Techniques to avoid OHSS and staying out of danger Midwest Reproductive Symposium - Nurse Practicum Workshop Chicago, USA June 19-21, 2014

20

Frank J BroekmansProfessor Reproductive MedicineUniversity Medical Center Utrecht, The Netherlands 30

Learning Objectives

Understand the pathofysiology of and risk factors of the OHSS

Understand the approach of primary prevention: avoid excessive response and/or hCG

Understand the approach in secondary prevention: avoid pregnancy

Have knowledge on treatment of the OHSS:

avoid hemoconcentration

Answer to Take Home

…the ovaries…

can explode…

OS and the High Responder

1. Ovarian Physiology

2. OS Backgrounds

3. OS Predicted High Responders

4. OS Actual High Responders

5. OHSS secondary prevention

6. Conclusions and take homers

Agenda

Folliculogenesis

Pro

po

rtio

n o

f p

oo

r q

uali

ty

oo

cyte

s(%)

102

103

104

105

106

Nu

mb

er

of

follic

les

107

0 10 20 30 40 50 60

50

75

100

25

Age (years)

Optimalfertility Declining

fertility End of fertility

Irregularcycles

Number of follicles

Proportion of poor quality oocytes

Menopause

Ovarian Ageing: The Young Ones

Redrawn after de Bruijn, te Velde. In: Preservation of fertility. London, Taylor & Francis, 2004:3.

PCO Syndrome – The Too Many

Let’s keep it simple:

Too many antral follicles

• Arrested follicle growth

• Too much androgens

• Too much AMH

Ovarian Response to COS

It is the cohortNot the FSH

And the

size may vary…

The OHSS: two components

The hCG

The Response

OS and the High Responder

1. Ovarian Physiology

2. OS Backgrounds

3. OS Predicted High Responders

4. OS Actual High Responders

5. OHSS secondary prevention

6. Conclusions and take homers

Agenda

Ovarian Hyperstimulation for IVFMany Muchas Multo Beaucoup Veel

Live Birth Rates: Response and Age

SunkaraHFEAN=400.000HR 2011

Looking at embryo quality using FISH, it appears that milder stimulation leaves the poorer oocytes in the ovaries…

Baart, HR 2007

OPR Mild versus Conventional:No difference

Baart 2007Hohman 2003

Quantity and Quality

Ovarian Response to COS

It is the cohortand 7 – 15 oocytes is sufficient/optimal

4

8

10

12

14

16

6100 IU 150 IU

Oo

cyte

Nu

mb

er

Pooled RCTs

150-200 IU 200-250 IU

3.6

1,3

There is a dose response range, but narrow…

Sterrenburg, HRU 2010

No difference in Clinical pregnancy rates

Message

In predicted high responders: be modest with the FSH dosage

OS and the High Responder

1. Ovarian Physiology

2. OS Backgrounds

3. OS Predicted High Responders

4. OS Actual High Responders

5. OHSS secondary prevention

6. Conclusions and take homers

Agenda

Risk Factors

• young age

• low body weight

• polycystic ovary syndrome (PCOS)

• higher doses of exogenous gonadotropins

• high absolute or rapidly rising serum E2 levels

• previous episodes of OHSS

Start with the End in mind…. Covey, The Seven Habits of Highly Effective People, 1989

Milestones in ART efficiency

• Ovarian Hyperstimulation

• LH peak prevention GnRH agonist

• TVS guided aspiration

• ICSI

• Cryopreservation embryo’s

• Personalisation…

• Oocyte vitrification..

Live birth rate and oocyte yield

0

5

10

15

20

25

30

35

1 3 5 7 9 11 13 15 17 19 21 23 25

Oocyte number

LB

R

OPR ↓

Discomfort ↑OHSS Risks ↑OPR ↓

Optimal

Balance…of hyperstimulation response

PredictionAnd Management

vd Gaast RBM 2008

6-10 mm

2-5 mm

0,1-2 mm

Primordial pool

Primary follicles

Pre-antral follicles

Circulating AMH

?

Broekmans, ER 2009Broer, COOG 2010

AFC

Ovarian Reserve tests

Prediction Excessive OR (> 15 oocytes)

The EXPORT - IPD study N= 5800 Broer, submittedAUC age: 0.61 (0.58-0.64)AUC age+AFC: 0.75 (0.71-0.79)AUC age+AMH: 0.81 (0.77-0.85)AUC AMH: 0.82 (0.77-0.86)AUC AMH+AFC: 0.85 (0.80-0.90)

AUC age+AMH+AFC+FSH: 0.85 (080-0.90)

Cut off levels

AMH: 2.5 pg/lAFC(2-10): 16 fo

Mol, Bossuyt Eijkemans, Dolleman, Broer, IMPORT study group, HRU 2012

Summary Current literature on High Response Prediction in Antagonist cycles

It seems as good as…

Agonist, Broer, HRU 2012

AFC and AMH based predictions in ANTA cycles

ROC curve with Area Under the Curve (AUC) = Accuracy

ROC Curve

1 - Specificity

1,00,75,50,250,00

Sensiti

vity

1,00

,75

,50

,25

0,00

0.90

PredictingWith false negatives and positives

PersonalisingOnly stimulate a part of the sensitive follicles?

