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Mila Cervar-Zivkovic
2014
Screening for Preeclampsia
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• early diagnosis of fetal anomalies
• early diagnosis of pregnancy-associated
diseases
Mila Cervar-Zivkovic
2014
1st Trimester-Screening
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Multivariable risk algorithm for 1st
trimester screening
• IUGR
• early onset preeclampsia
• late onset preeclampsia
• preterm delivery
• fetal anomalies
Mila Cervar-Zivkovic
2014
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Multivariable risk algorithm for
1st trimester, cutoffs
• IUGR 1:150
• early onset
preeclampsia 1:200
• fetal chromosomal
anomalies 1:300
Mila Cervar-Zivkovic
2014
• IUGR 55%
• early onset
preeclampsia 95 %
• fetal chromosomal
anomalies 95 %
Cutoffs Detection rate
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Maternal data included in multivariable
risk algorithm for 1st trimester screening
• chronic hypertension
• history of preeclampsia, IUGR, preterm
delivery
• associated diseases (diabetes, immunological,
renal, thrombophilia)
Mila Cervar-Zivkovic
2014
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Biophysical measurements included in
multivariable risk algorithm for 1st trimester
• blood pressure
• Doppler measurements of uterine arteries
• cervical length
• fetal 1st trimester sonography
Mila Cervar-Zivkovic
2014
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1st Trimester Prediction of early onset pre-eclampsia, multivariable risk algorithm:
maternal factors, biophysical and biochemical markers (PAPP-A, PlGF)
2nd Trimester
Prediction for adverse
pregnancy outcome:
sFlt-1/PlGF, prediction
time 4-5 weeks before
onset of disease
Screening for Preeclampsia
Mila Cervar-Zivkovic
2014
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Biochemical parameters included in
multivariable risk algorithm for 1st trimester
Mila Cervar-Zivkovic
2014
0
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0 2 4 6 8
PAPP-A (MoM)
0
0,2
0,4
0,6
0,8
1
1,2
0 1 2 3
PLGF (MoM)
0
0,05
0,1
0,15
0,2
0,25
0,3
0,35
0,4
0,45
0 5 10 15
ß-hCG (MoM)
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?• < 34. SSW• severeearly onset
• > 34. SSW• mildlate onset
Ätiologie
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anchoring villus
cell column
basal plate
spiral artery
decidua
syncytio-trophoblast
proliferative trophoblast
ETAETB
ETB
invasivetrophoblast
ET-1 im 1. Trimestar
JCEM, Aug. 2011ET-1 in early third trimester
placenta
0
2
4
6
8
10
12
Controls FGR PE PE + FGR
fold
ch
ang
e
-6-5-4-3-2-10123
fold
cha
nge
ET-1 in late third trimesterplacenta
Life Sci, 2011
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HealthyPräeklampsie
IUGR
De
zid
ua
My
om
etr
ium
I Trimester Termin I Trimester Termin
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Nelson DM, Walsh SW
AJOG 1987
TXA2 PGI2
Aspirin (100 mg)
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N %
Screened for preeclampsia 231
Pathologic uterine artery doppler (>2,35) 40 20
Positive medical history for preeclampsia 40 20
High risk for early-onset preeclampsia 21 10
High risk for late-onset preeclampsia 73 36
Women post partum 161
Onset of preeclampsia 2 1
1st trimester screening
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Mila Cervar-Zivkovic
2014
Effect of Aspirin Use After positive First Trimester
Screening on the Onset of Preeclampsia
I. Lakovschek, B. Csapo, V. Kolovetsiou-Kreiner, K. Mayer-
Pickel, C. Stern, D. Ulrich, U. Lang, M. Cervar-Zivkovic
1st Trimester Screening
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Placenta associated adverse pregnancy
outcome
Biomarkers
• PlGF
• sFLT-1
Mila Cervar-Zivkovic
2014
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Healthy Endothelium Dysfunction
PlGF & sFlt-1
PlGF PlGF
PlGF PlGFCell
membrane
Cell
membrane
Mila Cervar-Zivkovic
2014
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0
50
100
150
200
250
300
350
400
450
500
12 40weeks
PE and P.
