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Preeclampsia:Clinicalfeaturesanddiagnosis

OfficialreprintfromUpToDate
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Preeclampsia:Clinicalfeaturesanddiagnosis
Authors
PhyllisAugust,MD,MPH
BahaMSibai,MD

SectionEditor
CharlesJLockwood,MD,MHCM

DeputyEditor
VanessaABarss,MD,FACOG

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Mar2016.|Thistopiclastupdated:Jan18,2016.
INTRODUCTIONPreeclampsiaisamultisystemdisordercharacterizedbythenewonsetofhypertensionand
proteinuriaorendorgandysfunctionorbothinthelasthalfofpregnancy(table1).Althoughmostaffected
pregnanciesdeliverattermorneartermwithgoodmaternalandfetaloutcomes,thesepregnanciesareat
increasedriskformaternaland/orfetalmortalityorseriousmorbidity[1,2].
DEFINITIONSOFPREGNANCYRELATEDHYPERTENSIVEDISORDERSTherearefourmajor
hypertensivedisordersrelatedtopregnancy[3,4]:
PreeclampsiaPreeclampsiareferstothenewonsetofhypertensionandeitherproteinuriaorendorgan
dysfunctionorbothafter20weeksofgestationinapreviouslynormotensivewoman(table1).Severe
hypertensionandsigns/symptomsofendorganinjuryareconsideredtheseverespectrumofthedisease
(table2)[4].In2013,theAmericanCollegeofObstetriciansandGynecologistsremovedproteinuriaasan
essentialcriterionfordiagnosisofpreeclampsiawithseverefeatures.Theyalsoremovedmassiveproteinuria
(5grams/24hours)andfetalgrowthrestrictionaspossiblefeaturesofseverediseasebecausemassive
proteinuriahasapoorcorrelationwithoutcomeandfetalgrowthrestrictionismanagedsimilarlywhetheror
notpreeclampsiaisdiagnosed[4].Oliguriawasalsoremovedasacharacteristicofseveredisease.
Eclampsiareferstothedevelopmentofgrandmalseizuresinawomanwithpreeclampsia,intheabsenceof
otherneurologicconditionsthatcouldaccountfortheseizure.(See"Eclampsia".)
HELLPsyndrome(Hemolysis,ElevatedLiverenzymes,LowPlatelets)probablyrepresentsasevereformof
preeclampsia,butthisrelationshipremainscontroversialHELLPmaybeanindependentdisorder.Asmany
as15to20percentofaffectedpatientsdonothaveconcurrenthypertensionorproteinuria,leadingsome
expertstobelievethatHELLPsyndromeisaseparatedisorderfrompreeclampsia.(See"HELLP
syndrome".)
Chronic/preexistinghypertensionChronic/preexistinghypertensionisdefinedassystolicpressure140
mmHgand/ordiastolicpressure90mmHgthatantedatespregnancyorispresentbeforethe20thweekof
pregnancy(onatleasttwooccasions)orpersistslongerthan12weekspostpartum.Itcanbeprimary
(primaryhypertension,formerlycalled"essentialhypertension")orsecondarytoavarietyofmedical
disorders.(See"Overviewofhypertensioninadults".)
Preeclampsiasuperimposeduponchronic/preexistinghypertensionSuperimposedpreeclampsiais
definedbythenewonsetofeitherproteinuriaorendorgandysfunctionafter20weeksofgestationina
womanwithchronic/preexistinghypertension.Forwomenwithchronic/preexistinghypertensionwhohave
proteinuriapriortoorinearlypregnancy,superimposedpreeclampsiaisdefinedbyworseningorresistant
hypertension(especiallyacutely)inthelasthalfofpregnancyordevelopmentofsigns/symptomsofthe
severespectrumofthedisease(table2).
GestationalhypertensionGestationalhypertensionreferstohypertensionwithoutproteinuriaorother
signs/symptomsofpreeclampsiathatdevelopsafter20weeksofgestation(table3).Itshouldresolveby12
weekspostpartum.Ifhypertensionpersistsbeyond12weekspostpartum,thediagnosisisrevisedto
chronic/preexistinghypertensionthatwasmaskedbythephysiologicdecreaseinbloodpressurethatoccurs
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inearlypregnancy.Ifhypertensionresolvespostpartum,thediagnosisisrevisedtotransienthypertensionof
pregnancy.(See"Gestationalhypertension".)
PREVALENCEPreeclampsiaisestimatedtooccurin4.6percent(95%CI2.78.2)ofpregnanciesworldwide
[5].Variationsinprevalencereflect,atleastinpart,differencesinthematernalagedistributionandproportionof
primiparouswomenamongpopulations[2].TheprevalenceofpreeclampsiaintheUnitedStatesisabout3.4
percent,but1.5foldto2foldhigherinfirstpregnancies[6].Lateonsetdisease(34weeks)ismoreprevalentthan
earlyonsetdisease(<34weeks)(inonepopulationbasedstudy:2.7versus0.3percent,respectively[7]).
BURDENOFDISEASEWomenwithpreeclampsiaareatanincreasedriskforlifethreateningevents,
includingplacentalabruption,acutekidneyinjury,cerebralhemorrhage,hepaticfailureorrupture,pulmonary
edema,disseminatedintravascularcoagulation,andprogressiontoeclampsia.Worldwide,10to15percentof
directmaternaldeaths(ie,resultingfromobstetriccomplicationsofpregnancy)areassociatedwith
preeclampsia/eclampsia[8].IntheUnitedStates,preeclampsia/eclampsiaisoneoffourleadingcausesof
maternaldeath,alongwithhemorrhage,cardiovascularconditions,andthromboembolism[911].Thereis
approximatelyonematernaldeathduetopreeclampsiaeclampsiaper100,000livebirths,withacasefatalityrate
of6.4deathsper10,000cases[12,13].IntheNetherlandsbetween1993and2005,preeclampsiawasthemost
commoncauseofmaternaldeath,with3.5maternaldeathsper100,000livebirths[14].(See"Overviewof
maternalmortality".)
Morbidityandmortalityarealsoincreasedforthefetus/neonatebecauseofthegreaterriskofrestrictedfetal
growthandpretermbirthinaffectedpregnancies.
RISKFACTORSRiskfactorsforpreeclampsiaarelistedinthetable(table4).Themagnitudeofriskdepends
uponthespecificfactorandisdescribedbelowforselectedriskfactorsevaluatedinasystematicreviewof
controlledstudies[15].
Apasthistoryofpreeclampsiaincreasestheriskofdevelopingpreeclampsiainasubsequentpregnancy
sevenfoldcomparedtowomenwithoutthishistory(relativerisk[RR]7.19,95%CI5.858.83)[15].
Theseverityofpreeclampsiastronglyimpactsthisrisk.Womenwithseverefeaturesofpreeclampsiainthe
secondtrimesterareatgreatestriskofdevelopingpreeclampsiainasubsequentpregnancy:ratesof25to
65percenthavebeenreported[1619].Bycomparison,womenwithoutseverefeaturesofpreeclampsiain
theirfirstpregnancydeveloppreeclampsiain5to7percentofsecondpregnancies[20,21].Womenwhohad
anormotensivefirstdeliverydeveloppreeclampsiainlessthan1percentofsecondpregnancies.
Firstpregnancy(nulliparity)(RR2.91,95%CI1.286.61)[15].Itisunclearwhytheprimigravidstateisa
significantpredisposingfactor.Onetheoryisthatthesewomenmayhavehadlimitedrecentexposureto
paternalantigens,whichmayplayaroleinthepathogenesisofthedisease.
Afamilyhistoryofpreeclampsiainafirstdegreerelative(RR2.90,95%CI1.704.93)[15],suggestinga
heritablemechanisminsomecases[22,23].Thefatherofthebabymaycontributetotheincreasedrisk,as
thepaternalcontributiontofetalgenesmayhavearoleindefectiveplacentationandsubsequent
preeclampsia.(See"Preeclampsia:Pathogenesis",sectionon'Geneticfactors'.)
Preexistingmedicalconditions:
Pregestationaldiabetes(RR3.56,95%CI2.544.99)[15],aneffectthatisprobablyrelatedtoa
varietyoffactors,suchasunderlyingrenalorvasculardisease,highplasmainsulinlevels/insulin
resistance,andabnormallipidmetabolism[24].(See"Pregestationaldiabetes:Preconception
counseling,evaluation,andmanagement".)
Bloodpressure130/80mmHgatthefirstprenatalvisit(RR1.382.37)[15].Theriskof
superimposedpreeclampsiaishighestinwomenwithdiastolicbloodpressure110mmHg(RR5.2)
and100mmHg(RR3.2)before20weeksofgestation.
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Antiphospholipidantibodies(RR9.72,95%CI4.3421.75)[15].(See"Pregnancyinwomenwith
antiphospholipidsyndrome".)
Bodymassindex26.1(RR2.47,95%CI1.663.67)[15].(See"Theimpactofobesityonfemale
fertilityandpregnancy",sectionon'Pregnancyassociatedhypertension'.)
Chronickidneydisease(CKD)(relativeriskvariesdependingonthedegreeofreductionofglomerular
filtrationrate[GFR]andthepresenceorabsenceofhypertension).InwomenwithadvancedCKD
(stages3,4,5),asmanyas40to60percentmaybediagnosedwithpreeclampsiainthelatterhalfof
pregnancy[25,26].
Twinpregnancies(RR2.93,95%2.044.21)[15].Preeclampsiaisevenmorefrequentwithmultiorder
gestations(triplets,quadruplets)[27].
Advancedmaternalage(maternalage40RR1.96,95%CI1.342.87formultiparasandRR1.68,95%CI
1.232.29forprimiparas)[15].Olderwomentendtohaveadditionalriskfactors,suchasdiabetesmellitus
andchronichypertension.Whetheradolescentsareathigherriskofpreeclampsiaismorecontroversial[28]
asystematicreviewdidnotfindanassociation[15].(See"Effectofadvancedageonfertilityandpregnancy
inwomen".)
Ofnote,womenwhosmokecigaretteshavealowerriskofpreeclampsiathannonsmokers.(See"Cigarette
smokingandpregnancy",sectionon'Preeclampsia'.)
OVERVIEWOFPATHOPHYSIOLOGYThepathophysiologyofpreeclampsialikelyinvolvesbothmaternaland
fetal/placentalfactors.Abnormalitiesinthedevelopmentoftheplacentalvasculatureearlyinpregnancy,weeksto
monthsbeforedevelopmentofclinicalmanifestationsofthedisease,arewelldocumented[29,30].These
abnormalitiescanresultinplacentalunderperfusion,andpossiblyhypoxiaandischemia.Observationaldata
supportthehypothesisthatplacentalunderperfusion,hypoxia,and/orischemiamayleadtoreleaseofcirculating
antiangiogenicfactors(solublefmsliketyrosinekinase[sFlt1],solubleendoglin[sEng])andothersubstances
thatcancausewidespreadmaternalsystemicendothelialdysfunction(increasedvascularpermeability,
vasoconstriction,activationofcoagulationsystem,microangiopathichemolysis),resultinginhypertension,
proteinuria,andtheotherclinicalmanifestationsofpreeclampsia[31].Theseverityofthediseaseisinfluenced
primarilybymaternalandpregnancyspecificfactors,butpaternalandenvironmentalfactorsmayalsoplayarole
[32].(See"Preeclampsia:Pathogenesis".)
CLINICALMANIFESTATIONS
ClinicalpresentationThenewdevelopmentofhypertensionandeitherproteinuriaorendorgandysfunction
after20weeksofgestationisusuallyduetopreeclampsia,particularlyinanulliparouswoman.Inmostwomen,
thesefindingsfirstbecomeapparentafter34weeksofgestation,includingwhenthewomanisinlabor(ie,"late
onsetpreeclampsia")[33,34].Inabout10percentofwomen,preeclampsiadevelopsbefore34weeksofgestation
(ie,"earlyonsetpreeclampsia")[33],andinabout5percent,preeclampsiaisfirstrecognizedpostpartum(ie,
"postpartumpreeclampsia"),usuallywithin48hoursofdelivery[3537].
Thedegreeofmaternalhypertensionandproteinuria,andthepresence/absenceofotherclinicalmanifestationsof
thediseasearehighlyvariable[38].Mostpatientshavebloodpressuresbetween140/90and160/110mmHgand
proteinuriausuallyaccompaniedbyperipheraledema.About25percentdeveloponeormoreofthefollowing
nonspecificfindings,whichindicatethepresenceofseverediseaseandtheneedtoconsiderurgentdelivery:
Signsandsymptoms:
Severehypertension(systolicbloodpressure160mmHgordiastolic110mmHgontwooccasionsat
leastfourhoursapartoronlyonceiftreated)
Persistentand/orsevereheadache
Visualabnormalities(scotomata,photophobia,blurredvision,ortemporaryblindness[rare])
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Upperabdominalorepigastricpain
Nausea,vomiting
Dyspnea,retrosternalchestpain
Alteredmentalstatus

