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