ovarian hyperstimulation syndrome
TRANSCRIPT
Ovarian Hyperstimulation Ovarian Hyperstimulation SyndromeSyndrome
How to PreventHow to Prevent
What is itWhat is it
It is an iatrogenic conditionIt is an iatrogenic condition
Induced by the clinicianInduced by the clinician
Exact Pathogenesis is not clearExact Pathogenesis is not clear
High E2 is the underlying factorHigh E2 is the underlying factor
SeveritySeverity
In its severest forms, it is complicated by
hemoconcentration, venous thrombosis, electrolyte imbalance and renal and hepatic failure
StudyStudyMildMildModerateModerateSevereSevere
Rabau Rabau et et alal. (1967). (1967)
grade 1:grade 1: estrogen > 150 estrogen > 150
g andg and
grade 2grade 2: + : + enlarged ovariesenlarged ovaries
grade 3grade 3: grade : grade 2 + palpable 2 + palpable
cystscysts
grade 4grade 4:: grade grade 3 + vomiting3 + vomiting
grade 5grade 5: grade 4: grade 4 + +
AscitesAscites
grade 6grade 6:: grade 5 + grade 5 + changes in blood changes in blood
VolumeVolume
Golan et al. Golan et al. (1989)(1989)
grade 1grade 1:: distension and distension and
discomfortdiscomfort
grade 2grade 2:: grade 1 grade 1 + nausea, + nausea, vomiting, vomiting,
enlarged ovariesenlarged ovaries
grade 3grade 3:: grade 2 + grade 2 +
US US evidence of evidence of
ascitesascites
grade 4grade 4:: grade 3 + grade 3 + clinical evidence of clinical evidence of
ascites and/or ascites and/or breathing difficultiesbreathing difficulties
grade 5grade 5:: grade 4 + grade 4 + haemoconcentrationhaemoconcentration , ,
Classification of OHSS
Mild form of ovarian Mild form of ovarian hyperstimulation is hyperstimulation is almost always with almost always with ovulation inductionovulation induction
Life ThreatiningLife Threatining
Severe OHSS is a serious complication of ovulation induction
How to preventHow to prevent
Steps before stimulationSteps before stimulation
Steps during stimulationSteps during stimulation
Steps on impending severe OHSSSteps on impending severe OHSS
Steps before stimulationSteps before stimulation
Identifying the patients at risk before ovulation
PCOD patients
History of previous severe OHSS
Before stimulationBefore stimulation
After StimulationAfter Stimulation
Steps during StimulationSteps during Stimulation
Be aware of Large number of developing follicles (more than 20)
Be aware of High E2 level (more than 3000) on approaching day of hCG
If any or both, then what to do!!!!!
Steps during StimulationSteps during Stimulation
Gonadotrophin dose according to age and Gonadotrophin dose according to age and body weightbody weight
Young age <25 ys : 2 ampYoung age <25 ys : 2 amp
Thin woman < 60 kg 2 ampThin woman < 60 kg 2 amp
Low Gonadotropin doses
Starting with 150 IU for all patients at risk is
recommended
Type of gonadotropins: urinary vs recombinant
No significant difference in the occurrence of OHSS
Stop hMG and continue down regulation.
This is the only complete prevention. (Aboulghar and Mansour, 2003)
Not a preferred choice
for both doctors or patients
Active Steps
Cryopreservation of EmbryosCryopreservation of Embryos
Is not a guarantee Is not a guarantee against developing against developing severe OHSSsevere OHSS
Still occurs in oocyte Still occurs in oocyte donorsdonors
Risk of embryo Risk of embryo degeneration on degeneration on ThawingThawing
Not a preferred choiceNot a preferred choice
Coasting
withholding gonadotropins for few days before giving hCG until E2 drops to a safer level (below 3000)
Available evidence suggests that such “coasting” does not adversely affect outcome in IVF cycles unless it is prolonged (>2 days)
Mature follicles can survive for a few days
without exogenous FSH/hMG while small
follicles will undergo apoptosis / necrosis 33
Coasting diminishes the granulosa cell cohort
In the absence of gonadotropin stimulation, dominant follicles will In the absence of gonadotropin stimulation, dominant follicles will continue their growth, while intermediate and small ones will undergo continue their growth, while intermediate and small ones will undergo
atresiaatresia..