Laboratoryabnormalities:
Microangiopathichemolyticanemia(abnormalperipheralsmear,elevatedbilirubin,orlowserumhaptoglobin
levelsU/L)
Thrombocytopenia(<100,000/microL)
Elevatedserumcreatinineconcentration(>1.1mg/dL)
Elevatedliverenzymes(twicetheupperlimitofnormal)
AtypicalpresentationAtypicalpresentationsincludeanyofthefollowing[37,39]:
Onsetofsigns/symptomsat<20weeksofgestation
Hypertensionorproteinuria(butnotboth)withorwithoutcharacteristicsignsandsymptomsofsevere
preeclampsia
Delayedpostpartumonsetorexacerbationofdisease(>2dayspostpartum)
Onset<20weeksPreeclampsiapriorto20weeksofgestationisusuallyassociatedwithacompleteor
partialmolarpregnancy(see"Hydatidiformmole:Epidemiology,clinicalfeatures,anddiagnosis").Rarely,
characteristicsignsandsymptomsbefore20weekshavebeenattributedtoseverepreeclampsiaafterother
disorderswithsimilarfindings(eg,lupusnephritis,thromboticthrombocytopenicpurpura,hemolyticuremic
syndrome,antiphospholipidsyndrome,acutefattyliverofpregnancy)wereexcluded.(See'Differentialdiagnosis'
below.)
Hypertensionorproteinuria(notboth)Hypertensionorproteinuria(butnotboth)withcharacteristic
signsandsymptomsofseverepreeclampsiaisuncommon,butmaybeobservedin15percentofpatientswith
HELLPsyndromeandinsomepatientswitheclampsia.(See"Eclampsia",sectionon'Caneclampsiabepredicted
andprevented?'and"HELLPsyndrome".)
Womenwithhypertensionorproteinuria(butnotboth)maygoontodevelopfulldiagnosticcriteriafor
preeclampsia.Noprospectivestudieshavebeenperformedinpregnantwomenwithisolatedgestational
proteinuriatodeterminetheirriskofdevelopingpreeclampsialaterinpregnancy,andtherearefewretrospective
studies.Between15and25percentofwomenwithgestationalhypertensionsubsequentlydeveloppreeclampsia.
(See"Gestationalhypertension",sectionon'Riskofprogressiontopreeclampsia'.)
DelayedpostpartumonsetorexacerbationofdiseaseDelayedpostpartumpreeclampsiacanbe
definedassignsandsymptomsofthediseaseleadingtoreadmissionmorethantwodaysbutlessthansixweeks
afterdelivery[37],althoughvariousotherdefinitionshavebeenused.Signsandsymptomscanbeatypicalfor
example,thepatientmayhavethunderclapheadachesalternatingwithmildheadachesorintermittent
hypertension.Otheretiologiesofthesignsandsymptomsshouldbeconsidered,suchascerebralvasoconstriction
syndromeorevenimpendingstroke[4043].Riskfactorsfordelayedpostpartumpreeclampsiaappeartobesimilar
tothoseforpreeclampsiaduringpregnancy[37,44,45],butsomepatientshavenoriskfactors.
Inaretrospectivecohortstudyincluding152patientswithdelayedpostpartumpreeclampsia,63.2percenthadno
antecedentdiagnosisofhypertensivediseaseinthecurrentpregnancy,whereas18.4percenthadpreeclampsia,
9.2percenthadchronichypertension,4.6percenthadgestationalhypertension,and4.6percenthadpreeclampsia
superimposedonchronichypertensionduringtheperipartumperiod[37].Ofthesepatients,14.5percentdeveloped
postpartumeclampsia.
CoursePreeclampsiaisaprogressivedisease.Althoughmostwomendevelopsignsofthediseaseinlate
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pregnancywithgradualworseninguntildelivery,inabout25percentofwomen,especiallythosewithearlyonset
preeclampsia,hypertensionbecomessevereand/orsignsandsymptomsofendorgandamagebecomeapparent
overaperiodofdaystoweeks(table2)[46].Twopercentofthesewomendevelopeclampsia.
Preeclampsiacanbeassociatedwithseriousmaternaland/orfetalsequelae(eg,abruptioplacentaeliver
hematomaorrupturedisseminatedintravascularcoagulationstrokeneedformechanicalventilation,invasive
hemodynamicmonitoring,transfusion,ordialysis)[47,48].Itisimportanttonotethatseveresequelaecanoccurin
womenwithoutseverehypertensionwhohaveclinicalevidenceofsignificantendorgandysfunction.Chestpain,
dyspnea,andlowplateletcountappeartobeparticularlypredictiveofadverseoutcome[49].
Deliveryoftheplacentaalwaysresultsincompleteresolutionofsignsandsymptomsofthedisease,withsome
symptomsdisappearinginamatterofhours(eg,headache),whileothersmaytakemonths(eg,proteinuria).
Typically,mobilizationofthirdspacefluidanddiuresisbeginwithin48hoursofdelivery.Hypertensionmayworsen
duringthefirst,andoccasionallythesecond,postpartumweek,butnormalizesinmostwomenwithinfourweeks
postpartum[50].Rarely,hypertensionpersistsbeyondthreemonths.Proteinuriausuallybeginstoimprovewithina
fewdays,however,inwomenwithseveralgramsofproteinexcretion,completeresolutionmaytakeweeksto
monthsaprolongedtimetocompleteresolutionismorelikelywithseveredisease[51].Delayedpostpartum
onsetorexacerbationofdiseaseisatypical.(See'Delayedpostpartumonsetorexacerbationofdisease'above.)
Clinicalfeaturesandpathophysiologybyorgansystem
Cardiopulmonary
HypertensionHypertensionisgenerallytheearliestclinicalfindingofpreeclampsiaandisthemost
commonclinicalcluetothepresenceofthedisease.Thebloodpressureusuallyrisesgradually,reachingthe
hypertensiverange(140/90mmHg)sometimeinthethirdtrimester,oftenafterthe37thweekofgestation[33].
However,insomewomen,hypertensiondevelopsrapidlyorbefore34weeksofgestationorpostpartum.A
systolicbloodpressureof160mmHgordiastolicbloodpressureof110mmHgontwooccasionsatleastfour
hoursapartisafeatureofseveredisease[4].
IntravascularvolumeandedemaIntravascularvolumemaybereducedinpreeclampsiawithsevere
features.Thereisnoevidenceofunderfillingofthearterialcirculationrather,thereducedvolumeappearstobea
consequenceofvasoconstrictionfromenhancedresponsestovasoactivesubstances.Thisissuehasnotbeen
conclusivelyresolved.
Edemainpreeclampsiamaybeduetocapillaryleakingorrepresent"overfill"edema.Manypregnantwomenhave
edema,whetherornottheyhavepreeclampsia.However,suddenandrapidweightgain(eg,>5pounds/week)and
facialedemaaremorecommoninwomenwhodeveloppreeclampsia,thus,thesefindingswarrantevaluationfor
otherclinicalmanifestationsofdisease.
CardiacfunctionPreeclampsiadoesnotaffectthemyocardiumdirectly,buttheheartrespondsto
physiologicalchangesinducedbypreeclampsia.Leftventricularejectionfractionusuallyremainswithinnormal
limits[52],butreductionsinlongitudinal,circumferential,andradialsystolicstrainhavebeenobserved[53].The
decrementinleftventricularperformanceinwomenwithpreeclampsiahasbeenattributedtoaphysiologic
responsetoincreasedafterload[5254],butotherfactorsmayplayarolesincesystolicstrainwasdepressedin
preeclampticpatientscomparedtopregnantwomenwithnonproteinurichypertensionwithsimilarrestingblood
pressure[53].Thehighafterloadinpreeclampsiaisassociatedwithelevatedcardiacfillingpressures,reflectedby
fourfoldhigherconcentrationsofnatriureticpeptidesinwomenwithpreeclampsiacomparedtopregnantwomen
whoarenormotensiveorhavechronichypertension[55].
Severepreeclampsiacanbeassociatedwithahighlyvariablehemodynamicprofile[5458].Asmallsubgroupof
womenwithseverepreeclampsiadevelopsmyocardialdamageorglobaldiastolicdysfunction[59].TroponinI
levelsshouldbeobtainedwhenclinicallyindicated,suchaswhenthepatientcomplainsofchestpainsuggestive
ofmyocardialischemiaornewelectrocardiogramchangesareobserved[60,61].Preeclampsiaisnotassociated
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withelevatedtroponinlevelsintheabsenceofcardiacdisease[62].
PulmonaryedemaThepresenceofpulmonaryedemaisafeatureoftheseverespectrumofthe
disease.Theetiologyofpulmonaryedemainpreeclampsiaismultifactorial[6366].Excessiveelevationin
pulmonaryvascularhydrostaticpressurecomparedwithplasmaoncoticpressuremayproducepulmonaryedema
insomewomen,particularlyinthepostpartumperiod.However,notallpreeclampticpatientswithpulmonary
edemademonstratethisphenomenon.Othercausesofpulmonaryedemaarecapillaryleak,leftheartfailure,and
