Ovarian Hyperstimulation

Syndrome (OHSS)

Management in OI/IUI Cycles

Sandro Esteves, M.D., Ph.D.

Director, ANDROFERT

Andrology & Human Reproduction Clinic

Campinas, BRAZIL

ASPIRE III, Istanbul, September 2013

Esteves, 2

Know the Numbers

Aetiopathogenesis

Clinical Aspects

What is in it for me?

Esteves, 3

Review this Lecture at:

http://www.androfert.com.br/review

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OHSS: Management in

OI/IUI Cycles

Esteves, 4

Singleton live birth at term

Maximize Treatment

Beneficial Effects

Minimize Complications and Risks

Cycle Cancellation

Multiple Pregnancy OHSS

Esteves, 5

Incidence1: 3-6% moderate OHSS

~2% severe OHSS

OH

SS

1Aboulghar. Fertil Steril. 2012;97:523-6;

2Confidential Enquiry into Maternal and Child Health, 2007; 3ICMART

1.5 million cycles/year3

~500 deaths (last 10 years)

: 3/100,000 cycles2

Esteves, 6

Lower incidence; Mostly mild!!

OI/CC: 13.5% of mild forms1

IUI: 2-8% cycle cancellation2

Delvigne & Rozenberg Hum Reprod Update. 2003;9:77-96;

Cantineau et al., Cochrane Database Syst Rev. 2007; 18:CD005356

OH

SS

Having Difficulty

Conceiving

1Boivin J, et al. Hum Reprod 2007;6:1506; 2ObGyn Research 2003, EMD Serono; 3Domar AD. Fertil Steril 2004;81:271

Treated by

Infertility Specialist

20% stop treatment before finishing

clomiphene citrate (CC)2

23% complete CC and then stop2

45% never seek the doctor1 100

Treated by ObGyn

55

31 25-40% consult but never start

treatment2

60-65% drop out before completing

treatment3

20

8

Esteves, 8

Shift of Fluid from Intravascular to Third Space

hCG

Vascular Permeability

Intravascular Volume

Depletion and

Haemoconcentration

Extravascular Transudate

Accumulation

No direct vasoactive

activity

Vasoactive

Substances

VEGF

Aet

iop

ath

og

enes

is

Albert et al. Mol Hum Reprod. 2002;8:409; Chen et al. Hum Reprod. 2000;15:1037; Gómez et al. Endocrinology. 2002;143:4339

Esteves, 9

Va

sc

ula

r E

nd

oth

eli

al

Gro

wth

Fa

cto

r

1Yan et al, J Clin Endocrinol Metab 1993; 77:1723; 2Neulen et al, J Clin Endocrinol Metab

1995; 80:1967; ; 3Wang et al, J Clin Endocrinol Metab 2002; 87:3300; 4Pellicer et al, Fertil Steril 1999; 71:482;

Induces endothelial cell proliferation

Increases capillary permeability

VEGF and OHSS: • VEGF is expressed in human ovaries1

• VEGF mRNA expression increases in

granulosa cells after hCG administration2,3

• Elevated VEGF levels in serum, plasma, and

peritoneal fluids4

Esteves, 10

Early onset Late onset

Lyons CA et al., Hum Reprod 1994, 9:792.; Mathur RS, Fertil Steril 2000, 73:901;

Papanikolaou et al.,Hum Reprod. 2005; 20:636.

Clin

ica

l A

sp

ects

Exogenous hCG

administered for final

oocyte maturation

Endogenous hCG

produced by

implanting blastocyst

3–7 days after hCG 12 -17 days after hCG

Predicted by high number

of growing follicles and

elevated E2 levels

Predicted by number of

gestacional sacs

(multiple pregnancy)

Higher risk of preclinical

miscarriage

More likely to be

severe

Esteves, 11

Clin

ical A

sp

ects

Severity of symptoms, signs and

laboratory findings

Rabal et al., 1967

Schenker and Weinstein, 1978

Golan et al., 1989

Navot et al., 1992

Rizk & Aboughar, 1999

Esteves, 12

Abdominal distension/ discomfort

Mild nausea, vomiting

Diarrhea

Enlarged ovaries

No relevant

laboratorial

alteration

Lacking clinical

significance

Fiedler & Ezcurra. Reprod Biol Endocrinol 2012, 10:32

OH

SS

- C

lass

ific

atio

n

Similar to Mild +

Ascites

Hct >41%

WBC >15,000

Hypoproteinemia

Require careful

monitoring

Intractable nausea/vomiting

Severe dyspnea; Hydrothorax

Oliguria/anuria; Tense ascites

Low central venous pressure

Rapid weight gain; syncope

Severe abdominal pain

Venous thrombosis

Hct >55%; WBC >25,000

Creatinine >1.6

Creat. Clearance <50 mL/min

Hyponatremia: <135 mEq/L

Hyperpotassemia: >5 mEq/L

Elevated liver enzymes

Hospitalization;

Intensive care unit

Mild Moderate Severe

Esteves, 13

Papanikolaou et al.,Hum Reprod. 2005; ;20:636-41;

Humaidan et al., Fertil Steril. 2010; 94: 389-400.

