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WilliamsObstetrics,24e>

Chapter40:HypertensiveDisorders

Introduction
Howpregnancyincitesoraggravateshypertensionremainsunsolveddespitedecadesofintensiveresearch.Indeed,hypertensive
disordersremainamongthemostsignificantandintriguingunsolvedproblemsinobstetrics.

Hypertensivedisorderscomplicate5to10percentofallpregnancies,andtogethertheyareonememberofthedeadlytriadalong
withhemorrhageandinfectionthatcontributesgreatlytomaternalmorbidityandmortality.Ofthesedisorders,thepreeclampsia
syndrome,eitheraloneorsuperimposedonchronichypertension,isthemostdangerous.Assubsequentlydiscussed,newonset
hypertensionduringpregnancytermedgestationalhypertensionisfollowedbysignsandsymptomsofpreeclampsiaalmosthalf
thetime,andpreeclampsiaisidentifiedin3.9percentofallpregnancies(Martin,2012).

TheWorldHealthOrganization(WHO)systematicallyreviewsmaternalmortalityworldwide,andindevelopedcountries,16percent
ofmaternaldeathswerereportedtobeduetohypertensivedisorders(Khan,2006).Thisproportionisgreaterthanthreeotherleading
causesthatincludehemorrhage13percent,abortion8percent,andsepsis2percent.IntheUnitedStatesfrom1998to2005,
Bergandcolleagues(2010)reportedthat12.3percentof4693pregnancyrelatedmaternaldeathswerecausedbypreeclampsiaor
eclampsia.Theratewassimilartothatof10percentformaternaldeathsinFrancefrom2003through2007(Saucedo,2013).
Importantly,morethanhalfofthesehypertensionrelateddeathswerepreventable(Berg,2005).

TerminologyandDiagnosis
Inthiscountryforthepasttwodecades,pregnancyhypertensionwasconsideredusingtheterminologyandclassification
promulgatedbytheWorkingGroupoftheNationalHighBloodPressureEducationProgramNHBPEP(2000).Toupdatethese,a
TaskForcewasappointedbyPresidentJamesMartinfortheAmericanCollegeofObstetriciansandGynecologists(2013b)to
provideevidencebasedrecommendationsforclinicalpractice.Thebasicclassificationwasretained,asitdescribesfourtypesof
hypertensivedisease:

1.Gestationalhypertensionevidenceforthepreeclampsiasyndromedoesnotdevelopandhypertensionresolvesby12weeks
postpartum

2.Preeclampsiaandeclampsiasyndrome

3.Chronichypertensionofanyetiology

4.Preeclampsiasuperimposedonchronichypertension.

Importantly,thisclassificationdifferentiatesthepreeclampsiasyndromefromotherhypertensivedisordersbecauseitispotentially
moreominous.Thisconceptaidsinterpretationofstudiesthataddresstheetiology,pathogenesis,andclinicalmanagementof
pregnancyrelatedhypertensivedisorders.

DiagnosisofHypertensiveDisorders

Hypertensionisdiagnosedempiricallywhenappropriatelytakenbloodpressureexceeds140mmHgsystolicor90mmHgdiastolic.
KorotkoffphaseVisusedtodefinediastolicpressure.Previously,incrementalincreasesof30mmHgsystolicor15mmHgdiastolic
frommidpregnancybloodpressurevalueshadalsobeenusedasdiagnosticcriteria,evenwhenabsolutevalueswere<140/90mm
Hg.Theseincrementalchangesarenolongerrecommendedcriteriabecauseevidenceshowsthatsuchwomenarenotlikelyto
experienceincreasedadversepregnancyoutcomes(Levine,2000North,1999).Thatsaid,womenwhohaveariseinpressureof30
mmHgsystolicor15mmHgdiastolicshouldbeobservedmorecloselybecauseeclampticseizuresdevelopinsomeofthesewomen
whosebloodpressureshavestayed<140/90mmHg(Alexander,2006).Asuddenriseinmeanarterialpressurelaterinpregnancy
alsoknownasdeltahypertensionmayalsosignifypreeclampsiaevenifbloodpressureis<140/90mmHg(MacdonaldWallis,
2012Vollaard,2007).

ConceptofDeltaHypertension

Thesystolicanddiastolicbloodpressurelevelsof140/90mmHghavebeenarbitrarilyusedsincethe1950stodefinehypertension
innonpregnantindividuals.AsdiscussedindetailinChapter50(GeneralConsiderations),theselevelswereselectedbyinsurance
companiesforagroupofmiddleagedmen.Itseemsmorerealistictodefinenormalrangebloodpressuresthatfallbetweenanupper
andlowerlimitforbloodpressuremeasurementsforaparticularpopulationsuchasyoung,healthy,pregnantwomen.Aschematic
exampleisshowninFigure401usingarbitrarybloodpressurereadings.Datacurvesforbothwomenshowbloodpressure
measurementsnearthe25thpercentileuntil32weeks.ThesebegintoriseinpatientB,whobytermhassubstantivelyincreased
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bloodpressures.However,herpressuresarestill<140/90mmHg,andthussheisconsideredtobenormotensive.Wetermedthis
ratheracuteincreaseinbloodpressureasdeltahypertension.Asdiscussedlater,someofthesewomenwilldevelopeclamptic
seizuresorHELLP(hemolysis,elevatedliverenzymelevels,lowplateletcount)syndromewhilestillnormotensive.

Figure401

Schematicshowsnormalreferencerangesforbloodpressurechangesacrosspregnancy.PatientA(blue)hasbloodpressuresnearthe
20thpercentilethroughoutpregnancy.PatientB(red)hasasimilarpatternwithpressuresataboutthe25thpercentileuntilabout36
weekswhenbloodpressurebeginstoincrease.Byterm,itissubstantivelyhigherandinthe75thpercentile,butsheisstill
considerednormotensive.

GestationalHypertension

Thisdiagnosisismadeinwomenwhosebloodpressuresreach140/90mmHgorgreaterforthefirsttimeaftermidpregnancy,butin
whomproteinuriaisnotidentified(Table401).Almosthalfofthesewomensubsequentlydeveloppreeclampsiasyndrome,which
includesfindingssuchasheadachesorepigastricpain,proteinuria,andthrombocytopenia.Evenso,whenbloodpressureincreases
appreciably,itisdangeroustobothmotherandfetustoignorethisriseonlybecauseproteinuriahasnotyetdeveloped.AsChesley
(1985)emphasized,10percentofeclampticseizuresdevelopbeforeovertproteinuriacanbedetected.Finally,gestational
hypertensionisreclassifiedbysomeastransienthypertensionifevidenceforpreeclampsiadoesnotdevelopandthebloodpressure
returnstonormalby12weekspostpartum.

TABLE401DiagnosticCriteriaforPregnancyAssociatedHypertension
Condition CriteriaRequired
Gestationalhypertension BP>140/90mmHgafter20weeksinpreviouslynormotensivewomen
Preeclampsiahypertensionand:
300mg/24h,or

Protein:creatinineratio0.3or
Proteinuria
Dipstick1+persistenta

or
Platelets<100,000/L

Thrombocytopenia Creatinine>1.1mg/dLordoublingofbaselineb
Renalinsufficiency
Liverinvolvement Serumtransaminaselevelsctwicenormal
Cerebralsymptoms
Pulmonaryedema Headache,visualdisturbances,convulsions

aRecommendedonlyifsoleavailabletest.

bNopriorrenaldisease.

cAST(aspartateaminotransferase)orALT(alanineaminotransferase).

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ModifiedfromtheAmericanCollegeofObstetriciansandGynecologists,2013b.

PreeclampsiaSyndrome

Asemphasizedthroughoutthischapter,preeclampsiaisbestdescribedasapregnancyspecificsyndromethatcanaffectvirtually
everyorgansystem.And,althoughpreeclampsiaismuchmorethansimplygestationalhypertensionwithproteinuria,appearanceof
proteinuriaremainsanimportantdiagnosticcriterion.Thus,proteinuriaisanobjectivemarkerandreflectsthesystemwide
endothelialleak,whichcharacterizesthepreeclampsiasyndrome.

Abnormalproteinexcretionisarbitrarilydefinedby24hoururinaryexcretionexceeding300mgaurineprotein:creatinineratio
0.3orpersistent30mg/dL(1+dipstick)proteininrandomurinesamples(Lindheimer,2008a).Noneofthesevaluesissacrosanct,
andurineconcentrationsvarywidelyduringtheday,asdodipstickreadings.Thus,assessmentmayshowadipstickvalueof1+to2+
fromconcentratedurinespecimensfromwomenwhoexcrete<300mg/day.AsdiscussedonProteinuria,itislikelythat
determinationofaspoturine:creatinineratioisasuitablereplacementfora24hoururinemeasurement(Chap.4,Urinalysis).

Itisnowappreciatedthatovertproteinuriamaynotbeafeatureinsomewomenwiththepreeclampsiasyndrome(Sibai,2009).
Becauseofthis,theTaskForce(2013)suggestedotherdiagnosticcriteria,whichareshowninTable401.Evidenceofmultiorgan
involvementmayincludethrombocytopenia,renaldysfunction,hepatocellularnecrosis(liverdysfunction),centralnervoussystem
perturbations,orpulmonaryedema.

IndicatorsofPreeclampsiaSeverity

ThemarkerslistedinTable401arealsousedtoclassifypreeclampsiasyndromeseverity.Althoughmanyuseadichotomousmild
andsevereclassification,theTaskForce(2013)discouragestheuseofmildpreeclampsia.Itisproblematicthattherearecriteria
forthediagnosisofseverepreeclampsia,butthedefaultclassificationiseitherimpliedorspecificallytermedasmild,less
severe,ornonsevere(Alexander,2003Lindheimer,2008b).Therearenogenerallyagreedoncriteriaformoderate
preeclampsiaanelusivethirdcategory.WeusethecriterialistedinTable402,whicharecategorizedassevereversus
nonsevere.Importantly,whileitispragmaticthatnonsevereclassificationsincludemoderateandmild,thesehavenotbeen
specificallydefined.

TABLE402IndicatorsofSeverityofGestationalHypertensiveDisordersa
Abnormality Nonsevereb Severe
DiastolicBP <110mmHg 110mmHg
SystolicBP <160mmHg 160mmHg
Proteinuriac Nonetopositive Nonetopositive
Headache Absent Present
Visualdisturbances Absent Present
Upperabdominalpain Absent Present
Oliguria Absent Present
Convulsion(eclampsia) Absent Present
Serumcreatinine Normal Elevated
Thrombocytopenia(<100,000/L) Absent Present
Serumtransaminaseelevation Minimal Marked
Fetalgrowthrestriction Absent Obvious
Pulmonaryedema Absent Present

aComparewithcriteriainTable401.

bIncludesmildandmoderatehypertensionnotspecificallydefined.

cMostdisregarddegreesofproteinuriaasbeingnonsevereorsevere.

BP=bloodpressure.

Somesymptomsareconsideredtobeominous.Headachesorvisualdisturbancessuchasscotomatacanbepremonitorysymptoms
ofeclampsia.Epigastricorrightupperquadrantpainfrequentlyaccompanieshepatocellularnecrosis,ischemia,andedemathat
ostensiblystretchesGlissoncapsule.Thischaracteristicpainisfrequentlyaccompaniedbyelevatedserumhepatictransaminase
levels.Finally,thrombocytopeniaisalsocharacteristicofworseningpreeclampsiaasitsignifiesplateletactivationandaggregationas
wellasmicroangiopathichemolysis.Otherfactorsindicativeofseverepreeclampsiaincluderenalorcardiacinvolvementand
obviousfetalgrowthrestriction,whichalsoatteststoitsduration.

Aswillbediscussed,themoreprofoundthesesignsandsymptoms,thelesslikelytheycanbetemporized,andthemorelikely
deliverywillberequired.Acaveatisthatdifferentiationbetweennonsevereandseveregestationalhypertensionorpreeclampsiacan
bemisleadingbecausewhatmightbeapparentlymilddiseasemayprogressrapidlytoseveredisease.

Eclampsia

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Inawomanwithpreeclampsia,aconvulsionthatcannotbeattributedtoanothercauseistermedeclampsia.Theseizuresare
generalizedandmayappearbefore,during,orafterlabor.Theproportionwhodonotdevelopseizuresuntilafter48hours
postpartumapproximates10percent(Sibai,2005).Insomereports,uptoafourthofeclampticseizuresdevelopbeyond48hours
postpartum(Chames,2002).OurexperiencesfromParklandHospital,however,arethatdelayedpostpartumeclampsiacontinuesto
occurinabout10percentofcasessimilartowhatwefirstreportedmorethan20yearsago(Alexander,2006Brown,1987).This
lowerpercentagewasalsofoundin222womenwitheclampsiafromTheNetherlands(Zwart,2008).

PreeclampsiaSuperimposedonChronicHypertension

Regardlessofitscause,anychronichypertensivedisorderpredisposesawomantodevelopsuperimposedpreeclampsiasyndrome.
Chronicunderlyinghypertensionisdiagnosedinwomenwithdocumentedbloodpressures140/90mmHgbeforepregnancyor
before20weeksgestation,orboth.Hypertensivedisorderscancreatedifficultproblemswithdiagnosisandmanagementinwomen
whoarenotfirstseenuntilaftermidpregnancy.Thisisbecausebloodpressurenormallydecreasesduringthesecondandearlythird
trimestersinbothnormotensiveandchronicallyhypertensivewomen(Chap.50,AdversePregnancyEffects).Thus,awomanwith
previouslyundiagnosedchronicvasculardiseasewhoisseenbefore20weeksfrequentlyhasbloodpressureswithinthenormal
range.Duringthethirdtrimester,however,asbloodpressuresreturntotheiroriginallyhypertensivelevels,itmaybedifficultto
determinewhetherhypertensionischronicorinducedbypregnancy.Evenacarefulsearchforevidenceofpreexistingendorgan
damagemaybefutile,asmanyofthesewomenhavemilddiseaseandnoevidenceofventricularhypertrophy,retinalvascular
changes,orrenaldysfunction.

Insomewomenwithchronichypertension,theirbloodpressureincreasestoobviouslyabnormallevels,andthisistypicallyafter24
weeks.IfnewonsetorworseningbaselinehypertensionisaccompaniedbynewonsetproteinuriaorotherfindingslistedinTable
401,thensuperimposedpreeclampsiaisdiagnosed.Comparedwithpurepreeclampsia,superimposedpreeclampsiacommonly
developsearlierinpregnancy.Italsotendstobemoresevereandoftenisaccompaniedbyfetalgrowthrestriction.Thesamecriteria
showninTable402arealsousedtofurthercharacterizeseverityofsuperimposedpreeclampsia.

IncidenceandRiskFactors
PreeclampsiaSyndrome

Youngandnulliparouswomenareparticularlyvulnerabletodevelopingpreeclampsia,whereasolderwomenareatgreaterriskfor
chronichypertensionwithsuperimposedpreeclampsia.Theincidenceismarkedlyinfluencedbyraceandethnicityandthusby
geneticpredisposition.Bywayofexample,innearly2400nulliparasenrolledinaMaternalFetalMedicineUnits(MFMU)Network
study,theincidenceofpreeclampsiawas5percentinwhite,9percentinHispanic,and11percentinAfricanAmericanwomen
(Myatt,2012a,b).

Otherfactorsincludeenvironmental,socioeconomic,andevenseasonalinfluences(Lawlor,2005Palmer,1999Spencer,2009).
Withconsiderationforthesevicissitudes,inseveralworldwidestudiesreviewedbyStaffandcoworkers(2014),theincidenceof
preeclampsiainnulliparouspopulationsrangedfrom3to10percent.Theincidenceofpreeclampsiainmultiparasisalsovariablebut
islessthanthatfornulliparas.Specifically,populationstudiesfromAustralia,Canada,Denmark,Norway,Scotland,Sweden,and
Massachusettsindicateanincidenceof1.4to4percent(Roberts,2011).

Thereareseveralotherriskfactorsassociatedwithpreeclampsia.Theseincludeobesity,multifetalgestation,maternalage,
hyperhomocysteinemia,andmetabolicsyndrome(CondeAgudelo,2000Scholten,2013Walker,2000).Therelationshipbetween
maternalweightandtheriskofpreeclampsiaisprogressive.Itincreasesfrom4.3percentforwomenwithabodymassindex(BMI)
<20kg/m2to13.3percentinthosewithaBMI>35kg/m2(Fig.485,GestationalDiabetes).Inwomenwithatwingestation
comparedwiththosewithsingletons,theincidenceofgestationalhypertension13versus6percent,andtheincidenceof
preeclampsia13versus5percent,arebothsignificantlyincreased(Sibai,2000).Itisinterestingthatthislatterincidenceis
unrelatedtozygosity(Maxwell,2001).

Althoughsmokingduringpregnancycausesvariousadversepregnancyoutcomes,ironically,ithasconsistentlybeenassociatedwith
areducedriskforhypertensionduringpregnancy(Bainbridge,2005Zhang,1999).Krausandassociates(2013)positthatthisis
becausesmokingupregulatesplacentaladrenomedullinexpression,whichregulatesvolumehomeostasis.

Womenwithpreeclampsiainthefirstpregnancyareatgreaterriskinasecondpregnancycomparedwithwomennormotensive
duringtheirfirstpregnancy(McDonald,2009).Andconversely,inthewomanwhowasnormotensiveduringherfirstpregnancy,the
incidenceofpreeclampsiainasubsequentpregnancyismuchlowerthanforafirstpregnancy.Inapopulationbasedretrospective
cohortanalysis,Getahunandcolleagues(2007)studiedalmost137,000secondpregnanciesinsuchwomen.Theincidencefor
preeclampsiainsecundigravidawhitewomenwas1.8percentcomparedwith3percentinAfricanAmericanwomen.