• Yes: an individual stimulation dose, based on a model with age, AFC, basal FSH and BMI suggests that reduced dosage mitigates response without effects on pregnancy rates (n=161)

(wait for RCT, CONSORT) Olivennes, RBM 2009

• Yes: in a pseudorandomised comparison, antagonist protocols, in cases with AMH levels over 15 pMol/l, resulted in lower oocyte numbers, less OHSS and comparable pregnancy rates

Nelson HR 2009

Prediction of excessive response Individualize dose of FSH?

Predicted Excessive responders: antagonist with standard dose ??

Nelson, 2009, non randomised

Has the oocyte number distribution shifted to the left??

N=350

Sterrenburg,

unpublished data

The OPTIMIST trialOPTIMisation of cost effectiveness through Individualised FSH Stimulation dosages for IVF Treatment: a randomised trial. Dutch RM consortium

N=300

N=300

N=300

18 months treatment approach

Live birth rate with GnRH agonist 31.5% (95% CI 24.3, 39.7)with GnRH antagonist 30% (95% CI 20.9, 34.1)Difference: -1.5% (95% CI -22.9, 5.9). RR: 0.89 (95% CI 0.76, 1.04)

OPR with GnRH agonist 29.8% (95% CI 25.4, 34.6)with GnRH antagonist 27.8% (95% CI 22.9, 31.2)Difference -2.0% (95% CI -20.4, 4.5). RR: 0.91 (95% CI 0.83, 0.99).

OHSS ratewith GnRH agonist 6.4% (95% CI 4.3, 9.2)with GnRH antagonist 3.7% (95% CI 2.6, 6.4)Difference -2.7% (95% CI -0.9, -4.5). RR: 0.50 (95% CI 0.37, 0.66).

Antagonist stimulation: safer anyway??

OS and the High Responder

1. Ovarian Physiology

2. OS Backgrounds

3. OS Predicted High Responders

4. OS Actual High Responders

5. OHSS secondary prevention

6. Conclusions and take homers

Agenda

Actual High Responder

• In Agonist, use the Antagonist next time

• Reduce FSH dose next time

• Accept a “poorer” response

Actual High Responder

Avoid hCG exposure..injection or pregnancy

In Ago and Anta cycles•Cancellation (all guidelines)

– More than 25 follicles over 12 mm

– E2 levels over 16.000 pMol/l•Reduced dosage of hCG: no final evidence (Tsoumpou, RBM 2009,Lin, EJOGE 2011)

•Freeze all: effective prevention, no jeopardy for live birth rates (D’Angelo, Cochr 2007)

Actual High Responder

Avoid hCG exposure..injection or pregnancy

In Anta cycles only•GnRH agonist triggering: prevents OHSS, needs adjusted Luteal Support (Humaidan, HRU 2011)

OHSS rate

Actual High Responder

Ongoing preg rates

Delivery rates

Humaidan, HRU 2012

Agonist triggering

FSH

Antagonist

GnRH agonist trigger

Day 0 Day 1 Day 2 Day 3

Oocyte Pick Up

1500 IU hCG

Progesterone(/Estradiol)

Luteal Support after agonist triggering

OS and the High Responder

1. Ovarian Physiology

2. OS Backgrounds

3. OS Predicted High Responders

4. OS Actual High Responders

5. OHSS secondary prevention

6. Conclusions and take homers

Agenda

Symptoms

• transient lower abdominal discomfort

• nausea

• vomiting

• diarrhea

• abdominal distention

• rapid weight gain• tense ascites• hemodynamic

instability (orthostatic hypotension)

• respiratory difficulty• progressive oliguria• laboratory

abnormalities

First seek to understand…. Covey, The Seven Habits of Highly Effective People, 1989

Complications

• Thromboembolism, venous AND arterial• Hemorrhage from ovarian rupture

• Renal failure• Adult respiratory distress syndrome (ARDS)

• Multiple Organ Failure• Death

Be proactive….Covey, The Seven Habits of Highly Effective People, 1989

1. The supra-physiological levels of endogeneous estradiol levels result in a “prothrombotic state” in predisposed individuals. 2. The development of OHSS, is not a pre-requisite to the development of thrombosis

Literature cases of arterial and venous thrombosis: 72Died:

5

All had received hCG…3 had “early” OHSS..

OHSS in IVF - Secondary Prevention

• Withhold hCG

• Reduced dosage hCG

• Coasting

• GnAgonist trigger

• Iv Albumen

• Cabergoline

• Freeze all

FS, 2012

HR, 2010

Reduce Risk OR Eliminate??