abruption
P. abruption
IUGR, HELLPIUGRPE ITP
sFlt
/PlG
F
Normal
pregnancies
sFlt/PlGF
2nd trimester screening
Mila Cervar-Zivkovic
2014
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1st trimesterscreening
positive
2nd trimesterscreening
intensive follow up
negativepregnancy
managementas usually
Mila Cervar-Zivkovic
2014
Screening for Preeclampsia
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Recommendations for prevention of preeclampsia
� ASS 75 mg/day
� diagnostic of associated
maternal diseases
� low fat, high fiber, no salt
restriction, vitamins, 1-2 g
calcium
� avoiding of stress, moderate
physical activity
� 2nd trimester screening for
preeclampsia and associated
maternal diseases
� thrombophilia: LWMH
� previous preeclampsia:
psychological treatment
� interdisciplinary for
associated diseases
� all patients: high quality
obstetric treatment
Mila Cervar-Zivkovic
2014
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• Thrombophilia & Fetal Demise: 68
• Thrombophilia & Fetal Growth Restriction: 62
• Thrombophilia & Preeclampsia: 128
• Thrombophilia & Abruptio Placentae: 35
• Thrombophilia & Fetal Loss: 75
• Thrombophilia & Habitual Abortion: 82
• Thrombophilia Screening in Pregnancy: 358
• Thrombophilia and Pregnancy: 696
• Thrombophilia and Pregnancy Complications: 594
• Thrombophilia and Placental Complications: 176
Thrombophilia: publications in Pub Med - last 5
years
Mila Cervar-Zivkovic
2014
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• Preeclampsia & APC-R, PS, PC, AT III,
Prothrombin
• Fetal death & Prothrombin
• Habitual abortions & Prothrombin, PAI, Factor V
• Placental abruption & elevated Factor VIII
activity, APC-R
Coagulation and Pregnancy Complications
Mila Cervar-Zivkovic
2014
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Diagnosis, prophylaxis and treatment of pregnant women
with Activated Protein C Resistance- How can we optimize
the management of these patients?
Third Generation APC Resistance Testing Supersedes
Genetic Factor V Leiden Mutation Testing
F. Prüller, E.-C. Weiss, R. B . Raggam, M. Cervar-Zivkovic
W. Renner, J. Wagner
NEJM 371:7,2014
Mila Cervar-Zivkovic
2014
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• myostatin,
• irisin,
• follistatin,
• cytokeratin 19
• ...
Potential New Biomarkers
Mila Cervar-Zivkovic
2014
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Platelet proteomics - Biomarkers of platelet function
• Established workflow for proteome
analysis of patient-specific platelet
samples
• High-resolution LC-MS/MS
• Cost-effective semiquantitative analysis
using dimethyl labeling
• Enrichment of platelet membrane
proteins, when feasible
• Enrichment and network analysis of over-
and underexpressed proteins
• Western blot analysis of platelet receptor
levels.
• Correlation with platelet function testing
Figure: Network analysis of overexpressed proteins
Schlagenhauf A, Schweintzger S, Birner-Gruenberger R et al., Platelets 2010
Schlagenhauf A, Kozma N, Leschnik B et al., Transfusion 2012
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Biobank
Bioinformatics and biostatistics (also for public health)
Genetic, genomics
MetabolomicsAdditional advanced analytic methods
In silico modeling
Imaging
Biomarker Research
Medical University of Graz
Clinical research
Mila Cervar-Zivkovic
2014
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Mila Cervar-Zivkovic
2014
Biobank
Ob GynEndocrinology
ZMF
Cardiology
Hepatology
Center of
Clinical Research
Bayer Schering
Pharma AG
BG Stats
Consulting
BIOCRATES
Lifesciences AG
Biomarker Design
Forschungs GmbH
BioVendor
Laboratorni
medicina a.s.
IASON GmbH
IDS GmbH
JSW Lifesciences
GmbH
LBI Traumatologie
Lab. f. Molekular-
biol. Analytik
M&R
Automation
GmbHNoxygen Science
GmbH
Protagen AG
Proteopharm GmbH
Siemens Healthcare
Diagnostics GmbH
SustSol GmbH
TU Graz
Joanneum
Research
Biomarker Research, MUG
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Mila Cervar-Zivkovic
2014
Thank you for your attention!