Eclampsia

Presumablybecauseitissomewhatpreventablebyadequateprenatalcare,theincidenceofeclampsiahasdecreasedovertheyearsin
areaswherehealthcareismorereadilyavailable.Incountrieswithadequateresources,itsincidenceaverages1in2000deliveries.
Venturaandassociates(2000)estimatedthattheincidenceintheUnitedStatesin1998was1in3250births.AccordingtotheRoyal
CollegeofObstetriciansandGynaecologists(2006),itapproximates1in2000intheUnitedKingdom.Akkawiandcoworkers
(2009)reportedittobe1in2500inDublin,Andersgaardandassociates(2006)as1per2000forScandinavia,andZwartand
colleagues(2008)as1per1600forTheNetherlands.

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Etiopathogenesis
Anysatisfactorytheoryconcerningtheetiologyandpathogenesisofpreeclampsiamustaccountfortheobservationthatgestational
hypertensivedisordersaremorelikelytodevelopinwomenwiththefollowingcharacteristics:

Areexposedtochorionicvilliforthefirsttime

Areexposedtoasuperabundanceofchorionicvilli,aswithtwinsorhydatidiformmole

Havepreexistingconditionsofendothelialcellactivationorinflammationsuchasdiabetesorrenalorcardiovasculardisease

Aregeneticallypredisposedtohypertensiondevelopingduringpregnancy.

Afetusisnotarequisiteforpreeclampsiatodevelop.And,althoughchorionicvilliareessential,theyneednotbeintrauterine.For
example,Worleyandassociates(2008)reporteda30percentincidenceinwomenwithanextrauterinepregnancyexceeding18
weeksgestation.Regardlessofprecipitatingetiology,thecascadeofeventsleadingtothepreeclampsiasyndromeischaracterized
byabnormalitiesthatresultinvascularendothelialdamagewithresultantvasospasm,transudationofplasma,andischemicand
thromboticsequelae.

PhenotypicExpressionofPreeclampsiaSyndrome

Thepreeclampsiasyndromeiswidelyvariableinitsclinicalphenotypicexpression.Thereareatleasttwomajorsubtypes
differentiatedbywhetherornotremodelingofuterinespiralarteriolesbyendovasculartrophoblasticinvasionisdefective.This
concepthasgivenrisetothetwostagedisordertheoryofpreeclampsiaetiopathogenesis.NessandRoberts(1996)considerthat
thetwostagedisorderincludesmaternalandplacentalpreeclampsia.AccordingtoRedmanandcoworkers(2014),stage1is
causedbyfaultyendovasculartrophoblasticremodelingthatdownstreamcausesthestage2clinicalsyndrome.Importantly,stage2is
susceptibletomodificationbypreexistingmaternalconditionsthataremanifestbyendothelialcellactivationorinflammation.Such
conditionsincludecardiovascularorrenaldisease,diabetes,obesity,immunologicaldisorders,orhereditaryinfluences.

Suchcompartmentalizationisartificial,anditseemslogicaltousthatpreeclampsiasyndromepresentsclinicallyasaspectrumof
worseningdisease.Moreover,evidenceisaccruingthatmanyisoformsexistasdiscussedbelow.Examplesincludedifferencesin
maternalandfetalcharacteristics,placentalfindings,andhemodynamicfindings(Phillips,2010Valensise,2008vanderMerwe,
2010).

Etiology

Writingsdescribingeclampsiahavebeentracedasfarbackas2200bc(Lindheimer,2014).And,animposingnumberofmechanisms
havebeenproposedtoexplainitscause.Thosecurrentlyconsideredimportantinclude:

1.Placentalimplantationwithabnormaltrophoblasticinvasionofuterinevessels

2.Immunologicalmaladaptivetolerancebetweenmaternal,paternal(placental),andfetaltissues

3.Maternalmaladaptationtocardiovascularorinflammatorychangesofnormalpregnancy

4.Geneticfactorsincludinginheritedpredisposinggenesandepigeneticinfluences.

AbnormalTrophoblasticInvasion

Normalimplantationischaracterizedbyextensiveremodelingofthespiralarterioleswithinthedeciduabasalisasshown
schematicallyinFigure402(Chap.5,InvasionofSpiralArteries).Endovasculartrophoblastsreplacethevascularendothelialand
muscularliningstoenlargethevesseldiameter.Theveinsareinvadedonlysuperficially.Insomecasesofpreeclampsia,however,
theremaybeincompletetrophoblasticinvasion.Withthis,decidualvessels,butnotmyometrialvessels,becomelinedwith
endovasculartrophoblasts.Thedeepermyometrialarteriolesdonotlosetheirendothelialliningandmusculoelastictissue,andtheir
meanexternaldiameterisonlyhalfthatofcorrespondingvesselsinnormalplacentas(Fisher,2014).Ingeneral,themagnitudeof
defectivetrophoblasticinvasionisthoughttocorrelatewithseverityofthehypertensivedisorder(Madazli,2000).

Figure402

Schematicrepresentationofnormalplacentalimplantationshowsproliferationofextravilloustrophoblastsfromananchoringvillus.
Thesetrophoblastsinvadethedeciduaandextendintothewallsofthespiralarterioletoreplacetheendotheliumandmuscularwall
tocreateadilatedlowresistancevessel.Withpreeclampsia,thereisdefectiveimplantationcharacterizedbyincompleteinvasionof
thespiralarteriolarwallbyextravilloustrophoblasts.Thisresultsinasmallcalibervesselwithhighresistancetoflow.

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Usingelectronmicroscopy,DeWolfandcoworkers(1980)examinedarteriestakenfromtheimplantationsite.Theyreportedthat
earlypreeclampticchangesincludedendothelialdamage,insudationofplasmaconstituentsintovesselwalls,proliferationof
myointimalcells,andmedialnecrosis.Lipidaccumulatedfirstinmyointimalcellsandthenwithinmacrophages.Theselipidladen
cellchanges,showninFigure403,werereferredtoasatherosisbyHertig(1945).Nelsonandcolleagues(2014)completed
placentalexaminationinmorethan1200womenwithpreeclampsia.Theseinvestigatorsreportedthatvascularlesionsincluding
spiralarteriolenarrowing,atherosis,andinfarctsweremorecommoninplacentasfromwomendiagnosedwithpreeclampsiabefore
34weeks.

Figure403

Atherosisinabloodvesselfromaplacentalbed.A.Photomicrographshowsdisruptionoftheendotheliumthatresultsinanarrowed
lumenbecauseofsubendothelialaccumulationofplasmaproteinsandfoamymacrophages.Someofthefoamymacrophagesare
shownbycurvedarrows,andstraightarrowshighlightareasofendothelialdisruption.B.Schematicdiagramofthe
photomicrograph.(ModifiedfromRogers,1999,withpermission.)

Thus,theabnormallynarrowspiralarteriolarlumenlikelyimpairsplacentalbloodflow.McMahonandcolleagues(2014)have
providedevidencethatdecreasedsolubleantiangiogenicgrowthfactorsmaybeinvolvedinfaultyendovascularremodeling.
Diminishedperfusionandahypoxicenvironmenteventuallyleadtoreleaseofplacentaldebrisormicroparticlesthatincitea
systemicinflammatoryresponse(Lee,2012Redman,2012).FisherandRoberts(2014)haveprovidedanelegantreviewofthe
molecularmechanismsinvolvedintheseinteractions.

Defectiveplacentationispositedtofurthercausethesusceptible(pregnant)womantodevelopgestationalhypertension,the
preeclampsiasyndrome,pretermdelivery,agrowthrestrictedfetus,and/orplacentalabruption(Brosens,2011Kovo,2010
McElrath,2008Nelson,2014).Inaddition,Staffandcoworkers(2013)havehypothesizedthatacuteatherosisidentifiesagroupof
womenatincreasedriskforlateratherosclerosisandcardiovasculardisease.

ImmunologicalFactors

MaternalimmunetolerancetopaternallyderivedplacentalandfetalantigensisdiscussedinChapter5(BreaksinthePlacental
Barrier).Lossofthistolerance,orperhapsitsdysregulation,isanothertheorycitedtoaccountforpreeclampsiasyndrome
(Erlebacher,2013).Certainly,thehistologicalchangesatthematernalplacentalinterfacearesuggestiveofacutegraftrejection.
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Someofthefactorspossiblyassociatedwithdysregulationincludeimmunizationfromapreviouspregnancy,someinherited
humanleukocyteantigen(HLA)andnaturalkiller(NK)cellreceptorhaplotypes,andpossiblysharedsusceptibilitygeneswith
diabetesandhypertension(Fukui,2012Ward,2014).

Inferentialdataalsosuggestpreeclampsiatobeanimmunemediateddisorder.Forexample,theriskofpreeclampsiaisappreciably
enhancedincircumstancesinwhichformationofblockingantibodiestoplacentalantigenicsitesmightbeimpaired.Inthisscenario,
thefirstpregnancywouldcarryahigherrisk.Tolerancedysregulationmightalsoexplainanincreasedriskwhenthepaternal
antigenicloadisincreased,thatis,withtwosetsofpaternalchromosomesadoubledose.Namely,womenwithmolar
pregnancieshaveahighincidenceofearlyonsetpreeclampsia.Womenwithatrisomy13fetusalsohavea30to40percent
incidenceofpreeclampsia.Thesewomenhaveelevatedserumlevelsofantiangiogenicfactors,andthegeneforoneofthesefactors,
sFlt1,isonchromosome13(Bdolah,2006).Conversely,womenpreviouslyexposedtopaternalantigens,suchasapriorpregnancy
withthesamepartner,areimmunizedagainstpreeclampsia.Thisphenomenonisnotasapparentinwomenwithapriorabortion.
Stricklandandassociates(1986)studiedmorethan29,000pregnanciesatParklandHospital.Theseinvestigatorsreportedthat
hypertensivedisorderratesweredecreasedinwomenwhopreviouslyhadmiscarriedcomparedwithnulligravidas.However,the
difference,althoughstatisticallysignificant,wasnotgreat22versus25percent.Otherstudieshaveshownthatmultiparas
impregnatedbyanewconsorthaveanincreasedriskofpreeclampsia(Mostello,2002).

Redmanandcolleagues(2014)reviewedthepossibleroleofimmunemaladaptationinpreeclampsiapathophysiology.Inwomen
destinedtobepreeclamptic,extravilloustrophoblastsearlyinpregnancyexpressreducedamountsofimmunosuppressivenonclassic
HLAG.Blackwomenmorecommonlyhavethe1597Callelethatfurtherpredisposestopreeclampsia(Loisel,2013).Zhouand
coworkers(2012b)haveshownthistobeassociatedwithhighlevelsofplacentaloxidativeproducts.Thesechangesmaycontribute
todefectiveplacentalvascularizationinstage1ofthepreeclampsiasyndrome(Etiology).RecallthatasdiscussedinChapter4
(ImmunologicalFunctions),duringnormalpregnancy,Thelper(Th)lymphocytesareproducedsothattype2activityisincreasedin
relationtotype1termedtype2bias(Redman,2012,2014).Th2cellspromotehumoralimmunity,whereasTh1cellsstimulate
inflammatorycytokinesecretion.Beginningintheearlysecondtrimesterinwomenwhodeveloppreeclampsia,Th1actionis
increasedandtheTh1/Th2ratiochanges.Contributorstoanenhancedimmunologicallymediatedinflammatoryreactionare
stimulatedbyplacentalmicroparticlesandbyadipocytes(Redman,2012,2014).

EndothelialCellActivation

Inmanyways,inflammatorychangesarebelievedtobeacontinuationofthestage1changescausedbydefectiveplacentationas
discussedabove.Inresponsetoplacentalfactorsreleasedbyischemicchangesorbyanyotherincitingcause,acascadeofevents
begins(Davidge,2014).Thus,antiangiogenicandmetabolicfactorsandotherinflammatorymediatorsarethoughttoprovoke
endothelialcellinjury.

Endothelialcelldysfunctionmayresultfromanextremeactivatedstateofleukocytesinthematernalcirculation(Faas,2000
Gervasi,2001).Briefly,cytokinessuchastumornecrosisfactor(TNF)andtheinterleukins(IL)maycontributetotheoxidative
stressassociatedwithpreeclampsia.Thisischaracterizedbyreactiveoxygenspeciesandfreeradicalsthatleadtoformationofself
propagatinglipidperoxides(Manten,2005).Theseinturngeneratehighlytoxicradicalsthatinjureendothelialcells,modifytheir
nitricoxideproduction,andinterferewithprostaglandinbalance.Otherconsequencesofoxidativestressincludeproductionofthe
lipidladenmacrophagefoamcellsseeninatherosisandshowninFigure403activationofmicrovascularcoagulationmanifestby
thrombocytopeniaandincreasedcapillarypermeabilitymanifestbyedemaandproteinuria.

Theseobservationsontheeffectsofoxidativestressinpreeclampsiahavegivenrisetoincreasedinterestinthepotentialbenefitof
antioxidantstopreventpreeclampsia.Unfortunately,dietarysupplementationwithvitaminsE(tocopherol)andC(ascorbicacid)to
preventpreeclampsiahasthusfarprovenunsuccessful(TaskForce,2013).Thisisdiscussedsubsequently.

NutritionalFactors

Johnandcolleagues(2002)showedthatinthegeneralpopulation,adiethighinfruitsandvegetableswithantioxidantactivityis
associatedwithdecreasedbloodpressure.Zhangandassociates(2002)reportedthattheincidenceofpreeclampsiawasdoubledin
womenwhosedailyintakeofascorbicacidwaslessthan85mg.Thesestudieswerefollowedbyrandomizedtrialstostudydietary
supplementation.Villarandcoworkers(2006)showedthatcalciumsupplementationinpopulationswithalowdietarycalciumintake
hadasmalleffecttolowerperinatalmortalityratesbutnoeffectonpreeclampsiaincidence(Prevention).Accordingtothe2013Task
Force,inseveraltrials,supplementationwiththeantioxidantvitaminsCorEshowednobenefits.

GeneticFactors

Fromahereditaryviewpoint,preeclampsiaisamultifactorial,polygenicdisorder.Intheircomprehensivereview,WardandTaylor
(2014)citeanincidentriskforpreeclampsiaof20to40percentfordaughtersofpreeclampticmothers11to37percentforsistersof
preeclampticwomenand22to47percentfortwins.InastudybyNilssonandcolleagues(2004)thatincludedalmost1.2million
Swedishbirths,therewasageneticcomponentforgestationalhypertensionandforpreeclampsia.Theyalsoreported60percent
concordanceinmonozygoticfemaletwinpairs.

Thehereditarypredispositionforpreeclampsialikelyistheresultofinteractionsofliterallyhundredsofinheritedgenesboth
maternalandpaternalthatcontrolmyriadenzymaticandmetabolicfunctionsthroughouteveryorgansystem.Plasmaderived
factorsmayinducesomeofthesegenesinpreeclampsia(Mackenzie,2012).Thus,theclinicalmanifestationinanygivenwoman
withthepreeclampsiasyndromewilloccupyaspectrumaspreviouslydiscussed.Inthisregard,phenotypicexpressionwilldiffer
amongsimilargenotypesdependingoninteractionswithenvironmentalfactors(Yang,2013).

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CandidateGenes

Hundredsofgeneshavebeenstudiedfortheirpossibleassociationwithpreeclampsia(Buurma,2013Ward,2014).Severalofthose
thatmayhavepositivesignificantassociationwithpreeclampsiaarelistedinTable403.PolymorphismsofthegenesforFas
receptor,hypoxiainduciblefactor1protein(HIF1),IL1,lymphotoxin,transforminggrowthfactorbeta3(TGF3),
apolipoproteinE(ApoE),andTNFhavealsobeenstudiedwithvaryingresults(Borowski,2009Hefler,2001Jamalzei,2013
Lachmeijer,2001Livingston,2001Wilson,2009).Becauseoftheheterogeneityofthepreeclampsiasyndromeandespeciallyofthe
othergeneticandenvironmentalfactorsthatinteractwithitscomplexphenotypicexpression,itisdoubtfulthatanyonecandidate
genewillbefoundresponsible.Indeed,Majanderandassociates(2013)havelinkedpreeclampsiapredispositiontofetalgeneson
chromosome18.

TABLE403GeneswithPossibleAssociationswithPreeclampsiaSyndrome
Gene(Polymorphism) FunctionAffected
MTHFR(C677T) Methylenetetrahydrofolatereductase
F5(Leiden) FactorVLeiden
AGT(M235T) Angiotensinogen
HLA(Various) Humanleukocyteantigens
NOS3(Glu298Asp) Endothelialnitricoxide
F2(G20210A) Prothrombin(factorII)
ACE(I/DatIntron16) Angiotensinconvertingenzyme
CTLA4 CytotoxicTlymphocyteassociatedprotein
LPL Lipoproteinlipase
SERPINE1 Serinepeptidaseinhibitor

DatafromBuurma,2013StainesUrias,2012Ward,2014.

OtherGeneticVariables

Anextensivelistofothervariablesaffectgenotypicandphenotypicexpressionofthepreeclampsiasyndrome.Someinclude
maternalandpaternalgenotypes,associateddisorders,genomicethnicity,genegeneinteractions,epigeneticphenomena,andgene
environmentalinteractions.Combinationsoftheseareinfinite.Ethnoracialfactorsareimportantasdiscussedregardingthehigh
incidenceofpreeclampsiainAfricanAmericanwomen.ItmaybethatLatinawomenhavealowerprevalencebecauseof
interactionsofAmericanIndianandwhiteracegenes(Shahabi,2013).

Pathogenesis

Vasospasm

TheconceptofvasospasmwithpreeclampsiawasadvancedbyVolhard(1918)basedonhisdirectobservationsofsmallblood
vesselsinthenailbeds,ocularfundi,andbulbarconjunctivae.Itwasalsosurmisedfromhistologicalchangesseeninvarious
affectedorgans(Hinselmann,1924Landesman,1954).Endothelialactivationcausesvascularconstrictionwithincreasedresistance
andsubsequenthypertension.Atthesametime,endothelialcelldamagecausesinterstitialleakagethroughwhichbloodconstituents,
includingplateletsandfibrinogen,aredepositedsubendothelially.Wangandassociates(2002)havealsodemonstrateddisruptionof
endothelialjunctionalproteins.Suzukiandcoworkers(2003)describedultrastructuralchangesinthesubendothelialregionof
resistancearteriesinpreeclampticwomen.Themuchlargervenouscircuitissimilarlyinvolved,andwithdiminishedbloodflow
becauseofmaldistribution,ischemiaofthesurroundingtissuescanleadtonecrosis,hemorrhage,andotherendorgandisturbances
characteristicofthesyndrome.Oneimportantclinicalcorrelateisthemarkedlyattenuatedbloodvolumeseeninwomenwithsevere
preeclampsia(Zeeman,2009).

