc.,
coag. disorders
renal perfusion , oliguria
shock
OHSS incidence

Non IVF:
mild
moderate
severe
8.0 -23%
0.005 -7%
0.008 -10%

IVF
mild
moderate
severe
100%
21- 44%
1- 10%
estimated mortality
1/45.000-1/500.000
:
estimated morbidity
0.1-0.5%
Predisposing factors for OHSS







previous OHSS
patients constitution: young (< 30); lean
PCO(D): hyperinsulinaemia; high E2 and rapid
increase;
multiple immature follicles
stimulation protocol: GnRHa + gonadotropins
hCG: ovulation trigger, luteal support, pregnancy
high number of oocytes retrieved
genetical or familial: mutated FSH-receptor
Pathogenesis of Severe OHSS
Kidney (JGA)
Prorenin
ovary
hCG (LH)
E2
renin
ace
PG
Angiotensin II
A-tensin I
A-
tensinogen
(liver)
histamin
inflam. cytokines
(IL-1,IL-6,TNF)
ANGIOGENESIS
VEGF(ovary)
IL-2 (FF)
Capillary permeability
fluid shift
Pathogenesis of severe OHSS:
‘Capillary Leakage Syndrome’
Vaso Active Component
Capillary permeability
ovaries
uterus
peritoneum
omentum
pleura
in:
Severe OHSS: Acute SHIFT of body fluids
Vascular compartiment
hypovolemia
hemoconcentration
3th space
ascites
ovarian volume
(cysts,
edema)
albumine loss
hydrothorax/hydropericard
hydro urether
anasarca
weight
general edema
albumine loss
electrolyte imbalance
PG’s
SHIFT to 3th space in severe OHSS
Ascites
ovarian vol.
(cysts+stroma edema)
abdominal dystension
dyspnea
nausea, vomiting
diarrhaea
venous return
abdominal pain
ovarian torsion
cyst rupture/bleeding
thorax
hydro
pericard
Vascular fluid loss in severe OHSS
hypotension
HYPOVOLEMIA
HEMOCONC
renal perfusion
blood viscosity
tachycardia
uremia
hyperkalemia
activation of RAAS
oligo / anuria
thrombosis
sodium reabsortion
shock
limb amp.
death
hct
coag. fact
Diagnosis of severe OHSS

clinic:

U/S:
X-ray:
lab:


distended abdomen, nausea, vomiting, diarrhea
dyspnea, weight gain, hypotension,
tachycardia
enlarged ovaries (>12 cm) + ascites
pleural effusion
Hct > 45%
total proteins/albumine
trombocytes
ureum/creatinine ; creat.clear.
electrolyte imbalance ( K , acidosis)
liver enzyms
-hCG
signals in severe and critical OHSS
severe
ovaries
ascites/hydrothorax
hct
WBC
oliguria
creatinin
creat. clearence
renal failure
liver disfunction
complications
>12 cm
massive
>45%
>15.000
yes
1.0 - 1.5
>50 ml/min
not yet
yes
anasarca
critical
> 12 cm
tense
>55%
>25.000
extreme
>1.6
<50 ml/min
yes
yes
thrombo-emb.
ARDS
Alarm signals
patient at risk
 abdominal pain and distension
 nausea, vomiting
 dyspnoe
 weight gain > 2 kg
 low urine production

complications of severe OHSS

Thrombo embolism
 limb
amputation
 Aorto-subclavian embolism
 CVA
ARDS
 ovarian torsion (dd ectopic)
 acute hydrothorax
 death

Is OHSS predictable?
in patients at risk
 single factors are not predictable
 best predictable combination (78.5% in 128 cases):

log E2 + slope of log E2 + hMG dose + n oocytes + LH/FSH
Severe OHSS: high risk groups












young lean patients (<30y)
previous OHSS
PCO-like ovarian architecture and endocrinology
hMG stimulation, specifically after GnRHa
high number of small follicles
high E2 levels (38% if E2>6000, 25% if E2 < 2500pg/ml)
n immature/ n mature follicles
high number of oocytes (23% if >30)
high E2 levels plus high number of oocytes (80%)
hCG trigger (ovulation, luteal phase, pregnancy)
serum or urine detection of VEGF?
Genetical/familial: FSH receptor mutant
Treatment of OHSS
No causal treatment
Prevention is the
most effective
treatment
Prevention of OHSS
before stimulation

identify patients at risk:
 previous
OHSS, familial, genetic
 PCO, young, lean
avoid GnRHa in patients at risk: use GnRH
antgonists or no down regulation
 Ovarian drilling (PCO patients )

Prevention of OHSS
during stimulation

identify patients at risk:





low dose gonadotropins, slow increase or COASTING
Close monitoring by E2 and U/S
avoid hCG in risk patients ( E2 > 3500 pg/ml; > foll.)






high E2 levels and increase
high ratio small follicles/mature follicles
as ovulation trigger (sp. LH, GnRHa, hCG dose , rec LH or hCG)
during luteal phase
avoid pregnancy: cancel cycle; cryopreservation of all embryos
Early unilateral follicle aspiration (EUFA) +/- IVM
Albumin or 6% hydroxyethyl starch (HAES)at OPU
glucocorticosteroids
Withholding hCG
for prevention of OHSS
in PCO patients
 OHSS in previous cycle
 E2 > 3500 pg/ml
 rapid E2 increase (slope)
 presence of >25 small follicles