Psychological burden

High cycle cancellation rates

Higher risk of miscarriage

Severe Cases May Get Even Worse

Acute renal failure

Arrhythmia

Thromboembolism

Pericardial effusion

Massive hydrothorax

Arterial thrombosis

Sepsis

Adult respiratory

distress syndrome Co

mp

licati

on

s

Esteves, 14

The TRUTH is

that OHSS must

be PREVENTED

rather than

treated

Esteves, 15

Identify patients at risk

Mild ovarian stimulation

Cycle cancellation

GnRH-agonist for LH trigger

Intravenous colloids

Dopamine agonist

Antagonist in the luteal phase

Primary Prevention

Secondary Prevention

OH

SS

Man

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Esteves, 16

Young patients

Low BMI

Polycystic ovaries

PCOS

Previous OHSS

Easily

Recognized

Fiedler & Ezcurra. Reprod Biol and Endocrinol 2012, 10:32;

Humaidan et al., Fertil Steril. 2010; 94:389-400.

BIOMARKERS of

Ovarian Response

Sensitive ovaries

OH

SS

Man

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Esteves, 17

The Rotterdam Consensus

Polycystic ovary:

Ultrasound showing ≥12 follicles (2-9 mm)

AND/OR ovarian volume >10 cm3

Polycystic Ovary Syndrome: 2 out of 3

Oligo‐ and/or anovulation

Clinical and/or biochemical hyperandrogenism

Polycystic Ovary

OHSS Risk: PCOS > isolated PCOS characteristics

Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group.

Hum Reprod. 2004; 19:41-7.; Humaidan et al., Fertil Steril. 2010; 94:389-400

OH

SS

Man

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Esteves, 18

Which are the Biomarkers?

●Hormonal Biomarkers: FSH, Clomiphene

citrate challenge test, Inhibin-B,

Anti-Mullerian Hormone (AMH);

●Functional Biomarkers:

Antral Follicle Count (AFC);

●Genetic Biomarkers: Single Nucleotide

Polymorphisms for FSH-R; LH/LH-R; E2-R;

AMH-R. OH

SS

Man

ag

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en

t

Esteves, 19 La Marca et, Hum Reprod 2009;24:2264; Fleming et al, Fertil Steril 2012;98:1097.

Dimeric glycoprotein; ~140KDa

Product of GCs of early follicles Pre-antral and small antral (≤4-8mm)

AM

H

Esteves, 20

AM

H

Inter-cycle

Intra-cycle

ICC: 0.89; 95% IC: 0.83–0.94

Max. Variation: 17.4% Max. Variation: 108%

ICC: 0.55; 95% IC: 0.39–0.71

Fanchin et al, Hum Reprod 2005;20:923

Hehenkamp et al. JCEM 2006;91:4057

Esteves, 21

AM

H

Fleming et al. RBM online 2013;26:130;

Rustamov et al. Hum Reprod. 2012; 27:3085; Nelson & La Marca. RBM online 2011;23:411;

Assays have different performances

DSL and Immunotech

Beckman-Couter generation II

Fully automated ELISA (to be released)

Lack of international standardization

and EQC

Sample instability

Collection in EDTA

Storage at room temperature (up to 40% increase)

No separation of serum from blood before postage

Shortcomings and Pitfalls

Esteves, 22 Broekmans et al. Fertil Steril, 2010; 94:1044-51; Scheffer et al. Hum Reprod 2003;18:700

Sum of antral follicles in both

ovaries by TVUS at early

follicular phase (D2-D4): 2-10 mm (mean diameter)

Greatest 2D-plane

AF

C

Reflect No. AF at a given

time that can be

stimulated by medication

Esteves, 23

Lee et al., Hum Reprod 2008, 23:160–167

Cut-off: 3.36 ng/mL Sensitivity : 90.5%

Specificity: 70% in IVF

AMH

Cut-off: 16 AF Sensitivity: 100%

Specificity: 93%

AF

C

AFC

Checa et al. Fertil Steril. 2010; 94:1105-7

Prediction of excessive response

in IUI with 75 IU/d rec-hFSH

Esteves, 24

Low dose step-up gonadotropin protocol

Starting dose: 37.5 – 75 IU

Adjustments according to ovarian response

Sengoku et al. Hum Reprod. 1999; 14:349-53; Cantineau et al., Cochrane Database Syst Rev.