EndothelialCellInjury

AsdiscussedonImmunologicalFactors,duringthepasttwodecades,endothelialcellinjuryhasbecomethecenterpieceinthe
contemporaryunderstandingofpreeclampsiapathogenesis(Davidge,2014).Inthisscheme,proteinfactor(s)likelyplacentalare
secretedintothematernalcirculationandprovokeactivationanddysfunctionofthevascularendothelium.Manyofthefacetsofthe
clinicalsyndromeofpreeclampsiaarethoughttoresultfromthesewidespreadendothelialcellchanges.Grundmannandassociates
(2008)havereportedthatcirculatingendothelialcellCEClevelsareelevatedfourfoldintheperipheralbloodofpreeclamptic
women.Similarly,Petrozellaandcolleagues(2012)demonstratedincreasedlevelsofcirculatingendothelialmicroparticlesEMPs
inpreeclampticwomen.

Intactendotheliumhasanticoagulantproperties,andendothelialcellsblunttheresponseofvascularsmoothmuscletoagonistsby
releasingnitricoxide.Damagedoractivatedendothelialcellsmayproducelessnitricoxideandsecretesubstancesthatpromote
coagulationandincreasesensitivitytovasopressors(Gant,1974).Furtherevidenceofendothelialactivationincludesthe
characteristicchangesinglomerularcapillaryendothelialmorphology,increasedcapillarypermeability,andelevatedblood
concentrationsofsubstancesassociatedwithendothelialactivation.Theselattersubstancesaretransferable,andserumfromwomen
withpreeclampsiastimulatessomeofthesesubstancesingreateramounts.Itseemslikelythatmultiplefactorsinplasmaof
preeclampticwomencombinetohavethesevasoactiveeffects(Myers,2007Walsh,2009).

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IncreasedPressorResponses

AsdiscussedinChapter4(Renin,AngiotensinII,andPlasmaVolume),pregnantwomennormallydeveloprefractorinesstoinfused
vasopressors(AbdulKarim,1961).Womenwithearlypreeclampsia,however,haveincreasedvascularreactivitytoinfused
norepinephrineandangiotensinII(Raab,1956Talledo,1968).Moreover,increasedsensitivitytoangiotensinIIclearlyprecedesthe
onsetofgestationalhypertension(Gant,1974).

Prostaglandins

Severalprostanoidsarethoughttobecentraltopreeclampsiasyndromepathophysiology.Specifically,thebluntedpressorresponse
seeninnormalpregnancyisatleastpartiallyduetodecreasedvascularresponsivenessmediatedbyendothelialprostaglandin
synthesis.Forexample,comparedwithnormalpregnancy,endothelialprostacyclin(PGI2)productionisdecreasedinpreeclampsia.
ThisactionappearstobemediatedbyphospholipaseA2(Davidge,2014).Atthesametime,thromboxaneA2secretionbyplateletsis
increased,andtheprostacyclin:thromboxaneA2ratiodecreases.ThenetresultfavorsincreasedsensitivitytoinfusedangiotensinII
and,ultimately,vasoconstriction(Spitz,1988).Thesechangesareapparentasearlyas22weeksinwomenwholaterdevelop
preeclampsia(Chavarria,2003).

NitricOxide

Thispotentvasodilatorissynthesizedfromlargininebyendothelialcells.Withdrawalofnitricoxideresultsinaclinicalpicture
similartopreeclampsiainapregnantanimalmodel(Conrad,1989).Inhibitionofnitricoxidesynthesisincreasesmeanarterial
pressure,decreasesheartrate,andreversesthepregnancyinducedrefractorinesstovasopressors.Inhumans,nitricoxidelikelyisthe
compoundthatmaintainsthenormallowpressurevasodilatedstatecharacteristicoffetoplacentalperfusion(Myatt,1992Weiner,
1992).Italsoisproducedbyfetalendothelium,andhereitisincreasedinresponsetopreeclampsia,diabetes,andsepsis(Parra,
2001vonMandach,2003).

Theeffectsofnitricoxideproductioninpreeclampsiaareunclear(Davidge,2014).Itappearsthatthesyndromeisassociatedwith
decreasedendothelialnitricoxidesynthaseexpression,thusincreasingnitricoxideinactivation.Theseresponsesmayberacerelated,
withAfricanAmericanwomenproducingmorenitricoxide(Wallace,2009).

Endothelins

These21aminoacidpeptidesarepotentvasoconstrictors,andendothelin1(ET1)istheprimaryisoformproducedbyhuman
endothelium(George,2011).PlasmaET1levelsareincreasedinnormotensivepregnantwomen,butwomenwithpreeclampsiahave
evenhigherlevels(Ajne,2003Clark,1992).AccordingtoTaylorandRoberts(1999),theplacentaisnotthesourceofincreasedET
1concentrations,andtheylikelyarisefromsystemicendothelialactivation.Interestingly,treatmentofpreeclampticwomenwith
magnesiumsulfatelowersET1concentrations(Sagsoz,2003).

AngiogenicandAntiangiogenicProteins

Placentalvasculogenesisisevidentby21daysafterconception.Thereisaneverexpandinglistofproandantiangiogenic
substancesinvolvedinplacentalvasculardevelopment.Thefamiliesofvascularendothelialgrowthfactor(VEGF)andangiopoietin
(Ang)aremostextensivelystudied.Angiogenicimbalanceisusedtodescribeexcessiveamountsofantiangiogenicfactorsthatare
hypothesizedtobestimulatedbyworseninghypoxiaattheuteroplacentalinterface.Trophoblastofwomendestinedtodevelop
preeclampsiaoverproducesatleasttwoantiangiogenicpeptidesthatenterthematernalcirculation(Karumanchi,2014):

1.SolubleFmsliketyrosinekinase1(sFlt1)isavariantoftheFlt1receptorforplacentalgrowthfactor(PlGF)andforVEGF.
IncreasedmaternalsFlt1levelsinactivateanddecreasecirculatingfreePlGFandVEGFconcentrations,leadingtoendothelial
dysfunction(Maynard,2003).AsshowninFigure404,sFlt1levelsbegintoincreaseinmaternalserummonthsbefore
preeclampsiaisevident.Haggertyandcolleagues(2012)observedthatthesehighlevelsinthesecondtrimesterwere
associatedwithadoublingoftheriskforpreeclampsia.Thisdivergencefromnormallevelsappearstooccurevensoonerwith
earlyonsetpreeclampsia(Vatten,2012).

2.Solubleendoglin(sEng)isaplacentaderived65kDamoleculethatblocksendoglin,whichisasurfacecoreceptorforthe
TGFfamily.AlsocalledCD105,thissolubleformofendoglininhibitsvariousTGFisoformsfrombindingtoendothelial
receptorsandresultsindecreasedendothelialnitricoxidedependentvasodilatation(Levine,2006Venkatesha,2006).Serum
levelsofsEngalsobegintoincreasemonthsbeforeclinicalpreeclampsiadevelops(Haggerty,2012).

Figure404

Angiogenicandantiangiogenicfactorsinnormotensive(NT)andpreeclamptic(PE)womenacrosspregnancy.Bothpairsoffactors
aresignificantlydivergentby23to26weeks.sFlt=solubleFmsliketyrosinekinase1PlGF=placentalgrowthfactor.(Datafrom
Myatt,2013.)

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Thecauseofplacentaloverproductionofantiangiogenicproteinsremainsanenigma.Concentrationsofthesolubleformsarenot
increasedinthefetalcirculationoramnionicfluid,andtheirlevelsinmaternalblooddissipateafterdelivery(Staff,2007).Research
currentlyisfocusedonimmunologicalmechanisms,oxidativestress,mitochondrialpathology,andhypoxiagenes(Karumanchi,
2014).Clinicalresearchisdirectedatuseofantiangiogenicproteinsinthepredictionanddiagnosisofpreeclampsia.Inasystematic
review,Widmerandassociates(2007)concludedthatthirdtrimesterelevationofsFlt1levelsanddecreasedPlGFconcentrations
correlatewithpreeclampsiadevelopmentafter25weeks.Theseresultsrequireverificationinprospectivestudies.Subsequently,
Haggertyandcoworkers(2012)reportedthatdoublingofexpressionsofsFlt1andsEngincreasedthepreeclampsiarisk39and74
percent,respectively.

Pathophysiology
Althoughthecauseofpreeclampsiaremainsunknown,evidenceforitsmanifestationbeginsearlyinpregnancywithcovert
pathophysiologicalchangesthatgainmomentumacrossgestationandeventuallybecomeclinicallyapparent.Unlessdelivery
supervenes,thesechangesultimatelyresultinmultiorganinvolvementwithaclinicalspectrumrangingfromanattenuated
manifestationtooneofcataclysmicdeteriorationthatislifethreateningforbothmotherandfetus.Asdiscussed,thesearethoughtto
beaconsequenceofendothelialdysfunction,vasospasm,andischemia.Althoughthemanymaternalconsequencesofthe
preeclampsiasyndromeareusuallydescribedintermsofindividualorgansystems,theyfrequentlyaremultiple,andtheyoverlap
clinically.

CardiovascularSystem

Severedisturbancesofnormalcardiovascularfunctionarecommonwithpreeclampsiasyndrome.Thesearerelatedto:(1)increased
cardiacafterloadcausedbyhypertension(2)cardiacpreload,whichisaffectednegativelybypathologicallydiminished
hypervolemiaofpregnancyandisincreasedbyintravenouscrystalloidoroncoticsolutionsand(3)endothelialactivationwith
interendothelialextravasationofintravascularfluidintotheextracellularspaceandimportantly,intothelungs.

HemodynamicChangesandCardiacFunction

Thecardiovascularaberrationsofpregnancyrelatedhypertensivedisordersvarydependingonseveralmodifiers.Thesefactors
includehypertensionseverity,underlyingchronicdisease,preeclampsiaseverity,andinwhichpartoftheclinicalspectrumtheseare
studied.Insomewomen,thesecardiovascularchangesmayprecedehypertensiononset(DePaco,2008Easterling,1990Khalil,
2012Melchiorre,2013).Nevertheless,withtheclinicalonsetofpreeclampsia,cardiacoutputdeclines,dueatleastinpartto

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increasedperipheralresistance.Whenassessingcardiacfunctioninpreeclampsia,considerationisgiventoechocardiographic
measuresofmyocardialfunctionandtoclinicallyrelevantventricularfunction.

MyocardialFunction

Serialechocardiographicstudieshavedocumentedinpreeclampsiaevidenceforventricularremodelingthatisaccompaniedby
diastolicdysfunctionin40percentofwomen(Melchiorre,2012).Insomeofthesewomen,functionaldifferencespersistedupto16
monthsafterdelivery(Evans,2011).Ventricularremodelingwasjudgedtobeanadaptiveresponsetomaintainnormalcontractility
withtheincreasedafterloadofpreeclampsia.Intheotherwisehealthypregnantwoman,thesechangesareusuallyclinically
inconsequential.Butwhencombinedwithunderlyingventriculardysfunctionforexample,concentricventricularhypertrophyfrom
chronichypertensionfurtherdiastolicdysfunctionmaycausecardiogenicpulmonaryedemaasdiscussedinChapters47(Acute
RespiratoryDistressSyndrome)and49(HeartFailure).

VentricularFunction

Despitetherelativelyhighfrequencyofdiastolicdysfunctionwithpreeclampsia,inmostwomenclinicalcardiacfunctionis
appropriate.Thishasbeenshownbyseveralstudiesinwhichventricularfunctionwasassessedusinginvasivehemodynamic
methods(Hibbard,2014).Importantly,bothnormallypregnantwomenandthosewithpreeclampsiasyndromecanhavenormalor
slightlyhyperdynamicventricularfunction(Fig.405).Thus,bothhaveacardiacoutputthatisappropriateforleftsidedfilling
pressures.Datafrompreeclampticwomenobtainedbyinvasivehemodynamicstudiesareconfoundedbecauseoftheheterogeneity
ofpopulationsandinterventionsthatalsomaysignificantlyalterthesemeasurements.Someofthesearecrystalloidinfusions,
antihypertensiveagents,andmagnesiumsulfate.

Figure405

Ventricularfunctioninnormallypregnantwomen(stripedarea)andinwomenwitheclampsia(boxedarea)isplottedona
Braunwaldventricularfunctioncurve.NormalvaluesarefromClark,1989,andthoseforeclampsiaarefromHankins,1984.LVSWI
=leftventricularstrokeworkindexPCWP=pulmonarycapillarywedgepressure.

VentricularfunctionstudiesofpreeclampticwomenfromseveralinvestigationsareshowninFigure406.Althoughcardiacfunction
washyperdynamicinallwomen,fillingpressuresweredependentonthevolumeofintravenousfluids.Specifically,aggressive
hydrationresultedinovertlyhyperdynamicventricularfunctioninmostwomen.However,thiswasaccompaniedbyelevated
pulmonarycapillarywedgepressures.Insomeofthesewomen,pulmonaryedemamaydevelopdespitenormalventricularfunction
becauseofanalveolarendothelialepithelialleak.Thisiscompoundedbydecreasedoncoticpressurefromalowserumalbumin
concentration(AmericanCollegeofObstetriciansandGynecologists,2012b).

Figure406

VentricularfunctioninwomenwithseverepreeclampsiaeclampsiaplottedontheBraunwaldventricularfunctioncurve.The
pulmonarycapillarywedgepressures(PCWP)arelowerinthosemanagedwithrestrictedfluidadministration(stripedareainA)
comparedwithwomenmanagedwithaggressivefluidtherapy(stripedareainB).Inthosemanagedwithaggressivefluidinfusions,
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eightdevelopedpulmonaryedemadespitenormaltohyperdynamicventricularfunctioninallbutone.LVSWI=leftventricular
strokeworkindex.(DataforAfromBenedetti,1980Hankins,1984dataforBfromRafferty,1980Phelan,1982.)

Thus,increasedcardiacoutputandhyperdynamicventricularfunctionislargelyaresultoflowwedgepressuresandnotaresultof
augmentedmyocardialcontractility.Bycomparison,womengivenappreciablylargervolumesoffluidcommonlyhadfilling
pressuresthatexceedednormal,buttheirventricularfunctionremainedhyperdynamicbecauseofconcomitantlyincreasedcardiac
output.

Fromthesestudies,itisreasonabletoconcludethataggressivefluidadministrationtootherwisenormalwomenwithsevere
preeclampsiasubstantiallyelevatesnormalleftsidedfillingpressuresandincreasesaphysiologicallynormalcardiacoutputto
hyperdynamiclevels.

BloodVolume

Fornearly100years,hemoconcentrationhasbeenahallmarkofeclampsia.ThiswasnotpreciselyquantifieduntilZeemanand
colleagues(2009)expandedthepreviousobservationsofPritchardandassociates(1984)andshowedineclampticwomenthatthe
normallyexpectedhypervolemiaisseverelycurtailed(Fig.407).Womenofaveragesizeshouldhaveabloodvolumeofnearly4500
mLduringthelastseveralweeksofanormalpregnancy.Innonpregnantwomen,thisvolumeapproximatesonly3000mL.With
eclampsia,however,muchoralloftheanticipatednormalexcess1500mLislost.Suchhemoconcentrationresultsfromgeneralized
vasoconstrictionthatfollowsendothelialactivationandleakageofplasmaintotheinterstitialspacebecauseofincreased
permeability.Inwomenwithpreeclampsia,anddependingonitsseverity,hemoconcentrationisusuallynotasmarked.Womenwith
gestationalhypertension,butwithoutpreeclampsia,usuallyhaveanormalbloodvolume(Silver,1998).

Figure407

Thetwobargraphsontheleftcomparemeanbloodvolumesinnonpregnantandtermnormallypregnantwomen.Ontheright,
graphsdisplayvaluesforagroupof29womenwitheclampsiaandtheirnonpregnantvalues.Theredbarreflectsvaluesforasubset
of14whohadasubsequentnormotensivepregnancy.Extensionsabovebarsrepresentonestandarddeviation.Comparisonbetween
valueswithidenticallowercaseletters,thatis,aa,bb,cc,dd,aresignificantp<.001.(DatafromZeeman,2009,withpermission.)

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Forwomenwithseverehemoconcentration,itwasoncetaughtthatanacutefallinhematocritsuggestedresolutionofpreeclampsia.
Inthisscenario,hemodilutionfollowsendothelialhealingwithreturnofinterstitialfluidintotheintravascularspace.Althoughthisis
somewhatcorrect,itisimportanttorecognizethatasubstantivecauseofthisfallinhematocritisusuallytheconsequenceofblood
lossatdelivery(Chap.41,BloodLossEstimation).Itmayalsopartiallyresultfromincreasederythrocytedestructionas
subsequentlydescribed.Vasospasmandendothelialleakageofplasmamaypersistforavariabletimeafterdeliveryasthe
endotheliumisrestoredtonormalcy.Asthistakesplace,vasoconstrictionreverses,andasthebloodvolumeincreases,thehematocrit
usuallyfalls.Thus,womenwitheclampsia:

Areundulysensitivetovigorousfluidtherapyadministeredinanattempttoexpandthecontractedbloodvolumetonormal
pregnancylevels

Aresensitivetoamountsofbloodlossatdeliverythatareconsiderednormalforanormotensivewoman.

HematologicalChanges

Severalhematologicalabnormalitiesareassociatedwiththepreeclampsiasyndrome.Amongthosecommonlyidentifiedis
thrombocytopenia,whichattimesmaybecomesevereenoughtobelifethreatening.Occasionally,thelevelsofsomeplasmaclotting
factorsmaybedecreased,anderythrocytesdisplayabnormalmorphologyandundergorapidhemolysis.

