07/03/11 candidate biochemical markers for early … · 07/03/11 1 candidate biochemical markers...
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CANDIDATE BIOCHEMICAL CANDIDATE BIOCHEMICAL MARKERS FOR EARLY PREGNANCY MARKERS FOR EARLY PREGNANCY
SCREENING OF PREECLAMPSIASCREENING OF PREECLAMPSIA
JEANJEAN--CLAUDE FOREST, MD, PhD, FRCPCCLAUDE FOREST, MD, PhD, FRCPC
Axe de recherche en reproduction, santé périnatale et santé de l’enfantCENTRE DE RECHERCHE DU CHUQ
Département de biologie moléculaire, biochimie médicale et pathologieUNIVERSITÉ LAVALUNIVERSITÉ LAVALQUÉBEC, CANADA
2nd IFCC-Ortho Clinical Diagnostics Conference : Pregnancy Related Disorders:
Present Perspectives and Emerging ChallengesParis, France
February 25th – 26th, 2011
PREECLAMPSIA AND OTHER HYPERTENSIVE DISORDERS OF PREGNANCY
• What is preeclampsia ?• What is known about its pathophysiology ?• What can be done for prevention/treatment ?• What can be done for prevention/treatment ?• What are the tools for detection ?
– Maternal risk factors– Biochemical markers– Ultrasonographic markers
PERSPECTIVES
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• What are the screening strategies (why and when)?• Criteria for effective predictive algorithms• Benefits and risks
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Terms and AbbreviationsHDP : Hypertensive Disorders of PregnancyPE : PreeclampsiaGH : Gestational HypertensionHELLP: Hemolysis Elevated Liver enzymes
Low Platelet
AFP : Alpha-FetoproteinhCG : human Chorionic GonadotropinPAPP-A: Pregnancy-Associated Plasma
Protein-AInhA : Inhibin A
CH : Chronic Hypertension PlGF : Placental Growth FactorsEndog (TGFβ receptor) : soluble
Endoglin VEGF : Vascular Endothelial Growth
FactorVEGFR1 (sFlt-1) : soluble Vascular
Endothelial Growth Factor Recceptor-1 (soluble fms-like tyrosine kinase-1)
BP : Blood Pressure (SBP: systolic; DBP: diastolic)MAP: Mean Arterial Blood Pressure
BMI : Body Mass IndexPI : Pulsatility Index (Doppler)UtA : Uterine Artery
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tyrosine kinase 1)PP-13 : Placental Protein 13IGF : Insulin-like Growth Factor
UtA : Uterine Artery
PTB: Premature BirthIUGR: Intra Uterine Growth Restriction SGA : Small-for-Gestational AgeGDM : Gestational DiabetesT21, T18, T13: Trisomies 21, 18, 13FL: Fetal Loss
H i f h 20 h k f
A Definition of Preeclampsia(National High Blood Pressure Education Program Working
Group USA 2000)
Hypertension after the 20th week of pregnancy, remit after delivery
Systolic BP ≥ 140 mmHg
Diastolic BP ≥ 90 mmHg
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Normal BP prior
With proteinuria
Early onset: ≤ 34 wks ; late onset: > 34 wks
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Quantitative measurement of total protein excretion over 24h period
Proteinuria
- Proteinuria: ≥ 300 mg protein / 24h - supersedes all dipstick values
If 24-h urine data not available:– Spot concentration of 0.3 g/L on single random
urine specimen
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urine specimen– Proteinuria on dipsticks in at least 2 random mid-
stream samples at least 4h apart (2+ = 1 g/L)
Chronic Hypertension Normal Pre-Pregnancy BP
CH PE Severe PE GH PE Severe
PE
Hypertensive Disorders of Pregnancy
PE PEBP before pregnancy DBP ≥ 90 mmHg Normal
BP during pregnancy
DBP ≥ 90
mmHg
DBP ≥ 90 mmHg
SBP ≥ 160 mmHg or
DBP ≥ 110 mmHg
DBP ≥ 90 mmHg
DBP ≥ 90 mmHg
SBP ≥ 160 mmHg or
DBP ≥ 110 mmHg
Onset of PE b f 34
Onset of PE b f 34
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Onset before ≥ 20 wks before 34 wks but may happen later
≥ 20 wks ≥ 20 wks before 34 wks but may happen later
BP after pregnancy DBP ≥ 90 mmHg Normal
Adapted from Magee et al. (2008) JOGC 30 (suppl1):1-52
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Chronic Hypertension Normal Pre-Pregnancy BP
Hypertensive Disorders of Pregnancy
CH PE Severe PE GH PE Severe
PE
Proteinuria None
≥ 2+ dipstick ≥ 300 mg/d≥ 30 mg/ mmol creatinine
3-5 g/d None
≥ 2+ dipstick ≥ 300 mg/d≥ 30mg/ mmol creatinine
3-5 g/d
Onset of PE Onset of PE
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Onset before ≥ 20 wks before 34 wks but may happen later
≥20 wks ≥ 20 wks before 34
wks but may happen later
Adapted from Magee et al. (2008) JOGC 30 (suppl1):1-52
Chronic Hypertension Normal Pre-Pregnancy BP
CH PE Severe GH PE Severe
