Minimizing the Occurence and Complications of Preeclampsia

7/28/2019 Minimizing the Occurence and Complications of Preeclampsia

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Minimizing the Occurence andComplications of Preeclampsia:

Prevention and Prediction

Joserizal Serudji

MFU/Department of Obstetric and Gynecology

M. Djamil Hospital/MF of Andalas University

Padang


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Introduction

Preeclampsia is a major contributor to thematernal and neonatal mortality andmorbidity.

It is the 2nd largest cause of maternalmortality worldwide and affects 5% to 7% ofpregnant women worldwide.

M.Djamil Hospital : 14,7% (2010/within 1 yrpost-G30S disaster), 7,1% (2011) severepreeclampsia + eclampsia


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Introduction

West Sumatera (2009): hemorrhage,

Preclampsia/Eclampsia.

M.Djamil Hospt (bed exps): CFR Eclampsia 10% (2006), 30% (2007), 48 % or 10/21 (2008)

8,3% or 3/36 (2010) tim approach; neonatal

mortality : ??? prematurity.


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Introduction

Preeclampsia is a complex disease with

multifactorial causes.

To date, investigations of its prediction and

prevention have not been completely successful.Clinicians do not yet have predictive and

preventive standards for preeclampsia ???!!!.

The prediction and prevention of preeclampsiaremains a clinical issue in maternal and fetal

health (Matsubara, et al, 2009) ???!!!.


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Pathogenesis

The precise etiopathogenesis of preeclampsia

remains to be a subject of extensive research,

but it is believed that it is likely to be

multifactorial.

Nevertheless, it is accepted that it is the

presence of the placenta rather than the

fetus, which is responsible for development ofpreeclampsia.


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Although theplacenta plays a crucial role in

the development of preeclampsia, the onset,

severity, and progression is significantly

affected by the maternal response to

placentally derived factors and proteins.


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The diagram presents an overview of early trophoblast development

(Huppertz, 2008)
http://hyper.ahajournals.org/content/51/4/970/F1.expansion.html


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The diagram depicts the 2 different pathways leading to

preeclampsia or IUGR (Huppertz, 2008)


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A schematic of placentalvascular remodeling in

health (upper panel) and in

disease preeclampsia

(lower panel) (Chesley,2009).


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The diagram represents the early development of the

trophoblast lineage (Huppertz, 2008).

Inadequate

trophoblast

development vs

PIH?

PREVENTABLE?


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Redman, (1992): the processes driving maternalsystemic inflammation in pregnancy, whethernormal or pre-eclamptic, must originate in theplacenta, specifically from

the syncytiotrophoblast in direct contact with

maternal blood, orextravillous cytotrophoblast in direct contact with

decidua

central to management is delivery, which

removes the causative organ, namely theplacenta (Redman et al, 2006).


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It has been taken for granted that pre-eclampsiaoriginates with deficient placentation occurring duringthe first half of pregnancy and this has led to theconcept of a two stage disease(Redman 1991).

In this model the seeds for pre-eclampsia are sown inthefirst halfof pregnancy when full placentation fails.

The disease evolves over the second halfof pregnancywhen the signs of pre-eclampsia, are caused directly or

indirectly by increasing uteroplacental ischaemia.


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2-Stage Disorder:


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There are two components that make thesystemic inflammatory response abnormallyintense: an excessive placental stimulus, or

an overactive maternal response to a normal placental

stimulus. These two situations are termedPlacental and

Maternal pre-eclampsia respectively

Placental pre-eclampsia represents a disorder

that is specific to pregnancy whereas maternalpre-eclampsia is specific to the woman.


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The maternal illness of pre-eclampsia wasoriginally thought to be caused primarily bygeneralised maternal endothelial activation

and dysfunction (Robertset al. 1989). This concept was broadened by incorporating

endothelial dysfunction as one of severalcomponents of a maternal systemicinflammatory response in pre-eclampsia(Redman et al. 1999)


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Endothelial dysfunction in the pathogenesis

of preeclampsia (Chesley, 2009).

TRIAS ?


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Pathogenesis of Preeclampsia (Lam et al, 2005)


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Oxidant sources on the endothelium. In this

scheme, some of the potential sources of ROS derived from the

circulation or within endothelial cells are shown (Chesley, 2009)


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In placental pre-eclampsia the placenta isconsidered to suffer from the consequences ofinadequate perfusion secondary to spiral arterydysfunction, which leads to placental hypoxia,

oxidative stress and, in the most severe cases,infarction.