iatrogenicvolumeoverload.
RenalThekidneyistheorganmostlikelytomanifestendothelialinjuryrelatedtopreeclampsia.
ProteinuriaProteinuriainpreeclampsiaisdefinedas0.3gramsproteinina24hoururinespecimenor
persistent1+(30mg/dL)ondipstickorarandomprotein:creatinineratio>0.3.Althoughproteinuriainwomenwith
preeclampsiaismostoften<5g/day,preeclampsiaremainsthemostcommoncauseofsevereproteinuriain
pregnantwomenlevelsofproteinuria>10g/daymaybeseen.[note:theurineproteinconcentrationinaspot
sampleismeasuredinmg/dLandisdividedbytheurinecreatinineconcentrationalsomeasuredinmg/dL,yielding
anumberthatestimatesthe24hourproteinexcretioningramsperday(calculator1)[6775].IfSIunitsare
desired(mg/mmol),thisvalueismultipliedby1000anddividedby8.8](See"Proteinuriainpregnancy:Evaluation
andmanagement".)
Increasedurinaryproteinexcretionmaybealatefinding[76,77],butgenerallyincreasesaspreeclampsia
progresses.Itisdue,inpart,toimpairedintegrityoftheglomerularfiltrationbarrierandalteredtubularhandlingof
filteredproteins(hypofiltration)leadingtoincreasedproteinexcretion[78].Bothsizeandchargeselectivityofthe
glomerularbarrierareaffected[79].Usingspecialstudies,podocyturia(urinaryexcretionofpodocytes)hasbeen
observedinpatientswithpreeclampsia[80].Urinarysheddingofpodocytesmayindicatepodocytelossfromthe
glomerulus,whichmayleadtoadisruptionoftheglomerularfiltrationbarrierandconsequentproteinuria.Deficient
vascularendothelialgrowthfactor(VEGF)signalingappearstoaccount,atleastinpart,fortheseeffects.(See
"Preeclampsia:Pathogenesis",sectionon'Pathogenesisofsystemicendothelialdysfunction'.)
RenalfunctionGlomerularfiltrationrate(GFR)decreasesby30to40percentinpreeclampsia
comparedwithpregnantnormotensivecontrolsrenalplasmaflowalsodecreases,buttoalesserdegree.The
plasmacreatinineconcentrationisgenerallynormaloronlyslightlyelevated(1.0to1.5mg/dL[88to133
micromol/L]).Acreatinine>1.1mg/dLordoublingofthecreatinineconcentrationindicatesseverediseaseand
resultsfromrenalvasoconstrictionandsodiumretentionduetoreducedplasmavolumeandsystemic
vasoconstriction.Urineoutputmaydecreaseto<500mL/24hours.(See"Acutekidneyinjury(acuterenalfailure)
inpregnancy",sectionon'PreeclampsiawithorwithoutHELLP'.)
Theassociationofhyperuricemiawithpreeclampsiahasbeenknownfordecades.Thecauseismostlikelyrelated
tothereductioninGFR.However,theincreaseinserumuricacidisoftengreaterthanexpectedformild
reductionsinGFR,leadingtothehypothesisthatdecreasedtubularsecretionorincreasedreabsorptionplayarole
[81].Althoughmetaanalysespublishedin2006concludedthaturicacidlevelsarenotanaccuratepredictorof
complicationsassociatedwithpreeclampsia[82,83],thisissueremainscontroversial.Datafromanongoing
internationalprospectivestudyofwomenadmittedtothehospitalwithpreeclampsiashowedthatserumuricacid
correctedforgestationalageisclinicallyusefulinpredictingadverseperinatal,butnotmaternaloutcomes[84].
UrinesedimentTheurinesedimentistypicallybenign.
RenalhistologyTherenalhistologicchangesdescribedinwomenwithpreeclampsiawhohavehad
kidneybiopsies,andinautopsyspecimensobtainedfromwomenwhodiedofeclampsia,aretermedglomerular
endotheliosis.Lightandelectronmicroscopyofglomerularendotheliosisshowthefollowing(picture1AC)[85]:
Endothelialcellswelling
Lossoffenestrations
Occlusionofcapillarylumens
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Footprocesseffacementisnotaprominentfeature,despitemarkedproteinuria.
Glomerularendotheliosisshareshistologicfeatureswithnonpreeclampticthromboticmicroangiopathies[85],
exceptthrombiarerareinpreeclampsia(althoughfibrindepositionmaybeobservedbyimmunofluorescence
microscopy).Rarely,itmaybepresentwithoutproteinuriaandinnonpregnantwomen[86,87].
HematologicThemostcommoncoagulationabnormalityinpreeclampsiaisthrombocytopenia.
Microangiopathicendothelialinjuryandactivationresultinformationofplateletandfibrinthrombiinthe
microvasculature.Acceleratedplateletconsumptionleadstothrombocytopeniaimmunemechanismsmayalso
playarole[88].Aplateletcountlessthan100,000/microLupstagespreeclampsiafrommildtosevere.
Theprothrombintime,partialthromboplastintime,andfibrinogenconcentrationarenotaffectedunlessthereare
additionalcomplications,suchasabruptioplacentaeorsevereliverdysfunction[89].
Microangiopathichemolysismayalsooccurandisdetectedbyexaminationofabloodsmearforschistocytesand
helmetcells(picture2AB)orelevationintheserumlactatedehydrogenaseconcentration.Hemoconcentration
mayresultfromreductionofplasmavolumefromcapillaryleaking.Hemolysisisassociatedwithalowhematocrit,
whilehemoconcentrationisassociatedwithahighhematocritwhenbothhemolysisandreducedplasmavolume
arepresent,theeffectsonhematocritmaynegateeachother,resultinginanormalvalue.(See"Thrombocytopenia
inpregnancy"and"Preeclampsia:Pathogenesis"and"Hematologicchangesinpregnancy".)
Thewhitebloodcellcountmaybeslightlyhigherduetoneutrophilia.
HepaticPeriportalandsinusoidalfibrindepositionandmicrovesicularfatdepositionarehistologicfindings
observedintheliversofpreeclampticwomen[90,91].Reducedhepaticbloodflowcanleadtoischemiaand
periportalhemorrhage.Theclinicalmanifestationsofhepaticdysfunctionincluderightupperquadrantorepigastric
pain,elevatedtransaminaselevels,coagulopathy,and,inthemostseverecases,subcapsularhemorrhageor
hepaticrupture.Thesehepaticchangesupstagethepreeclampsiafrommildtosevere.Nauseaandvomitingmay
occur.
Epigastricpainisoneofthecardinalsymptomsofseverepreeclampsia.Areviewofthisnonspecificsymptom
revealedthatitistypicallyexperiencedasasevereconstantpainthatbeginsatnight,usuallymaximalinthelow
retrosternumorepigastrium,butmayradiatetotherighthypochondriumorback[92].Thepainisthoughttobedue
tostretchingofGlissonscapsuleduetohepaticswellingorbleeding.Itmaybetheonlysymptomonpresentation,
thusahighindexofsuspicionisimportanttomakethediagnosisofpreeclampsiaratherthangastroesophageal
reflux,whichiscommoninpregnantwomen,especiallyatnight.Thelivermaybetendertopalpation.
Rarely,transientdiabetesinsipidushasbeenreportedinpreeclampsiawithhepaticdysfunction.(See"Renaland
urinarytractphysiologyinnormalpregnancy".)
CentralnervoussystemandeyeCentralnervoussystemmanifestationsofpreeclampsiainclude
headache,visualsymptoms,andgeneralizedhyperreflexiasustainedankleclonusmaybepresent.
Headacheinpreeclampsiamaybetemporal,frontal,occipital,ordiffuse[93,94].Itisusuallyathrobbing/pounding
pain,butmaybepiercingpain.Althoughnotpathognomonic,afeaturethatsuggestspreeclampsiarelated
headacheratherthananothertypeofheadacheisthatitpersistsdespiteadministrationofoverthecounter
analgesicsanditmaybecomesevere(ie,incapacitating,"theworstheadacheofmylife").
Visualsymptomsarecaused,atleastinpart,byretinalarteriolarspasm[95].Symptomsincludeblurredvision,
flashinglightsorsparks(photopsia),andscotomata(darkareasorgapsinthevisualfield)[9698].Diplopiaor
amaurosisfugax(blindnessinoneeye)mayalsooccur.Corticalblindnessisrareandtypicallytransient[99].
Blindnessrelatedtoretinalpathology,suchasretinalarteryorveinocclusion,retinaldetachment,opticnerve
damage,retinalarteryspasm,andretinalischemia,maybepermanent[100].
Seizuresinapreeclampticwomansignifyachangeindiagnosistoeclampsia.Onein400mildlypreeclampticand
1in50severelypreeclampticwomendevelopeclampticseizures.
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Histopathologiccorrelatesincludehemorrhage,petechiae,cerebraledema,vasculopathy,ischemicbraindamage,
microinfarcts,andfibrinoidnecrosis[101,102].
