Patogenesis

dan Deteksi Dini Preeklampsia

wibowonoroyono@yahoo.com

Implanta;on begins Compact layer Spongy layer Basal layer

Gland

Menstrual phase

0 4 14 28
Follicular or prolifera;ve phase

Progesta;onal or secretory phase

Gravid phase

Transformasi

Synci:al knots Hyalin degenera:on Apoptosis - Necrosis

Flow: Pulsa:on
STBM

Flow: jet Stream

Atherosis Kegagalan remodeling VSM

< 8 mm > 12 mm

Mol Hum Reprod. 2000 Feb;6(2):178-84

Eng Inamma;on CRP Pentraxin3 RBP 4

NOO- O2- An:oxidant Ec SOD N HO-1 N

SEng

PP13
Angiogenic PLGF VEGF

MMP tPA PAI-1 N

Metabolic HOMA IR HOMA B

St-1

STBM

> 50% cotyledon rusak Keguguran IUGR Preterm PEE

Pathogenesis of Preeclampsia The Angiogenic Imbalance Theory

Ini;al mechanisms
Inammatory challenges (disorders); Altera;ons in the regula;on and signalling of angiogenesis pathways contribute to inadequate cytotrophoblas;c invasion; Up-regula;on of an;-angiogenic factors (sFlt-1, s-Endog); Down-regula;on of circula;ng angiogenic factors (VEGF, PlGF).

Young et al. Annu Rev Pathol Mech Dis 2010; 5: 173-192

Pathophysiology of Preeclampsia
Gene;c Suscep;bility Environment / Maternal Characteris;cs Immune / Inammatory Factors

Abnormal Uterine Vascular Remodelling during early Pregnancy

Placental Hypotrophia, Infarctus

Reduced Placental Perfusion Hypoxia (OxidaMve Stress)

Foetal Pain / Distress : Intrauterine Growth Restric;on Intrauterine Foetal Death

Placental DysfuncMon Release of Placental Mediators in Maternal CirculaMon Systemic Maternal Endothelial DysfuncMon
Hypertension Proteinuria Glomerular Endotheliosis HELLP syndrome Adapted from Gigure et al (2011) submiTed Eclampsia

Pathophysiology of PE - Biomarkers

Abnormal Uterine Vascular Remodelling during early Pregnancy
Abnormal prole of adhesion molecules ( VE-cadherin, VCAM-1, PECAM-1) Decrease of plasminogen ac:va:on ( urokinase, MMP-9, PAI-1) Modica:on of uterine angiogenesis ( sFlt-1, sEndog, PlGF, VEGF, hCG )

Placental DysfuncMon
AFP, hCG, PAPP-A, inhibin A, ac:vin A, PP-13

Release of Placental Mediators in Maternal CirculaMon

Growth Factors : EGF, IGF-II, TGF /, VEGF, PlGF, sFlt-1, sEndog; Cytokines : TNF; Interleukins 1, 6, 10; LIF; Interferon; Prostaglandins; Enzymes : PAI 1, PAI 2, MMP-2, MMP-9; Others : Peroxylated Lipids, Endothelins, Apopto:c/Necro:c debris, Cell-free foetal nucleic acids

Systemic Maternal Endothelial DysfuncMon

Adapted from Gigure et al (2011) submiTed

Altered Parameters before Occurrence of Clinical Symptoms of PE

Clinical (maternal history and characteris;cs, BMI, MAP, ) Blood and Urine Parameters Doppler Uterine Artery Blood Flow Velocity Measurements 3-Dimensional Doppler Ultrasonography (placental volume)

Early Predic;on of PE
Objec;ves:
To iden:fy women at high risk of developing preeclampsia later in pregnancy, and to oer specic preven:ve measures; To apply prophylac:c interven:ons at op:mal :me; To propose closer follow-up.