Two abnormalities affect the spiral arteries,which are the end-arteries that supply the

intervillous space: the arteries may be either toosmall or obstructed.


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In its purest form, maternal pre-eclampsia results fromthe interaction of a normal pregnancy and placentawith an abnormal maternal constitution(Redman,2006).

Some medical conditions are well known to predisposeto pre-eclampsia, including obesity, diabetes andchronic hypertension (tone/vasoconstriction).

The decompensation from excessive systemic

inflammation will happen earlier and at a lowerthreshold accounting for the predisposition of affectedwomen to pre-eclampsia (Redman, 2006).


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Mechanisms of insulin- mediated nitric oxide (NO) and endothelin 1 (ET-1)

production leading to vasodilatation and vasoconstriction, respectively

(Chesley, 2008)


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Systemic inflammation in pregnancy with and without conditions that cause

a chronic systemic inflammatory response (Chesley, 2009)


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Trophoblast apoptosis

Normal human syncytiotrophoblast becomes

apoptotic in relation to breaks in the syncytial

layer (Nelson 1996).

It plays a central role in turnover ofcytotrophoblast and renewal of the syncytial

surface of chorionic villi (Huppertz et al. 1998).

Oxidative stress has been shown to induceapoptotic cell death by targeting the

mitochondria directly.


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Apoptosis amounts to controlled cellfragmentation with release of subcellular

microparticles in forms that are easy to clear bymacrophages and other components of thereticuloendothelial system.

Various types of trophoblast debris (apoptotic

and non-apoptotic trophoblast fragments) thatmust originate in this way can be detected in thematernal circulation.

Not only can such debris be detected as evidence

of increased syncytiotrophoblast apoptosis but itrepresents one of the possible factors that maycause the maternal syndrome of the second stageof pre-eclampsia.


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Risk Factors(Matsubara et al, 2009)

Family history: mother vs mother in law = 14% :3%

NP vs MP = 64% vs 36%; RS M.Djamil (2010): 63vs 113 (36% vs 64%)

BMI >35: 4-fold greater

Multiple pregnancy: twin near 4-fold

Age > 40 years

Diabetic vs nondiabetic: 9.9% vs 4.3 %

ACA (+)

Long-term semen exposure


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Unadjusted probability of early preeclampsia (


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Screening Tests

Preeclampsia is an appropriate disease to

screen, as it is common, important, and

increases maternal and perinatal mortality.

However, although numerous screening tests

for preeclampsia have been proposed over the

past few decades, no test has so farbeen

shown to appropriately screen for the disease.


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Prediction

Prediction: the application of a test toasymptomatic people for the purpose ofclassifying them in respect to their likelihood ofdeveloping a particular disease at a later date

sensitivity, specificity, predictive values. When assessing a test during pregnancy, one

must also be aware that its accuracy isconditionedby the overall prevalence of the

disease in the population tested. A standard method for prediction and prevention

of PE has to be developed (Matsubara et al 2009)


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Predictive Approach(Matsubara et al, 2009)

Classical

Base theory: vascularreactivityis elevated inpregnant woman who

developed PE Blood Pressure

Roll Over Test (ROT)

Handgrip Test (HGT)

Angiotensi Sensitivity Test(AST)

Doppler Ultrasound (uterinearterial blood flow)

Modern

Endothelial Cell Activationor Dysfunction

Coagulation Cascade

Imflammatory Response

Angiogenic Growth Factor

Cell-Free Fetal DNA inMaternal Circulation

Neurokinin B Oxidative Stress


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Blood Pressure

BP 16-20 weeks, gradually toward

non pregnant level

DBP : good predictor Risk: 8% (MAP 85 mmHg)

2nd-TM MAP >90 mmHg: 62% sens, 82% spec;

>85 mmHg: 52 and 84%


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Averaged mean arterial blood pressures (W 1 SE) in women who remained normotensive

throughout pregnancy (oo), in women who developed preeclampsia (**), and in

women who developed hypertension (&&) by periods of 4 weeks (Chesley, 2009).