Hypertensive Disorders of Pregnancy
CH PE PE GH PE PE
Other adverse conditions(variable
• Maternal symptoms• Vision, Headache• Dyspnea
• Maternal signs of end-organ dysfunction
• Edema, eclampsia• Abnormal maternal
laboratory testing
• Maternal symptoms• Vision, Headache• Dyspnea
• Maternal signs of end-organ dysfunction
• Edema, eclampsia• Abnormal maternal
laboratory testing
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extent)laboratory testing
• HELLP : Liver (ALT, AST, LDH) + Platelet Count
• Fetal Morbidity
laboratory testing• HELLP : Liver (ALT, AST, LDH) + Platelet Count
• Fetal Morbidity
Adapted from Magee et al. (2008) JOGC 30 (suppl1):1-52
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Worldwide, hypertensive disorders of pregnancy affect up to 15% of pregnancies (specific reports of > 20%).
Preeclampsia affects between 2 and 8 % of pregnancies
Epidemiology of Preeclampsia
Preeclampsia affects between 2 and 8 % of pregnancies in developed countries.
Wide geographical variationSevere PE : 10 – 20 % of all PEEarly-onset PE ( ≤ 34 weeks): 10-20% of all PE
Is largely a disease of the first pregnancy.
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Is a major cause of maternal and perinatal morbidity and mortality (5-fold increase)
Is a cause of iatrogenic prematurity (15 % of preterm births are secondary to delivery for preeclampsia)Is a cause of intra uterine growth restriction (IUGR)
Maternal constitutional factors• Genetic predisposition
• Immunological maladaptation• Pre-existing vascular disease
Environmental factors
Pathophysiology of Preeclampsia
Environmental factors
Defective placentation
Placental ischemia
Oxidative stress
Cytotoxic factors
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Systemic maternal endothelial dysfunction
VasospasmHypertensionHypovolemia
Abnormal coagulationThrombosis
Endothelial damageIncreased permeability
Oedema Proteinuria
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– Couple-related risk factors– Limited sperm exposure– Primiparity / Primipaternity– In vitro fertilization
Some Risk Factors of Preeclampsia
– Maternal risk factors– Extremes of maternal age– Women’s own birth weight– Previous PE (or family history of PE)– Chronic hypertension or renal disease– Inflammatory diseases – Obesity and insulin resistance
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y
– Pregnancy-associated risk factors– Multiple pregnancy– Gestational diabetes– Hydrops fetalis / Hydatiform mole– Chromosomal anomalies (trisomy 13,…)– Various infections (urinary tract, gingivitis, …)
Adapted from Sibai et al. (2005) Lancet 365: 785.
Normal Placentation
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• Invasion of the decidua and the myometrium by the cytotrophoblastic cells occurs early in pregnancy.
• Transformation of the walls of the uterine spiral arteries: replacement of endothelial cells by cytotrophoblastic cells, creation of high-flow, low-resistance arteriolar system, and lost of maternal vasomotor control.
http://www.sgul.ac.uk/depts/immunology/~dash/troph/repro.pdf
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Endovascular Trophoblast Invasion
Interstitialtrophoblastic invasion
al b
edB
asal
Pla
te
Dec
idua
13
Plac
enta
Myo
met
rium
After Kaufman P et al. Biol Reprod 2003; 69: 1-7
Anatomopathology of Preeclampsia
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Abnormal uterine vascular remodelling during early pregnancy reduces blood flow from uterus to placenta
From: Bell (2004)
No Pregnancy NormalPregnancy with PE Pregnancy
Moffet-King Nature Reviews Immunology 2002; 2: 656-663
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15Adapted from Mosby’s Color Atlas and Text of Obstetrics and Gynecology, Greer et al., fig 7.8, p.160
Impaired trophoblast invasion of the myometrium (limited at the decidua);30 to 50 % of the placental bed’s spiral arteries escape
Placenta and Preeclampsia
entirely from endovascular trophoblastic invasion;Myometrial segments remain anatomically intact and adrenergic nerve supply to the spiral arteries remains also intact;Increased responsiveness of spiral arteries to vasoconstrictor mediators results in…
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placental hypoperfusion, local hypoxia,overproduction of various mediators,oxidative stress.
