Minimizing the Occurence and Complications of Preeclampsia
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Transcript of 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)
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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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