2007; 18:CD005356., Humaidan et al., Fertil Steril. 2010; 94:389-400

Pen devices: Precise dose delivery

Adjustments by small increments

Self-administration

OH

SS

Man

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Esteves, 25

2 RCT (n= 297)

Low dose step-up in IUI

Cantineau et al., Cochrane Database Syst Rev. 2007; 18(2):CD005356

OHSS 13% 2.7% 5.52 (95% CI: 1.85 to 16.52)

Pregnancy 31.1% 28.2% 1.15 (95% CI: 0.69 to 1.92)

OH

SS

Man

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Esteves, 26

GnRH-agonist

rather than hCG for

LH trigger

Patient frustration

Waste of time and money

Risk ovulation and

intercourse Risk of multiple pregnancy

and late OHSS onset

Cantineau et al., Cochrane Database Syst Rev. 2007;18:CD005356;

Delvigne & Rozenberg Hum Reprod Update. 2003;9:77-96

OH

SS

Man

ag

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en

t

Esteves, 27

LH/FSH Unload

Which and How: Triptorelin 0.2 mg

Leuprolide acetate 1 mg

Buserelin 0.2-0.5 mg

Griesinger et al. Hum Reprod Update. 2006;12:159-68.

When: Same criterion of hCG

14 h

20 h

14 h

48 h

20 h

4 h GnRHa LH surge vs natural cycle

OH

SS

Man

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t

Risk for OHSS markedly reduced:

3% 0% to 2.6%

Esteves, 28

GnRH-agonist vs hCG: 11 RCT – 1,055 women

Fresh

autologous

cycles (8 RCT)

Live birth Pregnancy Moderate/

severe OHSS

OR 0.44

(0.29 - 0.68)

OR 0.45

(0.31 - 0.65)

OR 0.10,

(0.01 to 0.82)

Youssef et al. Cochrane Database Syst Rev. 2011

Chance of Pregnancy also reduced:

30% 12% to 22%

OH

SS

Man

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t

Esteves, 29

Aboulghar & Mansour. Hum Reprod Update 2003;9:275;

Humaidan et al. Fertil Steril 2012 ;97:529; Engmann & Benadiva Fertil Steril 2012;97:531

Modified Luteal Support in IVF:

hCG bolus OPU day (1,500 UI) or 3x 500 UI boluses;

recLH; intense progesterone + estradiol; combined

Risk Difference for Pregnancy:

18% (Before) vs 6% (After Modified LP Support)

IVF: luteal phase insufficiency

LH suppressed due to Estrogen

Man

ag

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en

t

Study N Trigger Luteal

support Findings

Romeu

1997 761

hCG

X

1.5 mg

Leuprolide

Acetate

(2 doses

12/12h)

1,000- 2,500

IU hCG D0,

D2, D4 luteal

phase

99% ovulation rate; Similar E2

and P4 levels, miscarriage rates

Pregnancy Rates

LA (27.3%) vs hCG (17.3%;

p=0.0007); No OHSS in LA group

Romeu et al. J Assist Reprod Genet. 1997; 14:518;

Pirard et al. Hum Reprod. 2005; 20:1798; Diaz et al. J Reprod Med. 2008; 53:33.

LH

Tri

gg

er

wit

h G

nR

Ha

in

IU

I

Esteves, 30

Pirard

2005 24

hCG

X

0.2 mg

Buserelin

0.1 mg

Buserelin

different

schemes

Higher P4 levels at D14 with

every day buserelin

Diaz,

2008 48

hCG

X

0.2 mg

Triptorelin

-----

Higher FSH and LH rise 24h after

triptorelin;

Higher P4 levels 48h after hCG,

albeit suboptimal

Esteves, 31

Primary Prevention:

Identify patients at risk

Mild ovarian stimulation

Cycle cancellation

GnRH-agonist for LH trigger

Secondary Prevention:

Intravenous colloids

Dopamine agonist

GnRH Antagonist

Man

ag

em

en

t

Esteves, 32 Youssef et al. Cochrane Database Syst Rev. 2011;16:CD001302.