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Initial mechanisms
Pathogenesis of Preeclampsia The “Angiogenic Imbalance” Theory
– Inflammatory challenges (disorders);– Alterations in the regulation and signalling of
angiogenesis pathways contribute to inadequate cytotrophoblastic invasion;
– Up-regulation of anti-angiogenic factors (sFlt-1, s-Endog);
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g)– Down-regulation of circulating angiogenic factors
(VEGF, PlGF).Young et al. Annu Rev Pathol Mech Dis 2010; 5: 173-192
Abnormal Uterine Vascular Remodelling during early PregnancyAbnormal Uterine Vascular Remodelling during early Pregnancy
Immune / Inflammatory FactorsGenetic Susceptibility Environment / Maternal
Characteristics
Pathophysiology of Preeclampsia
Foetal Pain / Distress : Intrauterine Growth Restriction
Intrauterine Foetal Death
Placental Hypotrophia,Infarctus
Reduced Placental PerfusionReduced Placental Perfusion
Hypoxia (Oxidative Stress)Hypoxia (Oxidative Stress)
Placental DysfunctionPlacental Dysfunction
Release of Placental Mediators in Maternal CirculationRelease of Placental Mediators in Maternal Circulation
18Adapted from Giguère et al (2011) submitted
HypertensionProteinuria
Glomerular EndotheliosisHELLP syndrome
Eclampsia
Systemic Maternal Endothelial DysfunctionSystemic Maternal Endothelial Dysfunction
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Abnormal profile of adhesion molecules (∆ VE-cadherin, VCAM-1, PECAM-1)Decrease of plasminogen activation (∆ urokinase, MMP-9, PAI-1)
Abnormal Uterine Vascular Remodelling during early PregnancyAbnormal Uterine Vascular Remodelling during early Pregnancy
Pathophysiology of PE - Biomarkers
p g ( , , )Modification of uterine angiogenesis (∆ sFlt-1, sEndog, PlGF, VEGF, hCG )
Growth Factors : EGF, IGF-II, TGF α/β, VEGF, PlGF, sFlt-1, sEndog;C ki TNF I l ki 1 6 10 IF I f P l di
Placental DysfunctionPlacental Dysfunction
Release of Placental Mediators in Maternal CirculationRelease of Placental Mediators in Maternal Circulation
AFP, hCG, PAPP-A, inhibin A, activin A, PP-13
19Adapted from Giguère et al (2011) submitted
Cytokines : TNFα; Interleukins 1, 6, 10; LIF; Interferon; Prostaglandins;Enzymes : PAI 1, PAI 2, MMP-2, MMP-9;Others : Peroxylated Lipids, Endothelins, Apoptotic/Necrotic debris, Cell-free foetal nucleic acids
Systemic Maternal Endothelial DysfunctionSystemic Maternal Endothelial Dysfunction
Clinical (maternal history and
Altered Parameters before Occurrence of Clinical Symptoms of PE
Clinical (maternal history and characteristics, BMI, MAP, …)Blood and Urine ParametersDoppler Uterine Artery Blood Flow Velocity Measurements
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3-Dimensional Doppler Ultrasonography (placental volume)
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PREECLAMPSIA AND OTHER HYPERTENSIVE DISORDERS OF PREGNANCY
• What is preeclampsia ?• What is known about its pathophysiology ?• What can be done for prevention/treatment ?• What can be done for prevention/treatment ?• What are the tools for detection ?
– Maternal risk factors (maternal history)– Biochemical markers– Ultrasonographic markers
– PERSPECTIVES
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PERSPECTIVES • What are the screening strategies (why and when)?• Criteria for effective predictive algorithms• Benefits and risks
Objectives:
Early Prediction of PE
Object es• To identify women at high risk of developing
preeclampsia later in pregnancy, and to offer specific preventive measures;
• To apply prophylactic interventions at optimal time;T l f ll
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• To propose closer follow-up.
