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21/8/2016

Preeclampsia:PracticeEssentials,Overview,Pathophysiology

Preeclampsia
Author:KeeHakLim,MDChiefEditor:RonaldMRamus,MDmore...
Updated:Feb03,2016

PracticeEssentials
Preeclampsiaisadisorderofwidespreadvascularendothelialmalfunctionand
vasospasmthatoccursafter20weeks'gestationandcanpresentaslateas46
weekspostpartum.Itisclinicallydefinedbyhypertensionandproteinuria,withor
withoutpathologicedema.

Definitions
Preeclampsiaisdefinedasthepresenceof(1)asystolicbloodpressure(SBP)
greaterthanorequalto140mmHgoradiastolicbloodpressure(DBP)greater
thanorequalto90mmHgorhigher,ontwooccasionsatleast4hoursapartina
previouslynormotensivepatient,OR(2)anSBPgreaterthanorequalto160mm
HgoraDBPgreaterthanorequalto110mmHgorhigher(Inthiscase,
hypertensioncanbeconfirmedwithinminutestofacilitatetimelyantihypertensive
therapy.). [1]
Inadditiontothebloodpressurecriteria,proteinuriaofgreaterthanorequalto0.3
gramsina24hoururinespecimen,aprotein(mg/dL)/creatinine(mg/dL)ratioof0.3
orhigher,oraurinedipstickproteinof1+(ifaquantitativemeasurementis
unavailable)isrequiredtodiagnosepreeclampsia. [1]
Preeclampsiawithseverefeaturesisdefinedasthepresenceofoneofthe
followingsymptomsorsignsinthepresenceofpreeclampsia[1]:
SBPof160mmHgorhigherorDBPof110mmHgorhigher,ontwo
occasionsatleast4hoursapartwhilethepatientisonbedrest(unless
antihypertensivetherapyhaspreviouslybeeninitiated)
Impairedhepaticfunctionasindicatedbyabnormallyelevatedblood
concentrationsofliverenzymes(todoublethenormalconcentration),severe
persistentupperquadrantorepigastricpainthatdoesnotrespondto
pharmacotherapyandisnotaccountedforbyalternativediagnoses,orboth.
Progressiverenalinsufficiency(serumcreatinineconcentration>1.1mg/dLor
adoublingoftheserumcreatinineconcentrationintheabsenceofother
renaldisease)
Newonsetcerebralorvisualdisturances
Pulmonaryedema
Thrombocytopenia(plateletcount<100,000/L)
Inapatientwithnewonsethypertensionwithoutproteinuria,thenewonsetofany
ofthefollowingisdiagnosticofpreeclampsia:
Plateletcountbelow100,000/L
Serumcreatininelevelabove1.1mg/dLordoublingofserumcreatininein
theabsenceofotherrenaldisease
Livertransaminaselevelsatleasttwicethenormalconcentrations
Pulmonaryedema
Cerebralorvisualsymptoms
Eclampsiaisdefinedasseizuresthatcannotbeattributabletoothercausesina
womanwithpreeclampsia.HELLPsyndrome(hemolysis,elevatedliverenzyme,low
platelets)maycomplicateseverepreeclampsia.

Riskfactors
Riskfactorsforpreeclampsiaandtheiroddsratiosareasfollows[2]:
Nulliparity(3.1)
Ageolderthan40years(3:1)
Blackrace(1.5:1)
Familyhistory(5:1)
Chronicrenaldisease(20:1)
Chronichypertension(10:1)
Antiphospholipidsyndrome(10:1)
Diabetesmellitus(2:1)
Twingestation(butunaffectedbyzygosity)(4:1)
Highbodymassindex(3:1)
HomozygosityforangiotensinogengeneT235(20:1)
HeterozygosityforangiotensinogengeneT235(4:1)

Signsandsymptoms

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Becausetheclinicalmanifestationsofpreeclampsiacanbeheterogeneous,
diagnosingpreeclampsiamaynotbestraightforward.Preeclampsiawithoutsevere
featuresmaybeasymptomatic.Manycasesaredetectedthroughroutineprenatal
screening.
Patientswithpreeclampsiawithseverefeaturesdisplayendorganeffectsandmay
complainofthefollowing:
Headache
Visualdisturbances:Blurred,scintillatingscotomata
Alteredmentalstatus
Blindness:Maybecortical [3]orretinal
Dyspnea
Edema:Suddenincreaseinedemaorfacialedema
Epigastricorrightupperquadrantabdominalpain
Weaknessormalaise:Maybeevidenceofhemolyticanemia
Clonus:Mayindicateanincreasedriskofconvulsions

Diagnosis
Allwomenwhopresentwithnewonsethypertensionshouldhavethefollowing
tests:
CBC
Serumalanineaminotransferase(ALT)andaspartateaminotransferase
(AST)levels
Serumcreatinine
Uricacid
24hoururinecollectionforproteinandcreatinine(criterionstandard)orurine
dipstickanalysis
AdditionalstudiestoperformifHELLPsyndromeissuspectedareasfollows:
Peripheralbloodsmear
Serumlactatedehydrogenase(LDH)level
Indirectbilirubin
Althoughacoagulationprofile(prothrombintime[PT],activatedpartial
thromboplastintime[aPTT],andfibrinogen)shouldalsobeevaluated,itsclinical
valueisunclearwhentheplateletcountis100,000/mm3ormorewithnoevidence
ofbleeding. [4]
HeadCTscanningisusedtodetectintracranialhemorrhageinselected
patientswithanyofthefollowing:
Suddensevereheadaches
Focalneurologicdeficits
Seizureswithaprolongedpostictalstate
Atypicalpresentationforeclampsia
Otherprocedures
Ultrasonography:Transabdominal,toassessthestatusofthefetusand
evaluateforgrowthrestrictionumbilicalarteryDopplerultrasonography,to
assessbloodflow
Cardiotocography:Thestandardfetalnonstresstestandthemainstayof
fetalmonitoring

Management
Deliveryistheonlycureforpreeclampsia.Patientswithpreeclampsiawithout
severefeaturesareofteninducedafter37weeks'gestation.Beforethis,thepatient
isusuallyhospitalizedandmonitoredcarefullyforthedevelopmentofworsening
preeclampsiaorcomplicationsofpreeclampsia,andtheimmaturefetusistreated
withexpectantmanagementwithcorticosteroidstoacceleratelungmaturityin
preparationforearlydelivery.
Inpatientswithpreeclampsiawithseverefeatures,inductionofdeliveryshouldbe
consideredafter34weeks'gestation.Inthesecases,theseverityofdiseasemust
beweighedagainsttherisksofinfantprematurity.Intheemergencysetting,control
ofBPandseizuresshouldbepriorities.
Criteriafordelivery
Womenwithpreeclampsiawithseverefeatureswhoaremanagedexpectantlymust
bedeliveredunderthefollowingcircumstances:
Nonreassuringfetaltestingincluding(nonreassuringnonstresstest,
biophysicalprofilescore,and/orpersistentabsentorreverseddiastolicflow
onumbilicalarteryDopplervelocimetry)
Rupturedmembranes
UncontrollableBP(unresponsivetomedicaltherapy)
Oligohydramnios,withamnioticfluidindex(AFI)oflessthan5cm
Severeintrauterinegrowthrestrictioninwhichtheestimatedfetalweightis
lessthan5%
Oliguria(<500mL/24hr)
Serumcreatininelevelofatleast1.5mg/dL
Pulmonaryedema

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Shortnessofbreathorchestpainwithpulseoximetryof<94%onroomair
Headachethatispersistentandsevere
Rightupperquadranttenderness
DevelopmentofHELLPsyndrome
Eclampsia
Plateletcountlesstha100,000cells/microL
Placentalabruption
Unexplainedcoagulopathy
Seizuretreatmentandprophylaxis
Thebasicprinciplesofairway,breathing,andcirculation(ABC)should
alwaysbefollowed
Magnesiumsulfateisthefirstlinetreatmentforprimaryandrecurrent
eclampticseizures
TreatactiveseizureswithIVmagnesiumsulfate [5]:Aloadingdoseof4gis
givenbyinfusionpumpover510minutes,followedbyaninfusionof1g/hr
maintainedfor24hoursafterthelastseizure
Treatrecurrentseizureswithanadditionalbolusof2goranincreaseinthe
infusionrateto1.5or2gperhour
Prophylactictreatmentwithmagnesiumsulfateisindicatedforallpatients
withpreeclampsiawithseverefeatures
Lorazepamandphenytoinmaybeusedassecondlineagentsforrefractory
seizures
Acutetreatmentofseverehypertensioninpregnancy
Antihypertensivetreatmentisrecommendedforseverehypertension(SBP>160
mmHgDBP>110mmHg).ThegoalofhypertensiontreatmentistomaintainBP
around140/90mmHg.
MedicationsusedforBPcontrolincludethefollowing:
Hydralazine
Labetalol
Nifedipine
Sodiumnitroprusside(inseverehypertensiveemergencyrefractorytoother
medications)
Fluidmanagement
Diureticsshouldbeavoided
Aggressivevolumeresuscitationmayleadtopulmonaryedema
Patientsshouldbefluidrestrictedwhenpossible,atleastuntiltheperiodof
postpartumdiuresis
Centralvenouspressure(CVP)orpulmonaryarterypressuremonitoringmay
beindicatedincriticalcases
ACVPof5mmHginwomenwithnoheartdiseaseindicatessufficient
intravascularvolume,andmaintenancefluidsalonearesufficient
Totalfluidsshouldgenerallybelimitedto80mL/hror1mL/kg/hr
Postpartummanagement
Manypatientswillhaveabrief(upto6hours)periodofoliguriafollowing
delivery
Magnesiumsulfateseizureprophylaxisiscontinuedfor24hourspostpartum
Liverfunctiontestsandplateletcountsmustdocumentdecreasingvalues
priortohospitaldischarge
ElevatedBPmaybecontrolledwithnifedipineorlabetalolpostpartum
IfapatientisdischargedwithBPmedication,reassessmentandaBPcheck
shouldbeperformed,atthelatest,1weekafterdischarge
Unlessawomanhasundiagnosedchronichypertension,inmostcasesof
preeclampsia,theBPreturnstobaselineby12weekspostpartum
Patientsshouldbecarefullymonitoredforrecurrentpreeclampsia,whichmay
developupto4weekspostpartum,andforeclampsiathathasoccurredup
to6weeksafterdelivery

Overview
Preeclampsiaisadisorderofwidespreadvascularendothelialmalfunctionand
vasospasmthatoccursafter20weeks'gestationandcanpresentaslateas46
weekspostpartum.Itisclinicallydefinedbyhypertensionandproteinuria,withor
withoutpathologicedema. [6]
TheincidenceofpreeclampsiaintheUnitedStatesisestimatedtorangefrom2%
to6%inhealthy,nulliparouswomen. [7,8,9]Amongallcasesofthepreeclampsia,
10%occurinpregnanciesoflessthan34weeks'gestation.Theglobalincidenceof
preeclampsiahasbeenestimatedat514%ofallpregnancies.
Indevelopingnations,theincidenceofthediseaseisreportedtobe418%, [10,11]
withhypertensivedisordersbeingthesecondmostcommonobstetriccauseof
stillbirthsandearlyneonataldeathsinthesecountries. [12]
Medicalconsensusislackingregardingthevaluesthatdefinepreeclampsia,but
reasonablecriteriainawomanwhowasnormotensivebefore20weeks'gestation
includeasystolicbloodpressure(SBP)greaterthan140mmHgandadiastolicBP
(DBP)greaterthan90mmHgontwosuccessivemeasurements,4hoursapart.