E2
• The granulosa cells aspirated from coasted patients showed a ratio in favor of apoptosis, especially in smaller follicles.
• VEGF protein secretion and gene expression in granulosa cells especially in small and medium follicles were reduced in coasting 24
What happens when you start What happens when you start coastingcoasting??
Follicular growth will continue with the Follicular growth will continue with the same rate.same rate.
E2 will continue to rise then will platform E2 will continue to rise then will platform and then decline.and then decline.
Clinical and practical Tips
The Egyptian IVF-ET Center Experience
1. When to stop gonadotropins?
• When the leading follicles reach 16mm
2. how many days?
• Till the E2 drops to < 3000 pg/ml Fluker et al., 2000; Ohata et al., 2000)
The number of days of coasting
IS NOT the key issue
The focus should be on the E2 level
We should wait until it drops to 3000 pg/mL
Dose of hCG?5000 IU is enough
Special laboratory aspects?Extra time to identify the oocytes from the follicular fluid
TheThe Egyptian IVF-ET CenterEgyptian IVF-ET Center(May 2001 – May 2003)(May 2001 – May 2003)
No. of CyclesNo. of Cycles 49694969
No. of CoastingNo. of Coasting 560560
Mean EMean E22 on hCG day on hCG day 37423742 ++ 10741074
Days of CoastingDays of Coasting22 – – 66
No. of OocytesNo. of Oocytes1818 ++ 77
No. of Cancelled ET No. of Cancelled ET (cryopreservation of all (cryopreservation of all embryos)embryos)
33
OHSSOHSS(%) (%) 66) ) 1.21.2 per 1000per 1000((Clinical PregnancyClinical Pregnancy(%) (%) 265265) ) 47.32%47.32%((
Problems with coastingProblems with coasting
Occasionally E2 drops markedly to very Occasionally E2 drops markedly to very low levels and cycle is canceled.low levels and cycle is canceled.
Difficulty in identification of oocytes in Difficulty in identification of oocytes in aspirated follicular fluid after prolonged aspirated follicular fluid after prolonged coasting.coasting.
HoweverHowever
Pregnancy rates appear to decrease while Pregnancy rates appear to decrease while coasting during prolonged gonadotropin-coasting during prolonged gonadotropin-free periods (Ulug et al, 2004)free periods (Ulug et al, 2004)
WhyWhy
perhaps because perhaps because suspending gonadotropins suspending gonadotropins may starve the granulosa may starve the granulosa cells at a critical time of cells at a critical time of oocyte development when oocyte development when LH is necessaryLH is necessary
The role of GnRH antagonist
in the prevention of
OHSS
GnRH antagonist
In a Cochrane review by Al-Inany et al (2006)
comparing agonist and antagonist, significant
difference in the incidence of OHSS was found
))GnRHGnRH ( (antagonistsantagonists
A unique IdeaA unique Idea
Administration when follicle reach 16 mmAdministration when follicle reach 16 mm
Continue hMG (step down protocol)Continue hMG (step down protocol)
Monitor by E2Monitor by E2
Not more than 3 daysNot more than 3 days
ValueValue
allow continued stimulation while rapidly allow continued stimulation while rapidly decreasing the E2 level to a range that is decreasing the E2 level to a range that is clinically acceptable. clinically acceptable.