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• Improved socio-economic conditions
Interventions for the Prevention of Preeclampsia
p(perinatal policy)
• Structured prenatal counselling and follow-up
• Potential prophylactic therapies– Antiplatelet agents (aspirin)
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Antiplatelet agents (aspirin)• Inhibit thromboxane-mediated vasoconstriction
and pathological blood coagulation in the placenta
– Low-molecular weight heparin
Early recognition, key to prevention and treatment.– The objective is to prolong pregnancy whenever
Clinical Intervention and Treatment
The objective is to prolong pregnancy whenever possible to permit fœtal lung maturity while preventing progression to severe disease;
– Antiplatelet prophylactic therapy (aspirin);– Antihypertensive therapy (>160/100 mmHg:
methyldopa, labetalol, nifedipine);
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– The definitive treatment is delivery;
– Eclampsia: emergency; High-risk morbidity/mortality.
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PE can be Prevented by ASA
• 27 trials including 11,348 women
“ … current evidence indicates that low-dose aspirin started in
Trials using ASA
before 16 weeksRR: 0.47
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pearly pregnancy may reduce the incidence of PE, IUGR and PTB in women identified at moderate or high risk for PE.”Bujold et al. (2010) Obstet Gynecol 116: 402-414
Trials using ASA after
16 weeksRR: 0.81
PREECLAMPSIA AND OTHER HYPERTENSIVE DISORDERS OF PREGNANCY
• What is preeclampsia ?• What is known about its pathophysiology ?• What can be done for prevention/treatment ?• What can be done for prevention/treatment ?• What are the tools for detection ?
– Maternal risk factors (maternal history)– Biochemical markers – Ultrasonographic markers
PERSPECTIVES
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• What are the screening strategies (why and when)?• Criteria for effective predictive algorithms• Benefits and risks
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Recommendations for determination of HDP risk at 1st visit• Intensity of monitoring
– Ex.: Maternal age > 40 yrs; nulliparity, woman’s own birth
Clinical Maternal Risk Factors
g y ; p y,weight, pre-existing chronic hypertension, diabetes, previous PE, BMI > 30.
• Very few published data of performance– In one recent study by Poon et al. (J Hum Hypert (2010) 24 : 104-10),
logistic regression analysis of maternal characteristics shows:•At a false positive rate of 5 %, detection rates:f l PE 37% l t PE 29 % GH 20%
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for early PE: 37%; late PE: 29 %; GH: 20%.•Screening suggested by NICE (Natl. Inst. for Clinical Excellence):(essentially treats each factor as a separate screening test) false positive rate of 64 %; detection rate of 89, 93 and 85 % , respectively.
• Elements from maternal history may serve to
Maternal Risk Factors for HDP as a priori Risk
determine a priori risk using a multivariate approach.– Ethnicity, maternal age, woman’s own birth weight, prior PE,
BMI…
• As for screening for Trisomy 21, patient specific risk may be derived by multiplying a priori risk by the likelihood ratio associated with selected biochemical
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likelihood ratio associated with selected biochemical and biophysical parameters.
Cuckle (2011) Placenta 32: S42-S48
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PREECLAMPSIA AND OTHER HYPERTENSIVE DISORDERS OF PREGNANCY
• What is preeclampsia ?• What is known about its pathophysiology ?• What can be done for prevention/treatment ?• What can be done for prevention/treatment ?• What are the tools for detection ?
– Maternal risk factors (maternal history)– Biochemical markers – Ultrasonographic markers
PERSPECTIVES
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• What are the screening strategies (why and when)?• Criteria for effective predictive algorithms• Benefits and risks
Marker Altered levels during Assessed in combination with Associated withBefore onset
of PE (1st /2nd trim.)
After onset of PE
(3rd trim.)