Thrombocytopenia

Decreasedplateletconcentrationswitheclampsiaweredescribedasearlyas1922byStancke.Theplateletcountisroutinely
measuredinwomenwithanyformofgestationalhypertension.Thefrequencyandintensityofthrombocytopeniavaryandare
dependentontheseverityanddurationofthepreeclampsiasyndromeandthefrequencywithwhichplateletcountsareperformed
(Heilmann,2007Hupuczi,2007).Overtthrombocytopeniadefinedbyaplateletcount<100,000/Lindicatesseveredisease
(seeTable402).Ingeneral,thelowertheplateletcount,thehighertheratesofmaternalandfetalmorbidityandmortality(Leduc,
1992).Inmostcases,deliveryisadvisablebecausethrombocytopeniausuallycontinuestoworsen.Afterdelivery,theplateletcount
maycontinuetodeclineforthefirstdayorso.Itthenusuallyincreasesprogressivelytoreachanormallevelwithin3to5days.As
discussedonFurosemide,insomeinstanceswithHELLPsyndrome,theplateletcountcontinuestofallafterdelivery.Ifthesedonot
reachanadiruntil48to72hours,thenpreeclampsiasyndromemaybeincorrectlyattributedtooneofthethrombotic
microangiopathies(George,2013).ThesesyndromesarediscussedinChapter56(ThromboticMicroangiopathies).

OtherPlateletAbnormalities

Inadditiontothrombocytopenia,therearemyriadotherplateletalterationsdescribedwiththepreeclampsiasyndrome.Thesewere
reviewedbyKennyandcoworkers(2014)andincludeplateletactivationwithincreaseddegranulationproducing
thromboglobulin,factor4,andincreasedclearance.Paradoxically,inmoststudies,invitroplateletaggregationisdecreased
comparedwiththenormalincreasecharacteristicofpregnancy.Thislikelyisduetoplateletexhaustionfollowinginvivo
activation.Althoughthecauseisunknown,immunologicalprocessesorsimplyplateletdepositionatsitesofendothelialdamagemay
beimplicated.Plateletboundandcirculatingplateletbindableimmunoglobulinsareincreased,whichsuggestplateletsurface
alterations.

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NeonatalThrombocytopenia

Severethrombocytopeniadoesnotdevelopinthefetusorinfantborntopreeclampticwomendespiteseverematernal
thrombocytopenia(Kenny,2014Pritchard,1987).Importantly,maternalthrombocytopeniainhypertensivewomenisnotafetal
indicationforcesareandelivery.

Hemolysis

Severepreeclampsiaisfrequentlyaccompaniedbyevidenceofhemolysisasmanifestbyelevatedserumlactatedehydrogenaselevels
anddecreasedhaptoglobinlevels.Otherevidencecomesfromschizocytosis,spherocytosis,andreticulocytosisinperipheralblood
(Cunningham,1985Pritchard,1954,1976).Thesederangementsresultinpartfrommicroangiopathichemolysiscausedby
endothelialdisruptionwithplateletadherenceandfibrindeposition.SanchezRamosandcolleagues(1994)describedincreased
erythrocytemembranefluiditywithHELLPsyndrome.Cunninghamandcoworkers(1995)postulatedthatthesechangesweredueto
serumlipidalterations,andMackayandassociates(2012)foundsubstantivelydecreasedlongchainfattyacidcontentinerythrocytes
ofpreeclampticwomen.Erythrocyticmembranechanges,increasedadhesiveness,andaggregationmayalsopromotea
hypercoagulablestate(Gamzu,2001).

HELLPSyndrome

Subsequenttoreportsofhemolysisandthrombocytopeniawithseverepreeclampsia,descriptionsfollowedthatabnormallyelevated
serumlivertransaminaselevelswerecommonlyfoundandwereindicativeofhepatocellularnecrosis(Chesley,1978).Weinstein
(1982)referredtothiscombinationofeventsastheHELLPsyndromeandthismonikernowisusedworldwide.Also,andasshown
inTable402,facetsoftheHELLPsyndromeareincludedincriteriathatdifferentiateseverefromnonseverepreeclampsia.The
HELLPsyndromeisdiscussedinfurtherdetailonHELLPSyndrome.

CoagulationChanges

Subtlechangesconsistentwithintravascularcoagulation,andlessoftenerythrocytedestruction,commonlyarefoundwith
preeclampsiaandespeciallyeclampsia(Kenny,2014).SomeofthesechangesincludeincreasedfactorVIIIconsumption,increased
levelsoffibrinopeptidesAandBandofddimers,anddecreasedlevelsofregulatoryproteinsantithrombinIIIandproteinCandS.
Exceptforthrombocytopeniadiscussedabove,coagulationaberrationsgenerallyaremildandareseldomclinicallysignificant
(Kenny,2014Pritchard,1984).Unlessthereisassociatedplacentalabruption,plasmafibrinogenlevelsdonotdifferremarkably
fromlevelsfoundinnormalpregnancy.Fibrindegradationproductssuchasddimersareelevatedonlyoccasionally.Fibronectin,a
glycoproteinassociatedwithvascularendothelialcellbasementmembrane,iselevatedinwomenwithpreeclampsia(Brubaker,
1992).Aspreeclampsiaworsens,sodoabnormalfindingswiththromboelastography(PisaniConway,2013).Despitethesechanges,
routinelaboratoryassessmentsofcoagulation,includingprothrombintime,activatedpartialthromboplastintime,andplasma
fibrinogenlevel,werefoundtobeunnecessaryinthemanagementofpregnancyassociatedhypertensivedisorders(Barron,1999).

VolumeHomeostasis

Thenormalpregnancyinducedextraandintracellularvolumeincreasesthatareaccompaniedbyvasodilatationundergofurther
complexshiftswiththepreeclampsiasyndrome.InadditiontobloodvolumechangesshowninFigure407,therearemany
hormonal,fluid,andelectrolyteaberrations.

EndocrineChanges

Plasmalevelsofrenin,angiotensinII,angiotensin17,aldosterone,andatrialnatriureticpeptidearesubstantivelyincreasedduring
normalpregnancy.Deoxycorticosterone(DOC)isapotentmineralocorticoidthatisalsoincreasedremarkablyinnormalpregnancy
(Chap.4,MusculoskeletalSystem).ThiscompoundresultsfromconversionofplasmaprogesteronetoDOCratherthanincreased
maternaladrenalsecretion.Becauseofthis,DOCsecretionisnotreducedbysodiumretentionorhypertension.Thismayexplain
whywomenwithpreeclampsiaretainsodium(Winkel,1980).Inpregnancy,themineralocorticoidreceptorbecomeslesssensitiveto
aldosterone(Armanini,2012).

Vasopressinlevelsaresimilarinnonpregnant,normallypregnant,andpreeclampticwomeneventhoughthemetabolicclearanceis
increasedinthelattertwo(Drr,1999).

Atrialnatriureticpeptideisreleasedduringatrialwallstretchingfrombloodvolumeexpansion,anditrespondstocardiac
contractility(Chap.4,Renin,AngiotensinII,andPlasmaVolume).Serumlevelsriseinpregnancy,anditssecretionisfurther
increasedinwomenwithpreeclampsia(Borghi,2000Luft,2009).Levelsofitsprecursorproatrialnatriureticpeptidearealso
increasedinpreeclampsia(Sugulle,2012).

FluidandElectrolyteChanges

Inwomenwithseverepreeclampsia,thevolumeofextracellularfluid,manifestasedema,isusuallymuchgreaterthanthatinnormal
pregnantwomen.Themechanismresponsibleforpathologicalfluidretentionisthoughttobeendothelialinjury(Davidge,2014).In
additiontogeneralizededemaandproteinuria,thesewomenhavereducedplasmaoncoticpressure.Thisreductioncreatesafiltration
imbalanceandfurtherdisplacesintravascularfluidintothesurroundinginterstitium.

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Electrolyteconcentrationsdonotdifferappreciablyinwomenwithpreeclampsiacomparedwiththoseofnormalpregnantwomen.
Thismaynotbethecaseiftherehasbeenvigorousdiuretictherapy,sodiumrestriction,oradministrationoffreewaterwithsufficient
oxytocintoproduceantidiuresis.

Followinganeclampticconvulsion,theserumpHandbicarbonateconcentrationareloweredduetolacticacidosisand
compensatoryrespiratorylossofcarbondioxide.Theintensityofacidosisrelatestotheamountoflacticacidproducedmetabolic
acidosisandtherateatwhichcarbondioxideisexhaledrespiratoryacidosis.

Kidney

Duringnormalpregnancy,renalbloodflowandglomerularfiltrationrateareincreasedappreciably(Chap.4,OxygenDelivery).
Withdevelopmentofpreeclampsia,theremaybeanumberofreversibleanatomicalandpathophysiologicalchanges.Ofclinical
importance,renalperfusionandglomerularfiltrationarereduced.Levelsthataremuchlessthannormalnonpregnantvaluesare
infrequentandaretheconsequenceofseveredisease.

Asmalldegreeofdecreasedglomerularfiltrationmayresultfromreducedplasmavolume.Mostofthedecrement,however,isfrom
increasedrenalafferentarteriolarresistancethatmaybeelevateduptofivefold(Conrad,2014Cornelis,2011).Therearealso
morphologicalchangescharacterizedbyglomerularendotheliosisblockingthefiltrationbarrier.Thisisdiscussedfurther
subsequently.Diminishedfiltrationcausesserumcreatininelevelstorisetovaluesseeninnonpregnantindividuals,thatis,1mg/mL,
andsometimesevenhigher(Lindheimer,2008a).Abnormalvaluesusuallybegintonormalize10daysorlaterafterdelivery(Spaan,
2012a).

Inmostpreeclampticwomen,urinesodiumconcentrationiselevated.Urineosmolality,urine:plasmacreatinineratio,andfractional
excretionofsodiumalsoindicatethataprerenalmechanismisinvolved.Kirshonandcoworkers(1988)infuseddopamine
intravenouslyintooliguricwomenwithpreeclampsia,andthisrenalvasodilatorstimulatedincreasedurineoutput,fractionalsodium
excretion,andfreewaterclearance.AswasshowninFigure406,sodiumcontainingcrystalloidinfusionincreasesleftventricular
fillingpressure,andalthougholiguriatemporarilyimproves,rapidinfusionsmaycauseclinicallyapparentpulmonaryedema.
Intensiveintravenousfluidtherapyisnotindicatedastreatmentforpreeclampticwomenwitholiguria.Exceptionsarediminished
urineoutputfromhemorrhageorfluidlossfromvomitingorfever.

Plasmauricacidconcentrationistypicallyelevatedinpreeclampsia.Theelevationexceedsthereductioninglomerularfiltrationrate
andlikelyisalsoduetoenhancedtubularreabsorption(Chesley,1945).Atthesametime,preeclampsiaisassociatedwithdiminished
urinaryexcretionofcalcium,perhapsbecauseofincreasedtubularreabsorption(Taufield,1987).Anotherpossibilityisfrom
increasedplacentalurateproductioncompensatorytoincreasedoxidativestress.

Proteinuria

AsshowninTable401,somedegreeofproteinuriawillestablishthediagnosisofpreeclampsiasyndrome.Proteinuriamaydevelop
late,andsomewomenmayalreadybedeliveredorhavehadaneclampticconvulsionbeforeitappears.Forexample,10to15
percentofwomenwithHELLPsyndromedidnothaveproteinuriaatpresentation(Sibai,2004).Inanotherreport,17percentof
eclampticwomendidnothaveproteinuriabythetimeofseizures(Zwart,2008).

Problematically,theoptimalmethodofestablishingabnormallevelsofeitherurineproteinoralbuminremainstobedefined.Chen
andassociates(2008)haveshownthatcleancatchandcatheterizedurinespecimenscorrelatewell.Butdipstickqualitative
determinationsdependonurinaryconcentrationandarenotoriousforfalsepositiveandnegativeresults.Fora24hourquantitative
specimen,theconsensusthresholdvalueusedis>300mg/24h(TaskForce,2013).Tunandcolleagues(2012)haveshown
equivalentefficacyusingproteinexcretionof165mgina12hoursample.Importantly,thesevalueshavenotbeenirrefutably
established.

Determinationofurinaryprotein:creatinineratiomaysupplantthecumbersome24hourquantification(Ethridge,2013Kyle,2008
Morris,2012).Inasystematicreview,Papannaandassociates(2008)concludedthatrandomurineprotein:creatinineratiosthatare
below130to150mg/g,thatis,0.13to0.15,indicatealowlikelihoodofproteinuriaexceeding300mg/day.Midrangeratios,thatis,
300mg/gor0.3havepoorsensitivityandspecificity.Stoutandcolleagues(2013)foundthatvalues<0.08or>1.19hadnegativeor
positivepredictivevaluesof86and96percent,respectively.Atthistime,mostrecommendthatwithmidrangeratiovalues,24hour
proteinexcretionshouldbequantified.

Thereareseveralmethodsusedtomeasureproteinuria,andnonedetectallofthevariousproteinsnormallyexcreted(Nayeri,2013).
Amoreaccuratemethodinvolvesmeasurementofalbuminexcretion.Albuminfiltrationexceedsthatoflargerglobulins,andwith
glomerulardiseasesuchaspreeclampsia,mostoftheproteininurineisalbumin.Therearetestkitsthatpermitrapidmeasurementof
urinaryalbumin:creatinineratiosinanoutpatientsetting(Kyle,2008).

Althoughworseningornephroticrangeproteinuriahasbeenconsideredbymosttobeasignofseveredisease,thisdoesnotappear
tobethecase(Airoldi,2007).Certainly,thisconceptwasnotacceptedbythe2013TaskForce.Finally,increasingproteinuriais
morecommoninmultifetalpregnancycomplicatedbypreeclampsia(Zilberberg,2013).

AnatomicalChanges

SheehanandLynch(1973)commonlyfoundchangesidentifiableatautopsybylightandelectronmicroscopyinthekidneysof
eclampticwomen.Glomeruliareenlargedbyapproximately20percent,theyarebloodless,andcapillaryloopsvariablyaredilated
andcontracted.EndothelialcellsareswollentermedglomerularcapillaryendotheliosisbySpargoandassociates(1959).
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Endothelialcellsareoftensoswollenthattheyblockorpartiallyblockthecapillarylumens(Fig.408).Homogeneous
subendothelialdepositsofproteinsandfibrinlikematerialareseen.

Figure408

Schematicshowingglomerularcapillaryendotheliosis.Thecapillaryofthenormalglomerulusshownonthelefthaswide
endothelialfenestrations,andthepedicelsemanatingfromthepodocytesarewidelyspaced(arrow).Theillustrationontherightisof
aglomeruluswithchangesinducedbythepreeclampsiasyndrome.Theendothelialcellsareswollenandtheirfenestraenarrowed,as
arethepedicelsthatnowabuteachother.

Endothelialswellingmayresultfromangiogenicfactorwithdrawalcausedbyfreeangiogenicproteinscomplexingwiththe
circulatingantiangiogenicproteinreceptordiscussedonEndothelialCellInjury(Conrad,2014Eremina,2007Karumanchi,2009).
Theangiogenicproteinsarecrucialforpodocytehealth,andtheirinactivationleadstopodocytedysfunctionandendothelial
swelling.Onemarkerofthisisexcretionofpodocyteproteinssuchasnephrin,podocalyxin,andigh3(transforminggrowthfactor,
induced)(Wang,2012b).Also,eclampsiaischaracterizedbyincreasedexcretionofurinarypodocytes,aphenomenonsharedby
otherproteinuricdisorders(Garrett,2013Wagner,2012).Ofinterest,podocytesareepithelia,andthusrenalpathologyinvolvesboth
endothelialandepithelialcells(seeFig.408).

AcuteKidneyInjury

Rarelyisacutetubularnecrosiscausedbypreeclampsiaalone.Althoughmilddegreesareencounteredinneglectedcases,clinically
apparentrenalfailureisinvariablyinducedbycoexistenthemorrhagewithhypovolemiaandhypotension(Chap.41,Managementof
Hemorrhage).Thisisusuallycausedbysevereobstetricalhemorrhageforwhichadequatebloodreplacementisnotgiven.Drakeley
andcoworkers(2002)described72womenwithpreeclampsiaandrenalfailure.HalfhadHELLPsyndrome,andathirdhad
placentalabruption.AsdiscussedonPancreas,Haddadandcolleagues(2000)reportedthat5percentof183womenwithHELLP
syndromehadkidneyinjury.Halfofthese,however,alsohadaplacentalabruption,andmosthadpostpartumhemorrhage.Rarely,
irreversiblerenalcorticalnecrosisdevelops(Chap.53,LowerGenitalTractLesions).

Liver

Hepaticchangesinwomenwithfataleclampsiaweredescribedin1856byVirchow.Thecharacteristiclesionswereregionsof
periportalhemorrhageintheliverperiphery.Intheirelegantautopsystudies,SheehanandLynch(1973)describedthatsomedegree
ofhepaticinfarctionaccompaniedhemorrhageinalmosthalfofwomenwhodiedwitheclampsia.Thesecorrespondedwithreports
thathadappearedduringthe1960sdescribingelevatedserumhepatictransaminaselevels.Alongwiththeearlierobservationsby
Pritchardandassociates(1954),whodescribedhemolysisandthrombocytopeniawitheclampsia,thisconstellationofhemolysis,
hepatocellularnecrosis,andthrombocytopeniawaslatertermedHELLPsyndromebyWeinstein(1985)tocallattentiontoits
seriousness(Pancreas).

LesionsasextensiveasthoseshowninFigure409areunusual,evenintheautopsyseriesbySheehanandLynch(1973).Froma
pragmaticpoint,liverinvolvementwithpreeclampsiamaybeclinicallysignificantinseveralcircumstances.

Figure409

Grossliverspecimenfromawomanwithpreeclampsiawhodiedfromaspirationpneumonitis.Periportalhemorrhagicnecrosiswas
seenmicroscopically.(FromCunningham,1993.)