Interven;ons for the Preven;on of Preeclampsia

Improved socio-economic condi;ons (perinatal policy) Structured prenatal counselling and follow-up Poten;al prophylac;c therapies

An:platelet agents (aspirin)

Inhibit thromboxane-mediated vasoconstric:on and pathological blood coagula:on in the placenta

Low-molecular weight heparin

Clinical Interven;on and Treatment

Early recogni;on, key to preven;on and treatment.
The objec:ve is to prolong pregnancy whenever possible to permit foetal lung maturity while preven:ng progression to severe disease; An:platelet prophylac:c therapy (aspirin); An:hypertensive therapy (>160/100 mmHg: methyldopa, labetalol, nifedipine); The deni:ve treatment is delivery; Eclampsia: emergency; High-risk morbidity/mortality.

Preven;on of Preeclampsia and Intrauterine Growth Restric;on With Aspirin Started in Early Pregnancy
A Meta-Analysis

PE can be Prevented by ASA

Emmanuel Bujold, MD, MSc, Stphanie Roberge, MSc, Yves Lacasse, MD, MSc, Marc Burreau, MD, Franqois Audibert, MD, MSc, Sylvie Marcoux, MD, PhD, Jean-Claude Forest, MD, PhD, and Yves Gigute, MD, PhD
Treatment Study or subgroup Events Total Events Control Total Weight (%) Risk ra;o M-H, random (95% CI)
0.63 (0.17-2.33) 0.24 (0.03-2.10) 0.07 (0.00-1.25) Not es:mable 0.54 (0.37-0.78) 0.43 (0.12-1.56) 0.20 (0.02-1.66) 0.33 (0.04-3.04) 0.20 (0.05-0.86) 0.47 (0.34-0.65)

Risk ra;o M-H, random (95% CI)

1.1 16 or fewer weeks August 1994 3 24 5 Azar 1990 1 46 4 Beauts 1985 0 48 6 Banigni 1989 0 17 0 Ebrashy 2005 25 73 40 Hormida 1997 3 50 7 Michael 1992 1 55 5 Tulppala 1997 1 33 3 Vainio 2002 2 43 10 Subtotal (95% CI) 389 Total events 36 80 3 2 Heterogeneity: Tau =0.00; Chi =5.45; df=7 (P=.61), I2=O% Test for overall eect: Z=4.57 (P<.001) 1.2 More than 16 weeks Byaruhanga 1998 17 113 23 Cari:s 1996 111 663 118 CLASP 1994 91 1,259 80 Davies 1995 5 58 7 ECPPA 1996 16 284 22 Golding 1998 1 23 1 Ferrier 1996 66 1,253 50 Grab 2000 3 22 2 Hauth 1993 5 302 17 McParland 1990 1 48 10 Morris 1996 4 52 7 Rogers 1999 3 118 7 Roochell 1998 10 739 12 Schi 1989 1 34 7 Schrocksnadel 1992 0 22 6 Wallenburg 1986 0 23 7 Yu 2003 49 276 52 Zimmerman 1997 4 13 2 Subtotal (95% CI) 5,302 Total events 3 430 Heterogeneity: Tau2=0.09; Chi2=32.49; df=17 (P=.01), I2=48% Test for overall eect: Z=1.75 (P=.08) 5,691 Total (95% CI) 423 510 Total events Heterogeneity: Tau2=0.12; Chi2=51.55; df=25 (P=.001), I2=52% Test for overall eect: Z=3.19 (P=.001)

25 45 45 16 63 50 55 33 43 375

2.5 1.1 0.6 9.3 2.6 1.1 1.0 2.2 20.5

27 trials including 11,348 women

117 626 1,233 60 322 20 1,294 21 302 52 50 75 746 31 19 23 278 13 5,282 7.14 10.8 10.2 3.4 6.6 0.7 9.4 1.7 3.9 1.2 3.1 2.5 4.8 1.2 0.7 0.7 9.5 2 79.5 0.77 (0.43-1.35) 0.89 (0.70-1.12) 1.11 (0.83-1.49) 0.74 (0.25-2.20) 0.82 (0.44-1.54) 0.87 (0.06-13.02) 1.36 (0.95-1.95) 1.43 (0.27-7.73) 0.29 (0.11-0.79) 0.11 (0.01-0.81) 0.55 (0.17-1.76) 0.27 (0.07-1.02) 0.84 (0.37-1.94) 0.13 (0.02-1.00) 0.07 (0.00-1.11) 0.07 (0.00-1.10) 0.95 (0.67-1.35) 2.00 (0.44-9.08) 0.81 (0.63-1.03)

current evidence indicates that low-dose aspirin started in early pregnancy may reduce the incidence of PE, IUGR and PTB in women iden;ed at moderate or high risk for PE.