serum E2 decreased by 49.5% and 41.0% serum E2 decreased by 49.5% and 41.0% of pretreatment values (long luteal and of pretreatment values (long luteal and microdose flare, respectively) after microdose flare, respectively) after initiation of ganirelix, and 68.1% of the initiation of ganirelix, and 68.1% of the patients became pregnant. ( Gustofson , patients became pregnant. ( Gustofson , 2006)2006)
GnRH antagonist vs GnRH agonist
In patients at high risk of OHSS
Multicenter prospective comparative study Ragni et al., 2005
Hum Reprod
GnRHGnRH
agonistagonist
GnRHGnRH
antagonistantagonist
cyclescycles
cancelled cyclescancelled cycles
severe OHSSsevere OHSS
EE22 on day of hCG on day of hCG
pregnancy (%) per pregnancy (%) per ETET
8787
4949) ) 56.3%56.3%((
66
43224322
8787
2828) ) 32.2%32.2%((
11
25382538
1818) ) 31.6%31.6%((
P<0.001P<0.001
P=0.006P=0.006
P<0.001P<0.001
MetforminMetformin
positively modulates positively modulates the reproductive axis the reproductive axis (namely GnRH-LH (namely GnRH-LH episodic release) episodic release) (Genazzani et al, (Genazzani et al, 2004). 2004).
EvidenceEvidence
E2 was significantly E2 was significantly higher in cycles higher in cycles treated with FSH treated with FSH alonealone
than in those treated than in those treated with FSH and with FSH and metformin. (De Leo et metformin. (De Leo et al, 1999). al, 1999).
Metformin & OHSSMetformin & OHSS
Metformin was found to Metformin was found to decrease significantly decrease significantly the incidence of severe the incidence of severe OHSS (ESHRE award, OHSS (ESHRE award, 2005)2005)
It is now our routine to give metformin with It is now our routine to give metformin with the start of down regulation till the day of the start of down regulation till the day of hCGhCG
possible Mechanismspossible Mechanisms
lower intraovarian lower intraovarian androgen levels. androgen levels. (Visnova et al; (Visnova et al; 2003). 2003).
Improves Improves endothelial function. endothelial function. (J.De Jager et al; (J.De Jager et al; 2005, Orio et al; 2005, Orio et al; 2005). 2005).
The use of metformin for
women with PCOSProspective randomized placebo-controlled double-blind study
Tang et al., 2006Hum Reprod
MetforminMetformin
GroupGroup
controlcontrol
GroupGroup
PatientsPatients
Mean total FSHMean total FSH
Occytes retrievalOccytes retrieval
Fertilization rateFertilization rate
Clinical PR per ETClinical PR per ET
Clinical PR>12 weeksClinical PR>12 weeks
Severe OHSSSevere OHSS
5252
12001200 uu
17.217.2
52.9%52.9%
44.4%44.4%
38.5%38.5%
3.8%3.8%
4949
13001300 uu
16.216.2
54.9%54.9%
19%19%
16.3%16.3%
20.4%20.4%
P=0.022P=0.022
P=0.023P=0.023
P=023P=023
A systematic review and meta-analysis of randomized controlled trials on metformin co-administration during gonadotropins ovulation induction in PCOS patients
Significant reduction in OHSS
(OR=0.21; 95% CI = 0.11-0.41 P<0.00001)
Does not significantly improve the pregnancy rate
Costello et al., 2006
Hum Reprod
Luteal supportLuteal support
Avoid hCG Avoid hCG
Progesterone onlyProgesterone only
Close observationClose observation
.).)
OHSS is a preventable diseaseOHSS is a preventable disease
What if it HappensWhat if it Happens
How to ManageHow to Manage
Always rememberAlways remember
Investigations Investigations – HaematocriteHaematocrite– Liver functionsLiver functions– CreatinineCreatinine
Fluid monitoringFluid monitoring
Always rememberAlways remember
ICU JobICU Job
May do paracentesis : May do paracentesis :
if dyspnoeaif dyspnoea
massive ascitis (>3 liters)massive ascitis (>3 liters)
HydrothoraxHydrothorax