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Preeclampsiaandpreeclampsiawithseverefeatures
Severepreeclampsiaaccountsforapproximately25%ofallcasesofpreeclampsia.
[5]Initsextreme,thediseasemayleadtoliverandrenalfailure,disseminated
intravascularcoagulopathy(DIC),andcentralnervoussystem(CNS)abnormalities.
Ifpreeclampsiaassociatedseizuresdevelop,thedisorderhasdevelopedintothe
conditioncalledeclampsia.
Preeclampsiaisdefinedasthepresenceof(1)asystolicbloodpressure(SBP)
greaterthanorequalto140mmHgoradiastolicbloodpressure(DBP)greater
thanorequalto90mmHgorhigher,ontwooccasionsatleast4hoursapartina
previouslynormotensivepatient,OR(2)anSBPgreaterthanorequalto160mm
HgoraDBPgreaterthanorequalto110mmHgorhigher(Inthiscase,
hypertensioncanbeconfirmedwithinminutestofacilitatetimelyantihypertensive
therapy.). [1]
Inadditiontothebloodpressurecriteria,proteinuriaofgreaterthanorequalto0.3
gramsina24hoururinespecimen,aprotein(mg/dL)/creatinine(mg/dL)ratioof0.3
orhigher,oraurinedipstickproteinof1+(ifaquantitativemeasurementis
unavailable)isrequiredtodiagnosepreeclampsia. [1]
Preeclampsiawithseverefeaturesisdefinedasthepresenceofoneofthe
followingsymptomsorsignsinthepresenceofpreeclampsia[1]:
SBPof160mmHgorhigherorDBPof110mmHgorhigher,ontwo
occasionsatleast4hoursapartwhilethepatientisonbedrest(unless
antihypertensivetherapyhaspreviouslybeeninitiated)
Impairedhepaticfunctionasindicatedbyabnormallyelevatedblood
concentrationsofliverenzymes(todoublethenormalconcentration),severe
persistentupperquadrantorepigastricpainthatdoesnotrespondto
pharmacotherapyandisnotaccountedforbyalternativediagnoses,orboth.
Progressiverenalinsufficiency(serumcreatinineconcentration>1.1mg/dLor
adoublingoftheserumcreatinineconcentrationintheabsenceofother
renaldisease)
Newonsetcerebralorvisualdisturances
Pulmonaryedema
Thrombocytopenia(plateletcount<100,000/L)
Also,apatientwithnewonsethypertensionwithoutproteinuriacanbediagnosedif
anyofthefollowingispresent [1]:
Plateletcountbelow100,000/L
Serumcreatininelevelabove1.1mg/dLordoublingofserumcreatininein
theabsenceofotherrenaldisease
Livertransaminaselevelsatleasttwicethenormalconcentrations
Pulmonaryedema
Cerebralorvisualsymptoms

Classificationandcharacteristicsofhypertensivedisorders
Preeclampsiaispartofaspectrumofhypertensivedisordersthatcomplicate
pregnancy.AsspecifiedbytheNationalHighBloodPressureEducationProgram
(NHBPEP)WorkingGroup,theclassificationisasfollows[13]:
Gestationalhypertension
Chronichypertension
Preeclampsia/eclampsia
Superimposedpreeclampsia(onchronichypertension)
Althougheachofthesedisorderscanappearinisolation,theyarethoughtofas
progressivemanifestationsofasingleprocessandarebelievedtoshareacommon
etiology.

Gestationalhypertension
Thecharacteristicsofgestationalhypertensionareasfollows:
BPof140/90mmHgorgreaterforthefirsttimeduringpregnancy
Noproteinuria
BPreturnstonormallessthan12weeks'postpartum
Finaldiagnosismadeonlypostpartum

Chronichypertension
Chronichypertensionischaracterizedbyeither(1)aBP140/90mmHgorgreater
beforepregnancyordiagnosedbefore20weeks'gestationnotattributableto
gestationaltrophoblasticdiseaseor(2)hypertensionfirstdiagnosedafter20weeks'
gestationandpersistentafter12weekspostpartum.
Preexistingchronichypertensionmaypresentwithsuperimposedpreeclampsia
presentingasnewonsetproteinuriaafter20weeks'gestation.

Preeclampsia/eclampsia
Preeclampsia/eclampsiaischaracterizedbyaBPof140/90mmHgorgreaterafter
20weeks'gestationinawomenwithpreviouslynormalBPandwhohave

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proteinuria(0.3gproteinin24hurinespecimen).
Eclampsiaisdefinedasseizuresthatcannotbeattributabletoothercauses,ina
womanwithpreeclampsia

Superimposedpreeclampsia
Superimposedpreeclampsia(onchronichypertension)ischaracterizedby(1)new
onsetproteinuria(300mg/24h)inawomanwithhypertensionbutnoproteinuria
before20weeks'gestationand(2)asuddenincreaseinproteinuriaorBP,ora
plateletcountoflessthan100,000/mm3,inawomanwithhypertensionand
proteinuriabefore20weeks'gestation.

HELLPsyndrome
HELLPsyndrome(hemolysis,elevatedliverenzyme,lowplatelets)maybean
outcomeofseverepreeclampsia,althoughsomeauthorsbelieveittohavean
unrelatedetiology.Thesyndromehasbeenassociatedwithparticularlyhigh
maternalandperinatalmorbidityandmortalityratesandmaybepresentwithout
hypertensionor,insomecases,withoutproteinuria.

Proteinuria
Proteinuriaisdefinedasthepresenceofatleast300mgofproteinina24hour
urinecollection,aprotein(mg/dL)/creatinine(mg/dL)ratiogreaterthanorequalto
0.3,oraurinedipstickproteinof1+(ifaquantitativemeasurementisunavailable).
[14]Serialconfirmations6hoursapartincreasethepredictivevalue.Althoughmore
convenient,aurinedipstickvalueof1+ormore(30mg/dL)isnotreliableinthe
diagnosisofproteinuria.

Pathophysiology
Anestimated28%ofpregnanciesarecomplicatedbypreeclampsia,with
associatedmaternofetalmorbidityandmortality. [15]Inthefetus,preeclampsiacan
leadtoischemicencephalopathy,growthretardation,andthevarioussequelaeof
prematurebirth.
Eclampsiaisestimatedtooccurin1in200casesofpreeclampsiawhen
magnesiumprophylaxisinnotadministered.(SeeSeizureProphylaxis.)[16,17]

Cardiovasculardisease
Aspreviouslymentioned,preeclampsiaischaracterizedbyendothelialdysfunction
inpregnantwomen.Therefore,thepossibilityexiststhatpreeclampsiamaybea
contributortofuturecardiovasculardisease.Inametaanalysis,severalassociations
wereobservedbetweenanincreasedriskofcardiovasculardiseaseandapregnancy
complicatedbypreeclampsia.Theseassociationsincludedanapproximately4fold
increaseintheriskofsubsequentdevelopmentofhypertensionandan
approximately2foldincreaseintheriskofischemicheartdisease,venous
thromboembolism,andstroke. [18]Moreover,womenwhohadrecurrent
preeclampsiaweremorelikelytosufferfromhypertensionlaterinlife. [18]
Inareviewofpopulationbasedstudies,HarskampandZeemannoteda
relationshipbetweenpreeclampsiaandanincreasedriskoflaterchronic
hypertensionandcardiovascularmorbidity/mortality,comparedwithnormotensive
pregnancy.Moreover,womenwhodeveloppreeclampsiabefore36weeks'gestation
orwhohavemultiplehypertensivepregnancieswereathighestrisk. [19]
HarskampandZeemanalsofoundthattheunderlyingmechanismfortheremote
effectsofpreeclampsiaiscomplexandprobablymultifactorial.Theriskfactorsthat
aresharedbycardiovasculardiseaseandpreeclampsiaareasfollows:
Endothelialdysfunction
Obesity
Hypertension
Hyperglycemia
Insulinresistance
Dyslipidemia
Metabolicsyndrome,theinvestigatorsnoted,maybeapossibleunderlying
mechanismcommontocardiovasculardiseaseandpreeclampsia.

Mechanismsbehindpreeclampsia
Althoughhypertensionmaybethemostcommonpresentingsymptomof
preeclampsia,itshouldnotbeviewedastheinitialpathogenicprocess.
Themechanismsbywhichpreeclampsiaoccursisnotcertain,andnumerous
maternal,paternal,andfetalfactorshavebeenimplicatedinitsdevelopment.The
factorscurrentlyconsideredtobethemostimportantincludethefollowing[20]:
Maternalimmunologicintolerance
Abnormalplacentalimplantation
Genetic,nutritional,andenvironmentalfactors
Cardiovascularandinflammatorychanges

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ImmunologicFactorsinPreeclampsia
Immunologicfactorshavelongbeenconsideredtobekeyplayersinpreeclampsia.
Oneimportantcomponentisapoorlyunderstooddysregulationofmaternal
tolerancetopaternallyderivedplacentalandfetalantigens. [21]Thismaternalfetal
immunemaladaptationischaracterizedbydefectivecooperationbetweenuterine
naturalkiller(NK)cellsandfetalhumanleukocyteantigen(HLA)C,andresultsin
histologicchangessimilartothoseseeninacutegraftrejection.
Theendothelialcelldysfunctionthatischaracteristicofpreeclampsiamaybe
partiallyduetoanextremeactivationofleukocytesinthematernalcirculation,as
evidencedbyanupregulationoftype1helperTcells.