Other biochem. markers
Ultrasound markers
Maternal characteristics
VEGF UtA PI GH, GDM, HELLP, T21
Potential Biomarkers for PE – Summary
PlGFsFlt-1;PlGF;PAPP-A
UtA PI
Ethnicity, MAP,weight, history CH, smoking, Conception
GH, GDM, HELLP, PTB, IUGR, T21, T18, T13, triploidy, Turner
sFlt-1 PlGF;sEng; UtA PI GH, GDM, HELLP, FD, IUGR, stillbirth, T13
sEndog PlGF;sFlt-1; PAPP-A UtA PI weight GH, HELLP, FD, IUGR,
SGA,
AFP hCG UtA PIGDM, GH, HELLP, PTB, FL, SGA, T21, Neural t be defectstube defects
hCG AFP, PAPP-A UtA PI GDM, GH, PTB, T21
Inhibin A PAPP-A, activin A UtA PI Ethnicity, parity,
BMIGDM, GH, HELLP, PTB, SGA, T21
PAPP-AsEng, PlGFPP-13, inhibinA
UtA PI
Weight, BMI, MAP, ethnicity, CH, parity, age conception, fetal CRL, smoking
GDM, GH, HELLP, PTB,FD, SGA, T21, T18,Turner
From Giguère et al. 2011 submitted
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Marker Altered levels during Assessed in combination with Associated with
Before onset of PE
(1st /2nd trim.)
After onset of PE
(3rd trim.)
Other biochem. markers
Ultrasound markers
Maternal characteristics
Cell free
Potential Biomarkers for PE – Summary
Cell freefetal DNA IUGR
Cell freefetal RNA
P-Selectin UtA PI
Ethnicity, weight, history CH, smoking, MAP,conception
GH, PTB, SGA
VCAM GDM, GH, HELLP, SGA
HELLP PTB T18 T13
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PP-13 PAPP-A UtA PI Weight, smoking HELLP, PTB, T18, T13,Turner
ADAM-12 SGA
Visfatin GDM, PTB, SGA
PTX3 GH, PPROM, PTB, IUGR
From Giguère et al. 2011 submitted
Challenges with Measurement of Biochemical Markers to Predict PE Early in Pregnancy
• Concentration of marker changes during pregnancy;• Necessity to express results in Multiple of Median – MoM
• Lack of standardized methods and reference materials, commercial availability and automation, CE label;
• Overlap of results between normal pregnancy and HDP.
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Which of the putative biomarkers
Potential Biomarkers for PE
Which of the putative biomarkers – Are predictive of preeclampsia and other
adverse pregnancy outcomes ?– Have demonstrated clinical utility ?
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Condition • Important health problem;• Natural history understood;• Recognizable latent or early symptomatic stage;
Summary of Criteria for ScreeningJungner & Wilson WHO (1968); Holland et al. WHO (2006)
• Recognizable latent or early symptomatic stage;
Diagnosis • Suitable diagnostic test available, safe and acceptable to the population concerned;
• Agreed policy, based on respectable test findings and national standards, as to whom to regard as patients;
• Whole process, continuing;
Treatment • Accepted and established treatment / intervention for
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individuals identified as having the disease or pre-disease condition;
• Facilities for treatment should be available;
Cost • Cost of case-finding (including diagnosis and treatment) should be economically balanced in relation to possible expenditure on medical care.
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Summary of Criteria for Evaluation of Screening Tests (Holland et al. WHO (2006))
Simplicity The test should be simple to perform, easy to interpret and, where possible, capable of use by paramedics and other personnel.
Acceptability Since participation in screening is voluntary, the test must be acceptable to those undergoing it.
Accuracy The test must give a true measurement of the condition or symptom under investigation.
Cost The expense of the test must be considered in relation to the benefits of early detection of the disease.
Repeatability The test should give consistent results in repeated
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Repeatability e test s ou d g e co s ste t esu ts epeatedtrials.
Sensitivity The test should be capable of giving a positive finding when the individual being screened has the condition being sought.
Specificity The test should be capable of giving a negative finding when the individual being screened does not have the condition being sought.
• Until now, numerous systematic reviews have been unable to demonstrate a single biochemical marker capable of detecting, early in pregnancy, those women susceptible to develop PE.
Systematic Reviews of Combinations of Biomarkers
Conde-Argudelo et al. Obstet Gynecol. 2004; 104: 1367-1391.Cnossens et al. Health Techn. Assess. 2008; 12(6):1-128.
• Because of the heterogeneous nature of PE, a combination of independent biomarkers, each reflecting a different pathophysiological process, should increase the likelihood to derive suitable predictive algorithms.
• Indeed, combinations of biochemical and ultrasonographic markers into algorithms derived by multivariate analysis improve
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markers into algorithms derived by multivariate analysis improve the performance of early prediction of PE.
• From the perspective of integrative medicine, there is a clear need for prospective large-scale studies with rigorous study design criteria to determine the clinical usefulness of combinations of biomarkers in different geographic and healthcare environments.