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ROT

BP stimulated by a change of maternal

position

DBP bedrest vs DBP after the change of

position (recumbent supine)

(+): DBP >20 mmHg

NPV: higher, reproducibility: poor


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HGT

Before 15 week gestation

BP changes by 3-5 min of sustained isometric

exercise

(+):SBP >15 mmHG during exercise or 14

mmHg immediately after exercise

NPV: 98%


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AST

Increase sensitiviy to AngII

Dose of AngII required to 20 mmHg SBP at

26-32 weeks gestation


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UABF

Fail spiral arteries remodelling utero-placental perfusionreduced

UA flow reflects SA flow PI and RI

RI: mean RI uterine arteries > 0,58 95% sens, 31% spec

PI : >1.45 80% sens, 95% spec

Arterial notch: associated with ischemic pathologic ofplacenta

Any notch 77% sens, 85% spec; Bilateral notch 65%sens, 95% spec

Reliability of PI and RI: placental position, uterinecontraction, maternal heartbeat

Easy and non-invasive methode

Sensitivity 75 %, NPV 88%


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Normal and mildly abnormal

uterine artery waveforms

(Hobbins, 2008)

notch


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Endothelial Cell Activation or Dysfunction

Endothelial cells maintain homeostasis of :

coagulation cascade, imflammatory process, and

vascular tone activation or dysfunction:

thrombosis, imflammation, HT Hemoconcentration: endot-dysf lead to

hipertensive disorder

Plasental ischemia: endot release molecules, ex.Fibronectin

Plasma fibronectin conc.: significantly increased


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Coagulation Cascade

APTT, PT, factor VIIIa, free protein S

PAI-1/PAI-2

PlGF

Serum PAI-1 level in PE and normal pregnancy

108.96 + 29.93 ng/ml and 40.67 ng/ml

(p


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Imflammatory Response

In rats: TNF and proimflammatory citokin

caused hypertension

Serum TNF before the onset of PE

soluble adhesion molecules sE-selectin and

sICAM-1 in the 1st trimester TNF promotes ICAM-1 and sE-selectin activation

on endoth cells and facilitates the membranebound ICAM-1 and sE-selectin into the blood by

shedding

TNF activated endoth cells and promotes theexpression of adhesion molecules


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Imflammatory Response (contd)

Endoth activation or dysfuntionprostacyclin and NO impaired vascularrelaxation

Significantly of serum NO level in PE

compared with normal pregnancy (Erwandiand Joserizal, 2006)

Significantlymaternal inflammatoryresponse (leucocyte, neutrophyl, monocyte,kalprotectin) in PE compared with normalpregnancy (Taufiq and Joserizal, 2010)


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Angiogenic Growth Factor

VEGF and PlGF: pro-angiogenic factor

role in spiral arteryremodelling

Serum PlGF level 1st and 2nd tm, peaking early in 3rd tm

before 20 weeks: in who would later develop PE

Soluble fms-like tyrosine kinase 1 (sFlt-1), anti angiogenic proteinin PE

sFlt-1 binds with VEGF and PlGF preventing interaction withendothelial dysfunction

sFlt-1 + VEGF and Pl GF 5 weeks before the onset of PE

2528 weeks + sFlt-1 957 ng/L 88% sens, 100% spec (Chesley,2009)

Simas et al (2007): sFlt- and sFlt-1/PlGF ratio are altered prior to PEonset and may be predictive of PE.

sFlt-1 level was associated with hystory of PE (Roni and Joserizal,2010)


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Mean levels of sFlt1/PlGFand soluble endoglin

(sEng) and by weeks before

the onset of preeclampsia.

(Chesley, 2009)


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Cell-Free Fetal DNA

Primarily derived from placenta; is not correlated withfetal white or nucleated RBC counts, or the amount offetal DNA

Syncytiotrophoblast microparticles (including cel-free

DNA and mRNA) are released from the surface ofplacenta into the maternal circulation

Significant in the shedding of cellular debris, iesyncytiotrophoblast-microparticles (due to sincytial

apoptosis caused by placental hypoxia in PE) The sensitivity and specificity:ranged between 33 and

67%, 82 and 95% (Chesley, 2009)


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Neurokinin B

Biological actions: smooth muscle contraction,pain transmission, neurogenic imflammation,activation of immune system

Originate mainly from the placenta

Normally: can be detected in early 9th weeksgestation, in mid and late pregnancy, rapidlyafter delivery

Markedly in PE; and so its receptor TAC3.

Activation of TAC3 by neurokinin B bloodflow through the liver to satisfy the needs of theuterus and placenta


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Oxidative Stress

Beneficial effect of uric acid: antioxidant activity,

conversly its has prooxidant activity (due to thepotential of urat free radical to oxidatively modifyplacental protein and lipids) when other antioxidantsare at low level, and stimulates the imflammatoryprocess that lead to endothelial dysfunction.

In PE: plasma concentration of uric acid at about 10weeks preceed the clinical presentation of PE.