PlacentationinPreeclampsia
Placentalimplantationwithabnormaltrophoblasticinvasionofuterinevesselsisa
majorcauseofhypertensionassociatedwithpreeclampsiasyndrome. [22,23]Infact,
studieshaveshownthatthedegreeofincompletetrophoblasticinvasionofthe
spiralarteriesisdirectlycorrelatedwiththeseverityofsubsequentmaternal
hypertension.Thisisbecausetheplacentalhypoperfusionresultingfromthe
incompleteinvasionleadsbyanunclearpathwaytothereleaseofsystemic
vasoactivecompoundsthatcauseanexaggeratedinflammatoryresponse,
vasoconstriction,endothelialdamage,capillaryleak,hypercoagulability,andplatelet
dysfunction,allofwhichcontributetoorgandysfunctionandthevariousclinical
featuresofthedisease. [6]

Normalplacentationandpseudovascularization
Innormalpregnancies,asubsetofcytotrophoblastscalledinvasivecytotrophoblasts
migratethroughtheimplantationsiteandinvadedeciduatunicamediaofmaternal
spiralarteriesandreplaceitsendotheliuminaprocesscalledpseudovascularization.
[24]Thetrophoblastdifferentiationalongtheinvasivepathwayinvolvesalterationin
theexpressionofanumberofdifferentclassesofmolecules,includingcytokines,
adhesionmolecules,extracellularmatrix,metalloproteinases,andtheclassIbmajor
histocompatibilitycomplex(MHC)molecule,HLAG. [25,26]
Forexample,duringnormaldifferentiation,invadingtrophoblastsaltertheir
adhesionmoleculeexpressionfromthosethatarecharacteristicofepithelialcells
(integrinsalpha6/beta1,alphaV/beta5,andEcadherin)tothoseofendothelial
cells(integrinsalpha1/beta1,alphaV/beta3,andVEcadherin).
Asaresultofthesechanges,thematernalspiralarteriesundergotransformation
fromsmall,musculararteriolestolargecapacitance,lowresistancevessels.This
allowsincreasedbloodflowtothematernalfetalinterface.Remodelingofthese
arteriolesprobablybeginsinthefirsttrimesterandendsby1820weeks'gestation.
However,theexactgestationalageatwhichtheinvasionstopsisunknown.

Failureofpseudovascularizationinpreeclampsia
Theshallowplacentationnotedinpreeclampsiaresultsfromthefactthatthe
invasionofthedecidualarteriolesbycytotrophoblastsisincomplete.Thisisduetoa
failureinthealterationsinmolecularexpressionnecessaryforthedifferentiationof
thecytotrophoblasts,asrequiredforpseudovascularization.Forexample,the
upregulationofmatrixmetalloproteinase9(MMP9)andHLAG,2moleculesnoted
innormallyinvadingcytotrophoblasts,doesnotoccur.
Theinvasivecytotrophoblaststhereforefailtoreplacetunicamedia,whichmeans
thatmostlyintactarterioles,whicharecapableofvasoconstriction,remain.
Histologicevaluationoftheplacentalbeddemonstratesfewcytotrophoblasts
beyondthedeciduallayer.
Theprimarycauseforthefailureoftheseinvasivecytotrophoblaststoundergo
pseudovascularizationandinvadematernalbloodvesselsisnotclear.However,
immunologicandgeneticfactorshavebeenproposed.Earlyhypoxicinsultto
differentiatingcytotrophoblastshasalsobeenproposedasacontributingfactor.

EndothelialDysfunction
Datashowthatanimbalanceofproangiogenicandantiangiogenicfactorsproduced
bytheplacentamayplayamajorroleinmediatingendothelialdysfunction.
Angiogenesisiscriticalforsuccessfulplacentationandthenormalinteraction
betweentrophoblastsandendothelium.(SeeAngiogenicFactorsinPreeclampsia,
below.)
Severalcirculatingmarkersofendothelialcellinjuryhavebeenshowntobe
elevatedinwomenwhodeveloppreeclampsiabeforetheybecamesymptomatic.
Theseincludeendothelin,cellularfibronectin,andplasminogenactivatorinhibitor1,
withanalteredprostacyclin/thromboxaneprofilealsopresent. [3,27]
Evidencealsosuggeststhatoxidativestress,circulatorymaladaptation,
inflammation,andhumoral,mineral,andmetabolicabnormalitiescontributetothe
endothelialdysfunctionandpathogenesisofpreeclampsia.

AngiogenicFactorsinPreeclampsia
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Thecirculatingproangiogenicfactorssecretedbytheplacentaincludevascular
endothelialgrowthfactor(VEGF)andplacentalgrowthfactor(PlGF).The
antiangiogenicfactorsincludesolublefmsliketyrosinekinaseIreceptor(sFlt1)
(otherwiseknownassolubleVEGFreceptortypeI)andsolubleendoglin(sEng).

VEGFandPlGF
VEGFandPlGFpromoteangiogenesisbyinteractingwiththeVEGFreceptor
family.Althoughbothgrowthfactorsareproducedbyplacenta,theserumlevelof
PlGFrisesmuchmoresignificantlyinpregnancy.Inastudy,Tayloretal
demonstratedthattheserumlevelofPlGFdecreasedinwomenwholater
developedpreeclampsia. [28]Thefallinserumlevelwasnotableasearlyasthe
secondtrimesterinwomenwhodevelopedpreeclampsiaandintrauterinegrowth
restriction.
Inanotherinvestigation,MaynardetalobservedthattheserumlevelsofVEGFand
PlGFweredecreasedinwomenwithpreeclampsia. [29]However,themagnitudeof
decreasewaslesspronouncedforVEGF,asitsserumlevelwasnotashighasthat
ofPlGF,eveninnormalpregnancy.Otherinvestigatorshaveconfirmedthisfinding
andhaveshownthattheserumlevelofPlGFdecreasedinwomenbeforethey
developedpreeclampsia. [30,31]
BillsetalsuggestthatcirculatingVEGFAlevelsinpreeclampsiaarebiologically
activebecauseofalossofrepressionofVEGFreceptor1signalingbyPlGF1,and
VEGF165bmaybeinvolvedintheincreasedvascularpermeabilityofpreeclampsia.
[32]

Solublefmsliketyrosinekinase1receptor
ThereceptorsFlt1isasolubleisoformofFlt1,whichisatransmembranereceptor
forVEGF.AlthoughsFlt1lacksthetransmembranedomain,itcontainstheligand
bindingregionandiscapableofbindingcirculatingVEGFandPlGF,preventing
thesegrowthfactorsfrombindingtotransmembranereceptors.Thus,sFlt1hasan
antiangiogeniceffect.
Inadditiontoangiogenesis,VEGFandPlGFareimportantinmaintaining
endothelialhomeostasis.SelectiveknockoutoftheglomerularVEGFgenehas
beenshowntobelethalinrats,whereastheheterozygoteswerebornwith
glomerularendotheliosis(therenallesioncharacteristicofpreeclampsia)and
eventuallyrenalfailure.Furthermore,sFlt1,wheninjectedintopregnantrats,
producedhypertensionandproteinuriaalongwithglomerularendotheliosis. [29]
Inadditiontoanimalstudies,multiplestudiesinhumanshavedemonstratedthat
excessproductionofsFlt1isassociatedwithanincreasedriskofpreeclampsia.In
acasecontrolstudythatmeasuredlevelsofsFlt1,VEGF,andPlGF,investigators
foundanearlierandgreaterincreaseintheserumlevelofsFlt1inwomenwho
developedpreeclampsia(2124wk)thaninwomenwhodidnotdevelop
preeclampsia(3336wk),whereastheserumlevelsofVEGFandPlGFdeceased.
Furthermore,theserumlevelofsFlt1washigherinwomenwhodevelopedsevere
preeclampsiaorearlypreeclampsia(<34wk)thanitwasinwomenwhodeveloped
mildpreeclampsiaatterm. [30]

Solubleendoglin
sEngisasolubleisoformofcoreceptorfortransforminggrowthfactorbeta(TGF
beta).EndoglinbindstoTGFbetainassociationwiththeTGFbetareceptor.
BecausethesolubleisoformcontainstheTGFbetabindingdomain,itcanbindto
circulatingTGFbetaanddecreasecirculatinglevels.Inaddition,TGFbetaisa
proangiogenicmolecule,sotheneteffectofhighlevelsofsEngisantiangiogenic.
SeveralobservationssupporttheroleofsEnginthepathogenesisofpreeclampsia.
Itisfoundinthebloodofwomenwithpreeclampsiaupto3monthsbeforethe
clinicalsignsofthecondition,itslevelinmaternalbloodcorrelateswithdisease
severity,andthelevelofsEngintheblooddropsafterdelivery. [33]
Instudiesonpregnantrats,administrationofsEngresultsinvascularpermeability
andcauseshypertension.Thereisalsoevidencethatithasasynergistic
relationshipwithsFlt1,becauseitincreasestheeffectsofsFlt1inpregnantrats
thisresultsinHELLPsyndrome,asevidencedbyhepaticnecrosis,hemolysis,and
placentalinfarction. [34]Moreover,sEnginhibitsTGFbetainendothelialcellsand
alsoinhibitsTGFbeta1activationofnitricoxidemediatedvasodilatation.

GeneticFactorsinPreeclampsia
Preeclampsiahasbeenshowntoinvolvemultiplegenes.Over100maternaland
paternalgeneshavebeenstudiedfortheirassociationwithpreeclampsia,including
thoseknowntoplayaroleinvasculardiseases,BPregulation,diabetes,and
immunologicfunctions.
Importantly,theriskofpreeclampsiaispositivelycorrelatedbetweencloserelatives
astudyshowedthat2040%ofdaughtersand1137%ofsistersofwomenwith
preeclampsiaalsodevelopedthedisease. [21]Twinstudieshaveshownahigh
correlationaswell,approaching40%.

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Becausepreeclampsiaisageneticallyandphenotypicallycomplexdisease,itis
unlikelythatanysinglegenewillbeshowntoplayadominantroleinits
development.

AdditionalFactorsinPreeclampsia
Othersubstancesthathavebeenproposed,butnotproven,tocontributeto
preeclampsiaincludetumornecrosisfactor,interleukins,variouslipidmolecules,
andsyncytialknots. [35]

RiskFactorsforPreeclampsia
Theincidenceofpreeclampsiaishigherinwomenwithahistoryofpreeclampsia,
multiplegestations,andchronichypertensionorunderlyingrenaldisease.In
addition,Lykkeetalfoundthatpreeclampsia,spontaneouspretermdelivery,orfetal
growthdeviationinafirstsingletonpregnancypredisposeswomentothose
complicationsintheirsecondpregnancy,especiallyifthecomplicationswere
severe. [36]

Gestationalage
Inaregistrybasedcohortstudyof536,419Danishwomen,deliverybetween32and
36weeksgestationincreasedtheriskofpretermdeliveryinthesecondpregnancy
from2.7%to14.7%andincreasedtheriskofpreeclampsiafrom1.1%to1.8%.A
firstdeliverybefore28weeksincreasedtheriskofasecondpretermdeliveryto26%
andincreasedtheriskofpreeclampsiato3.2%.
Preeclampsiainafirstpregnancy,withdeliverybetween32and36weeks'
gestation,increasedtheriskofpreeclampsiainasecondpregnancyfrom14.1%to
25.3%.Fetalgrowth23standarddeviationsbelowthemeaninafirstpregnancy
increasedtheriskofpreeclampsiafrom1.1%to1.8%inthesecondpregnancy. [36]
Primigravidpatientsinparticularseemtobepredisposedtopreeclampsia.