5,657 100.0

0.68 (0.54-086) 0.05 0.2 1 5 20 Favors experimental Favors control

Fig.2 . Forest plot of trials studying preeclampsia. Aspirin treatment to prevent preeclampsia according to gesta:onal age at the ini:a:on of interven:on. CI, condence interval; M-H, Mantel- Haentszel. Bujold. Preeclampsia and IUGR Preven<on With Aspirin. Obstet Gynecol 2010.

Bujold et al. (2010) Obstet Gynecol 116: 402-414

Clinical Maternal Risk Factors

Recommenda;ons for determina;on of HDP risk at 1st visit

Intensity of monitoring Ex.: Maternal age > 40 yrs; nulliparity, womans own birth weight, pre- exis:ng 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), logis:c regression analysis of maternal characteris:cs shows:
At a false posi:ve rate of 5 %, detec:on rates: for early PE 37% l t PE 29 % GH 20% Screening suggested by NICE (Natl. Inst. for Clinical Excellence): (essen:ally treats each factor as a separate screening test) false posi:ve rate of 64 %; detec:on rate of 89, 93 and 85 % , respec:vely.

Maternal Risk Factors for HDP as a priori Risk

Elements from maternal history may serve to

determine a priori risk using a mulMvariate approach.
Ethnicity, maternal age, womans own birth weight, prior PE, BMI

As for screening for Trisomy 21, pa;ent specic risk

may be derived by mul;plying a priori risk by the likelihood ra;o associated with selected biochemical and biophysical parameters.

Cuckle (2011) Placenta 32: S42-S48

Poten;al Biomarkers for PE Summary

Marker Altered levels during
Before onset of PE st (1 /2nd trim.) Ajer onset of PE rd (3 trim.)

Assessed in combina;on with

Other biochem. markers Ultrasound markers Maternal characteris;cs

Associated with

VEGF PIGF sFlt-1 sEndog AFP hCG Inhibin A PAPP-A

sFlt-1; PIGF; PAPP-A PIGF; sEng; PIGF; sFlt-1; PAPP-A hCG AFP, PAPP-A PAPP-A, ac:vin A sEng, PlGF PP-13, inhibinA

UtA PI UtA PI UtA PI UtA PI UtA PI UtA PI UtA PI Ethnicity, parity, BMI Weight, BMI, MAP, ethnicity, CH, parity, age concep:on, fetal CRL, smoking Weight Ethnicity, MAP, weight, history CH, smoking, Concep:on

GH, GDM, HELLP, T21 GH, GDM, HELLP, PTB, IUGR, T21, T18, T13, triploidy, Turner GH, GDM, HELLP, FD, IUGR, s:llbirth, T13 GH, HELLP, FD, IUGR, SGA, GDM, GH, HELLP, PTB, FL, SGA, T21, Neural tube defects GDM, GH, PTB, T21 GDM, GH, HELLP, PTB, SGA, T21 GDM, GH, HELLP, PTB, FD, SGA, T21, T18, Turner

UtA PI

Poten;al Biomarkers for PE Summary

Marker Altered levels during
Before onset of PE st (1 /2nd trim.) Ajer onset of PE rd (3 trim.)

Assessed in combina;on with

Other biochem. markers Ultrasound markers Maternal characteris;cs

Associated with

Cell free fetal DNA Cell free fetal RNA P-Selec;n

Ethnicity, MAP, weight, history CH, smoking, MAP, Concep:on

IUGR

UtA PI

GH, PTB, SGA

VCAM PP-13 ADAM-12 Visfa;n PTX3

PAPP-A UtA PI Weight, smoking

GDM, GH, HELLP, SGA HELLP, PTB, T18, T13, Turner SGA GDM, PTB, SGA GH, PPROM, PTB, IUGR

From Gigure et al. 2011 submiTed

Challenges with Measurement of Biochemical Markers to Predict PE Early in Pregnancy

Concentra;on of marker changes during pregnancy;
Necessity to express results in Mul;ple of Median MoM

Lack of standardized methods and reference materials, commercial availability and automa;on, CE label; Overlap of results between normal pregnancy and HDP.