Thecerebrovascularmanifestationsofseverepreeclampsiaarepoorlyunderstood.Cerebraledemaand
ischemic/hemorrhagicchangesintheposteriorhemispheresobservedoncomputedtomographyandmagnetic
resonanceimaginghelptoexplain,butdonotfullyaccountfor,theclinicalfindings[103,104].Thesefindingsmay
resultfromgeneralizedendothelialcelldysfunctionleadingtovasospasmofthecerebralvasculatureinresponse
toseverehypertensionormayresultfromlossofcerebrovascularautoregulationleadingtoareasofboth
vasoconstrictionandforcedvasodilationandthusrepresentaformofposteriorreversibleleukoencephalopathy
syndrome(PRES)[105,106].PRESistypicallyassociatedwithseverehypertension,butcanoccurwithrapid
increasesinbloodpressureinpatientswithendothelialdamage[107].(See"Reversibleposterior
leukoencephalopathysyndrome"and"Eclampsia",sectionon'Clinicalpresentationandfindings'.)
Strokeleadingtodeathordisabilityisthemostseriouscomplicationofseverepreeclampsia/eclampsia,whichis
responsibleforapproximately36percentofpregnancyassociatedstroke[108].Moststrokesinthissettingare
hemorrhagicandprecededbysevereheadacheandsevereandfluctuatingbloodpressurelevels.Eclamptic
seizuresoccurinsome,butnotallcases.Riskfactorsforhemorrhagicstrokeinwomenwithpreeclampsiainclude
persistentseverehypertension(ie,persistentsystolicbloodpressures160mmHgand/ordiastolicblood
pressures110mmHg)associatedwithsignificantheadacheand/orseizures.Loweringbloodpressuremay
reducetheriskhowever,criteriaforpersistenthypertensionandtimingofinitiationofacuteantihypertensive
therapy(after15minutes,30minutes,or>60minutes)areunclear.
OthermaternalmanifestationsWomenwithpreeclampsiaappeartohavegreaterchangesinlipid
metabolism(eg,elevatedtotalcholesterolandtriglyceridelevels)thannormotensivepregnantwomen[109,110].
Acutepancreatitisisararecomplicationofpreeclampsia[111]andcanmimicpreeclampsia[112].
FetusThefetalconsequencesofchronicplacentalhypoperfusionarefetalgrowthrestrictionand
oligohydramnios.
Severeandearlyonsetpreeclampsiaresultinthegreatestdecrementsinbirthweightcomparedwithnormotensive
pregnancies,12and23percentlowerthanexpectedforgestationalage,respectively[113].Bycomparison,late
onsetpreeclampsiacanbeassociatedwithhigherthanaveragebirthweight[114118],possiblyrelatedtogreater
placentalperfusion[119],whichmaybeduetoelevatedcardiacoutputsometimesobservedwithlateonset
disease.However,thisassociationmayalsobetheresultofconfoundersassociatedwithbothpreeclampsiaand
birthoflargeforgestationalageinfants(eg,obesity,impairedglucosetolerance)[120].
Inlargestudies,earlyonsetpreeclampsiasubstantiallyincreasedtherisksforbothfetaldeath[121,122]and
perinataldeath/severeneonatalmorbidity[121].Incontrast,lateonsetpreeclampsiawasassociatedwithmuch
lowerrisksforfetaldeath[121,122]andperinataldeath/severeneonatalmorbidity[121].
Indicatedpretermdeliveryisasecondaryresultoffetalormaternalcomplications.Preeclampsiadoesnotappear
toacceleratefetalmaturation,asoncebelieved.Thefrequencyofneonatalmorbiditiessuchasrespiratory
distress,intraventricularhemorrhage,andnecrotizingenterocolitisissimilarininfantsofpreeclampticwomenand
agematchednonhypertensivecontrols[123].
Inapopulationbasedstudy,preeclampsiawasassociatedwithasmallbutstatisticalincreaseinnoncriticalheart
defectsinoffspringwomenwithonsetofpreeclampsiabefore34weeksalsohadanincreasedriskofcritical
heartdefectsinoffspring[124].Furtherstudyisrequiredtoconfirmthisobservationand,ifconfirmed,todetermine
thenatureoftherelationship.
PlacentaAbruptioplacentaisinfrequent(lessthan1percent)inwomenwithpreeclampsiawithoutsevere
features,buthasbeenreportedin3percentofthosewithseverefeatures[125].(See"Placentalabruption:Clinical
featuresanddiagnosis".)
Impairedplacentationcanleadtoincreasedimpedancetoflowintheuterinearteries,manifestedbyelevationof
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thepulsatilityindexaccompaniedbyuterinearterynotchingonuterinearteryDopplervelocimetry.However,this
findingisneithersensitivenorspecificforpreeclampsia.(See"Predictionofpreeclampsia",sectionon'Uterine
arteryDopplervelocimetry'.)
IncreasedresistanceintheplacentalvasculatureisalsoreflectedbyrisingDopplerindicesoftheumbilicalartery.
Absentandreversedenddiastolicflowarethemostsevereabnormalitiesandassociatedwithapoorperinatal
outcome.(See"Dopplerultrasoundoftheumbilicalarteryforfetalsurveillance".)
Placentalhistologyisdescribedseparately.(See"Theplacentalpathologyreport",sectionon'Parenchymal
infarcts,syncytialknotting,andotherlesionsassociatedwithmalperfusion'.)
DIAGNOSISInternationalguidelinesgenerallyagreethatthediagnosisofpreeclampsiashouldbemadeina
previouslynormotensivewomanwithnewonsetofhypertensionandeitherproteinuriaorendorgandysfunction
after20weeksofgestation[4,126128].Criteriafordiagnosisare[4]:
Systolicbloodpressure140mmHgordiastolicbloodpressure90mmHg,and
Proteinuria0.3gramsina24hoururinespecimenorprotein:creatinineratio0.3,or
Signsofendorgandysfunction(plateletcount<100,000/microliter,serumcreatinine>1.1mg/dLor
doublingoftheserumcreatinine,elevatedserumtransaminasestotwicenormalconcentration)
Severehypertensionandsigns/symptomsofendorganinjuryareconsideredtheseverespectrumofthedisease
(table2).
Initialassessmentforproteinuriaiscommonlyperformedbydippingapaperteststripintoafreshcleanvoided
midstreamurinespecimen.Proteinuria+1ondipstickshouldbeconfirmedbyquantitativeassessment(24urine
collectionorprotein:creatinineratio).(See"Proteinuriainpregnancy:Evaluationandmanagement".)
Mildlyelevatedbloodpressureshouldbedocumentedbyatleasttwomeasurementsatleastfourhoursapart
asymptomaticoutpatientswithmildhypertensioncanbereassessedwithinthreetosevendays[4].Ifsystolic
bloodpressureis160mmHgordiastolicbloodpressureis110mmHg,confirmationwithinminutesissufficient.
Thetechniqueforbloodpressuremeasurementisdescribedseparately.(See"Bloodpressuremeasurementinthe
diagnosisandmanagementofhypertensioninadults".)
Forwomenwithchronic/preexistinghypertensionwhohaveproteinuriapriortoorinearlypregnancy,superimposed
preeclampsiaisdifficulttodiagnosedefinitively,butshouldbesuspectedwhenthereisasignificantworseningof
hypertension(especiallyacutely)inthelasthalfofpregnancyordevelopmentofsigns/symptomsassociatedwith
theseverespectrumofdisease.
Whenevaluatingwomenforpossiblepreeclampsia,itisgenerallysafertoassumethatnewonsethypertensionin
pregnancyisduetopreeclampsia,evenifallthediagnosticcriteriaarenotfulfilledandthebloodpressureisonly
mildlyelevated,sincepreeclampsiamayprogresstoeclampsiaorothersevereformsofthediseaseinashort
periodoftime.Womenwithmildelevationsofbloodpressurewhodonotmeetcriteriaforpreeclampsiahave
gestationalhypertensionandshouldbefollowedcloselyandmonitored,since25percentwilldeveloppreeclampsia
laterinpregnancy.
PostdiagnosticevaluationThepurposeofthepostdiagnosticevaluationistodeterminetheseverityof
diseaseandassessmaternalandfetalwellbeing.Thesefactors,aswellasgestationalage,guidemanagement.
(See"Preeclampsia:Managementandprognosis".)
Preeclampsiaisgenerallyclassifiedashavingseverefeaturesifanyofthefollowingarepresentinawomanwith
preeclampsia(table2)[3,4,126129]:
Severehypertension(systolicbloodpressure160mmHgordiastolicbloodpressure110mmHg)
Signs/symptomsofendorganinjury(thrombocytopenia,impairedliverfunction,progressiverenal
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insufficiency,pulmonaryedema,newonsetcerebralorvisualdisturbances)
Therefore,thehistoryandphysicalexaminationshouldevaluatethepatientfor:

Persistentand/orsevereheadache
Visualabnormalities(scotomata,photophobia,blurredvision,ortemporaryblindness)
Upperabdominalorepigastricpain
Nausea,vomiting
Dyspnea
Alteredmentalstatus

Theminimumpostdiagnosticlaboratory/imagingevaluationshouldinclude:

Plateletcount
Serumcreatinine
Serumaspartateaminotransferase(AST)oralanineaminotransferase(ALT)
Obstetricalultrasound(fetalweight,amnioticfluidvolume)
Fetalassessment(biophysicalprofileornonstresstest)

Additionalteststhatcanbeinformativeincludebloodsmearandserumlactatedehydrogenase(LDH)andbilirubin
concentrations.MicroangiopathichemolysisissuggestedbyelevatedLDHandindirectbilirubinlevelsandredcell
fragmentation(schistocytesorhelmetcells)onperipheralbloodsmear(picture2AB).Hemoconcentrationoccurs
inpreeclampsia,buthemolysis,ifpresent,candecreasethehematocrittonormaloranemiclevels.
Coagulationfunctiontests(eg,prothrombintime,activatedpartialthromboplastintime,fibrinogenconcentration)
areusuallynormalinpatientswithoutthrombocytopeniaorliverdysfunctiontherefore,theyarenotchecked
routinely[130].
Differentialdiagnosis
PreexistinghypertensionversuspreeclampsiaBecauseofthereductioninbloodpressurethattypically
occursearlyinpregnancy,awomanwithpreexistenthypertensionmaybenormotensivewhenfirstseenbythe
obstetricalprovider.Laterinpregnancywhenherbloodpressurereturnstoitsprepregnancybaseline,shemay
appeartobedevelopingmildpreeclampsiaiftherearenodocumentedprepregnancybloodpressure
measurements.
Inthissetting,avarietyoffactorscanbehelpfulinestablishingthelikelydiagnosis:
Hypertensionoccurringbeforethe20thweekisusuallyduetopreexistinghypertensionratherthanto
preeclampsia.
Proteinuriaispresentandincreaseswithtimeinpreeclampsia,occasionallyreachingthenephroticrangeby
comparison,proteinexcretionisusuallyabsentorlessthan1g/dayinhypertensivenephrosclerosis[20].
(See"Clinicalfeatures,diagnosis,andtreatmentofhypertensivenephrosclerosis".)
Preeclampsiaismorecommoninnulliparasthaninmultiparas.
Preeclampsiaismorecommoninolder(>40years)nulliparas,althoughthesewomenarealsomorelikelyto
havepreexistinghypertension,asareoldermultiparouswomen(see'Riskfactors'above).
SuperimposedpreeclampsiaInwomenwithknownprimary(essential)hypertensionandincreasingblood
pressureand/orproteinuria,thepresenceofsystemicmanifestationsofseverefeaturesofpreeclampsia,suchas
thrombocytopenia,increasedserumlevelsofaminotransferases,andvisualsymptomsstronglysuggest
developmentofsuperimposedpreeclampsia(table2)[131].Reproductiveagewomenwithprimary(essential)
hypertensiontypicallyhavenoormildproteinuriasosevereproteinuriasuggestsdevelopmentofsuperimposed
preeclampsia.
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ExacerbationofpreexistingrenaldiseaseSuperimposedpreeclampsiafrequentlydevelopsinwomenwith
preexistingprimaryorsecondaryrenaldisease[132,133].However,worseninghypertensionandproteinuriaina
womanwithpreexistingrenaldiseasemayalsorepresentanexacerbationoftheunderlyingdiseaseorthe
physiologicaleffectsofpregnancy.Theabilitytoaccuratelydistinguishamongthesepossibilitiesisimportant,as
managementandcomplicationsaredifferent.
Significantcluestothediagnosisofpreeclampsiawithseverefeaturesarethepresenceofsystemic
manifestationsofthedisorder,suchasthrombocytopenia,increasedserumlevelsofaminotransferases,and
visualsymptoms(table2)[131].Onsetofdiseaseinthefirsthalfofpregnancysuggestsexacerbationof
underlyingrenaldisease,ratherthanpreeclampsia.
Laboratoryevidencesuggestiveofexacerbationofrenaldiseaseincludesthepresenceoffindingsspecificfor
diseaseactivity(eg,lowcomplementlevelsinapatientwithsystemiclupuserythematosus,urinalysisconsistent
withaproliferativeglomerulardisorder[redandwhitecellsand/orcellularcasts]).Anactiveurinesedimentisnota
featureofpreeclampsia.(See"Pregnancyinwomenwithunderlyingrenaldisease"and"Pregnancyinwomenwith
diabetickidneydisease".)
AntiphospholipidsyndromeHypertension,proteinuria,andthrombocytopenia,andothersignsofend
organdysfunctioncanbeseeninantiphospholipidsyndrome.Theabsenceoflaboratoryevidenceof
antiphospholipidantibodiesexcludesthisdiagnosis.(See"Clinicalmanifestationsoftheantiphospholipid
syndrome"and"Diagnosisoftheantiphospholipidsyndrome"and"Pregnancyinwomenwithantiphospholipid
syndrome".)
AFLP,TTP,HUS,SLEAlthoughpreeclampsia/HELLPisthemostcommoncauseofhypertension,
thrombocytopenia,liverabnormalities,andrenalabnormalitiesinpregnantwomen,thefollowingconditionsshould
beconsideredandexcluded,ifpossible.Laboratoryfindingsinthesedisordersarecomparedinthetables(table
5AB).
Acutefattyliverofpregnancy(AFLP).Anorexia,nausea,andvomitingarecommonclinicalfeaturesofAFLP.
LowgradefevercanbepresentinAFLP,butdoesnotoccurinpreeclampsia/HELLP.AFLPisassociated
withmoreseriousliverdysfunction:hypoglycemiaanddisseminatedintravascularcoagulationarecommon
features,whileunusualinpreeclampsia/HELLP.AFLPisalsousuallyassociatedwithmoresignificantrenal
dysfunctioncomparedtopreeclampsia/HELLP.(See"Acutefattyliverofpregnancy".)
Thromboticthrombocytopenicpurpura(TTP)orhemolyticuremicsyndrome(HUS).Althoughneurologic
abnormalitiesandacuterenalfailureoftenareseeninTTPandHUS,respectively,theyarenotalwaysseen,
andthesedisordersmaybeindistinguishablefromseverepreeclampsia/HELLPsyndrome.
Preeclampsia/HELLPbeginstoresolvewithin48hoursafterdelivery,whileTTPandHUSdonotresolve
withdelivery.DistinguishingamongTTP,HUS,andrelatedthromboticmicroangiopathysyndromesmaybe
challenging.AnapproachtothepatientsuspectedtohaveTTPorHUS,includingurgentinterventionsbefore
thediagnosisisestablished,ispresentedseparately.(See"ApproachtothepatientwithsuspectedTTP,
HUS,orotherthromboticmicroangiopathy(TMA)".)
Exacerbationofsystemiclupuserythematosus(SLE).FlaresofSLEarelikelytobeassociatedwith
hypocomplementemiaandincreasedtitersofantiDNAantibodiesbycomparison,complementlevelsare
usually,butnotalways,normalorincreasedinpreeclampsia.Acuteonset,acceleratedhypertensionismore
likelytobeduetopreeclampsiathanalupusflare.(See"Pregnancyinwomenwithsystemiclupus
erythematosus".)
MirrorsyndromeFetalhydropsfromanycause(nonimmuneorimmune)canresultinmaternalsymptoms
identicaltothoseseenintypicalpreeclampsia.ThisdisorderiscalledmirrororBallantynesyndromeandresolves
withoutdeliveryifhydropsresolves.(See"Nonimmunehydropsfetalis",sectionon'Mirrorsyndrome'.)
MeasurementofangiogenicfactorsInthefuture,measurementofurinaryorplasmaangiogenicfactors
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(solublefmsliketyrosinekinase,placentalgrowthfactor)maybeusefulfordistinguishingpreeclampsiafromother
hypertensiveproteinuricdisordersthistestiscommerciallyavailablebutinvestigationalandshouldbelimitedto
patientsinresearchstudies[134136].