Maternalage
Womenaged35yearsandolderhaveamarkedlyincreasedriskofpreeclampsia.

Race
IntheUnitedStates,theincidenceofpreeclampsiais1.8%amongwhitewomen
and3%inblackwomen.

Additionalriskfactors
Someriskfactorscontributetopoorplacentation,whereasotherscontributeto
increasedplacentalmassandpoorplacentalperfusionsecondarytovascular
abnormalities. [2]
Inadditiontothosediscussedabove,preeclampsiariskfactorsalsoincludethe
following:
Hydatidiformmole
Obesity
Thrombophilia
Oocytedonationordonorinsemination
Urinarytractinfection
Diabetesmellitus:Womenwithpregnancyrelatedhypertensiveconditions,
includingpreeclampsia,pluspreexistingdiabetesorearlygestational
diabetesappeartoremainatincreasedriskforpoorpregnancyoutcomes
evenwhenthegestationaldiabeteswasidentifiedearlyandtreated. [37]
Collagenvasculardisease
Periodontaldisease [38]
OneliteraturereviewsuggeststhatmaternalvitaminDdeficiencymayincreasethe
riskofpreeclampsiaandfetalgrowthrestriction.Anotherstudydeterminedthat
vitaminDdeficiency/insufficiencywascommoninagroupofwomenathighriskfor
preeclampsia.However,itwasnotassociatedwiththesubsequentriskofan
adversepregnancyoutcome. [39]
Studieshavesuggestedthatsmokingduringpregnancyisassociatedwithareduced
riskofgestationalhypertensionandpreeclampsiahowever,thisiscontroversial. [26]
Placentapreviahasalsobeencorrelatedwithareducedriskofpreeclampsia.
Bodyweightisstronglycorrelatedwithprogressivelyincreasedpreeclampsiarisk,
rangingfrom4.3%forwomenwithabodymassindex(BMI)below20kg/m2to
13.3%inthosewithaBMIover35kg/m2.AUnitedKingdomstudyonobesity
showedthat9%ofextremelyobesewomenwerepreeclamptic,comparedwith2%
ofmatchedcontrols. [40]
Ananalysisof456,668singletonbirthsfoundthatearlyonset(<34weeks'gestation)
andlateonset(34weeks'gestation)preeclampsiasharedsomeetiologicfeatures,
buttheirriskfactorsandoutcomesdiffered.Sharedriskfactorsforearlyandlate
onsetpreeclampsiaincludedoldermaternalage,Hispanicrace,NativeAmerican

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race,smoking,unmarriedstatus,andmalefetus.Riskfactorsmorestrongly
associatedwithearlyonsetpreeclampsiathanlateonsetdiseaseincludedblack
race,chronichypertension,andcongenitalanomalies,whileyoungermaternalage,
nulliparity,anddiabetesmellitusweremorestronglyassociatedwithlateonset
preeclampsiathanwithearlyonsetdisease. [41,42]
Earlyonsetpreeclampsiawassignificantlyassociatedwithahighriskforfetaldeath
(adjustedoddsratio[AOR],5.8),butlateonsetpreeclampsiawasnot(AOR,1.3).
However,theAORforperinataldeath/severeneonatalmorbiditywassignificantfor
bothearlyonset(16.4)andlateonset(2.0)preeclampsia. [41,42]
Inaddition,theincidenceofpreeclampsiaincreasedsharplyasgestation
progressed:therateforearlyonsetpreeclampsiawas0.38%comparedwith2.72%
forlateonsetpreeclampsia. [41,42]
Table1liststheriskfactorsandtheiroddsratiosforpreeclampsia. [2]
Table1.RiskFactorsforPreeclampsia*(OpenTableinanewwindow)
Nulliparity

3:1

Age>40y

3:1

Blackrace

1.5:1

Familyhistory

5:1

Chronicrenaldisease

20:1

Chronichypertension

10:1

Antiphospholipidsyndrome

10:1

Diabetesmellitus

2:1

Twingestation(butunaffectedbyzygosity)

4:1

Highbodymassindex

3:1

AngiotensinogengeneT235

Homozygous

20:1

Heterozygous

4:1

*AdaptedfromACOGTechnicalBulletin219,Washington,DC1996. [1]

EvaluationofPreeclampsia
Becausetheclinicalmanifestationsofpreeclampsiacanbeheterogeneous,
diagnosingpreeclampsiamaynotbestraightforward.Inparticular,becausethefinal
diagnosisofgestationalhypertensioncanonlybemadeinretrospect,aclinician
maybeforcedtotreatsomewomenwithgestationalhypertensionasiftheyhave
preeclampsia.Inaddition,ifawomanhasunderlyingrenalorcardiovascular
disease,thediagnosisofpreeclampsiamaynotbecomeclearuntilthedisease
becomessevere.
Mildtomoderatepreeclampsiamaybeasymptomatic.Manycasesaredetected
throughroutineprenatalscreening.
Preeclampsiainapreviouspregnancyisstronglyassociatedwithrecurrencein
subsequentpregnancies.Ahistoryofgestationalhypertensionorpreeclampsia
shouldstronglyraiseclinicalsuspicion.

Physicalfindings
Patientswithpreeclampsiawithseverefeaturesdisplayendorganeffectsandmay
complainofthefollowing:
Headache
Visualdisturbances:Blurred,scintillatingscotomata
Alteredmentalstatus
Blindness:Maybecortical [3]orretinal
Dyspnea
Edema
Epigastricorrightupperquadrantabdominalpain
WeaknessormalaiseMaybeevidenceofhemolyticanemia
Edemaexistsinmanypregnantwomen,butasuddenincreaseinedemaorfacial
edemaissuggestiveofpreeclampsia.Theedemaofpreeclampsiaoccursbya
distinctmechanismthatissimilartothatofangioneuroticedema.
Hepaticinvolvementoccursin10%ofwomenwithseverepreeclampsia.The
resultingpain(epigastricorrightupperquadrantabdominalpain)isfrequently
accompaniedbyelevatedserumhepatictransaminaselevels.
Thepresenceofclonusmayindicateanincreasedriskofconvulsions.
AstudybyCoorayetalfoundthatthemostcommonsymptomsthatimmediately
precedeeclampticseizuresareneurologicsymptoms(ie,headache,withorwithout
visualdisturbance),regardlessofdegreeofhypertension.Thissuggeststhatclosely
monitoringpatientswiththesesymptomsmayprovideanearlywarningfor
eclampsia. [43]

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Recurrenceofpreeclampsia
Uncommonly,patientshaveantepartumpreeclampsiathatistreatedwithdelivery
butthatrecursinthepostpartumperiod. [44]Recurrentpreeclampsiashouldbe
consideredinpostpartumpatientswhopresentwithhypertensionandproteinuria.
(SeePrognosis.)
Inpatientswhoaresufferingarecurrenceofpreeclampsia,findingsonphysical
examinationmayincludethefollowing(seePrognosis):
Alteredmentalstatus
Decreasedvisionorscotomas
Papilledema
Epigastricorrightupperquadrantabdominaltenderness
PeripheraledemaHyperreflexiaorclonus:Althoughdeeptendonreflexesare
moreusefulinassessingmagnesiumtoxicity,thepresenceofclonusmay
indicateanincreasedriskofconvulsions.
Seizures
Focalneurologicdeficit

MeasurementofHypertension
HypertensionisdiagnosedwhentwoBPreadingsof140/90mmHgorgreaterare
noted4hoursapartwithina1weekperiod.MeasuringBPwithanappropriatesized
cuffplacedontherightarmatthesamelevelastheheartisimportant.Thepatient
mustbesittingand,ideally,havehadachancetorestforatleast10minutes
beforetheBPmeasurement.Sheshouldnotbelyingdowninalateraldecubitus
position,asthearmoftenusedtomeasurethepressureinthispositionwillbe
abovetherightatrium.
TheKorotkoffVsoundshouldbeusedforthediastolicpressure.Incasesinwhich
theKorotkoffVsoundisnotpresent,theKorotkoffIVsoundmaybeused,butit
shouldbenotedassuch.ThedifferencebetweentheKorotkoffIVandVsounds
maybeasmuchas10mmHg.Whenanautomatedcuffisused,itmustbeableto
recordtheKorotkoffVsound.Whenserialreadingsareobtainedduringan
observationalperiod,thehighervaluesshouldbeusedtomakethediagnosis.

Lackofhypertensiononexamination
Althoughhypertensionisanimportantcharacteristicofpreeclampsia,becausethe
underlyingpathophysiologyofpreeclampsiaisadiffuseendothelialcelldisorder
influencingmultipleorgans,hypertensiondoesnotnecessarilyneedtoprecede
otherpreeclampticsymptomsorlaboratoryabnormalities.Presentingsymptoms
otherthanhypertensionmayinclude,aspreviouslymentioned,edema,visual
disturbances,headache,andepigastricorrightupperquadranttenderness.

DiagnosticConsiderations
Gestationalhypertension
Duringdiagnosis,preeclampsiamustbedifferentiatedfromgestational
hypertensionalthoughgestationalhypertensionismorecommonandmaypresent
withsymptomssimilartothoseofpreeclampsia,includingepigastricdiscomfortor
thrombocytopenia,itiswhichisnotcharacterizedbyproteinuria.(SeeClassification
andCharacteristicsofHypertensiveDisorders.)

Placentalhypoperfusion
Placentalhypoperfusionorischemiainpreeclampsiahasmanycauses.Preexisting
vasculardisorders,suchashypertensionandconnectivetissuedisorders,canresult
inpoorplacentalcirculation.Incasesofmultiplegestationorincreasedplacental
mass,itisnotsurprisingfortheplacentatobecomeunderperfused.However,most
womenwhodeveloppreeclampsiaarehealthyanddonothaveunderlyingmedical
conditions.Inthisgroupofwomen,abnormallyshallowplacentationhasbeen
showntoberesponsibleforplacentalhypoperfusion.(SeePlacentationin
Preeclampsia.)