Giguère et al. Clin. Chem. 2010; 56(3): 361-374.Cetin et al. Placenta 2011; 32:S4-S16.
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Clinical Screening Strategies for PEExisting Clinical Investigations
Dating, Nuchal translucencyTrisomy screening
Trisomy screening
Fetal Development(Ultrasound)
Screening for
Fetal Development(Ultrasound)
Trisomy screening(Biochemistry)
Screening forGestational Diabetes
0 4010 -13(1st trim.)
14 -17 20 24 -28(2nd trim.)
30, 32, 36 (depending)
(3rd trim.)
PREGNANCY
Development of Preeclampsia
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Screening Strategies
1st trimester:Prediction of HDP / PE
(Preventive treatment for high-risk women)
2nd trimester:Late identification of imminent
HDP / PE(Closer follow-up of high-risk
women)
Benefits• To develop an approach using biomarkers to
detect, as early as possible, women at risk of d l i l i ith t
Clinical screening strategies for PE
developing preeclampsia with a greater performance than that of conventional methods in order to offer, in a targeted manner, prophylactic interventions, specific surveillance and / or closer management.
Risks
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• False positive results creating anxiety and possibly unnecessary interventions
• False negative results causing false reassurance or reduction of surveillance.
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• What should be the expected performance to reach clinical utility?
Challenges
• Will the same factors for calculation of a priori risk and biomarkers (biochemical / biophysical) perform uniformly in different environments?
• Commercial availability of best performing markers?C t ff ti t di ?
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• Cost-effectiveness studies?• Optimal time to screen?
• No individual biochemical or biophysical markers have met the criteria for a screening test.
In Summary
• Maternal history & risk factors, have as a whole poor predictive value; with some guidelines, 2/3 of the patients would be falsely classified as high risk.
• A growing body of evidence suggests that the combination of maternal factors (BMI age parity
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combination of maternal factors (BMI, age, parity, ethnicity, past history,...) with serum markers and UtA Doppler indices may identify early in pregnancy women at risk of developing preeclampsia.
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In Summary
There is a need for large-scale prospective studies to determine the usefulness ofstudies to determine the usefulness of multivariate risk-prediction algorithms early in pregnancy, in different populations.
This may lead to the implementation of an efficient screening procedure to identify
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efficient screening procedure to identify women at risk for PE who would benefit from early targeted interventions.
• Bujold et al. (2010) “Prevention of Preeclampsia and Intrauterine Growth Restriction With Aspirin Started in Early Pregnancy - A Meta-Analysis” Obstet Gynecol 116:402–14)
• Cetin et al. (2011) “Pregenesys pre-eclampsia markers consensus meeting: What do we require from markers, risk assessment and model systems to tailor preventive strategies?” Placenta 32: S4-S16.
References
• Cuckle, H. (2011) “Screening for Pre-eclampsia - Lessons from Aneuploidy Screening” Placenta 32: S40-S48.
• Giguère et al. (2010) “Combining Biochemical and Ultrasonographic Markers in Predicting Preeclampsia: A Systematic Review” Clin Chem. 56 : 361-374.
• Grill et al. (2009) “Potential markers of preeclampsia – a review” Reproductive Biology and Endocrinology 7:70.
• Lindheimer et al. (2009) “ASH Position Paper: Hypertension in Pregnancy” J Clin Hypertens (Greenwich) 11:214–225.
• Silasi et al. (2010) “Abnormal Placentation, Angiogenic Factors, and the Pathogenesis of P l i ” Ob t t G l Cli N A 37 239 253
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Preeclampsia” Obstet Gynecol Clin N Am 37 : 239–253.• Steegers et al (2010) “Preeclampsia” Lancet 2010; 376: 631–44.
• Wang et al. (2009) “Preeclampsia: The role of angiogenic factors in its pathogenesis”. Physiology 24:147-158.
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• Yves Giguère, Jacques Massé, Emmanuel Bujold, Julie Lafond, Jean-Marie Moutquin, François Rousseau
• Aziz Aris Joël Girouard Sébastien Lévesque
Acknowledgements
Aziz Aris, Joël Girouard, Sébastien Lévesque, Patrice Savard, Nathalie Bernard, Mélissa Laroche
• Marc Charland, Véronique Goulet, Mylène Badeau, Nathalie Bernard, Francine Déchenes, Monique Longpré, Pierre DeGrandpré, nurses and laboratory technicians
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MERCI!MERCI!
THANK YOU!THANK YOU!
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