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First,symptomaticinvolvementisconsideredasignofseveredisease.Ittypicallymanifestsbymoderatetosevererightupper
quadrantormidepigastricpainandtenderness.Inmanycases,suchwomenalsohaveelevatedlevelsofserumaminotransferase,
namely,aspartateaminotransferase(AST)oralanineaminotransferase(ALT).Insomecases,however,theamountofhepatictissue
involvedwithinfarctionmaybesurprisinglyextensiveyetstillclinicallyinsignificant.Inourexperiences,infarctionmaybe
worsenedbyhypotensionfromobstetricalhemorrhage,anditoccasionallycauseshepaticfailuresocalledshockliver(Alexander,
2009).

Second,asymptomaticelevationsofserumhepatictransaminaselevelsASTandALTarealsoconsideredmarkersforsevere
preeclampsia.Valuesseldomexceed500U/L,buthavebeenreportedtobegreaterthan2000U/Linsomewomen(Chap.55,
ClinicalPresentation).Ingeneral,serumlevelsinverselyfollowplateletlevels,andtheybothusuallynormalizewithin3days
followingdeliveryaspreviouslydiscussedonHematologicalChanges.

Inathirdexampleofliverinvolvement,hemorrhagicinfarctionmayextendtoformahepatichematoma.Theseinturnmayextendto
formasubcapsularhematomathatmayrupture.Theycanbeidentifiedusingcomputedtomography(CT)scanningormagnetic
resonance(MR)imagingasshowninFigure4010.Unrupturedhematomasareprobablymorecommonthanclinicallysuspectedand
aremorelikelytobefoundwithHELLPsyndrome(Carlson,2004VigilDeGracia,2012).Althoughonceconsideredasurgical
condition,contemporaneousmanagementusuallyconsistsofobservationandconservativetreatmentofhematomasunless
hemorrhageisongoing.Insomecases,however,promptsurgicalinterventionmaybelifesaving.VigilDeGraciaandcoworkers
(2012)reviewed180casesofhepatichematomaorrupture.Morethan90percenthadHELLPsyndrome,andin90percent,the
capsulehadruptured.Thematernalmortalityratewas22percent,andtheperinatalmortalityratewas31percent.Inrarecases,liver
transplantisnecessary(Hunter,1995Wicke,2004).

Figure4010

AbdominalCTimagingperformedpostpartuminawomanwithsevereHELLPsyndromeandrightupperquadrantpain.Alarge
subcapsularhematoma(asterisk)isseenconfluentwithintrahepaticinfarctionandhematoma(arrowhead).Numerousflameshaped
hemorrhagesareseenatthehematomainterface(arrows).

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Last,acutefattyliverofpregnancyissometimesconfusedwithpreeclampsia(Nelson,2013Sibai,2007a).Ittoohasanonsetinlate
pregnancy,andoftenthereisaccompanyinghypertension,elevatedserumtransaminaseandcreatininelevels,andthrombocytopenia
(Chap.55,AcuteFattyLiverofPregnancy).

HELLPSyndrome

Thereisnouniversallyacceptedstrictdefinitionofthissyndrome,andthusitsincidencevariesbyinvestigator.Whenitisidentified,
thelikelihoodofhepatichematomaandruptureissubstantiallyincreased.Inamulticenterstudy,Haddadandcolleagues(2000)
described183womenwithHELLPsyndromeofwhom40percenthadadverseoutcomesincludingtwomaternaldeaths.The
incidenceofsubcapsularliverhematomawas1.6percent.Othercomplicationsincludedeclampsia6percent,placentalabruption
10percent,acutekidneyinjury5percent,andpulmonaryedema10percent.Otherseriouscomplicationsincludedstroke,
coagulopathy,acuterespiratorydistresssyndrome,andsepsis.

WomenwithpreeclampsiacomplicatedbytheHELLPsyndrometypicallyhaveworseoutcomesthanthosewithoutthesefindings
(Kozic,2011Martin,2012,2013).Intheirreviewof693womenwithHELLPsyndrome,Keiserandcoworkers(2009)reportedthat
10percenthadconcurrenteclampsia.Sepandassociates(2009)alsodescribedasignificantlyincreasedriskforcomplicationsin
womenwithHELLPsyndromecomparedwiththosewithisolatedpreeclampsia.Theseincludedeclampsia15versus4percent
pretermbirth93versus78percentandperinatalmortalityrate9versus4percent,respectively.Becauseofthesemarkedclinical
differences,theseinvestigatorspostulatethatHELLPsyndromehasadistinctpathogenesis.Othershaveshownadifferenceinthe
ratioofantiangiogenicandinflammatoryacutephaseproteinsinthesetwoconditionsandhavereachedsimilarconclusions(Reimer,
2013).GivenallofthevariablescontributingtotheincidenceandpathophysiologyofpreeclampsiaasdiscussedonPathophysiology,
thisisareasonableconclusion.SibaiandStella(2009)havediscussedsomeoftheseaspectsundertherubricofatypical
preeclampsiaeclampsia.

Pancreas

AccordingtoSheehanandLynch(1973),therearenoconvincingdatathatthepancreashasspecialinvolvementwithpreeclampsia
syndrome.Ifso,theoccasionalcasereportsofconcurrenthemorrhagicpancreatitisarelikelyunrelated(Swank,2012).Thatsaid,
severehemoconcentrationmaypredisposetopancreaticinflammation.

Brain

Headachesandvisualsymptomsarecommonwithseverepreeclampsia,andassociatedconvulsionsdefineeclampsia.Theearliest
anatomicaldescriptionsofbraininvolvementcamefromautopsyspecimens,butCTandMRimagingandDopplerstudieshave
addedmanyimportantinsightsintocerebrovascularinvolvement.

NeuroanatomicalLesions

Mostgrossanatomicaldescriptionsofthebrainineclampticwomenaretakenfromeraswhenmortalityrateswerehigh.One
consistentfindingwasthatbrainpathologyaccountedforonlyaboutathirdoffatalcasessuchastheoneshowninFigure4011.In
fact,mostdeathswerefrompulmonaryedema,andbrainlesionswerecoincidental.Thus,althoughgrossintracerebralhemorrhage
wasseeninupto60percentofeclampticwomen,itwasfatalinonlyhalfofthese(Melrose,1984Richards,1988Sheehan,1973).
AsshowninFigure4012,otherprincipallesionsfoundatautopsyofeclampticwomenwerecorticalandsubcorticalpetechial
hemorrhages.Theclassicmicroscopicvascularlesionsconsistoffibrinoidnecrosisofthearterialwallandperivascularmicroinfarcts

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andhemorrhages.Otherfrequentlydescribedmajorlesionsincludesubcorticaledema,multiplenonhemorrhagicareasofsoftening
throughoutthebrain,andhemorrhagicareasinthewhitematter.Therealsomaybehemorrhageinthebasalgangliaorpons,often
withruptureintotheventricles.

Figure4011

Thisautopsybrainsliceshowsafatalhypertensivehemorrhageinaprimigravidawitheclampsia.

Figure4012

Compositeillustrationshowinglocationofcerebralhemorrhagesandpetechiaeinwomenwitheclampsia.Insertshowsthelevelof
thebrainfromwhichthemainimagewasconstructed.(DatafromSheehan,1973.)

CerebrovascularPathophysiology

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Clinical,pathological,andneuroimagingfindingshaveledtotwogeneraltheoriestoexplaincerebralabnormalitieswitheclampsia.
Importantly,endothelialcelldysfunctionthatcharacterizesthepreeclampsiasyndromelikelyplaysakeyroleinboth.Thefirst
theorysuggeststhatinresponsetoacuteandseverehypertension,cerebrovascularoverregulationleadstovasospasm(Trommer,
1988).Thispresumptionisbasedontheangiographicappearanceofdiffuseormultifocalsegmentalnarrowingssuggestiveof
vasospasm(Ito,1995).Inthisscheme,diminishedcerebralbloodflowishypothesizedtoresultinischemia,cytotoxicedema,and
eventuallytissueinfarction.Althoughthistheorywaswidelyembracedformanyyears,thereislittleobjectiveevidencetosupportit.

Thesecondtheoryisthatsuddenelevationsinsystemicbloodpressureexceedthenormalcerebrovascularautoregulatorycapacity
(Hauser,1988Schwartz,2000).Regionsofforcedvasodilationandvasoconstrictiondevelop,especiallyinarterialboundaryzones.
Atthecapillarylevel,disruptionofendcapillarypressurecausesincreasedhydrostaticpressure,hyperperfusion,andextravasationof
plasmaandredcellsthroughendothelialtightjunctionopenings.Thisleadstovasogenicedema.Thistheoryisincompletebecause
veryfeweclampticwomenhavemeanarterialpressuresthatexceedlimitsofautoregulationapproximately160mmHg.

Itseemsreasonabletoconcludethatthemostlikelymechanismisacombinationofthetwo.Thus,apreeclampsiaassociated
interendothelialcellleakdevelopsatbloodpressure(hydraulic)levelsmuchlowerthanthoseusuallycausingvasogenicedemaand
iscoupledwithalossofupperlimitautoregulation(Zeeman,2009).Withimagingstudies,thesechangesmanifestasfacetsofthe
reversibleposteriorleukoencephalopathysyndrome(Hinchey,1996).Thissubsequentlybecamereferredtoastheposterior
reversibleencephalopathysyndromePRES.ThistermismisleadingbecausealthoughPRESlesionsprincipallyinvolvethe
posteriorbraintheoccipitalandparietalcorticesinatleastathirdofcases,theyalsoinvolveotherbrainareas(Edlow,2013
Zeeman,2004a).Themostfrequentlyaffectedregionistheparietooccipitalcortextheboundaryzoneoftheanterior,middle,and
posteriorcerebralarteries.Also,inmostcases,theselesionsarereversible(Cipolla,2014).

CerebralBloodFlow

Autoregulationisthemechanismbywhichcerebralbloodflowremainsrelativelyconstantdespitealterationsincerebralperfusion
pressure.Innonpregnantindividuals,thismechanismprotectsthebrainfromhyperperfusionwhenmeanarterialpressuresincreaseto
ashighas160mmHg.Thesearepressuresfargreaterthanthoseseeninallbutaveryfewwomenwitheclampsia.Thus,toexplain
eclampticseizures,itwastheorizedthatautoregulationmustbealteredbypregnancy.Althoughspeciesdifferencesmustbe
considered,studiesbyCipollaandcolleagues(2007,2009,2014)haveconvincinglyshownthatautoregulationisunchangedacross
pregnancyinrodents.Thatsaid,some,butnotothers,haveprovidedevidenceofimpairedautoregulationinwomenwith
preeclampsia(Janzarik,2014vanVeen,2013).

Zeemanandassociates(2003)showedthatcerebralbloodflowduringthefirsttwotrimestersofnormalpregnancyissimilarto
nonpregnantvalues,butthereafter,itsignificantlydecreasesby20percentduringthelasttrimester.Theseinvestigatorsalso
documentedsignificantlyincreasedcerebralbloodflowinwomenwithseverepreeclampsiacomparedwiththatofnormotensive
pregnantwomen(Zeeman,2004b).Takentogether,thesefindingssuggestthateclampsiaoccurswhencerebralhyperperfusionforces
capillaryfluidinterstitiallybecauseofendothelialdamage,whichleadstoperivascularedemacharacteristicofthepreeclampsia
syndrome.Inthisregard,eclampsiaisanexampleoftheposteriorreversibleencephalopathysyndromeaspreviouslydiscussed.

NeurologicalManifestations

Thereareseveralneurologicalmanifestationsofthepreeclampsiasyndrome.Eachsignifiessevereinvolvementandrequires
immediateattention.First,headacheandscotomataarethoughttoarisefromcerebrovascularhyperperfusionthathasapredilection
fortheoccipitallobes.AccordingtoSibai(2005)andZwartandcoworkers(2008),50to75percentofwomenhaveheadachesand
20to30percenthavevisualchangesprecedingeclampticconvulsions.Theheadachesmaybemildtosevereandintermittentto
constant.Inourexperiences,theyareuniqueinthattheydonotusuallyrespondtotraditionalanalgesia,buttheydoimproveafter
magnesiumsulfateinfusionisinitiated.

Convulsionsareasecondpotentialmanifestationandarediagnosticforeclampsia.Thesearecausedbyexcessivereleaseof
excitatoryneurotransmittersespeciallyglutamatemassivedepolarizationofnetworkneuronsandburstsofactionpotentials
(Meldrum,2002).Clinicalandexperimentalevidencesuggestthatextendedseizurescancausesignificantbraininjuryandlaterbrain
dysfunction.

Asathirdmanifestation,blindnessisrarewithpreeclampsiaalone,butitcomplicateseclampticconvulsionsinupto15percentof
women(Cunningham,1995).Blindnesshasbeenreportedtodevelopuptoaweekormorefollowingdelivery(Chambers,2004).
Thereareatleasttwotypesofblindnessasdiscussedsubsequently.

Last,generalizedcerebraledemamaydevelopandisusuallymanifestbymentalstatuschangesthatvaryfromconfusiontocoma.
Thissituationisparticularlydangerousbecausefataltranstentorialherniationmayresult.

NeuroimagingStudies

WithCTimaging,localizedhypodenselesionsatthegrayandwhitematterjunction,primarilyintheparietooccipitallobes,are
typicallyfoundineclampsia.Suchlesionsmayalsobeseeninthefrontalandinferiortemporallobes,thebasalganglia,andthalamus
(Brown,1988).Thespectrumofbraininvolvementiswide,andincreasinginvolvementcanbeidentifiedwithCTimaging.Edema
oftheoccipitallobesordiffusecerebraledemamaycausesymptomssuchasblindness,lethargy,andconfusion(Cunningham,2000).
Inthelattercases,widespreadedemashowsasamarkedcompressionorevenobliterationofthecerebralventricles.Suchwomen
maydevelopsignsofimpendinglifethreateningtranstentorialherniation.

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SeveralMRimagingacquisitionsareusedtostudyeclampticwomen.CommonfindingsarehyperintenseT2lesionsposterior
reversibleencephalopathysyndrome(PRES)inthesubcorticalandcorticalregionsoftheparietalandoccipitallobes(Fig.4013).
Thereisalsorelativelycommoninvolvementofthebasalganglia,brainstem,andcerebellum(Brewer,2013Zeeman,2004a).
AlthoughthesePRESlesionsarealmostuniversalinwomenwitheclampsia,theirincidenceinwomenwithpreeclampsiaisless
frequent.Theyaremorelikelytobefoundinwomenwhohaveseverediseaseandwhohaveneurologicalsymptoms(Schwartz,
2000).Andalthoughusuallyreversible,afourthofthesehyperintenselesionsrepresentcerebralinfarctionsthathavepersistent
findings(Loureiro,2003Zeeman,2004a).

Figure4013

Cranialmagneticresonanceimaginginanulliparawitheclampsia.MultilobeT2FLAIRhighsignallesionsareapparent.FLAIR=
fluidattenuatedinversionrecovery.(ImagecontributedbyDr.GerdaZeeman.)

VisualChangesandBlindness

Scotomata,blurredvision,ordiplopiaarecommonwithseverepreeclampsiaandeclampsia.Theseusuallyimprovewithmagnesium
sulfatetherapyand/orloweredbloodpressure.Blindnessislesscommon,isusuallyreversible,andmayarisefromthreepotential
areas.Thesearethevisualcortexoftheoccipitallobe,thelateralgeniculatenuclei,andtheretina.Intheretina,pathologicallesions
maybeischemia,infarction,ordetachment(Roos,2012).

OccipitalblindnessisalsocalledamaurosisfromtheGreekdimming.Affectedwomenusuallyhaveevidenceofextensiveoccipital
lobevasogenicedemaonimagingstudies.Of15womencaredforatParklandHospital,occipitalblindnesslastedfrom4hoursto8
days,butitresolvedcompletelyinallcases(Cunningham,1995).Rarely,extensivecerebralinfarctionsmayresultintotalorpartial
visualdefects(Fig.4014).

Figure4014

Cranialmagneticresonanceimagingperformed3dayspostpartuminawomanwitheclampsiaandHELLPsyndrome.Neurovisual
defectspersistedat1year,causingjobdisability.(FromMurphy,2005,withpermission.)

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Blindnessfromretinallesionsiscausedeitherbyserousretinaldetachmentorrarelybyretinalinfarction,whichistermedPurtscher
retinopathy(Fig.4015).Serousretinaldetachmentisusuallyunilateralandseldomcausestotalvisualloss.Infact,asymptomatic
serousretinaldetachmentisrelativelycommon(Saito,1998).Inmostcasesofeclampsiaassociatedblindness,visualacuity
subsequentlyimproves,butifcausedbyretinalarteryocclusion,visionmaybepermanentlyimpaired(LaraTorre,2002Roos,
2012).Insomewomen,thesefindingsareadditive.MosemanandShelton(2002)describedawomanwithpermanentblindnessdue
toacombinationofretinalinfarctionsandbilaterallesionsinthelateralgeniculatenuclei.

Figure4015

Purtscherretinopathycausedbychoroidalischemiaandinfarctioninpreeclampsiasyndrome.A.Ophthalmoscopyshowsscattered
yellowish,opaquelesionsoftheretina(arrows).B.Thelatephaseoffluoresceinangiographyshowsareasofintense
hyperfluorescencerepresentingpoolingofextravasateddye.(FromLam,2001,withpermission.)

CerebralEdema

Clinicalmanifestationssuggestingwidespreadcerebraledemaareworrisome.During13yearsatParklandHospital,10of175
womenwitheclampsiawerediagnosedwithsymptomaticcerebraledema(Cunningham,2000).Symptomsrangedfromlethargy,
confusion,andblurredvisiontoobtundationandcoma.Inmostcases,symptomswaxedandwaned.Mentalstatuschangesgenerally
correlatedwiththedegreeofinvolvementseenwithCTandMRimagingstudies.Thesewomenareverysusceptibletosuddenand
severebloodpressureelevations,whichcanacutelyworsenthealreadywidespreadvasogenicedema.Thus,carefulbloodpressure
controlisessential.Inthe10womenwithgeneralizededema,threebecamecomatoseandhadimagingfindingsofimpending
transtentorialherniation.Oneofthesethreediedfromherniation.Considerationisgivenfortreatmentwithmannitolor
dexamethasone.

LongTermNeurocognitiveSequelae

Womenwitheclampsiahavebeenshowntohavesomecognitivedeclinewhenstudied5to10yearsfollowinganeclamptic
pregnancy.ThisisdiscussedfurtheronRenalSequelae.