Multiplestudieshavedemonstratedthatangiogenicfactors(sFLT1andPlGF)arealteredinwomenwithclinical
featuresofpreeclampsia(see"Preeclampsia:Pathogenesis",sectionon'sFlt1,VEGF,PIGF').Ithasalsobeen
demonstratedthattheratioofsFLT1/PlGFisparticularlysensitiveinmakingaclinicaldiagnosis.Whatremainsto
bedeterminediswhether,andinwhatcircumstances,measurementofangiogenicfactorscouldbeclinically
usefulandimprovepatientoutcomes.Oneparticularscenariothatisclinicallychallengingisdeterminingwhethera
womanwithsignsofpreeclampsia,suchasanincreaseinbloodpressureoraslightlyelevatedlevelofurinary
protein,requiresmedicalintervention,suchashospitalizationorevendelivery.Abiomarkertestthatimprovedour
abilitytopredictpatientswhorequireordonotrequireahigherdegreeofmedicalinterventionwouldbehelpful.
Aprospective,multicenter,internationalobservationalstudy(PROGNOSIS)attemptedtoderiveandvalidatea
serumsFlt1:PlGFratiothatwouldpredicttheabsenceorpresenceofpreeclampsiaintheshortterminwomen
whoalreadyhadsignssuggestiveofpreeclampsia,suchasanincreaseinbloodpressureand/orproteinuria[137].
Thestudyincluded500womenwithsingletonpregnanciesat24to366/7thsweeksofgestationwithsuspected
preeclampsiabasedononeormoreofthefollowing:newincreaseinbloodpressurebutlessthan140/90mmHg,
newproteinuriabutlessthan2+dipstick,preeclampsiarelatedlaboratoryfindingsbutnotmeetingcriteriafor
HELLPsyndrome,preeclampsiarelatedsymptoms(edema,headache,visualchanges,suddenweightgain).
AlthoughtheauthorsconcludedthatansFlt1:PlGFratiocutoffof38usingaspecificautomatedcommercial
assayhadanegativepredictivevalue(nopreeclampsiainthenextsevendays)of99.3percent(95%CI97.9
99.9),withsensitivityof80percent(95%CI51.995.7)andspecificityof78.3percent(95%CI74.681.7),we
questiontheclinicalusefulnessofthisconclusionsincethewomenenrolledinthestudyappearedtohavea
clinicalprofileofmilddiseaseandtheprevalenceofpreeclampsiawasquitelowinthisgroup.Thepositive
predictivevalueforpreeclampsiawasonly36.7percentinthenextfourweeks(95%CI28.445.7).Whetherthis
ratiowillbehelpfulinreducingiatrogenicmorbidityduetooverdiagnosisinwomenwithsuggestivesignsof
preeclampsiaisunclear.Furtherexplorationofthistestiswarranted,includingdeterminingwhetherthecutoff
variesamonglaboratoriesandpatientpopulations,thebestintervalforrepeattesting,andhowthisinformation
affectsclinicaloutcomesandcosts.
PREDICTINGWOMENWHOWILLDEVELOPPREECLAMPSIANotestperformedinearlypregnancy
performswellforselectingwomenwhoarelikelytodeveloppreeclampsia.(See"Predictionofpreeclampsia".)
INFORMATIONFORPATIENTSUpToDateofferstwotypesofpatienteducationmaterials,"TheBasics"and
"BeyondtheBasics."TheBasicspatienteducationpiecesarewritteninplainlanguage,atthe5thto6thgrade
readinglevel,andtheyanswerthefourorfivekeyquestionsapatientmighthaveaboutagivencondition.These
articlesarebestforpatientswhowantageneraloverviewandwhoprefershort,easytoreadmaterials.Beyond
theBasicspatienteducationpiecesarelonger,moresophisticated,andmoredetailed.Thesearticlesarewritten
atthe10thto12thgradereadinglevelandarebestforpatientswhowantindepthinformationandarecomfortable
withsomemedicaljargon.
Herearethepatienteducationarticlesthatarerelevanttothistopic.Weencourageyoutoprintoremailthese
topicstoyourpatients.(Youcanalsolocatepatienteducationarticlesonavarietyofsubjectsbysearchingon
"patientinfo"andthekeyword(s)ofinterest.)
Basicstopics(see"Patientinformation:Preeclampsia(TheBasics)"and"Patientinformation:Highblood
pressureandpregnancy(TheBasics)"and"Patientinformation:HELLPsyndrome(TheBasics)")
BeyondtheBasicstopics(see"Patientinformation:Preeclampsia(BeyondtheBasics)")
SUMMARYANDRECOMMENDATIONS
Thefourmajorhypertensivedisordersrelatedtopregnancyarepreeclampsia,chronichypertension,
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preeclampsiasuperimposeduponchronichypertension,andgestationalhypertension(table3).(See
'Definitionsofpregnancyrelatedhypertensivedisorders'above.)
Majorriskfactorsfordevelopmentofpreeclampsiaincludepasthistoryofpreeclampsia,nulliparity,
pregestationaldiabetes,chronichypertension,obesity,familyhistoryofpreeclampsia,andmultiplegestation.
(See'Riskfactors'above.)
Thegradualdevelopmentofhypertensionandproteinuriainthelasthalfofpregnancyisusuallydueto
preeclampsia,particularlyinanullipara.Thesefindingstypicallybecomeapparentafter34weeksof
gestationandprogressuntildelivery,butsomewomendevelopsymptomsearlieringestation,intrapartum,or
postpartum.(See'Clinicalpresentation'above.)
Thediagnosisofpreeclampsiaisbasedonthenewonsetofhypertensionandeitherproteinuriaorendorgan
dysfunctionafter20weeksofgestationinapreviouslynormotensivewoman(table1)(see'Diagnosis'
above):
Systolicbloodpressure140mmHgordiastolicbloodpressure90mmHg,and
Proteinuria0.3gramsina24hoururinespecimenorprotein:creatinineratio0.3,or
Signsofendorgandysfunction(plateletcount<100,000/microliter,serumcreatinine>1/1mg/dLor
doublingoftheserumcreatinine,elevatedserumtransaminasestotwicenormalconcentration)
Thegoalofthepostdiagnosticevaluationistodeterminetheseverityofdiseaseandassessmaternaland
fetalwellbeing.Findingsindicativeofseverediseasearelistedinthetable(table2).Postdiagnostic
laboratory/imagingevaluationshouldinclude(see'Postdiagnosticevaluation'above):
Plateletcount
Serumcreatinine
Serumaspartateaminotransferase(AST)oralanineaminotransferase(ALT)
Obstetricalultrasound(fetalweight,amnioticfluidvolume)
Fetalassessment(biophysicalprofileornonstresstest)
Differentialdiagnosisincludesexacerbationofunderlyingrenaldisease,acutefattyliverofpregnancy,
thromboticthrombocytopenicpurpura(TTP)orhemolyticuremicsyndrome(HUS),andexacerbationof
systemiclupuserythematosus.(See'Differentialdiagnosis'above.)
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
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GRAPHICS
Criteriaforthediagnosisofpreeclampsia
Systolicbloodpressure140mmHgordiastolicbloodpressure90mmHgontwooccasionsat
leastfourhoursapartafter20weeksofgestationinapreviouslynormotensivepatient
Ifsystolicbloodpressureis160mmHgordiastolicbloodpressureis110mmHg,confirmation
withinminutesissufficient
and
Proteinuria0.3gramsina24hoururinespecimenorprotein(mg/dL)/creatinine(mg/dL)ratio
0.3
Dipstick1+ifaquantitativemeasurementisunavailable
Inpatientswithnewonsethypertensionwithoutproteinuria,thenewonsetofanyof
thefollowingisdiagnosticofpreeclampsia:
Plateletcount<100,000/microliter
Serumcreatinine>1.1mg/dLordoublingofserumcreatinineintheabsenceofotherrenal
disease
Livertransaminasesatleasttwicethenormalconcentrations
Pulmonaryedema
Cerebralorvisualsymptoms
Adaptedfrom:Hypertensioninpregnancy:ReportoftheAmericanCollegeofObstetriciansand
Gynecologists'TaskForceonHypertensioninPregnancy.ObstetGynecol2013122:1122.
Graphic79977Version12.0