Differentialdiagnosis
AbdominalTrauma,Blunt
AbruptioPlacentae
Aneurysm,Abdominal
Appendicitis,Acute
CholecystitisandBiliaryColic
Cholelithiasis
CongestiveHeartFailureandPulmonaryEdema
DomesticViolence
EarlyPregnancyLoss

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Encephalitis
Headache,Tension
HypertensiveEmergencies
Hyperthyroidism,ThyroidStorm,andGravesDisease
MigraineHeadache
OvarianTorsion
Pregnancy,Eclampsia
StatusEpilepticus
Stroke,Hemorrhagic
Stroke,Ischemic
SubarachnoidHemorrhage
SubduralHematoma
ThromboticThrombocytopenicPurpura
Toxicity,Amphetamine
Toxicity,Sympathomimetic
Toxicity,ThyroidHormone
TransientIschemicAttack
UrinaryTractInfection,Female
WithdrawalSyndromes
Cerebrovascularaccidents
Seizuredisorders
Braintumors
Metabolicdiseases
Metastaticgestationaltrophoblasticdisease
Thromboticthrombocytopenicpurpura

RoutineStudies
Allwomenwhopresentwithnewonsethypertensionshouldhavethefollowing
laboratorytests:
Completebloodcell(CBC)count
Serumalanineaminotransferase(ALT)andaspartateaminotransferase
(AST)levels
Serumcreatinine
Uricacid
Inaddition,aperipheralsmearshouldbeperformed,serumlactatedehydrogenase
(LDH)levelsshouldbemeasured,andanindirectbilirubinshouldbecarriedoutif
HELLP(hemolysis,elevatedliverenzyme,lowplatelets)syndromeissuspected.
Althoughacoagulationprofile(prothrombintime[PT],activatedpartial[aPTT],and
fibrinogen)shouldalsobeevaluated,theclinicaluseofroutineevaluationisunclear
whentheplateletcountis100,000/mm3ormorewithnoevidenceofbleeding. [4]
LaboratoryvaluesforpreeclampsiaandHELLPsyndrome [13,45]
Renalvaluesareasfollows:
Proteinurialevelabove300mg/24hours
Urinedipstickover1+
Protein/creatinineratiogreaterthan0.3*
Serumuricacidlevelabove5.6mg/dL*
Serumcreatininelevelover1.1mg/dL
Platelet/coagulopathyrelatedresultsareasfollows:
Plateletcountbelow100,000/mm 3
ElevatedPToraPTT*
Decreasedfibrinogen*
Increasedddimerlevel*
Hemolysisrelatedresultsareasfollows:
Abnormalperipheralsmear*
Indirectbilirubinlevelover1.2mg/dL*
LDHlevelgreaterthan600U/L*

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Inaddition,elevatedliverenzymes(serumAST>70U/L)arefoundinpreeclampsia
andHELLPsyndrome. [24]

Urinetests
Todiagnoseproteinuria,a24hoururinecollectionforproteinandcreatinineshould
beobtainedwheneverpossible.Upto30%ofwomenwithgestationalhypertension
whohavetraceproteinnotedonrandomurinesamplesmayhave300mgofprotein
ina24hoururinecollection. [46]Thus,a24hoururineproteinanalysisremainsthe
criterionstandardforproteinuriadiagnosis.Alternatively,greaterthan1+proteinon
adipstickanalysisonarandomsampleissufficienttomakethediagnosisof
proteinuria.
Randomurinesamplescanbeusedtocalculatetheproteincreatinineratio.
Thresholdsof0.140.3havebeenproposedfordiagnosingproteinuria. [47]However,
thereisnoagreementyetastothebestthresholdforidentifyingpregnantwomen
withsignificantproteinuria.Moreover,upto10%ofpatientswithpreeclampsiaand
20%ofpatientswitheclampsiamaynothaveproteinuria. [48,49](HELLPsyndrome
hasbeenknowntooccurwithouthypertensionorproteinuria.)
Hyperuricemiaisoneoftheearliestlaboratorymanifestationsofpreeclampsia.It
hasalowsensitivity,rangingfrom0%to55%,butarelativelyhighspecificityof77
95%. [50]Seriallevelsmaybeusefultoindicatediseaseprogression.
Bawejaetalsuggestthatwhenmeasuringurinaryalbuminusinghighperformance
liquidchromatographyinanearlyanduncomplicatedpregnancy,spoturinary
albumin:creatinineratio(ACR)valuesarehigher.Ifmeasuredearlyinthesecond
trimester,anACRof35.5mg/mmolorhighermaypredictpreeclampsiabefore
symptomsarise. [51]

Congoreddye
AstudyatYaleUniversityshowedpreliminaryresultssuggestingthatCongored
(CR),adyecurrentlyusedtolocateatypicalamyloidaggregatesinAlzheimer
disease,mayalsobeeffectiveintheearlydiagnosisofpreeclampsia. [50]Itwas
thoughtthatthisfindingmightleadtoaspoturinetestthatcouldbeusedin
emergencydepartmentsandinternationally,especiallyinresourcepoorcountries
wherepreeclampsiacontinuestobeunderdiagnosedandaccountsforalarge
percentageofmaternalandfetalmortality.
Inastudyof40pregnantwomenwithseverepreeclampsiaand40healthypregnant
controls,Buhimschietalfoundthattheurineandplacentasofwomenwith
preeclampsiacontainaggregatesofmisfoldedproteins. [52,53]Theysuggestedthat
urineCRspottingtests(CRbindstomisfoldedproteins)maybebetterthan
currentlyusedcurrentdipstickmethodsatdiagnosingpreeclampsiaandindicating
theneedformedicallyindicateddelivery. [52,53]
Inthisstudy,acutoffvalueofa15%measureofrednessontheCRspottingtest
had100%sensitivityand100%specificityfordistinguishingwomenwithsevere
preeclampsiafromcontrolsubjects. [53]Inaseparatevalidationcohortof563
pregnantwomen,thetesthadasensitivityof85.9%,aspecificityof85.0%,a
positivelikelihoodratioof5.7,andanegativelikelihoodratioof0.17.

Liverenzymes
Althoughcontroversyexistsoverthethresholdforelevatedliverenzyme,thevalues
proposedbySibaietal(ASTof>70U/LandLDHof>600U/L)appeartobethe
mostwidelyaccepted.Alternatively,valuesthatarethreestandarddeviationsaway
fromthemeanforeachlaboratoryvaluemaybeusedforAST. [45]

Histology
Thepresenceofschistocytes,burrcells,orechinocytesonperipheralsmears,or
elevatedindirectbilirubinandlowserumheptoglobinlevels,maybeusedas
evidenceofhemolysisindiagnosingHELLPsyndrome.Thedifferentialdiagnosisfor
HELLPsyndromemustincludevariouscausesforthrombocytopeniaandliverfailure
suchasacutefattyliverofpregnancy,hemolyticuremicsyndrome,acute
pancreatitis,fulminanthepatitis,systemiclupuserythematosus,cholecystitis,and
thromboticthrombocytopenicpurpura.

Additionallaboratorytests
Otherlaboratoryvaluessuggestiveofpreeclampsiaincludeanelevationin
hematocritandariseinserumcreatinineand/oruricacid.Adecreasedlevelof
placentalgrowthfactor(PlGF)inthebloodisalsosuggestiveofpreeclampsia. [54,
55]Althoughtheselaboratoryabnormalitiesincreasethesuspicionforpreeclampsia,
noneoftheselaboratorytestsshouldbeusedtodiagnosepreeclampsia.
Inastudyof540womenwithtype1diabetes,Holmesandcolleaguesfoundthat
thosewomenwhodevelopedpreeclampsiahadabnormalserumlevelsof
angiogenicandantiangiogeniccompoundsinthesecondtrimester.At26weeks
gestation,womenwholaterdevelopedpreeclampsiahadsignificantlylowerlevelsof
theangiogenicfactorPlGF,significantlyhigherlevelsoftheantiangiogenicfactors
solublefmsliketyrosinekinase1(sFlt1)andsolubleendoglin(sEng),aswellas
alterationintheratioofPlGFtosEngortheratioofsFlt1toPlGF. [56,57]

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AtestthatmeasuresthePIGFlevelintheblood(Triage)accuratelyidentified
preeclampsiarequiringdeliveryinaprospectivestudyof625pregnantwomen
presentingbefore35weeks'gestationwithsuspectedpreeclampsia.Ofthe625
subjects,346(55%)developedconfirmedpreeclampsia. [54,55]
Between20and34weeks'gestation,thesensitivityoftheTriagetestinpredicting
theneedfordeliverywithin14dayswas0.96(95%confidenceinterval[CI],0.89
0.99),andthenegativepredictivevaluewas0.98(95%CI0.930.995). [54,55]
Between35and36weeks'gestation,thesensitivitywas0.70(95%CI,0.580.81),
andthenegativepredictivevaluewas0.69(95%CI0.570.80).At37weeks'
gestationormore,thesensitivitywas0.57(95%CI,0.460.68),andthenegative
predictivevaluewas0.70(95%CI,0.620.78). [54,55]
APlGFlevelbelow100pg/mLwasjustasgoodasaPlGFlevelbelowthefifth
centileforgestationalageatpredictingpreeclampsiarequiringdeliverywithin14
days.PIGFlevelslowerthan12pg/mLindicatedanaveragetimetodeliveryofjust
9days.Usedaloneorincombination,thePlGFtestwassignificantly(P<0.001)
betterthanothercommonlyusedtests,includingsystolicanddiastolicblood
pressure,uricacid,alaninetransaminase,andproteinuria,inpredicting
preeclampsiarequiringdeliverywithin14days. [54,55]
Amulticenter,prospectiveobservationalstudyoftheratioofsFlt1toPlGFin
womenwithaclinicalsuspicionofpreeclampsiaorHELLPsyndrome,whowere
between24and37weeks'gestationalage,hasdemonstratedthatansFlt1to
PlGFratioof38orlowertohaveimportantpredictivevalue[58]:AnsFlt1:PlGF
ratioof38orlowerhadanegativepredictivevalueof99.3%(95%confidence
interval[CI],97.9to99.9),suggestinganextremelyunlikelydevelopmentof
preeclampsiaorHELLPwithin1week.However,thepositivepredictivevalueofan
sFlt1:PlGFratioabove38foradiagnosisofpreeclampsiawithin4weekswas
36.7%(95%CI,28.4to45.7).TheauthorsconcludedthatansFlt1:PlGFratioof
38orlowercanbeusedtopredicttheshorttermabsenceofpreeclampsiain
womeninwhomthesyndromeissuspectedclinically. [58]

CTScanningandMRI
Computedtomography(CT)scanningandmagneticresonanceimaging(MRI)scans
haverevealednumerousabnormalitiesinpatientswitheclampsia,suchascerebral
edema,focalinfarction,intracranialhemorrhage,andposterior
leukoencephalopathy. [59]
Currently,however,thereisnopathognomonicCTscanorMRIfindingfor
eclampsia.Furthermore,cerebralimagingisnotnecessaryfortheconditions
diagnosisandmanagement.However,headCTscanningisusedtodetect
intracranialhemorrhageinselectedpatientswithsuddensevereheadaches,focal
neurologicdeficits,seizureswithaprolongedpostictalstate,oratypicalpresentation
foreclampsia.