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UteroplacentalPerfusion

Defectsinendovasculartrophoblasticinvasionandplacentationgermanetodevelopmentofthepreeclampsiasyndromeandfetal
growthrestrictionwerediscussedonEtiology.Ofimmenseclinicalimportance,compromiseduteroplacentalperfusionisalmost
certainlyamajorculpritintheincreasedperinatalmorbidityandmortalityrates.Thus,measurementofuterine,intervillous,and
placentalbloodflowwouldlikelybeinformative.Attemptstoassesstheseinhumanshavebeenhamperedbyseveralobstaclesthat
includeinaccessibilityoftheplacenta,thecomplexityofitsvenouseffluent,andtheneedforradioisotopesorinvasivetechniques.

Measurementofuterinearterybloodflowvelocityhasbeenusedtoestimateresistancetouteroplacentalbloodflow(Chap.17,
CurrentAntenatalTestingRecommendations).Vascularresistanceisestimatedbycomparingarterialsystolicanddiastolicvelocity
waveforms.Bythecompletionofplacentation,impedancetouterinearterybloodflowismarkedlydecreased,butwithabnormal
placentation,abnormallyhighresistancepersists(Everett,2012Ghidini,2008Napolitano,2012).Earlierstudiesweredoneto
assessthisbymeasuringpeaksystolic:diastolicvelocityratiosfromuterineandumbilicalarteriesinpreeclampticpregnancies.The
resultswereinterpretedasshowingthatinsomecases,butcertainlynotall,therewasincreasedresistance(Fleischer,1986
Trudinger,1990).

AnotherDopplerwaveformuterinearterynotchinghasbeenreportedtobeassociatedwithincreasedrisksforpreeclampsiaor
fetalgrowthrestriction(Groom,2009).IntheMFMUNetworkstudyreportedbyMyattandcolleagues(2012a),however,notching
hadalowpredictivevalueexceptforearlyonsetseveredisease.

MatijevicandJohnson(1999)measuredresistanceinuterinespiralarteries.Impedancewashigherinperipheralthanincentral
vesselsasocalledringlikedistribution.Meanresistancewashigherinallwomenwithpreeclampsiacomparedwiththatin
normotensivecontrols.Ongandassociates(2003)usedMRimagingandothertechniquestoassessplacentalperfusionexvivointhe
myometrialarteriesremovedfromwomenwithpreeclampsiaorfetalgrowthrestriction.Theseinvestigatorsconfirmedthatinboth
conditionsmyometrialarteriesexhibitedendotheliumdependentvasodilatoryresponse.Moreover,otherpregnancyconditionsare
alsoassociatedwithincreasedresistance(Urban,2007).Onemajoradverseeffect,fetalgrowthrestriction,isdiscussedinChapter44
(FetalGrowthRestriction).

Pimentaandcolleagues(2013)assessedplacentalvascularityusingathreedimensionalpowerDopplerhistogram.Theseresearchers
describedtheplacentalvascularityindex,whichwasdecreasedinwomenwithanypregnancyassociatedhypertensivedisorders
11.1percentcomparedwith15.2percentinnormalcontrols.

Despitethesefindings,evidenceforcompromiseduteroplacentalcirculationisfoundinonlyafewwomenwhogoontodevelop
preeclampsia.Indeed,whenpreeclampsiadevelopsduringthethirdtrimester,onlyathirdofwomenwithseverediseasehave
abnormaluterinearteryvelocimetry(Li,2005).Inastudyof50womenwithHELLPsyndrome,onlyathirdhadabnormaluterine
arterywaveforms(Bush,2001).Ingeneral,theextentofabnormalwaveformscorrelateswithseverityoffetalinvolvement(Ghidini,
2008Groom,2009).

PredictionandPrevention
Prediction

Measurementduringearlypregnancyoracrosspregnancyofvariousbiological,biochemical,andbiophysicalmarkersimplicated
inpreeclampsiasyndromepathophysiologyhasbeenproposedtopredictitsdevelopment.Attemptshavebeenmadetoidentifyearly
markersoffaultyplacentation,impairedplacentalperfusion,endothelialcellactivationanddysfunction,andactivationof
coagulation.Forthemost,thesehaveresultedintestingstrategieswithpoorsensitivityandwithpoorpositivepredictivevaluefor
preeclampsia(CondeAgudelo,2014Lindheimer,2008bOdibo,2013).Currently,noscreeningtestsarepredictablyreliable,valid,
andeconomical(Kleinrouweler,2012).Thereare,however,combinationsoftests,someyettobeadequatelyevaluated,thatmaybe
promising(Dugoff,2013Kuc,2011Navaratnam,2013Olsen,2012).

Thelistofpredictivefactorsevaluatedduringthepastthreedecadesislegion.Althoughmosthavebeenevaluatedinthefirsthalfof
pregnancy,somehavebeentestedaspredictorsofseverityinthethirdtrimester(Chaiworapongsa,2013Mosimann,2013Rana,
2012).Othershavebeenusedtoforecastrecurrentpreeclampsia(Demers,2014).SomeofthesetestsarelistedinTable404,which
isbynomeansallinclusive.CondeAgudeloandcoworkers(2014)haverecentlyprovidedathoroughreviewofmanyofthese
testingstrategies.

TABLE404PredictiveTestsforDevelopmentofthePreeclampsiaSyndrome
TestingRelated
Examples
To:
Placental Rollovertest,isometrichandgriporcoldpressortest,pressorresponsetoaerobicexercise,angiotensinII
perfusion/vascular infusion,midtrimestermeanarterialpressure,plateletangiotensinIIbinding,renin,24hourambulatoryblood
resistance pressuremonitoring,uterinearteryorfetaltranscranialDopplervelocimetry
Fetalplacental Humanchorionicgonadotropin(hCG),alphafetoprotein(AFP),estriol,pregnancyassociatedproteinA(PAPP
unitendocrine A),inhibinA,activinA,placentalprotein13,corticotropinreleasinghormone,Adisintegrin,ADAM12,
dysfunction kisspeptin
Serumuricacid,microalbuminuria,urinarycalciumorkallikrein,microtransferrinuria,Nacetyl
Renaldysfunction
glucosaminidase,cystatinC,podocyturia

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TestingRelated
Examples
To:
Plateletcountandactivation,fibronectin,endothelialadhesionmolecules,prostaglandins,prostacyclin,MMP9,
Endothelial thromboxane,Creactiveprotein,cytokines,endothelin,neurokininB,homocysteine,lipids,insulinresistance,
dysfunction/ antiphospholipidantibodies,plasminogenactivatorinhibitor(PAI),leptin,pselectin,angiogenicfactorssuchas
oxidantstress placentalgrowthfactor(PlGF),vascularendothelialgrowthfactor(VEGF),fmsliketyrosinekinasereceptor1
(sFlt1),endoglin
AntithrombinIII(AT3),atrialnatriureticpeptide(ANP),2microglobulin,haptoglobin,transferrin,ferritin,25
Others hydroxyvitaminD,geneticmarkers,cellfreefetalDNA,serumandurineproteomicsandmetabolomicmarkers,
hepaticaminotransferases

ADAM12=ADAMmetallopeptidasedomain12MMP=matrixmetalloproteinase.

AdaptedfromCondeAgudelo,2014.

VascularResistanceTestingandPlacentalPerfusion

Mostofthesearecumbersome,timeconsuming,andoverallinaccurate.

ProvocativePressorTests

Threetestshavebeenextensivelyevaluatedtoassessthebloodpressureriseinresponsetoastimulus.Therollovertestmeasures
thehypertensiveresponseinwomenat28to32weekswhoarerestingintheleftlateraldecubituspositionandthenrollovertothe
supineposition.Increasedbloodpressuresignifiesapositivetest.Theisometricexercisetestemploysthesameprincipleby
squeezingahandball.TheangiotensinIIinfusiontestisperformedbygivingincrementallyincreasingdosesintravenously,andthe
hypertensiveresponseisquantified.Intheirupdatedmetaanalysis,CondeAgudeloandassociates(2014)foundsensitivitiesofall
threeteststorangefrom55to70percent,andspecificitiesapproximated85percent.

UterineArteryDopplerVelocimetry

Faultytrophoblasticinvasionofthespiralarteries,whichisdepictedinFigure402,resultsindiminishedplacentalperfusionand
upstreamincreaseduterinearteryresistance.IncreaseduterinearteryvelocimetrydeterminedbyDopplerultrasoundinthefirsttwo
trimestersshouldprovideindirectevidenceofthisprocessandthusserveasapredictivetestforpreeclampsia(Gebb,2009a,b
Groom,2009).AsdescribedonCerebralEdemaandinChapter10(DuctusArteriosus),increasedflowresistanceresultsinan
abnormalwaveformrepresentedbyanexaggerateddiastolicnotch.Thesehavevalueforfetalgrowthrestrictionbutnot
preeclampsia(AmericanCollegeofObstetriciansandGynecologists,2013a).Severalflowvelocitywaveformsaloneorin
combinationhavebeeninvestigatedforpreeclampsiaprediction.Insomeofthese,predictivevaluesforearlyonsetpreeclampsia
werepromising(Herraiz,2012).Atthistime,however,noneissuitableforclinicaluse(CondeAgudelo,2014Kleinrouweler,2012
Myatt,2012a).

PulseWaveAnalysis

Liketheuterineartery,fingerarterialpulsestiffnessisanindicatorofcardiovascularrisk.Investigatorshavepreliminarily
evaluateditsusefulnessinpreeclampsiaprediction(Vollebregt,2009).

FetalPlacentalUnitEndocrineFunction

SeveralserumanalytesthathavebeenproposedtohelppredictpreeclampsiaareshowninTable404.Neweronesarecontinuously
added(Jeyabalan,2009Kanasaki,2008Kenny,2009).Manyofthesegainedwidespreaduseinthe1980stoidentifyfetal
malformationsandwerealsofoundtobeassociatedwithotherpregnancyabnormalitiessuchasneuraltubedefectsandaneuploidy
(Chap.14,FirstTrimesterScreening).Althoughtoutedforhypertensionprediction,ingeneral,noneofthesetestshasbeenshownto
beclinicallybeneficialforthatpurpose.

TestsofRenalFunction

SerumUricAcid

Oneoftheearliestlaboratorymanifestationsofpreeclampsiaishyperuricemia(Powers,2006).Itlikelyresultsfromreduceduric
acidclearancefromdiminishedglomerularfiltration,increasedtubularreabsorption,anddecreasedsecretion(Lindheimer,2008a).It
isusedbysometodefinepreeclampsia,butCnossenandcoworkers(2006)reportedthatitssensitivityrangedfrom0to55percent,
andspecificitywas77to95percent.

Microalbuminuria

Asapredictivetestforpreeclampsia,microalbuminuriahassensitivitiesrangingfrom7to90percentandspecificitiesbetween29
and97percent(CondeAgudelo,2014).Poonandcolleagues(2008)likewisefoundunacceptablesensitivityandspecificityforurine
albumin:creatinineratios.

EndothelialDysfunctionandOxidantStress

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AsdiscussedonImmunologicalFactors,endothelialactivationandinflammationaremajorparticipantsinthepathophysiologyofthe
preeclampsiasyndrome.Asaresult,compoundssuchasthoselistedinTable404arefoundincirculatingbloodofaffectedwomen,
andsomehavebeenassessedfortheirpredictivevalue.

Fibronectins

Thesehighmolecularweightglycoproteinsarereleasedfromendothelialcellsandextracellularmatrixfollowingendothelialinjury
(Chavarria,2002).Morethan30yearsago,plasmaconcentrationswerereportedtobeelevatedinwomenwithpreeclampsia(Stubbs,
1984).Followingtheirsystematicreview,however,Leeflangandassociates(2007)concludedthatneithercellularnortotal
fibronectinlevelswereclinicallyusefultopredictpreeclampsia.

CoagulationActivation

ThrombocytopeniaandplateletdysfunctionareintegralfeaturesofpreeclampsiaasdiscussedonHematologicalChanges.Platelet
activationcausesincreaseddestructionanddecreasedconcentrations,andmeanplateletvolumerisesbecauseofplateletimmaturity
(Kenny,2014).Althoughmarkersofcoagulationactivationareincreased,thesubstantiveoverlapwithlevelsinnormotensive
pregnantwomenstultifiestheirpredictivevalue.

OxidativeStress

Increasedlevelsoflipidperoxidescoupledwithdecreasedantioxidantactivityhaveraisedthepossibilitythatmarkersofoxidative
stressmightpredictpreeclampsia.Forexample,malondialdehydeisamarkeroflipidperoxidation.Othermarkersarevarious
prooxidantsortheirpotentiators.Theseincludeiron,transferrin,andferritinbloodlipids,includingtriglycerides,freefattyacids,
andlipoproteinsandantioxidantssuchasascorbicacidandvitaminE(Bainbridge,2005CondeAgudelo,2014Mackay,2012
Powers,2000).Thesehavenotbeenfoundtobepredictive,andtreatmenttopreventpreeclampsiawithsomeofthemhasbeen
studiedasdiscussedonPrevention.

Hyperhomocysteinemiacausesoxidativestressandendothelialcelldysfunctionandischaracteristicofpreeclampsia.Although
womenwithelevatedserumhomocysteinelevelsatmidpregnancyhadathreetofourfoldriskofpreeclampsia,thesetestshavenot
beenshowntobeclinicallyusefulpredictors(DAnna,2004Mignini,2005Zeeman,2003).

AngiogenicFactors

AsdiscussedonEndothelialCellInjury,evidencehasaccruedthatanimbalancebetweenproangiogenicandantiangiogenicfactorsis
relatedtopreeclampsiapathogenesis.Serumlevelsofsomeproangiogenicfactorsvascularendothelialgrowthfactor(VEGF)and
placentalgrowthfactor(PlGF)begintodecreasebeforeclinicalpreeclampsiadevelops.And,recallasshowninFigure404thatat
thesametimelevelsofsomeantiangiogenicfactorssuchassFlt1andsEngbecomeincreased(Maynard,2008).Inonestudy,these
abnormalitieswereidentifiedcoincidentallywithrisinguterinearteryDopplerresistance(Coolman,2012).

CondeAgudeloandcolleagues(2014)reviewedthepredictiveaccuracyofsomeofthesefactorsforseverepreeclampsia.
Sensitivitiesforallcasesofpreeclampsiarangedfrom30to50percent,andspecificitywasabout90percent.Theirpredictive
accuracywashigherforearlyonsetpreeclampsia.Thesepreliminaryresultssuggestaclinicalroleforpreeclampsiaprediction.
However,untilthisroleisbettersubstantiated,theirgeneralclinicaluseisnotcurrentlyrecommended(Boucoiran,2013
Kleinrouweler,2012Widmer,2007).Automatedassaysarebeingstudied,andtheWorldHealthOrganization(WHO)begana
multicentertrialin2008toevaluatethesefactors(Sunderji,2009).

CellFreeFetalDNA

AsdiscussedinChapter13(FetalDNAintheMaternalCirculation),cellfreefetalDNAcanbedetectedinmaternalplasma.Ithas
beenreportedthatfetalmaternalcelltraffickingisincreasedinpregnanciescomplicatedbypreeclampsia(Holzgreve,1998).Itis
hypothesizedthatcellfreeDNAisreleasedbyacceleratedapoptosisofcytotrophoblasts(DiFederico,1999).Fromtheirreview,
CondeAgudeloandassociates(2014)concludedthatcellfreefetalDNAquantificationisnotyetusefulforpredictionpurposes.

Proteomic,Metabolomic,andTranscriptomicMarkers

Methodstostudyserumandurinaryproteinsandcellularmetaboliteshaveopenedanewvistaforpreeclampsiaprediction.
Preliminarystudiesindicatethatthesemaybecomeuseful(BahadoSingh,2013Carty,2011Liu,2013Myers,2013).

Prevention

Variousstrategiesusedtopreventormodifypreeclampsiaseverityhavebeenevaluated.SomearelistedinTable405.Ingeneral,
noneofthesehasbeenfoundtobeconvincinglyandreproduciblyeffective.

TABLE405SomeMethodstoPreventPreeclampsiaThatHaveBeenEvaluatedinRandomizedTrials
Dietarymanipulationlowsaltdiet,calciumorfishoilsupplementation
Exercisephysicalactivity,stretching
Cardiovasculardrugsdiuretics,antihypertensivedrugs
Antioxidantsascorbicacid(vitaminC),tocopherol(vitaminE),vitaminD
Antithromboticdrugslowdoseaspirin,aspirin/dipyridamole,aspirin+heparin,aspirin+ketanserin

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ModifiedfromStaff,2014.

DietaryandLifestyleModifications

Afavoriteofmanytheoristsandfaddistsforcenturies,dietarytreatmentforpreeclampsiahasproducedsomeinterestingabusesas
chronicledbyChesley(1978).

LowSaltDiet

Oneoftheearliestresearcheffortstopreventpreeclampsiawassaltrestriction(DeSnoo,1937).Thisinterdictionwasfollowedby
yearsofinappropriatediuretictherapy.Althoughthesepracticeswerediscarded,itironicallywasnotuntilrelativelyrecentlythatthe
firstrandomizedtrialwasdoneandshowedthatasodiumrestricteddietwasineffectiveinpreventingpreeclampsiain361women
(Knuist,1998).GuidelinesfromtheUnitedKingdomNationalInstituteforHealthandClinicalExcellence(2010)recommend
againstsaltrestrictions.

CalciumSupplementation

Studiesperformedinthe1980soutsidetheUnitedStatesshowedthatwomenwithlowdietarycalciumintakewereatsignificantly
increasedriskforgestationalhypertension(Belizan,1980LpezJaramillo,1989Marya,1987).Calciumsupplementationhasbeen
studiedinseveraltrials,includingonebytheNationalInstituteofChildHealthandHumanDevelopment(NICHD)thatincluded
morethan4500nulliparouswomen(Levine,1997).Inonerecentmetaanalysis,Patrelliandcoworkers(2012)reportedthatincreased
calciumintakeloweredtheriskforpreeclampsiainhighriskwomen.Inaggregate,mostofthesetrialshaveshownthatunless
womenarecalciumdeficient,supplementationhasnosalutaryeffects(Staff,2014).