Risk ea, Hum Reprod , 1991
hCG dose and oocyte recovery rate
dose
2.000 IU
5.000 IU
10.000 IU
recovery%
77.0
95.5
98.1
Abdalla ea, Fertil Steril, 1987
coasting
Definition: stop exogenous gonadotropins and postpone hCG
administration until E2 levels are ‘safer’
Meta-analysis: Delvigne e.a. 2002 : 493 pts in 11 studies:
conclusions:
- to heterogenous studies for comparison
- 16% ascites and 2.5 % hospitalisation
- impact of decreasing E2 on endometrium?
Coasting duration and outcome
duration
1 or 2
3 days
4 days
cycles
100 (48.2%)
49 (23.6%)
58 (28.2%)
IR : implantation rate; PR pregnancy rate
IR %
PR %
41.0
18.4
10.5
55.7
27.9
26.7
Ulug e.a. Hum Reprod 2002
Coasting in the prevention of severe OHSS
cochrane review
Review:
R.C.T. : 13 studies identified
1 met inclusion criteria
ODDS ratio + 95% CI
% of mod./severe OHSS (n = 30)
clinical PR
(n = 30)
0.76 (0.18 - 3.24)
0.75 (0.17 - 3.33)
D’Angelo e.a. Cochrane library 2003
Albumin vs placebo (at OPU) in severe
OHSS prevention: a Cochrane review
Review:
R.C.T. : 7 studies identified
5 met the inclusion criteria (378 pts)
Conclusion: clear benefit of IV Albumin in OHSS prevention
albumin
severe OHSS :
4/193 (2.1%)
placebo
14/185 (7.6%)
OR + 95 % CI
0.28(0.11 – 0.73)
Aboulghar e.a. Hum. Reprod 2003
GnRH agonists vs GnRH antogonists
and OHSS
GnRHa (long)
n= 85
OHSS
PR
PR pregnancy rate
cetrorelix
n= 188
P
6.5%
1.1%
0.03
26.0 %
22%
NS
Ludwig e.a. 2001 Gynecol/obstet
Embryo freesing for prevention of
OHSS: a cochrane review
Review: R.C.T up to juli 2001 : 17 studies identified
2 met the criteria
Interventions compared:
1. cryopreservation of all embryos vs IV albumin
2. freesing all embryos vs fresh embryo transfer
Conclusions:
1. insuff. evidence to support routine cryopreservation
2. insuff. evidence to determine the relative merits of albumin vs cryo
Does OHSS influence the pregnancy?

increased E2 levels and altered P4/E2 ratios may impair
endometrial receptivity

a higher incidence of trombophilia may induce abortions, pre
eclampsia and placental insufficient

high levels of LH may induce abortions

chronic hypoxia (pleural effusion) may induce abortion
OHSS and obstetric outcome
clinical PR
miscarriage rate
multips
premature delivery
cesarian section
low birth weight
hypertensive disorders
abruptio placentae
fetal malformations
%
73.0
29.8
57.0
44.0
44.0 (24.1 singleton)
62.1 (34.1 singleton)
13.2
40.4
1.9
Abramov e.a. hum reprod 1998 : 10 y study
Treatment of severe OHSS
1. IN hospital : bedrest
2. maintain plasma volume with:
(under CVP control)
Crystalloids (NaCL or ringers)
Albumin ( 50-100 ml/2-12 h)
3. maintain renal perfusion: NO diuretics (unless hemodilution)
Dopamin (4 mg/kg/day)
4. reduce capillary permeability:
?,anti- VEGF Antibodies?
indomethacin?, ACE-inhibitors
(captopril) ?, anti histaminic drugs
5. paracentesis of ascites ( reinfusion) /pleural effusions
6. Heparin : as prevention or treatment (only if thromboembolic problems)
7. surgery: only with ovarian tumor, rupture or ectopic
8. pregnancy interruption?
paracentesis in severe OHSS:
indications
need for symptomatic pain relief
 tense ascites
 oliguria with impaired renal function
 hemoconcentration unresponsive to
medical treatment

paracentesis :
treatment for severe OHSS
paracentesis
age
E2 (PG/ml)
days in hosp.
conventional
n = 11
n = 10
31.9
6.900
4
29.8
6.400
9
Aboulgar ea, Fertil Steril, 1990
severe OHSS: treatment
hemoconcentration/ascites
crystalloids
albumin
relative hemodilution
hct < 45%
crystalloids
albumin
lasix
tense ascites
hct >45%
WBC>25000
crystalloids
albumin
paracentesis
diuresis
impaired renal function
recovery
crystalloids
albumin
paracentesis
I.C.U. /dopamin
renal failure ARDS Thromb.
termination
heparin
Conclusions 1

severe OHSS is a serious, iatrogenic
complication of ovulation induction
with high morbidity and sometimes
mortality, mostly in young healthy
patients

The incidence is related to the
stimulation protocol, the underlying
fertility problem (PCO-like), the use of
hCG and the occurence of pregnancy
Conclusions 2

The underlying pathology is an acute
shift of body fluids from the vascular
compartiment to the 3th space.

Vaso active components (ovarian
renine-angiotensine system, histamine,
PG’s, PRL, inflammatory cytokines,
VEGF) will stimulate angiogenesis
under influence of LH (hCG) and E2 ,
and thus increase capillary
permeability.
Conclusions 3




Prevention is the best treatment.
Absolute prevention: no hCG or cycle cancellation
Relative prevention: coasting, albumin or HAES,
cryopreservation of all embryos, ovulation trigger by
lower hCG dose or GnRHa or rec-LH or rec-hCG.
The pilars of treatment are :bedrest, maintaining
plasma volume, reducing capillary permeability and
draining of ascites while surgery is only indicated in
case of torsion or ectopic.