Withhold hCG

Avoid hCG exposure..injection or pregnancy

In Ago and Anta cycles•Cancellation (all guidelines)

– More than 25 follicles over 12 mm

– E2 levels over 16.000 pMol/l

The majority of studies concluded that the clinical outcomes were similar between women receiving 5000 or 10,000 IU of u-HCG. The

incidence of OHSS was not reduced in the high-risk population even with lower dose of u-HCG

Symposium: Update on prediction and management of OHSS. Optimal dose of HCG for final oocyte maturation in IVF cycles: absence of evidence?Tsoumpou, 2009, RBM online

Reduced dosage hCG

Coasting

D’Angelo, COCHR 2011Coasting works but pregnancy rates may be under pressure…

GnRH-Agonist trigger

Clear reducing effect on OHSS, but: OPR under pressure Youssef, COCHR 2011

Avoid hCG exposure..injection or pregnancyIn Anta cycles only

GnRH agonist triggering: needs adjusted Luteal Support (Humaidan, HRU 2011)

Agonist Triggering

Agonist Triggering

Ongoing preg rates

Delivery rates

Humaidan, HRU 2012

Agonist triggeringWith LS adjustment

FSH

Antagonist

GnRH agonist trigger

Day 0 Day 1 Day 2 Day 3

Oocyte Pick Up

1500 IU hCG

Progesterone/Estradiol

Luteal Support after agonist triggering

?

?

Agonist Induced LH peak

hCG peak10.000 IU

days0 1 2 3 4

hCG peak 1500 IU

Although the Humaidan protocol decreases the risk of severe OHSS, it can still occur: 5 out of 23 high risk patients

Agonist Triggering

IntraVenous Albumen or HESAt time of Foll Aspiration

It works…but may affect pregnancy ratesYoussef, COCHR 2011 Jee GOI 2010

Cabergoline

Cabergoline 0.5 mg/day orally for 7 days

starting from the day of agonist trigger affects the VEGF receptor, so biological plausible, but may only prevent the small problemTang, COCHR 2012

Freeze all

The OHSS rate

The Live Birth rate

It works without effect on Pregnancy ratesD’Angelo COCHR 2007

The Prevention of the OHSS

ELIMINATE..?? Or REDUCE..??

Cancel

Versus

Ago trigger and Freeze all

Risk of ovarian hyperstimulation syndrome (OHSS)

Estimate of death due to OHSS in stimulated cycles: 1:400,000–1:500,0002,3

1. Andersen et al. Hum Reprod 2008;23:756 2. Brinsden et al. Br J Obstet Gynaecol 1995;102:767 3. Balen 2005 Available at www.hfea.gov.uk. Accessed 23 July 2008

OHSS stages

OHSS stages

OHSS stages

OHSS stages

Criteria for hospitalizationHaemoconcentration > 45%Any sign of severe OHSS

Maintain diuresisIntravenous administration of Ringer Lactate solutionPlasma expandersAlbumin administration (Once hypo-albuminemia is proven)

AnticoagulantsHeparin therapy (5,000 U SC, every 12 hours)

Ascites drainage Patient discomfort is important or when biological anomalies are not corrected

Transfer to ICU If threatening (multiple) organ failure.

Once moderate to severe OHSS

ESHRE ASRMlocal guidelines

OS and the High Responder

1. Ovarian Physiology

2. OS Backgrounds

3. OS Predicted High Responders

4. OS Actual High Responders

5. OHSS secondary prevention

6. Conclusions and take homers

Agenda

Advice to Take Home

…do not let the ovaries…

explode…

Advice to Take Home

In predicted or actual HIGH responders:

•Reduce FSH dosage OR apply Antagonist system

•Use dosages in the range 100-150

•Be better safe than sorry: cancellation, agonist trigger, freeze all, surveillance

Frank BroekmansProfessorReproductive Medicine and SurgeryUniversity Medical Centre UtrechtThe Netherlands

Simone Broer Jeroen van DisseldorpMonique SterrenburgMarieke VerbergDave HendriksEllen KlinkertIlse van RooijLaszlo BancsiKim Broeze (AMC)Brent Opmeer (AMC)Madeleine Dolleman Bart FauserNick Macklon (Southampton)

Ben W Mol (AMC)Nils Lambalk (VUMC)

Thank You the IMPORT* studygroup Richard A. AndersonMahnaz Ashrafi László Bancsi, Ettore Caroppo, Alan B. Copperman, Thomas Ebner, Talia Eldar-Geva,Mehmet Erdem, Ellen M. Greenblatt, Kannamannadiar. Jayaprakasan, Nick Raine-Fenning,Ellen Klinkert, Janet Kwee, Antonio La Marca, MyvanwyMcIlveen, Luis T. Merce, Shanthi Muttukrishna, Scott M. Nelson, Ernest H.Y. Ng, Biljana Popovic Todorovic, Jesper M.J. Smeenk, Candido TomásPaul J.Q. Van der Linden,K.Vladimirov, Patrick Bossuyt