FishOilSupplementation

CardioprotectivefattyacidsfoundinsomefattyfishesareplentifulindietsofScandinaviansandAmericanEskimos.Themost
commondietarysourcesareEPAeicosapentaenoicacid,ALAalphalinoleicacid,andDHAdocosahexaenoicacid.With
proclamationsthatsupplementationwiththesefattyacidswouldpreventinflammatorymediatedatherogenesis,itwasnotaquantum
leaptopositthattheymightalsopreventpreeclampsia.Unfortunately,randomizedtrialsconductedthusfarhaveshownnosuch
benefits(Makrides,2006Olafsdottir,2006Olsen,2000Zhou,2012a).

Exercise

Thereareafewstudiesdonetoassesstheprotectiveeffectsofphysicalactivityonpreeclampsia.Intheirsystematicreview,
Kasawaraandassociates(2012)reportedatrendtowardriskreductionwithexercise.Moreresearchisneededinthisarea(Staff,
2014).

AntihypertensiveDrugs

Becauseoftheputativeeffectsofsodiumrestriction,diuretictherapybecamepopularwiththeintroductionofchlorothiazidein1957
(Finnerty,1958Flowers,1962).Intheirmetaanalysis,Churchillandcolleagues(2007)summarizedninerandomizedtrialsthat
includedmorethan7000pregnancies.Theyfoundthatwomengivendiureticshadadecreasedincidenceofedemaandhypertension
butnotofpreeclampsia.

Becausewomenwithchronichypertensionareathighriskforpreeclampsia,severalrandomizedtrialsonlyafewplacebo
controlledhavebeendonetoevaluatevariousantihypertensivedrugstoreducetheincidenceofsuperimposedpreeclampsia.A
criticalanalysisofthesetrialsbyStaffandcoworkers(2014)failedtodemonstratesalutaryeffects.

Antioxidants

Thereareinferentialdatathatanimbalancebetweenoxidantandantioxidantactivitymayplayanimportantroleinthepathogenesis
ofpreeclampsia(TestsofRenalFunction).Thus,naturallyoccurringantioxidantsvitaminsC,D,andEmightdecreasesuch
oxidation.Indeed,womenwhodevelopedpreeclampsiawerefoundtohavereducedplasmalevelsoftheseantioxidants(DeRegil,
2012Raijmakers,2004).Therehavenowbeenseveralrandomizedstudiestoevaluatevitaminsupplementationforwomenathigh
riskforpreeclampsia(Poston,2006Rumbold,2006Villar,2007).TheonebytheMFMUNetworkincludedalmost10,000lowrisk
nulliparas(Roberts,2009).NoneofthesestudiesshowedreducedpreeclampsiaratesinwomengivenvitaminsCandEcompared
withthosegivenplacebo.TherecentmetaanalysisbyDeRegilandcolleagues(2012)likewiseshowednobenefitsofvitaminD
supplementation.

Therationalefortheuseofstatinstopreventpreeclampsiaisthattheystimulatehemoxygenase1expressionthatinhibitssFlt1
release.Therearepreliminaryanimaldatathatstatinsmaypreventhypertensivedisordersofpregnancy.TheMFMUNetworkplans
arandomizedtrialtotestpravastatinforthispurpose(Costantine,2013).

AntithromboticAgents

Therearesoundtheoreticalreasonsthatantithromboticagentsmightreducetheincidenceofpreeclampsia.Asdiscussedon
NutritionalFactors,thesyndromeischaracterizedbyvasospasm,endothelialcelldysfunction,andinflammation,aswellas
activationofplateletsandthecoagulationhemostasissystem.Moreover,prostaglandinimbalance(s)maybeoperative,andother
sequelaeincludeplacentalinfarctionandspiralarterythrombosis(Nelson,2014).
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LowDoseAspirin

Inoraldosesof50to150mgdaily,aspirineffectivelyinhibitsplateletthromboxaneA2biosynthesisbuthasminimaleffectson
vascularprostacyclinproduction(Wallenburg,1986).However,clinicaltrialshaveshownlimitedbenefits.Forexample,resultsin
Table406arefromtheMFMUNetwork,andnoneoftheoutcomesshownweresignificantlyimproved.Somereportsaremore
favorable.Forexample,theParisCollaborativeGroupperformedametaanalysisthatincluded31randomizedtrialsinvolving32,217
women(Askie,2007).Forwomenassignedtoreceiveantiplateletagents,therelativeriskfordevelopmentofpreeclampsia,
superimposedpreeclampsia,pretermdelivery,oranyadversepregnancyoutcomewassignificantlydecreasedby10percent.Another
reviewandmetaanalysisreportedmarginalbenefitsforlowdoseaspirinandseverepreeclampsia(Roberge,2012).Arecentsmall
Finnishmulticentertrialincluded152womenathighriskforpreeclampsia(Villa,2013).Althoughtherewerenobenefitstolow
doseaspirin,theaccompanyingmetaanalysisreportedaloweringofrisk.The2013TaskForcerecommendedtheuseoflowdose
aspirininsomehighriskwomentopreventpreeclampsia.

TABLE406MaternalFetalMedicineUnitsNetworkTrialofLowDoseAspirininWomenatHighRiskforPreeclampsia
Preeclampsia(%)a
RiskFactors No. Aspirin Placebo
Normotensive,noproteinuria 1613 14.5 17.7
Proteinuriaplushypertension 119 31.7 22.0
Proteinuriaonly 48 25.0 33.3
Hypertensiononly 723 24.8 25.0
Insulindependentdiabetes 462 18.3 21.6
Chronichypertension 763 26.0 24.6
Multifetalgestation 678 11.5 15.9
Previouspreeclampsia 600 16.7 19.0

aNostatisticallysignificantdifferenceforanycomparisonbetweengroups.

DatafromCaritis,1998.

LowDoseAspirinplusHeparin

Inwomenwithlupusanticoagulant,treatmentwithlowdoseaspirinandheparinmitigatesthromboticsequelae(Chap.59,Adverse
PregnancyOutcomes).Becauseofthehighprevalenceofplacentalthromboticlesionsfoundwithseverepreeclampsia,observational
trialshavebeendonetoevaluatesuchtreatmentsforaffectedwomen.Sergisandassociates(2006)reviewedeffectsofprophylaxis
withlowmolecularweightheparinpluslowdoseaspirinonpregnancyoutcomesinwomenwithahistoryofsevereearlyonset
preeclampsiaandlowbirthweightneonates.Theyreportedbetterpregnancyoutcomesinwomengivenlowmolecularweight
heparinpluslowdoseaspirincomparedwiththosegivenlowdoseaspirinalone.Similarfindingswerereportedinatrialthat
included139womenwiththrombophiliaandahistoryofearlyonsetpreeclampsia(deVries,2012).Despitethesesmalltrials,
evidenceisinsufficienttorecommendtheseregimenstopreventpreeclampsia(NationalInstituteforHealthandClinicalExcellence,
2010Staff,2014).

Management
Pregnancycomplicatedbygestationalhypertensionismanagedbasedonseverity,gestationalage,andpresenceofpreeclampsia.
Withpreeclampsia,managementvarieswiththeseverityofendothelialcellinjuryandmultiorgandysfunction.

Preeclampsiacannotalwaysbediagnoseddefinitively(TerminologyandDiagnosis).Thus,theTaskForceoftheAmericanCollege
ofObstetriciansandGynecologists(2013b)recommendsmorefrequentprenatalvisitsifpreeclampsiaissuspected.Increasesin
systolicanddiastolicbloodpressurecanbeeithernormalphysiologicalchangesorsignsofdevelopingpathology.Increased
surveillancepermitsmorepromptrecognitionofominouschangesinbloodpressure,criticallaboratoryfindings,andclinicalsigns
andsymptoms(MacdonaldWallis,2012).

Thebasicmanagementobjectivesforanypregnancycomplicatedbypreeclampsiaare:(1)terminationofpregnancywiththeleast
possibletraumatomotherandfetus,(2)birthofaninfantwhosubsequentlythrives,and(3)completerestorationofhealthtothe
mother.Inmanywomenwithpreeclampsia,especiallythoseatornearterm,allthreeobjectivesareservedequallywellbyinduction
oflabor.Oneofthemostimportantclinicalquestionsforsuccessfulmanagementispreciseknowledgeoffetalage.

EarlyDiagnosisofPreeclampsia

Traditionally,thefrequencyofprenatalvisitsisincreasedduringthethirdtrimester,andthisaidsearlydetectionofpreeclampsia.
Womenwithoutoverthypertension,butinwhomearlydevelopingpreeclampsiaissuspectedduringroutineprenatalvisits,areseen
morefrequently.TheprotocolusedsuccessfullyformanyyearsatParklandHospitalforwomenwithnewonsetdiastolicblood
pressures>80mmHgbut<90mmHgorwithsuddenabnormalweightgainofmorethan2poundsperweekincludes,atminimum,
returnvisitsat7dayintervals.Outpatientsurveillanceiscontinuedunlessoverthypertension,proteinuria,headache,visual
disturbances,orepigastricdiscomfortsupervene.Womenwithovertnewonsethypertensioneitherdiastolicpressures90mmHg
orsystolicpressures140mmHgareadmittedtodetermineiftheincreaseisduetopreeclampsia,andifso,toevaluateits
severity.Womenwithpersistentseverediseasearegenerallydelivered,asdiscussedsubsequently.Conversely,womenwith

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apparentlymilddiseasecanoftenbemanagedasoutpatients,althoughthereshouldbealowthresholdforcontinuedhospitalization
forthenullipara,especiallyifthereisproteinuria.

Evaluation

Hospitalizationisconsideredatleastinitiallyforwomenwithnewonsethypertension,especiallyifthereispersistentorworsening
hypertensionordevelopmentofproteinuria.Asystematicevaluationisinstitutedtoincludethefollowing:

Detailedexamination,whichisfollowedbydailyscrutinyforclinicalfindingssuchasheadache,visualdisturbances,
epigastricpain,andrapidweightgain

Weightdetermineddaily

Analysisforproteinuriaorurineprotein:creatinineratioonadmittanceandatleastevery2daysthereafter

Bloodpressurereadingsinthesittingpositionwithanappropriatesizecuffevery4hours,exceptbetween2400and0600
unlesspreviousreadingshadbecomeelevated

Measurementsofplasmaorserumcreatinineandhepaticaminotransferaselevelsandahemogramthatincludesplatelet
quantification.Thefrequencyoftestingisdeterminedbyhypertensionseverity.Somerecommendmeasurementofserumuric
acidandlacticaciddehydrogenaselevelsandcoagulationstudies.However,thevalueofthesetestshasbeencalledinto
question(Cnossen,2006CondeAgudelo,2014Thangaratinam,2006).

Evaluationoffetalsizeandwellbeingandamnionicfluidvolume,witheitherphysicalexaminationorsonography.

Goalsofmanagementincludeearlyidentificationofworseningpreeclampsiaanddevelopmentofamanagementplanfortimely
delivery.IfanyoftheseobservationsleadtoadiagnosisofseverepreeclampsiaaspreviouslydefinedbythecriteriainTable402,
furthermanagementissubsequentlydescribed.

Reducedphysicalactivitythroughoutmuchofthedayislikelybeneficial,butasthe2013TaskForceconcluded,absolutebedrestis
notdesirable.Ampleproteinandcaloriesshouldbeincludedinthediet,andsodiumandfluidintakeshouldnotbelimitedorforced.
Furthermanagementdependson:(1)preeclampsiaseverity,(2)gestationalage,and(3)conditionofthecervix.

Fortunately,manycasesaresufficientlymildandnearenoughtotermthattheycanbemanagedconservativelyuntillabor
commencesspontaneouslyoruntilthecervixbecomesfavorableforlaborinduction.Completeabatementofallsignsandsymptoms,
however,isuncommonuntilafterdelivery.Almostcertainly,theunderlyingdiseasepersistsuntildeliveryisaccomplished.

ConsiderationforDelivery

Terminationofpregnancyistheonlycureforpreeclampsia.Headache,visualdisturbances,orepigastricpainareindicativethat
convulsionsmaybeimminent,andoliguriaisanotherominoussign.Severepreeclampsiademandsanticonvulsantandfrequently
antihypertensivetherapy,followedbydelivery.Treatmentisidenticaltothatdescribedsubsequentlyforeclampsia.Theprime
objectivesaretoforestallconvulsions,topreventintracranialhemorrhageandseriousdamagetoothervitalorgans,andtodelivera
healthynewborn.

Whenthefetusispreterm,thetendencyistotemporizeinthehopethatafewmoreweeksinuterowillreducetheriskofneonatal
deathorseriousmorbidityfromprematurity.Asdiscussed,suchapolicycertainlyisjustifiedinmildercases.Assessmentsoffetal
wellbeingandplacentalfunctionareperformed,especiallywhenthefetusisimmature.Mostrecommendfrequentperformanceof
variousteststoassessfetalwellbeingasdescribedbytheAmericanCollegeofObstetriciansandGynecologists(2012a).These
includethenonstresstestorthebiophysicalprofile(Chap.17,ContractionStressTestingandAcousticStimulationTests).
Measurementofthelecithinsphingomyelin(L/S)ratioinamnionicfluidmayprovideevidenceoflungmaturity(Chap.34,
AmniocentesisforFetalLungMaturity).

Withmoderateorseverepreeclampsiathatdoesnotimproveafterhospitalization,deliveryisusuallyadvisableforthewelfareof
bothmotherandfetus.Thisistrueevenwhenthecervixisunfavorable(Tajik,2012).Laborinductioniscarriedout,usuallywith
preinductioncervicalripeningfromaprostaglandinorosmoticdilator(Chap.26,PreinductionCervicalRipening).Wheneverit
appearsthatinductionalmostcertainlywillnotsucceedorattemptshavefailed,thencesareandeliveryisindicated.

Forawomannearterm,withasoft,partiallyeffacedcervix,evenmilderdegreesofpreeclampsiaprobablycarrymorerisktothe
motherandherfetusinfantthandoesinductionoflabor(Tajik,2012).Thedecisiontodeliverlatepretermfetusesisnotclear.Barton
andcoworkers(2009)reportedexcessiveneonatalmorbidityinwomendeliveredbefore38weeksdespitehavingstable,mild,
nonproteinurichypertension.TheNetherlandsstudyof4316newbornsdeliveredbetween340/7and366/7weeksalsodescribed
substantiveneonatalmorbidityinthesecases(Langenveld,2011).Mostofthesedeliverieswerebefore36weeks,andthehigher
cesareandeliveryrateswereassociatedwithmorerespiratorycomplications.Conversely,onerandomizedtrialof756womenwith
mildpreeclampsiasupporteddeliveryafter37weeks(Koopmans,2009).

ElectiveCesareanDelivery

Onceseverepreeclampsiaisdiagnosed,laborinductionandvaginaldeliveryhavetraditionallybeenconsideredideal.Temporization
withanimmaturefetusisconsideredsubsequently.Severalconcerns,includinganunfavorablecervix,aperceivedsenseofurgency

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becauseofpreeclampsiaseverity,andaneedtocoordinateneonatalintensivecare,haveledsometoadvocatecesareandelivery.
Alexanderandcolleagues(1999)reviewed278singletonlivebornneonatesweighing750to1500gdeliveredofwomenwithsevere
preeclampsiaatParklandHospital.Inhalfofthewomen,laborwasinduced,andtheremainderunderwentcesareandeliverywithout
labor.Inductionwassuccessfulinaccomplishingvaginaldeliveryinathird,anditwasnotharmfultotheverylowbirthweight
infants.Alanisandassociates(2008)reportedsimilarobservations.Theresultsofasystematicreviewalsoconfirmedthese
conclusions(LeRay,2009).

HospitalizationversusOutpatientManagement

Forwomenwithmildtomoderatestablehypertensionwhetherornotpreeclampsiahasbeenconfirmedsurveillanceiscontinued
inthehospital,athomeforsomereliablepatients,orinadaycareunit.Atleastintuitively,reducedphysicalactivitythroughout
muchofthedayseemsbeneficial.Severalobservationalstudiesandrandomizedtrialshaveaddressedthebenefitsofinpatientcare
andoutpatientmanagement.

Somewhatrelated,Abenhaimandcoworkers(2008)reportedaretrospectivecohortstudyof677nonhypertensivewomen
hospitalizedforbedrestbecauseofthreatenedpretermdelivery.Whenoutcomesofthesewomenwerecomparedwiththoseofthe
generalobstetricalpopulation,bedrestwasassociatedwithasignificantlyreducedrelativeriskRR0.27ofdeveloping
preeclampsia.Inareviewoftwosmallrandomizedtrialstotaling106womenathighriskforpreeclampsia,prophylacticbedrestfor
4to6hoursdailyathomewassuccessfulinsignificantlyloweringtheincidenceofpreeclampsiabutnotgestationalhypertension
(Meher,2006).

Theseandotherobservationssupporttheclaimthatrestrictedactivityalterstheunderlyingpathophysiologyofthepreeclampsia
syndrome.Thatsaid,completebedrestisnotrecommendedbythe2013TaskForce.First,thisispragmaticallyunachievable
becauseofthesevererestrictionsitplacesonotherwisewellwomen.Also,asdiscussedinChapter52(Thrombophilias),itlikely
alsopredisposestothromboembolism(Knight,2007).

HighRiskPregnancyUnit

Theconceptofprolongedhospitalizationforwomenwithhypertensionaroseduringthe1970s.AtParklandHospital,aninpatient
antepartumunitwasestablishedin1973byDr.PeggyWhalleyinlargeparttoprovidecareforsuchwomen.Initialresultsfromthis
unitwerereportedbyHauth(1976)andGilstrap(1978)andtheircolleagues.Mosthospitalizedwomenhaveabeneficialresponse
characterizedbyameliorationorimprovementofhypertension.Thesewomenarenotcured,andnearly90percenthaverecurrent
hypertensionbeforeorduringlabor.By2013,morethan10,000nulliparaswithmildtomoderateearlyonsethypertensionduring
pregnancyhadbeenmanagedsuccessfullyinthisunit.Providercostsnotchargesforthisrelativelysimplephysicalfacility,
modestnursingcare,nodrugsotherthanironandfolatesupplements,andfewessentiallaboratorytestsareminimalcomparedwith
thecostofneonatalintensivecareforapreterminfant.Noneofthesewomenhavesufferedthromboembolicdisease.