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Thepresenceofoneormoreofthefollowingindicatesadiagnosisof
"preeclampsiawithseverefeatures"
Symptomsofcentralnervoussystemdysfunction:
Newonsetcerebralorvisualdisturbance,suchas:
Photopsia,scotomata,corticalblindness,retinalvasospasm
Severeheadache(ie,incapacitating,"theworstheadacheI'veeverhad")orheadachethatpersists
andprogressesdespiteanalgesictherapy
Alteredmentalstatus

Hepaticabnormality:
Severepersistentrightupperquadrantorepigastricpainunresponsivetomedicationandnotaccounted
forbyanalternativediagnosisorserumtransaminaseconcentrationtwicenormal,orboth

Severebloodpressureelevation:
Systolicbloodpressure160mmHgordiastolicbloodpressure110mmHgontwooccasionsatleast
fourhoursapartwhilethepatientisonbedrest(unlessthepatientisonantihypertensivetherapy)

Thrombocytopenia:
<100,000platelets/microL

Renalabnormality:
Progressiverenalinsufficiency(serumcreatinine>1.1mg/dLordoublingofserumcreatinine
concentrationintheabsenceofotherrenaldisease)

Pulmonaryedema

Incontrasttooldercriteria,the2013criteriadonotincludeproteinuria>5grams/24hours
andfetalgrowthrestrictionasfeaturesofseveredisease.
Adaptedfrom:Hypertensioninpregnancy:ReportoftheAmericanCollegeofObstetriciansand
Gynecologists'TaskForceonHypertensioninPregnancy.ObstetGynecol2013122:1122.
Graphic76975Version8.0

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Criteriaforgestationalhypertension
Systolicbloodpressure140mmHg
OR
Diastolicbloodpressure90mmHg
ANDnoproteinuria
DevelopingAFTERthe20thweekofgestationinwomenknowntobenormotensivebefore
pregnancy.Bloodpressureshouldbeelevatedonatleasttwooccasionsatleastsixhoursapart.
Graphic56709Version1.0

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Factorsassociatedwithanincreasedriskofdeveloping
preeclampsia
Nulliparity
Preeclampsiainapreviouspregnancy
Age>40yearsor<18years
Familyhistoryofpreeclampsia
Chronichypertension
Chronicrenaldisease
Antiphospholipidantibodysyndromeorinheritedthrombophilia
Vascularorconnectivetissuedisease
Diabetesmellitus(pregestationalandgestational)
Multifetalgestation
Highbodymassindex
Blackrace
Malepartnerwhosemotherorpreviouspartnerhadpreeclampsia
Hydropsfetalis
Unexplainedfetalgrowthrestriction
Womanherselfwassmallforgestationalage
Fetalgrowthrestriction,abruptioplacentae,orfetaldemiseinapreviouspregnancy
Prolongedinterpregnancyinterval