Oxidative stressmalonedialdehyde )MDA/majormetabolite of lipid peroxida) endothelial cellactivation

In PE: antioxidant capacity, glutathione and vit C

In PE: significant negative corelation between vit Cintake and MDA level (Azadivon and Joserizal, 2008)


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Prevention

Prevention of preeclampsia: a big disappointment (Sibai,

1996) Most studies designed on theoretical bases to reduce the

incidence of preeclampsia in either low- or high-riskwomen have been disappointingmainly due to lowsensitivity and positive-predictive value, and thus are not

suitable for routine clinical use. Regimens that have been studied by randomized controlled

trials Dietary manipulations (Low-salt diet Fish oil supplementation

Calcium supplementation)

Cardiovascular drugs (DiureticsAntihypertensive drugs) Antioxidants (Ascorbic acid / vit C), a-Tocopherol / vit E)

Antithrombotic drugs (Low-dose aspirin Aspirin/dipyridamole,Aspirin + heparin, Aspirin + ketanserin)


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PreventionAspirin

Sibai (1998): hoped-for benefit from low-dose aspirin has not beenrealized, and lowdose aspirin might not be the wonder drugafter all.

Heyborne (2000): it is premature to abandon the use of low-doseaspirin therapy to pE prevention

A systematic review of 14 trials using low-dose aspirin (60-150mg/d) in women with risk factors for preeclampsia concluded thataspirin reduced the risk of preeclampsia and perinatal death,although it did not significantly affect birth weight or the risk ofabruption.

Low-dose aspirin in unselected nulliparous women seems to reduce

the incidence of preeclampsia only slightly (Chesley, 2009). For women with risk factors for preeclampsia, starting low-dose

aspirin (commonly, 1 tablet of baby aspirin per day), beginning at12-14 weeks' gestation, is reasonable. The safety of low-doseaspirin use in the second and third trimesters is well established.


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Prevention

Heparin

The use of lowmolecular weight heparin in

women with thrombophilia who have a

history of adverse outcome has been

investigated. To date, however, no data

suggest that the use of heparin prophylaxis

lowers the incidence of preeclampsia.


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Prevention

Dietary manipulations Knuist et al. (1998): no benefits of prescribing a lowsodium

intake in reducing the rate of preeclampsia (a randomizedmulticenter trial).

In a multicenter, randomized, controlled trial, Villar et alfound that at the doses used for supplementation, vitaminsC and E were not associated with a reduction ofpreeclampsia, eclampsia, gestational hypertension, or anyother maternal outcome (from Chesley, 2009).Supplementation with vit C and E during pregnancy does

not prevent PE; metaanalysis ( Agudelo et al, 2011). Lowbirthweight, small for gestational age, and perinatal deathswere also unaffected.


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Prevention

Dietary manipulations

Morris et al (2001): no indication that the intake

of any nutrient was related to the incidence of PE

or pregnancy-associated hypertension (evidencefrom a large cohort study)

PE prevention with calcium supplementation is

unlikely to be achieved except perhaps in high-risk populations that are chronically calcium

deficient(Chesley,2009, from several studies).


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Hypothetic Model

Preventable ??!!

Encourage patient participation

Early detection

Colaboration between Health Services andReligion Department:

Premarital Counceling : (+)

Message card (included in Buku Nikah)greeting, guarding against signs and symptoms,prompt consultation


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Selamat BerbahagiaSemoga Mendapatkan Keturunan yangSehat dan SolehWaspadailah kehamilan disertai

preeklampsia, penyebab utamakematian ibu dan bayi; dengan gejala

dan tanda:

Tekanan darah lebih dari 140/90

Adanya pembengkakan pada kaki dantangan

Sakit kepala berat

Nyeri ulu hati

Pandangan kabur

Buang air kecil keruh

Jangan tunggu munculnya gejala dantanda, lebih baik konsultasi dini

kehamilan ke rumah sakit denganfasilitas yang lengkap.


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Padang city (Dept. of Religion):

6,996 new couples in 2010.

7 % infert : m/l 1.000 couples

6,000 PG 60% beyond 20 weeks(3,600)

>250 PE/E-PG pats per year

Compared to the inc. of 2010: 4 folds (250 vs 63)

about to start.

Plausible ???


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Perspectives and Conclusions

It is evident at the present time that there is

no clinically useful test to predict

preeclampsia.

Investigations of PE prediction and prevention

have not been completely successful

The prediction and prevention of PE remains a

clinical issue in maternal and fetal health areally challenge in FM field!!!


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Documents

Minimizing the Occurence and Complications of Preeclampsia