Poten;al Biomarkers for PE

Which of the puta;ve biomarkers Are predic;ve of preeclampsia and other adverse pregnancy outcomes ? Have demonstrated clinical u;lity ?

Summary of Criteria for Screening

Jungner & Wilson WHO (1968); Holland et al. WHO (2006)
Condi;on : - Important health problem; - Natural history understood; - Recognizable latent or early symptoma:c stage; Diagnosis : - Suitable diagnos:c test available, safe and acceptable to the popula:on concerned; - Agreed policy, based on respectable test ndings and na:onal standards, as to whom to regard as pa:ents; - Whole process, con:nuing; Treatment : - Accepted and established treatment / interven:on for individuals iden:ed as having the disease or predisease condi:on; - Facili:es for treatment should be available; Cost : - Cost of case-nding (including diagnosis and treatment) should be economically balanced in rela:on to possible expenditure on medical care.

Summary of Criteria for Evalua;on of Screening Tests (Holland et al. WHO (2006))
Simplicity Acceptability Accuracy Cost Repeatability Sensi;vity Specicity The test should be simple to perform, easy to interpret and, where possible, capable of use by paramedics and other personnel. Since par:cipa:on in screening is voluntary, the test must be acceptable to those undergoing it. The test must give a true measurement of the condi:on or symptom under inves:ga:on. The expense of the test must be considered in rela:on to the benets of early detec:on of the disease. The test should give consistent results in repeated trials. The test should be capable of giving a posi:ve nding when the individual being screened has the condi:on being sought. The test should be capable of giving a nega:ve nding when the individual being screened does not have the condi:on being sought.

Systema;c Reviews of Combina;ons of Biomarkers

Un;l now, numerous systema;c reviews have been unable to demonstrate a
single biochemical marker capable of detec;ng, early in pregnancy, those women suscep;ble to develop PE.
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 combina;on of independent Indeed, combina;ons of biochemical and ultrasonographic markers into From the perspec;ve of integra;ve medicine, there is a clear need for
biomarkers, each reec;ng a dierent pathophysiological process, should increase the likelihood to derive suitable predic;ve algorithms.

algorithms derived by mul;variate analysis improve the performance of early predic;on of PE. prospec;ve large-scale studies with rigorous study design criteria to determine the clinical usefulness of combina;ons of biomarkers in dierent geographic and healthcare environments.
Gigure et al. Clin. Chem. 2010; 56(3): 361-374. CeMn et al. Placenta 2011; 32:S4-S16.

Predic;on of pre-eclampsia
Multivariable model (ENG, FLT-1, PlGF and parity)
Sensitivity
1.00 .75 .50 .25
0.00

ROC curve of mul;variable model

1. Gene expression levels of angiogenesis- and oxida;ve stress- related genes changed in the cellular component of maternal blood before the onset of preeclampsia 2. Predic;on of preeclampsia is feasible with high detec;on rate by analysis of cellular RNA in maternal blood.

AUC 0.884
95%CI: 0.844-0.922 p<0.001

1 - Specificity

.25

.50

.75

1.00

Sekizawa A, et al. Br J Obstet Gynecol. 2010

Clinical Screening Strategies for PE

Exis;ng Clinical Inves;ga;ons
Da;ng, Nuchal translucency Trisomy screening Trisomy screening (Biochemistry) Fetal Development (Ultrasound) Fetal Development (Ultrasound) Screening for Gesta;onal Diabetes

PREGNANCY
0
(1st trim.) 10-13 14-17 20 (2nd trim.) 24-28 30, 32, 36 (depending) (3rd trim.)