Partnerrelatedfactors(newpartner,limtedspermexposure[eg, previoususeof
barriercontraception])
Hydatidiformmole
Susceptibilitygenes

Bycomparison,smokingdecreasestheriskofpreeclampsia
Graphic61266Version2.0

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Preeclampsia

Lightmicrographinpreeclampsiashowingglomerularendotheliosis.
Theprimarychangesareswellingofdamagedendothelialcells,
leadingtopartialclosureofmanyofthecapillarylumens(large
arrows).Mitosiswithinanendothelialcell(smallarrow)isasignof
cellularrepair.
CourtesyofHelmutRennke,MD.
Graphic78879Version2.0

Normalglomerulus

Lightmicrographofanormalglomerulus.Thereareonly1or2
cellspercapillarytuft,thecapillarylumensareopen,thethickness
oftheglomerularcapillarywall(longarrow)issimilartothatofthe
tubularbasementmembranes(shortarrow),andthemesangial
cellsandmesangialmatrixarelocatedinthecentralorstalk
regionsofthetuft(arrows).
CourtesyofHelmutGRennke,MD.
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Preeclampsia

Electronmicrographinpreeclampsiashowingnarrowingofthe
capillarylumenduetoexpansionofthemesangium,swellingofthe
endothelial(Endo)cellcytoplasm(arrow),andsubendothelial
depositionofhyaline(Hy)materialwhichrepresentslarge
macromoleculessuchasIgM.Thedamagedendothelialcellhas
becomepartiallyseparated(*)fromtheglomerularbasement
membrane(GBM).
CourtesyofHelmutRennke,MD.
Graphic59970Version2.0

Electronmicrographofanormalglomerulus

Electronmicrographofanormalglomerularcapillaryloopshowing
thefenestratedendothelialcell(Endo),theglomerularbasement
membrane(GBM),andtheepithelialcellswithitsinterdigitating
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footprocesses(arrow).TheGBMisthin,andnoelectrondense
depositsarepresent.Twonormalplateletsareseeninthecapillary
lumen.
CourtesyofHelmutGRennke,MD.
Graphic50018Version7.0

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IgMdepositioninpreeclampsia

ImmunofluorescencemicroscopyinpreeclampsiashowingdiffuseIgM
deposition.Thisrepresentsnonspecificentrapmentoflargerproteins
inthemorepermeableglomerularcapillarywall,ratherthanthe
formationofdiscreteimmunecomplexes.Thereis,forexample,
generallynodepositionofIgG.
CourtesyofHelmutRennke,MD.
Graphic68634Version2.0

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Peripheralsmearinmicroangiopathichemolytic
anemiashowingpresenceofschistocytes

Peripheralbloodsmearfromapatientwithamicroangiopathic
hemolyticanemiawithmarkedredcellfragmentation.Thesmear
showsmultiplehelmetcells(smallblackarrows),otherfragmented
redcells(largeblackarrow)microspherocytesarealsoseen(blue
arrows).Theplateletnumberisreducedthelargeplateletinthe
center(redarrow)suggeststhatthethrombocytopeniaisdueto
enhanceddestruction.
CourtesyofCarolavonKapff,SH(ASCP).
Graphic70851Version6.0

Normalperipheralbloodsmear

Highpowerviewofanormalperipheralbloodsmear.Several
platelets(arrows)andanormallymphocyte(arrowhead)canalso
beseen.Theredcellsareofrelativelyuniformsizeandshape.
Thediameterofthenormalredcellshouldapproximatethatofthe
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nucleusofthesmalllymphocytecentralpallor(dashedarrow)
shouldequalonethirdofitsdiameter.
CourtesyofCarolavonKapff,SH(ASCP).
Graphic59683Version3.0

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Helmetcellsinmicroangiopathichemolyticanemia

Peripheralsmearsfromtwopatientswithmicroangiopathichemolytic
anemia,showinganumberofredcellfragments(ie,schistocytes),
someofwhichtaketheformofcombat(redarrow),bicycle(thickblack
arrow),orfootball(bluearrow)"helmets."Microspherocytesarealso
seen(thinblackarrows),alongwithanucleatedredcell(greenarrow).
CourtesyofCarolavonKapff,SH(ASCP).
Graphic50715Version3.0

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Frequencyofvarioussignsandsymptomsamongimitatorsof
preeclampsiaeclampsia
HELLP
syndrome,
percent

Signsand
symptoms

AFLP,
percent

TTP,
percent

HUS,
percent

Exacerbation
ofSLE,
percent

Hypertension

85

50

2075

8090

80withAPA,
nephritis

Proteinuria

9095

3050

With
hematuria

8090

100withnephritis

Fever

Absent

2532

2050

NR

Commonduring
flare

Jaundice

510

4090

Rare

Rare

Absent

Nauseaand
vomiting

40

5080

Common

Common

OnlywithAPA

Abdominalpain

6080

3550

Common

Common

OnlywithAPA

Central
nervous
system

4060

3040

6070

NR

50withAPA

HELLP:hemolysis,elevatedliverenzymes,lowplateletsAFLP:acutefattyliverofpregnancyTTP:
thromboticthrombocytopenicpurpuraHUS:hemolyticuremicsyndromeSLE:systemiclupus
erythematosusAPA:antiphospholipidantibodieswithorwithoutcatastrophicantiphospholipid
syndromeNR:valuesnotreportedCommon:reportedasthemostcommonpresentation.
Reproducedwithpermissionfrom:SibaiBM.Imitatorsofseverepreeclampsia.ObstetGynecol2007
109:956.Copyright2007LippincottWilliams&Wilkins.
Graphic64296Version8.0

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Frequencyandseverityoflaboratoryfindingsamongimitatorsof
preeclampsiaeclampsia
Laboratory
findings

HELLP
syndrome

AFLP

TTP

HUS

Exacerbation
ofSLE

Thrombocytopenia(less
than100,000/mm 3)

Morethan
20,000

More
than
50,000

20,000
orless

More
than
20,000

Morethan20,000

Hemolysis(percent)

50100

1520

100

100

1423withAPA

Anemia(percent)

Lessthan50

Absent

100

100

1423withAPA

DIC(percent)

Lessthan20

50100

Rare

Rare

Rare

Hypoglycemia(percent)

Absent

50100

Absent

Absent

Absent

VWfactormultimers
(percent)

Absent

Absent

8090

80

Lessthan10

ADAMTS13lessthan5
percent(percent)

Absent

Absent

33100

Rare

Rare

Impairedrenalfunction
(percent)

50

90100

30

100

4080

LDH(IU/L)

600ormore

Variable

More
than
1000

More
than
1000

WithAPA

Elevatedammonia
(percent)

Rare

50

Absent

Absent

Absent

Elevatedbilirubin
(percent)

5060

100

100

NA

Lessthan10

Elevatedtransaminases
(percent)

100

100

Usually
mild*

Usually
mild*

WithAPA

HELLP:hemolysis,elevatedliverenzymes,lowplateletsAFLP:acutefattyliverofpregnancyTTP:
thromboticthrombocytopenicpurpuraHUS:hemolyticuremicsyndromeSLE:systemiclupus
erythematosusAPA:antiphospholipidantibodieswithorwithoutcatastrophicantiphospholipid
syndromeDICdisseminatedintravascularcoagulopathy:VW:vonWillebrandADAMTS:vonWillebrand
factorcleavingmetalloproteaseLDH:lacticdehydrogenaseNR:valuesarenotavailable.
*Levelslessthan100IU/L.
Reproducedwithpermissionfrom:SibaiBM.Imitatorsofseverepreeclampsia.ObstetGynecol2007
109:956.Copyright2007LippincottWilliams&Wilkins.
Graphic65674Version9.0

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ContributorDisclosures
PhyllisAugust,MD,MPHNothingtodisclose.BahaMSibai,MDNothingtodisclose.CharlesJLockwood,
MD,MHCMConsultant/AdvisoryBoards:Celula[Aneuploidyscreening(PrenatalandcancerDNAscreeningtests
indevelopment)].VanessaABarss,MD,FACOGNothingtodisclose.
Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseare
addressedbyvettingthroughamultilevelreviewprocess,andthroughrequirementsforreferencestobeprovided
tosupportthecontent.AppropriatelyreferencedcontentisrequiredofallauthorsandmustconformtoUpToDate
standardsofevidence.
Conflictofinterestpolicy

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