Ultrasonography
Ultrasonographyisusedtoassessthestatusofthefetusaswellastoevaluatefor
growthrestriction(typicallyasymmetricaluseabdominalcircumference). [60]Aside
fromtransabdominalultrasonography,umbilicalarteryDopplerultrasonography
shouldbeperformedtoassessbloodflow.ThevalueofDopplerultrasonographyin
otherfetalvesselshasnotbeendemonstrated.

Cardiotocography
Cardiotocographyisthestandardfetalnonstresstestandthemainstayoffetal
monitoring.Althoughitgivescontinuinginformationaboutfetalwellbeing,ithas
littlepredictivevalue.

ManagementofPreeclampsia
Theoptimalmanagementofawomanwithpreeclampsiadependsongestational
ageanddiseaseseverity.Becausedeliveryistheonlycureforpreeclampsia,
cliniciansmusttrytominimizematernalriskwhilemaximizingfetalmaturity.The
primaryobjectiveisthesafetyofthemotherandthenthedeliveryofahealthy
newborn.Obstetricconsultationshouldbesoughtearlytocoordinatetransfertoan
obstetricfloor,asappropriate. [61]
Patientswithpreeclampsiawithoutseverefeaturesareofteninducedafter37
weeks'gestation.Beforethis,theimmaturefetusistreatedwithexpectant
managementwithcorticosteroidstoacceleratelungmaturityinpreparationforearly
delivery.
Inpatientswithpreeclampsiawithseverefeatures,inductionofdeliveryshouldbe
consideredafter34weeks'gestation.Inthesecases,theseverityofdiseasemust
beweighedagainsttherisksofinfantprematurity.Intheemergencysetting,control
ofBPandseizuresshouldbepriorities.Ingeneral,thefurtherthepregnancyisfrom
term,thegreatertheimpetustomanagethepatientmedically.

PrehospitalTreatment
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Prehospitalcareforpregnantpatientswithsuspectedpreeclampsiaincludesthe
following:
Oxygenviafacemask
Intravenousaccess
Cardiacmonitoring
Transportationofpatientinleftlateraldecubitusposition
Seizureprecautions

CareinPreeclampsiaWithoutSevereFeatures
Before37weeks,expectantmanagementisappropriate.Inmostcases,patients
shouldbehospitalizedandmonitoredcarefullyforthedevelopmentofworsening
preeclampsiaorcomplicationsofpreeclampsia.Althoughrandomizedtrialsin
womenwithgestationalhypertensionandpreeclampsiademonstratethesafetyof
outpatientmanagementwithfrequentmaternalandfetalevaluations,mostofthe
patientsinthesestudieshadmildgestationalhypertension. [62]Therefore,thesafety
ofmanagingawomanwithpreeclampsiawithoutseverefeaturesasanoutpatient
stillneedstobeinvestigated.
Althoughbedresthasbeenrecommendedinwomenwithpreeclampsia,little
evidencesupportsitsbenefit.Infact,prolongedbedrestduringpregnancyincreases
theriskofthromboembolism.
Apregnancycomplicatedbypreeclampsiawithoutseverefeaturesatorbeyond37
weeksshouldbedelivered.Althoughthepregnancyoutcomeissimilarinthese
womenasitisinwomenwithanormotensivepregnancy,theriskofplacental
abruptionandprogressiontoseverediseaseisslightlyincreased. [63,64]Thus,
regardlessofcervicalstatus,inductionoflaborshouldberecommended.Cesarean
sectionmaybeperformedbasedonstandardobstetriccriteria.
Antepartumtestingisgenerallyindicatedduringexpectantmanagementofpatients
withpreeclampsiawithoutseverefeatures.However,thereislittleconsensus
regardingthetypesofteststobeusedandthefrequencyoftesting.Mostclinicians
offeranonstresstest(NST)andabiophysicalprofile(BPP)atthetimeofthe
diagnosisandusuallytwiceperweekuntildelivery. [2,1]
Ifapatientisat34weeks'gestationormoreandhasrupturedmembranes,
abnormalfetaltesting,orprogressivelaborinthesettingofpreeclampsia,delivery
isrecommended.

CarePreeclampsiaWithSevereFeatures
Whenpreeclampsiawithseverefeaturesisdiagnosedafter34weeksgestation,
deliveryismostappropriate.Themodeofdeliveryshoulddependontheseverityof
thediseaseandthelikelihoodofasuccessfulinduction.Wheneverpossible,
however,vaginaldeliveryshouldbeattemptedandcesareansectionshouldbe
reservedforroutineobstetricindications.
Womenwithpreeclampsiawithseverefeatureswhohavenonreassuringfetal
status,rupturedmembranes,labor,ormaternaldistressshouldbedelivered
regardlessofgestationalage.Ifawomanwithpreeclampsiawithseverefeaturesis
at32weeks'gestationormoreandhasreceivedacourseofsteroids,sheshouldbe
deliveredaswell.
Patientspresentingwithsevere,unremittingheadache,visualdisturbance,andright
upperquadranttendernessinthepresenceofhypertensionand/orproteinuria
shouldbetreatedwithutmostcaution.

Expectantmanagementofpreeclampsiawithseverefeatures
Ifapatientpresentswithpreeclampsiawithseverefeaturesbefore34weeks'
gestationbutappearstobestable,andifthefetalconditionisreassuring,expectant
managementmaybeconsidered,providedthatthepatientmeetsthestrictcriteria
setbySibaietal(seeLaboratoryvaluesforpreeclampsiaandHELLPsyndrome).
[65]Thistypeofmanagementshouldbeconsideredonlyinatertiarycenter.In
addition,becausedeliveryisalwaysappropriateforthemother,someauthorities
considerdeliveryasthedefinitivetreatmentregardlessofgestationalage.However,
deliverymaynotbeoptimalforafetusthatisextremelypremature.Therefore,ina
carefullychosenpopulation,expectantmanagementmaybenefitthefetuswithout
greatlycompromisingmaternalhealth.
Allofthesepatientsmustbeevaluatedinalaboranddeliveryunitfor24hours
beforeadecisionforexpectantmanagementcanbemade.Duringthisperiod,
maternalandfetalevaluationmustshowthatthefetusdoesnothaveseveregrowth
restrictionorfetaldistress.Inaddition,maternalurineoutputmustbeadequate.
Thewomanmusthaveessentiallynormallaboratoryvalues(withtheexclusive
exceptionofmildlyelevatedliverfunctiontestresultsthatarelessthantwicethe
normalvalue)andhypertensionthatcanbecontrolled.
Fetalmonitoringshouldincludedailynonstresstestingandultrasonography
performedtomonitorforthedevelopmentofoligohydramniosanddecreasedfetal
movement.Inaddition,fetalgrowthdeterminationat2weekintervalsmustbe
performedtodocumentadequatefetalgrowth.A24hoururinecollectionforprotein
mayberepeated.Corticosteroidsforfetallungmaturityshouldbeadministered
priorto34weeks.

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Dailybloodtestsshouldbeperformedforliverfunctiontests(LFTs),CBCcount,
uricacid,andLDH.Patientsshouldbeinstructedtoreportanyheadache,visual
changes,epigastricpain,ordecreasedfetalmovement.

Criteriafordelivery
Womenwithseverepreeclampsiawhoaremanagedexpectantlymustbedelivered
underthefollowingcircumstances:
Nonreassuringfetaltestingincludingnonreassuringnonstresstest,
biophysicalprofilescore,and/orpersistentabsentorreverseddiastolicflow
onumbilicalarteryDopplervelocimetry
Rupturedmembranes
UncontrollableBP(unresponsivetomedicaltherapy)
Oligohydramnios,withamnioticfluidindex(AFI)oflessthan5cm
Severeintrauterinegrowthrestrictioninwhichtheestimatedfetalweightis
lessthan5%
Oliguria(<500mL/24hours)
Serumcreatininelevelofatleast1.5mg/dL
Pulmonaryedema
Shortnessofbreathorchestpainwithpulseoximetryof<94%onroomair
Headachethatispersistentandsevere
Rightupperquadranttenderness
DevelopmentofHELLP(hemolysis,elevatedliverenzyme,low
platelets)syndrome
Eclampsia
Plateletcountlessthan100,000/L
Placentalabruption
Unexplainedcoagulopathy

SeizureTreatmentandProphylaxisWithMagnesium
Sulfate
Thebasicprinciplesofairway,breathing,andcirculation(ABC)shouldalwaysbe
followedasageneralprincipleofseizuremanagement.
Magnesiumsulfateisthefirstlinetreatmentforthepreventionofprimaryand
recurrenteclampticseizures.Foreclampticseizuresthatarerefractoryto
magnesiumsulfate,lorazepamandphenytoinmaybeusedassecondlineagents.
TheAmericanCollegeofObstetriciansandGynecologists(ACOG)andtheSociety
forMaternalFetalMedicine(SMFM)continuetosupporttheshortterm(usually<48
hours)useofmagnesiumsulfateinobstetriccareforconditionsandtreatment
durationsthatincludethefollowing[66]:
Forpreventionandtreatmentofseizuresinwomenwithpreeclampsia
oreclampsia
Forfetalneuroprotectionbeforeanticipatedearlypreterm(<32weeksof
gestation)delivery
Forshorttermprolongationofpregnancy(48hours)toallowforthe
administrationofantenatalcorticosteroidsinpregnantwomenwhoareatrisk
ofpretermdeliverywithin7days
Activeseizuresshouldbetreatedwithintravenousmagnesiumsulfateasafirstline
agent. [5]Aloadingdoseof4gshouldbegivenbyaninfusionpumpover510
minutes,followedbyaninfusionof1g/hmaintainedfor24hoursafterthelast
seizure.Recurrentseizuresshouldbetreatedwithanadditionalbolusof2goran
increaseintheinfusionrateto1.5gor2gperhour.
Prophylactictreatmentwithmagnesiumsulfateisindicatedforallpatientswith
severepreeclampsia.However,noconsensusexistsastowhetherpatientswith
mildpreeclampsianeedmagnesiumseizureprophylaxis.AlthoughACOG
recommendsmagnesiumsulfateinseverepreeclampsia,ithasnotrecommended
thistherapyinallcasesofmildpreeclampsia.
SomepractitionerswithholdmagnesiumsulfateifBPisstableand/ormildly
elevatedandifthelaboratoryvaluesforLFTsandplateletsaremildlyabnormal
and/orstable.Otherphysiciansfeelthatevenpatientswithgestationalhypertension
shouldreceivemagnesium,asasmallpercentageofthesepatientsmayeitherhave
preeclampsiaormaydevelopit.Theultimatedecisionshoulddependonthe
comfortlevelofthelaboranddeliverystaffinadministeringintravenous(IV)
magnesiumsulfate.Anestimated100patientsneedtobetreatedwithmagnesium
sulfatetherapytoprevent1caseofeclampsia. [5,67,68]

AcuteTreatmentofSevereHypertensionin
Pregnancy
Inthesettingofseverehypertension(SBP>160mmHgDBP>110mmHg),
antihypertensivetreatmentisrecommended.Thegoalofhypertensiontreatmentis
tolowerBPtopreventcerebrovascularandcardiaccomplicationswhilemaintaining
uteroplacentalbloodflow(ie,maintainBParound140/90mmHg).However,
althoughantihypertensivetreatmentdecreasestheincidenceofcerebrovascular
problems,itdoesnotaltertheprogressionofpreeclampsia.Controlofmildly
increasedBPdoesnotappeartoimproveperinatalmorbidityormortality,andit
may,infact,reducebirthweight.

