Techniques to avoid OHSS and staying out of danger Midwest Reproductive Symposium - Nurse Practicum...
-
Upload
merryl-robinson -
Category
Documents
-
view
219 -
download
0
Transcript of Techniques to avoid OHSS and staying out of danger Midwest Reproductive Symposium - Nurse Practicum...
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
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