40

Development of Preeclampsia

Screening Strategies
1st trimester: Predic:on of HDP/ PE (Preven:ve treatment for high-risk women) 2nd trimester: Late iden:ca:on of imminent HDP / PE (Closer follow-up of high-risk women)

Clinical screening strategies for PE

Benets
To develop an approach using biomarkers to detect, as early as possible, women at risk of developing preeclampsia with a greater performance than that of conven:onal methods in order to oer, in a targeted manner, prophylac:c interven:ons, specic surveillance and or closer management.

Risks
False posi:ve results crea:ng anxiety and possibly unnecessary interven:ons False nega:ve results causing false reassurance or reduc:on of surveillance.

Challenges
What should be the expected performance to reach clinical
u;lity?

Will the same factors for calcula;on of a priori risk and Commercial availability of best performing markers? Cost-eec;veness studies? Op;mal ;me to screen?

biomarkers (biochemical / biophysical) perform uniformly in dierent environments?

In Summary

No individual biochemical or biophysical markers have met the criteria for a screening test. Maternal history & risk factors, have as a whole poor predic;ve value; with some guidelines, 2/3 of the pa;ents would be falsely classied as high risk. A growing body of evidence suggests that the combina;on of maternal factors (BMI age parity BMI, age, parity, ethnicity, past history,...) with serum markers and UtA Doppler indices may iden;fy early in pregnancy women at risk of developing preeclampsia.

In Summary
There is a need for large-scale prospec;ve studies
to determine the usefulness of mul;variate risk- predic;on algorithms early in pregnancy, in dierent popula;ons.

This may lead to the implementa;on of an ecient

screening procedure to iden;fy women at risk for PE who would benet from early targeted interven;ons.

References
Bujold et al. (2010) Preven<on of Preeclampsia and Intrauterine Growth Restric<on With Aspirin Started in Early Pregnancy - A Meta-Analysis Obstet Gynecol 116:40214) Ce:n et al. (2011) Pregenesys pre-eclampsia markers consensus mee<ng: What do we require from markers, risk assessment and model systems to tailor preven<ve strategies? Placenta 32: S4-S16. Cuckle, H. (2011) Screening for Pre-eclampsia - Lessons from Aneuploidy Screening Placenta 32: S40-S48. Gigure et al. (2010) Combining Biochemical and Ultrasonographic Markers in Predic<ng Preeclampsia: A Systema<c Review Clin Chem. 56 : 361-374. Grill et al. (2009) Poten<al markers of preeclampsia a review Reproduc<ve Biology and Endocrinology 7:70. Lindheimer et al. (2009) ASH Posi<on Paper: Hypertension in Pregnancy J Clin Hypertens (Greenwich) 11:214225. Silasi et al. (2010) Abnormal Placenta<on, Angiogenic Factors, and the Pathogenesis of Preeclampsia Obstet Gynecol Clin Am : 239253. Steegers et al (2010) Preeclampsia Lancet 2010; 376: 63144. Wang et al. (2009) Preeclampsia: The role of angiogenic factors in its pathogenesis. Physiology 24:147-158.

Genetic Factors?

Microalbuminuria Serum uric acid Urinary calcium excretion Serapine 1

Renal Dysfunction

Fetoplacental Unit Endocrine Dysfunction

Human chronic gonadotropin Alpha fetoprotein Inhibin A Activin A Pregnancy-associated plasma protein A Insulin resistance Sex hormone-binding globulin Adiponectin

Placental Perfusion and Vascular Resistance Dysfunction

Mean blood pressure in second trimester 24-hour ambulatory blood pressure monitoring Doppler ultrasound Renin Platelet Platelet angiotensin II binding Platelet calcium response to arginine vasopressin PP13

Endothelial Dysfunction, growth factors and oxidative stress Proteomics Metabolomics

Antiphospholipid antibodies Antithrombin III Plasminogen activator inhibitor Serum lipids Apoliprotein E Endothelin Prostacyclin Thromboxane Cytokines Placenta growth factor Isoprostanes Soluble FMS-like tyrosine kinase Soluble endoglin ADMA

Pre-eclampsia

Trends Cardiovasc Med. 2008 July ; 18(5-24): 186194