IVF 20% Human

Albumin (50 mL)

6% Hydroxyethyl

starch (HES); 1L

No. Studies

(patients)

8 RCT

(n=1,660)

3 RCT

(n=487)

Severe OHSS OR: 0.67

(95% CI: 0.45-0.99)

OR: 0.12

(0.04-0.40)

CPR OR: 0.76

(0.48-1.21)

OR: 1.2

(0.49-2.95)

OI and IUI: Data Not Available Ho

w t

o A

vo

id O

HS

S

Increase oncotic pressure and reverse leakage of fluid

Bind mediators of ovarian origin

Esteves, 33

Youssef et al., Hum Reprod Update. 2010;16:459-66;

Tang et al. Cochrane Database Syst Rev. 2012; 15;2:CD008605.

IVF Youssef, 2010

4 RCT (n=570)

Tang, 2010

2 RCT (n=230)

OHSS OR = 0.41

(95% CI: 0.25-0.66)

OR 0.40

(95% CI: 0.20-0.77)

Severe

OHSS

OR 0.50

(0.20-1.26)

OR 0.77

(0.24-2.45)

CPR OR 1.07

(0.70-1.62)

OR 0.94

(0.56-.59)

Miscarriage

Rate

OR 0.31

(0.03-3.07)

OR 0.31

(0.03-3.07)

Ho

w t

o A

vo

id O

HS

S

Decrease incidence of early-onset OHSS

Esteves, 34

Cabergoline, Quinagolide, Bromocriptine dopamine agonists

Basu et al. Nat Med 2001;7:569–74; Gomez et al. Endocrinology 2006; 147:5400–11.;

Soares. Fertil Steril. 2012; 97:517-22.

Ho

w t

o A

vo

id O

HS

S

In vitro studies:

Activation of dopamine receptor-2 (Dpr2) promote

internalization of VEGFR-2 (become

unreachable for VEGF);

Cabergoline in rats:

Phosphorylation of VEGFR-2 reduced by 42%;

Inhibition of VEGF production in cultured granulosa cells

exposed to hCG.

Esteves, 35

Most effective regimen: 0.5 mg daily for 8 days

Start on the day of hCG

administration;

Ideally a few hours before hCG is

given

Soares. Fertil Steril. 2012; 97(3):517-22.

Ho

w t

o A

vo

id O

HS

S

No major complications

Esteves, 36

1Minaretzis et al. J Clin Endocrinol Metab. 1995;80:430; 2Fridén & Nilsson. Acta Obstet Gynecol Scand.

2005;84:812; 3Asimakopoulos et al. Fertil Steril. 2006;86:636; 4Taylor et al. J Endocrinol. 2004;183:1; 5Lainas et al. Reprod Biol Endocrinol. 2012;10:69; 6Lainas et al. Hum Reprod. 2013; April 26.

Ho

w t

o A

vo

id O

HS

S

Supress endogenous LH secretion (luteolytic effect)

Decrease vasoactive cytokines producted by corpus luteum1

Direct effect on the ovary reducing VEGF production2,3,4

Lainas et al., 20125

40 pts.; early-onset severe OHSS

Ganirelix (0.25 mg) daily from

D5-D8 after oocyte retrieval +

embryo freezing

NO HOSPITALIZATION;

Rapid resolution of OHSS

Lainas et al., 20136

22 pts.; early-onset severe OHSS

Ganirelix (0.25 mg) daily from D5-D7

after OPU + embryo transfer; 172

controls at risk of OHSS

NO HOSPITALIZATION;

Rapid resolution of OHSS;

No late-onset OHSS;

LBR: 41% (Antag.) vs 43% (controls)

Esteves, 37

OHSS has a dramatic psychological effect

in patients’ life; those who suffer from it

are unwilling to continue treatment.

OHSS must be PREVENTED rather than

treated.

Improving patients’ welfare starts at

identifying who are at risk for OHSS, and

continues by individualization of the

ovulation induction protocol. Key M

es

sag

es

OHSS: Management in

OI/IUI Cycles

Esteves, 38

Improving patients’ welfare starts at

identifying who are at risk for OHSS, and

continues by individualization of the

ovulation induction protocol.

Key M

es

sag

es

GnRH-agonists LH trigger virtually

eliminates OHSS; luteal phase support

is required.

OHSS: Management in

OI/IUI Cycles

Esteves, 39

Secondary prevention by albumin, HES

and carbegoline are useful but not fully

eliminate the risk.

GnRH Antagonists during luteal phase

holds promise to treat OHSS in early

stages.

Key M

es

sag

es

OHSS: Management in

OI/IUI Cycles