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Hydralazine
Hydralazineisadirectperipheralarteriolarvasodilatorand,inthepast,waswidely
usedasthefirstlinetreatmentforacutehypertensioninpregnancy. [69,70]This
agenthasaslowonsetofaction(1020min)andpeaksapproximately20minutes
afteradministration.HydralazineshouldbegivenasanIVbolusatadoseof510
mg,dependingontheseverityofhypertension,andmaybeadministeredevery20
minutesuptoamaximumdoseof30mg.
Thesideeffectsofhydralazineareheadache,nausea,andvomiting.Importantly,
hydralazinemayresultinmaternalhypotension,whichcansubsequentlyresultina
nonreassuringfetalheartratetracinginthefetus. [13]
Inametaanalysis,Mageeetalpointedoutthathydralazinewasassociatedwith
worsematernalandperinataloutcomesthanwerelabetalolandnifedipine.
Furthermore,hydralazinewasassociatedwithmorematernalsideeffectsthanwere
labetalolandnifedipine. [69]

Labetalol
Labetalolisaselectivealphablockerandanonselectivebetablockerthatproduces
vasodilatationandresultsinadecreaseinsystemicvascularresistance.Thedosage
forlabetalolis20mgIVwithrepeatdoses(40,80,80,and80mg)every10
minutesuptoamaximumdoseof300mg.DecreasesinBPareobservedafter5
minutes(incontrasttothesloweronsetofactionofhydralazine),andthedrug
resultsinlessovershoothypertensionthandoeshydralazine.
Labetaloldecreasessupraventricularrhythmandslowstheheartrate,reducing
myocardialoxygenconsumption.Nochangeinafterloadisobservedaftertreatment
withlabetalol.Thesideeffectsoflabetalolaredizziness,nausea,andheadaches.
AftersatisfactorycontrolwithIVadministrationhasbeenachieved,anoral
maintenancedosecanbestarted. [13,69]

Nifedipine
Calciumchannelblockersactonarteriolarsmoothmuscleandinducevasodilatation
byblockingcalciumentryintothecells.Nifedipineistheoralcalciumchannel
blockerthatisusedinthemanagementofhypertensioninpregnancy.Thedosage
ofnifedipineis10mgPOevery1530minutes,withamaximumof3doses.The
sideeffectsofcalciumchannelblockersincludetachycardia,palpitations,and
headaches.Concomitantuseofcalciumchannelblockersandmagnesiumsulfateis
tobeavoided.Nifedipineiscommonlyusedpostpartuminpatientswith
preeclampsia,forBPcontrol. [13,69]

Sodiumnitroprusside
Inaseverehypertensiveemergency,whentheabovementionedmedicationshave
failedtolowerBP,sodiumnitroprussidemaybegiven.Nitroprussideresultsinthe
releaseofnitricoxide,whichinturncausessignificantvasodilation.Preloadand
afterloadarethengreatlydecreased.Theonsetofactionisrapid,andsevere
reboundhypertensionmayresult.Cyanidepoisoningmayoccursubsequenttoits
useinthefetus.Therefore,sodiumnitroprussideshouldbereservedforusein
postpartumcareorforadministrationjustbeforethedeliveryofthefetus. [13]

FluidManagement
Littleclinicalevidenceexistsinthepublishedliteratureonwhichtobasedecisions
regardingthemanagementoffluidsduringpreeclampsia.Currently,noprospective
studiesonthistopicareavailable,andguidelinesarelargelybasedonconsensus
andretrospectivereview.
Despitethepresenceofperipheraledema,patientswithpreeclampsiaare
intravascularlyvolumedepleted,withhighperipheralvascularresistance.Diuretics
shouldbeavoided.
Aggressivevolumeresuscitationmayleadtopulmonaryedema,whichisacommon
causeofmaternalmorbidityandmortality.Pulmonaryedemaoccursmost
frequently4872hourspostpartum,probablyduetomobilizationofextravascular
fluid.Becausevolumeexpansionhasnodemonstratedbenefit,patientsshouldbe
fluidrestrictedwhenpossible,atleastuntiltheperiodofpostpartumdiuresis.
Volumeexpansionhasnotbeenshowntoreducetheincidenceoffetaldistressand
shouldbeusedjudiciously.
Centralvenousorpulmonaryarterypressuremonitoringmaybeindicatedincritical
cases.Acentralvenouspressure(CVP)of5mmHginwomenwithnoheart
diseaseindicatessufficientintravascularvolume,andmaintenancefluidsaloneare
sufficient.Totalfluidsshouldgenerallybelimitedto80mL/hor1mL/kg/h.
Carefulmeasurementoffluidinputandoutputisadvisable,particularlyinthe
immediatepostpartumperiod.Manypatientswillhaveabrief(upto6h)periodof
oliguriafollowingdeliverythisshouldbeanticipatedandnotovercorrected.

PostpartumManagement
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Preeclampsiaresolvesafterdelivery.However,patientsmaystillhaveanelevated
BPpostpartum.Liverfunctiontestsandplateletcountsmustbeperformedto
documentdecreasingvaluespriortohospitaldischarge.Inaddition,onethirdof
seizuresoccurinthepostpartumperiod,mostwithin24hoursofdelivery,and
almostallwithin48hours. [71]Therefore,magnesiumsulfateseizureprophylaxisis
continuedfor24hourspostpartum.(SeeSeizureTreatmentandProphylaxisWith
MagnesiumSulfate.)
Rarely,apatientmayhaveelevatedliverenzymes,thrombocytopenia,andrenal
insufficiencymorethan72hoursafterdelivery.Inthesecases,thepossibilityof
hemolyticuremicsyndrome(HUS)orthromboticthrombocytopenicpurpura(TTP)
mustbeconsidered.Insuchsituations,plasmapheresis,alongwithcorticosteroid
therapy,maybeofsomebenefittosuchpatientsandmustbediscussedwithrenal
andhematologyconsultants.
Inaddition,theuseofdexamethasone(10mgIVq612hfor2dosesfollowedby5
mgIVq612hfor2doses)hasbeenproposedinthepostpartumperiodtorestore
plateletcounttonormalrangeinpatientswithpersistentthrombocytopenia. [72,73]
Theeffectivenessofthistherapyinpreventingseverehemorrhageorameliorating
thediseasecourseneedsfurtherinvestigation.
ElevatedBPmaybecontrolledwithnifedipineorlabetalolpostpartum.Ifapatient
isdischargedwithBPmedication,reassessmentandaBPcheckshouldbe
performed,atthelatest,1weekafterdischarge.Unlessawomanhasundiagnosed
chronichypertension,inmostcasesofpreeclampsia,theBPreturnstobaselineby
12weekspostpartum.
Eclampsiaiscommonafterdeliveryandhasoccurredupto6weeksafterdelivery.
AlSafietalsuggestthatthefirstweekafterdischargeisthemostcriticalperiodfor
thedevelopmentofpostpartumeclampsia.Discussingtherisksandeducating
patientsaboutthepossibilityofdelayedpostpartumpreeclampsiaisimportant,
regardlessofwhethertheydevelophypertensivediseasepriortodischarge. [74]
Patientsatriskforeclampsiashouldbecarefullymonitoredpostpartum. [75]
Additionally,patientswithpreeclampsiawhoweresuccessfullytreatedwithdelivery
maypresentwithrecurrentpreeclampsiaupto4weekspostpartum.

PreventionandPredictionofPreeclampsia
Effortstopreventpreeclampsiahavebeendisappointing. [76]

Aspirin
Asystematicreviewof14trialsusinglowdoseaspirin(60150mg/d)inwomenwith
riskfactorsforpreeclampsiaconcludedthataspirinreducedtheriskofpreeclampsia
andperinataldeath,althoughitdidnotsignificantlyaffectbirthweightortheriskof
abruption. [77]Lowdoseaspirininunselectednulliparouswomenseemstoreduce
theincidenceofpreeclampsiaonlyslightly. [78]Forwomenwithriskfactorsfor
preeclampsia,startinglowdoseaspirin(commonly,1tabletofbabyaspirinperday),
beginningat1214weeks'gestation,isreasonable.Thesafetyoflowdoseaspirin
useinthesecondandthirdtrimestersiswellestablished. [77,79]
Onthebasisoflimitedevidencefromasystematicreviewandmetaanalysis,the
additionoflowmolecularweightheparinorunfractionatedheparintolowdose
aspirinhasthepotentialtoreducetheprevalenceofpreeclampsiaandbirthof
smallforgestationalageneonatesinwomenwithahistoryofpreeclampsia. [80]

Heparin
Theuseoflowmolecularweightheparininwomenwiththrombophiliawhohavea
historyofadverseoutcomehasbeeninvestigated.Todate,however,nodata
suggestthattheuseofheparinprophylaxislowerstheincidenceofpreeclampsia.

Calciumandvitaminsupplements
ResearchintotheuseofcalciumandvitaminCandEsupplementationsinlowrisk
populationsdidnotfindareductionintheincidenceofpreeclampsia. [81,82,83]Ina
multicenter,randomized,controlledtrial,Villaretalfoundthatatthedosesusedfor
supplementation,vitaminsCandEwerenotassociatedwithareductionof
preeclampsia,eclampsia,gestationalhypertension,oranyothermaternaloutcome.
Lowbirthweight,smallforgestationalage,andperinataldeathswerealso
unaffected. [84]
AstudybyVadilloOrtegaetalsuggeststhatinahighriskpopulation,
supplementationduringpregnancywithaspecialfood(eg,bars)containingL
arginineandantioxidantvitaminsmayreducetheriskofpreeclampsia.However,
antioxidantvitaminsalonedonotprotectagainstpreeclampsia.Morestudies
performedonlowriskpopulationsareneeded. [85]
ResultsfromtheNorwegianMotherandChildCohortStudysuggestthat
supplementationofmilkbasedprobioticsmayreducetheriskofpreeclampsiain
primiparouswomen.Aprospectiverandomizedtrialhasnotyetbeendoneto
evaluatethisintervention. [86]

ScreeningTests
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Preeclampsiaisanappropriatediseasetoscreen,asitiscommon,important,and
increasesmaternalandperinatalmortality.However,althoughnumerousscreening
testsforpreeclampsiahavebeenproposedoverthepastfewdecades,notesthas
sofarbeenshowntoappropriatelyscreenforthedisease. [87](Measurementof
urinarykallikreinwasshowntohaveahighpredictivevalue,butitwasnot
reproducible. [88,89])
Morerecently,aprospectivestudydemonstratedthatansFlt1:PlGFratioof38or
lowerhadanegativepredictivevalueof99.3%(95%confidenceinterval[CI],97.9
to99.9),suggestinganextremelyunlikelydevelopmentofpreeclampsiaorHELLP
(hemolysis,elevatedliverenzyme,lowplatelets)syndromewithin1week,inwomen
withaclinicalsuspicionofpreeclampsiaorHELLPsyndrome. [58]Therefore,ansFlt
1:PlGFratioof38orlowermayhaveapotentialroleinpredictingtheshortterm
absenceofpreeclampsiainwomeninwhomthesyndromeissuspectedclinically.
[58]Arandomizedtrialisnecessarytodeterminetheintervalofsuchtestingin
womensuspectedonhavingpreeclampsiaorHELLPsyndrome,aswellasthe
effectofthisscreeningtestonmaternalandfetaloutcomes.
Currently,theclinicalvalueofanaccuratepredictivetestforpreeclampsiaisnot
clear,aseffectivepreventionisstilllacking.Intensivemonitoringinwomenwhoare
atincreasedriskfordevelopingpreeclampsia,whenidentifiedbyapredictivetest,
maylowertheincidenceofadverseoutcomeforthemotherandtheneonate.
However,theeffectivenessofsuchastrategymustberigorouslyinvestigated.

Prognosis
Morbidityandmortality
Worldwide,preeclampsiaandeclampsiaareestimatedtoberesponsiblefor
approximately14%ofmaternaldeathsperyear(50,00075,000). [21]Morbidityand
mortalityinpreeclampsiaandeclampsiaarerelatedtothefollowingconditions:
Systemicendothelialdysfunction
Vasospasmandsmallvesselthrombosisleadingtotissueandorgan
ischemia
Centralnervoussystem(CNS)events,suchasseizures,strokes,and
hemorrhage
Acutetubularnecrosis
Coagulopathies
Placentalabruptioninthemother
Fetalexposuretopreeclampsiamaybelinkedtoautismanddevelopmentaldelay
(DD). [90,91]Inapopulationbasedstudyof1061childrenfromsingleton
pregnanciesincluding517withautismspectrumdisorder(ASD),194withDD,
and350whoweretypicallydeveloping(TD)fetalexposuretopreeclampsiawas
associatedwithagreaterthantwofoldincreaseintheriskofASDandagreater
thanfivefoldincreaseintheriskofDD. [90,91]
OfthechildrenwithASD,7.7%hadbeenexposedtopreeclampsiainutero,
comparedwith5.1%ofthosewithDDand3.7%ofthosewithTD. [91]After
adjustmentforparity,maternaleducation,andprepregnancyobesity,theadjusted
oddsratio(aOR)forASDwithexposuretopreeclampsiawas2.36(95%confidence
interval[CI],1.184.68).Inanalyseslimitedtowomenwhohadhadsevere
preeclampsia,theaORforASDwas2.29(95%CI,0.975.43),andtheaORforDD
was5.49(95%CI,2.0614.64).

Recurrence
Ingeneral,therecurrenceriskofpreeclampsiainawomanwhoseprevious
pregnancywascomplicatedbypreeclampsianeartermisapproximately10%. [48]If
awomanhaspreviouslysufferedfrompreeclampsiawithseverefeatures(including
HELLP[hemolysis,elevatedliverenzyme,lowplatelets]syndromeand/or
eclampsia),shehasa20%riskofdevelopingpreeclampsiasometimeinher
subsequentpregnancy. [92,93,94,95,96,97]
IfawomanhashadHELLPsyndromeoreclampsia,therecurrenceriskofHELLP
syndromeis5%[93]andofeclampsiaitis2%. [95,96,97]Theearlierthedisease
manifestsduringtheindexpregnancy,thehigherthechanceofrecurrencerises.If
preeclampsiapresentedclinicallybefore30weeks'gestation,thechanceof
recurrencemaybeashighas40%. [98]
ThefullPIERSmodelhasbeenvalidatedandwassuccessfulinpredictingadverse
outcomesinadvancetherefore,itispotentiallyabletoinfluencetreatmentchoices
beforecomplicationsarise. [99]

ContributorInformationandDisclosures
Author
KeeHakLim,MDClinicalAssociateProfessor,DepartmentofObstetricsandGynecology,HarvardMedical
SchoolPhysicianinMaternalFetalMedicine,BethIsraelDeaconessMedicalCenter
KeeHakLim,MDisamemberofthefollowingmedicalsocieties:AmericanCollegeofObstetriciansand
Gynecologists,AmericanInstituteofUltrasoundinMedicine,SocietyforMaternalFetalMedicine,JohnsHopkins
MedicalandSurgicalAssociation

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Preeclampsia:PracticeEssentials,Overview,Pathophysiology

Disclosure:Nothingtodisclose.
Coauthor(s)
GuySteinberg,MD,MPH,MScFellowinMaternalFetalMedicine,BethIsraelDeaconessMedical
Center/HarvardMedicalSchool
Disclosure:Nothingtodisclose.
ChiefEditor
RonaldMRamus,MDProfessorofObstetricsandGynecology,Director,DivisionofMaternalFetalMedicine,
VirginiaCommonwealthUniversitySchoolofMedicine
RonaldMRamus,MDisamemberofthefollowingmedicalsocieties:AmericanCollegeofObstetriciansand
Gynecologists,AmericanInstituteofUltrasoundinMedicine,MedicalSocietyofVirginia,SocietyforMaternal
FetalMedicine
Disclosure:Nothingtodisclose.
Acknowledgements
ADavidBarnes,MD,PhD,MPH,FACOGConsultingStaff,DepartmentofObstetricsandGynecology,
MammothHospital(MammothLakes,California),PioneerValleyHospital(SaltLakeCity,Utah),WarrenGeneral
Hospital(Warren,Pennsylvania),andMountainWestHospital(Tooele,Utah)
ADavidBarnes,MD,PhD,MPH,FACOGisamemberofthefollowingmedicalsocieties:AmericanCollegeof
ForensicExaminers,AmericanCollegeofObstetriciansandGynecologists,AmericanMedicalAssociation,
AssociationofMilitarySurgeonsoftheUS,andUtahMedicalAssociation
Disclosure:Nothingtodisclose.
PamelaLDyne,MDProfessorofClinicalMedicine/EmergencyMedicine,UniversityofCalifornia,LosAngeles,
DavidGeffenSchoolofMedicineAttendingPhysician,DepartmentofEmergencyMedicine,OliveViewUCLA
MedicalCenter
PamelaLDyne,MDisamemberofthefollowingmedicalsocieties:AmericanAcademyofEmergencyMedicine,
AmericanCollegeofEmergencyPhysicians,andSocietyforAcademicEmergencyMedicine
Disclosure:Nothingtodisclose.
MertErogul,MDAssistantProfessorofEmergencyMedicine,UniversityHospitalofBrooklyn:ConsultingStaff,
DepartmentofEmergencyMedicine,KingsCountyHospitalCenter
MertErogul,MDisamemberofthefollowingmedicalsocieties:AmericanCollegeofEmergencyPhysicians,
AmericanMedicalAssociation,andSocietyforAcademicEmergencyMedicine
Disclosure:Nothingtodisclose.
JohnJKavanaghJrMD,Chief,Professor,DepartmentofInternalMedicine,SectionofGynecologicaland
MedicalTherapeutics,MDAndersonCancerCenter,UniversityofTexasMedicalSchoolatHouston
JohnJKavanaghJrisamemberofthefollowingmedicalsocieties:AmericanAssociationforCancerResearch,
AmericanAssociationfortheAdvancementofScience,AmericanAssociationfortheHistoryofMedicine,
AmericanCollegeofPhysicians,AmericanFederationforMedicalResearch,AmericanMedicalAssociation,
SocietyofGynecologistOncologists,SouthernMedicalAssociation,andTexasMedicalAssociation
Disclosure:Nothingtodisclose.
AssaadJSayah,MDChief,DepartmentofEmergencyMedicine,CambridgeHealthAlliance
AssaadJSayah,MDisamemberofthefollowingmedicalsocieties:NationalAssociationofEMSPhysicians
Disclosure:Nothingtodisclose.
ZinaSemenovskaya,MDResidentPhysician,DepartmentofEmergencyMedicine,KingsCountyHospital,
StateUniversityofNewYorkDownstateMedicalCenterCollegeofMedicine
Disclosure:Nothingtodisclose.
AashitKShah,MD,FAAN,FANAProfessorofNeurology,Director,ComprehensiveEpilepsyProgram,Program
Director,ClinicalNeurophysiologyFellowship,DetroitMedicalCenter,WayneStateUniversitySchoolofMedicine
AashitKShah,MD,FAAN,FANAisamemberofthefollowingmedicalsocieties:AmericanAcademyof
Neurology,AmericanClinicalNeurophysiologySociety,AmericanEpilepsySociety,andAmericanNeurological
Assocation
Disclosure:UCBPharma,Consultingfee,SpeakingandteachingCyberonics,Consultingfee,ConsultingUCB
Pharma,Grant/researchfunds,Other
GuySteinberg,MD,MPH,MScFellowinMaternalFetalMedicine,BethIsraelDeaconessMedical
Center/HarvardMedicalSchool
Disclosure:Nothingtodisclose.
FranciscoTalavera,PharmD,PhDAdjunctAssistantProfessor,UniversityofNebraskaMedicalCenterCollege
ofPharmacyEditorinChief,MedscapeDrugReference
Disclosure:MedscapeSalaryEmployment
MarkZwanger,MD,MBAAssistantProfessor,DepartmentofEmergencyMedicine,JeffersonMedicalCollege
ofThomasJeffersonUniversity

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Preeclampsia:PracticeEssentials,Overview,Pathophysiology

MarkZwanger,MD,MBAisamemberofthefollowingmedicalsocieties:AmericanAcademyofEmergency
Medicine,AmericanCollegeofEmergencyPhysicians,andAmericanMedicalAssociation
Disclosure:Nothingtodisclose.

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