HomeHealthCare

Manycliniciansbelievethatfurtherhospitalizationisnotwarrantedifhypertensionabateswithinafewdays,andthishaslegitimized
thirdpartypayerstodenyhospitalizationreimbursement.Consequently,manywomenwithmildtomoderatehypertensionare
managedathome.Outpatientmanagementmaycontinueaslongaspreeclampsiasyndromedoesnotworsenandfetaljeopardyisnot
suspected.Sedentaryactivitythroughoutthegreaterpartofthedayisrecommended.Thesewomenareinstructedindetailtoreport
symptoms.Homebloodpressureandurineproteinmonitoringorfrequentevaluationsbyavisitingnursemayprovebeneficial.
Cautionisexercisedregardinguseofcertainautomatedhomebloodpressuremonitors(Lo,2002Ostchega,2012).

InanobservationalstudybyBartonandassociates(2002),1182nulliparaswithmildgestationalhypertension20percenthad
proteinuriaweremanagedwithhomehealthcare.Theirmeangestationalageswere32to33weeksatenrollmentand36to37
weeksatdelivery.Severepreeclampsiadevelopedinapproximately20percent,about3percentdevelopedHELLPsyndrome,and
twowomenhadeclampsia.Perinataloutcomesweregenerallygood.Inapproximately20percent,therewasfetalgrowthrestriction,
andtheperinatalmortalityratewas4.2per1000.

Severalprospectivestudieshavebeendesignedtocomparecontinuedhospitalizationwitheitherhomehealthcareoradaycareunit.
InapilotstudyfromParklandHospital,Horsagerandcolleagues(1995)randomlyassigned72nulliparaswithnewonset
hypertensionfrom27to37weekseithertocontinuedhospitalizationortooutpatientcare.Inallofthesewomen,proteinuriahad
recededtolessthan500mgperdaywhentheywererandomized.Outpatientmanagementincludeddailybloodpressuremonitoring
bythepatientorherfamily.Weightanddipstickspoturineproteindeterminationswereevaluatedthreetimesweekly.Ahomehealth
nursevisitedtwiceweekly,andthewomenwereseenweeklyintheclinic.Perinataloutcomesweresimilarineachgroup.Theonly
significantdifferencewasthatwomeninthehomecaregroupdevelopedseverepreeclampsiasignificantlymorefrequentlythan
hospitalizedwomen42versus25percent.

AlargerrandomizedtrialreportedbyCrowtherandcoworkers(1992)included218womenwithmildgestationalnonproteinuric
hypertension.Afterevaluation,halfremainedhospitalized,whereastheotherhalfwasmanagedasoutpatients.AsshowninTable
407,themeandurationofhospitalizationwas22.2daysforwomenwithinpatientmanagementcomparedwithonly6.5daysinthe
homecaregroup.Pretermdeliverybefore34andbefore37weekswasincreasedtwofoldintheoutpatientgroup,butmaternaland
infantoutcomesotherwiseweresimilar.

TABLE407RandomizedClinicalTrialsComparingHospitalizationversusRoutineCareforWomenwithMildGestational
HypertensionorPreeclampsia

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MaternalCharacteristicsAdmission MaternalCharacteristicsDelivery PerinatalOutcomes

Para0 ChronicHTN EGA Prot EGA <37wk <34wk MeanHosp MeanBW SGA PMR
StudyGroups No.
(%) (%) (wk) (%) (wk) (%) (%) (d) (g) (%) (%)
Crowther
(1992) 218a

110 13 14 35.3 0 38.3 12 1.8 22.2 3080 14 0
Hospitalization
Outpatient 108 13 17 34.6 0 38.2 22 3.7 6.5 3060 14 0
Tuffnell
54
(1992)
DayUnit 24 57 23 36 0 39.8 1.1 3320 0
UsualCare 30 54 21 36.5 21 39 5.1 3340 0
Turnbull
(2004) 374b

125 63 0 35.9 22 39 8.5 3330 3.8 0
Hospitalization
DayUnit 249 62 0 36.2 22 39.7 7.2 3300 2.3 0

aExcludedwomenwithproteinuriaatstudyentry.

bIncludedwomenwith1+proteinuria.

BW=birthweightEGA=estimatedgestationalageHTN=hypertensionPara0=nulliparasPMR=perinatalmortalityrateProt=
proteinuriaSGA=smallforgestationalage.

DayCareUnit

Anotherapproach,popularinEuropeancountries,isdaycare(Milne,2009).Thisapproachhasbeenevaluatedbyseveral
investigators.InthestudybyTuffnellandassociates(1992),54womenwithhypertensionafter26weeksgestationwereassignedto
eitherdaycareorroutineoutpatientmanagement(seeTable407).Progressiontoovertpreeclampsiaandlaborinductionswere
significantlyincreasedintheroutinemanagementgroup.Turnbullandcoworkers(2004)enrolled395womenwhowererandomly
assignedtoeitherdaycareorinpatientmanagement(seeTable407).Almost95percenthadmildtomoderatehypertension.Of
enrolledwomen,288werewithoutproteinuria,and86had1+proteinuria.Therewerenoperinataldeaths,andnoneofthewomen
developedeclampsiaorHELLPsyndrome.Surprisingly,costsforeitherschemewerenotsignificantlydifferent.Perhapsnot
surprisingly,generalsatisfactionfavoreddaycare.

SummaryofHospitalizationversusOutpatientManagement

Fromtheabove,eitherinpatientorcloseoutpatientmanagementisappropriateforawomanwithmilddenovohypertension,
includingthosewithnonseverepreeclampsia.Mostofthesestudieswerecarriedoutinacademiccenterswithdedicatedmanagement
teams.Thatsaid,thekeytosuccessisclosefollowupandaconscientiouspatientwithgoodhomesupport.

AntihypertensiveTherapyforMildtoModerateHypertension

Theuseofantihypertensivedrugsinattemptstoprolongpregnancyormodifyperinataloutcomesinpregnanciescomplicatedby
varioustypesandseveritiesofhypertensivedisordershasbeenofconsiderableinterest.Treatmentforwomenwithchronic
hypertensioncomplicatingpregnancyisdiscussedindetailinChapter50(AntihypertensiveDrugs).

DrugtreatmentforearlymildpreeclampsiahasbeendisappointingasshowninrepresentativerandomizedtrialslistedinTable408.
Sibaiandcolleagues(1987a)evaluatedtheeffectivenessoflabetalolandhospitalizationcomparedwithhospitalizationalonein200
nulliparaswithgestationalhypertensionfrom26to35weeksgestation.Althoughwomengivenlabetalolhadsignificantlylower
meanbloodpressures,therewerenodifferencesbetweenthegroupsintermsofmeanpregnancyprolongation,gestationalageat
delivery,orbirthweight.Thecesareandeliveryratesweresimilar,aswerethenumberofinfantsadmittedtospecialcarenurseries.
Thefrequencyofgrowthrestrictedinfantswasdoubledinwomengivenlabetalol19versus9percent.Thethreeotherstudieslisted
inTable408wereperformedtocomparelabetalolorthecalciumchannelblockers,nifedipineandisradipine,withplacebo.Except
forfewerepisodesofseverehypertension,noneofthesestudiesshowedanybenefitsofantihypertensivetreatment.Moreover,there
mayhavebeentreatmentinducedadversefetalgrowth(VonDadelszen,2002).

TABLE408RandomizedPlaceboControlledTrialsofAntihypertensiveTherapyforEarlyMildGestationalHypertension
Study Severe Mean Growth
Pregnancy Cesarean Placental Neonatal
Study Drug Birthweight Restriction
Prolonged(d) HTNa(%) Delivery(%) Abruption(%) Deaths(No.)
(No.) (g) (%)
Sibai
Labetalol
(1987a)a (100)
21.3 5 36 2 2205 19c 1
200inpatients

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Study Severe Mean Growth

Pregnancy Cesarean Placental Neonatal
Study Drug Birthweight Restriction
Prolonged(d) HTNa(%) Delivery(%) Abruption(%) Deaths(No.)
(No.) (g) (%)
Placebo
(100)
20.1 15c 32 0 2260 9 0

Sibai(1992)b Nifedipine
200 22.3 9 43 3 2405 8 0
(100)
outpatients
Placebo
(100)
22.5 18b 35 2 2510 4 0
Pickles
(1992) Labetalol
26.6 9 24 NS NS NS NS
144 (70)
outpatients
Placebo
23.1 10 26 NS NS NS NS
(74)
Wide
Isradipine
Swensson 23.1 22 26 NS NS NS 0
(54)
(1995)
111 Placebo
29.8 29 19 NS NS NS 0
outpatients (57)

aAllwomenhadpreeclampsia.

bIncludespostpartumhypertension.

cp<.05whenstudydrugcomparedwithplacebo.

HTN=hypertensionNS=notstated.

Abalosandassociates(2007)reviewed46randomizedtrialsofactiveantihypertensivetherapycomparedwitheithernotreatmentor
placebogiventowomenwithmildtomoderategestationalhypertension.Exceptforahalvingoftheriskfordevelopingsevere
hypertension,activeantihypertensivetherapyhadnobeneficialeffects.Theyfurtherreportedthatfetalgrowthrestrictionwasnot
increasedintreatedwomen.Inthisvein,itisalsocontroversialwhetherblockingagentscausefetalgrowthrestrictionifgivenfor
chronichypertension(August,2014Umans,2014).Thus,anysalutaryoradverseeffectsofantihypertensivetherapyseemminimal
atmost.

DelayedDelivery

Upthroughtheearly1990s,itwasthepracticethatallwomenwithseverepreeclampsiaweredeliveredwithoutdelay.Duringthe
past25years,however,anotherapproachforwomenwithpretermseverepreeclampsiahasbeenadvocated.Thisapproachcallsfor
conservativeorexpectantmanagementwiththeaimofimprovingneonataloutcomewithoutcompromisingmaternalsafety.
Aspectsofsuchmanagementalwaysincludecarefuldailyandusuallymorefrequentinpatientmonitoringofthemotherandher
fetus.

ExpectantManagementofPretermSeverePreeclampsia

Theoretically,antihypertensivetherapyhaspotentialapplicationwhenseverepreeclampsiadevelopsbeforeintactneonatalsurvivalis
likely.Suchmanagementiscontroversial,anditmaybedangerous.Inoneofthefirststudies,SibaiandtheMemphisgroup(1985)
attemptedtoprolongpregnancybecauseoffetalimmaturityin60womenwithseverepreeclampsiabetween18and27weeks.The
resultsweredisastrous.Theperinatalmortalityratewas87percent.Althoughnomothersdied,13sufferedplacentalabruption,10
hadeclampsia,threedevelopedrenalfailure,twohadhypertensiveencephalopathy,andoneeachhadanintracerebralhemorrhage
andarupturedhepatichematoma.

Becauseofthesecatastrophicoutcomes,theMemphisgroupredefinedtheirstudycriteriaandperformedarandomizedtrialof
expectantversusaggressivemanagementfor95womenwhohadseverepreeclampsiabutwithmoreadvancedgestationsof28to32
weeks(Sibai,1994).WomenwithHELLPsyndromewereexcludedfromthistrial.Aggressivemanagementincludedglucocorticoid
administrationforfetallungmaturationfollowedbydeliveryin48hours.Expectantlymanagedwomenwereobservedatbedrest
andgiveneitherlabetalolornifedipineorallyiftherewasseverehypertension.Inthisstudy,pregnancywasprolongedforameanof
15.4daysintheexpectantmanagementgroup.Anoverallimprovementinneonataloutcomeswasalsoreported.

Followingtheseexperiences,expectantmanagementbecamemorecommonlypracticed,butwiththecaveatthatwomenwith
HELLPsyndromeorgrowthrestrictedfetuseswereusuallyexcluded.Butinasubsequentfollowupobservationalstudy,the
Memphisgroupcomparedoutcomesin133preeclampticwomenwithand136withoutHELLPsyndromewhopresentedbetween24
and36weeks(Abramovici,1999).Womenweresubdividedintothreestudygroups.Thefirstgroupincludedthosewithcomplete
HELLPsyndrome.ThesecondgroupincludedwomenwithpartialHELLPsyndromedefinedaseitheroneortwobutnotallthree
ofthedefininglaboratoryfindings.ThethirdgroupincludedwomenwhohadseverepreeclampsiawithoutHELLPsyndrome

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laboratoryfindings.Perinataloutcomesweresimilarineachgroup,andimportantly,outcomeswerenotimprovedwith
procrastination.Despitethis,theinvestigatorsconcludedthatwomenwithpartialHELLPsyndromeandthosewithsevere
preeclampsiaalonecouldbemanagedexpectantly.

SibaiandBarton(2007b)reviewedexpectantmanagementofseverepreeclampsiafrom24to34weeks.Morethan1200women
wereincluded,andalthoughtheaveragetimegainedrangedfrom5to10days,thematernalmorbidityrateswereformidable.As
showninTable409,seriouscomplicationsinsomeoftheseandinlaterstudiesincludedplacentalabruption,HELLPsyndrome,
pulmonaryedema,renalfailure,andeclampsia.Moreover,perinatalmortalityratesaveraged90per1000.Fetalgrowthrestriction
wascommon,andinthestudyfromTheNetherlandsbyGanzevoortandassociates(2005a,b),itwasanastounding94percent.
Perinatalmortalityratesaredisproportionatelyhighinthesegrowthrestrictedinfants,butmaternaloutcomeswerenotappreciably
differentfrompregnanciesinwomenwithoutgrowthrestrictedfetuses(Haddad,2007Shear,2005).

TABLE409MaternalandPerinatalOutcomesReportedSince2005withExpectantManagementofSeverePreeclampsiafrom24
to34Weeks
MaternalOutcomes PerinatalOutcomes
(%) (%)
Days Pulm.
Study No. PlacentalAbruption HELLP ARF Eclampsia FGR PMR
Gained Edema
Oettle(2005) 131a 11.6 23 4.6 0.8 2.3 2.3 NS 13.8
Shear(2005) 155 5.3 5.8 27 3.9 NS 1.9 62 3.9
Ganzevoort(2005a,
216 11 1.8 18 3.6 NS 1.8 94 18
b)
Sarsam(2008) 35 9.2 5.7 11 2.9 2.9 18 31 2.8
Bombrys(2009) 66 5 11 8 9 3 0 27 1.5
AbdelHady(2010) 211 12 3.3 7.6 0.9 6.6 0.9 NS 48
VigilDeGracia
131 10.3 7.6 14 1.5 4.5 0.8 22 8.7
(2013)
2.3 1.5
Range 945 512 1.823 4.627 0.93.9 0.918 2794
6.6 48

aIncludesonematernaldeath.

ARF=acuterenalfailureEGA=estimatedgestationalageFGR=fetalgrowthrestrictionHELLP=hemolysis,elevatedliver
enzymelevels,lowplateletcountsyndromeNS=notstatedPMR=perinatalmortalityratePulm.=pulmonary.

TheMEXPRELatinStudywasamulticentertrialthatrandomlyassigned267womenwithseverepreeclampsiaat28to32weeksto
promptdeliveryortoexpectantmanagement(VigilDeGracia,2013).Theperinatalmortalityrateapproximated9percentineach
group,andtheseinvestigatorsfoundnoimprovementsincompositeneonatalmorbiditywithexpectantmanagement.Ontheother
hand,fetalgrowthrestriction22versus9percentandplacentalabruption7.6versus1.5percentweresignificantlyhigherin
thegroupmanagedexpectantly.

Barberandassociates(2009)conducteda10yearreviewof3408womenwithseverepreeclampsiafrom24to32weeks.Theyfound
thatincreasinglengthsofantepartumhospitalstayswereassociatedwithslightbutsignificantlyincreasedratesofmaternaland
neonatalmorbidity.

ExpectantManagementofMidtrimesterSeverePreeclampsia

Severalsmallstudieshavefocusedonexpectantmanagementofseverepreeclampsiasyndromebefore28weeks.Intheirreview,
Bombrysandcoworkers(2008)foundeightsuchstudiesthatincludednearly200womenwithseverepreeclampsiawithanonset<
26completedweeks.Maternalcomplicationswerecommon.Becausetherewerenoneonatalsurvivorsinwomenpresentingbefore
23weeks,theTaskForceoftheAmericanCollegeofObstetriciansandGynecologists(2013b)recommendspregnancytermination.
Forwomenwithslightlymoreadvancedpregnancies,however,thedecisionislessclear.Forexample,at23weeksgestation,the
perinatalsurvivalratewas18percent,butlongtermperinatalmorbidityisyetunknown.Forwomenwithpregnanciesat24to26
weeks,perinatalsurvivalapproached60percent,anditaveragedalmost90percentforthoseat26weeks.

Therehavebeenatleastfivestudiespublishedsince2005ofwomenwithseveremidtrimesterpreeclampsiawhoweremanaged
expectantly(AbdelHady,2010Belghiti,2011Bombrys,2008Budden,2006GauglerSenden,2006).Maternalcomplications
developedin60percent,andtherewasonedeath.Perinatalmortalitywas65percent.Atthistime,therearenocomparativestudies
attestingtotheperinatalbenefitsofsuchexpectanttreatmentversusearlydeliveryinthefaceofseriousmaternalcomplicationsthat
approach50percent.

GlucocorticoidsforLungMaturation

Inattemptstoenhancefetallungmaturation,glucocorticoidshavebeenadministeredtowomenwithseverehypertensionwhoare
remotefromterm.Treatmentdoesnotseemtoworsenmaternalhypertension,andadecreaseintheincidenceofrespiratorydistress
andimprovedfetalsurvivalhasbeencited.Thatsaid,thereisonlyonerandomizedtrialofcorticosteroidsgiventohypertensive
womenforfetallungmaturation.Thistrial,byAmorimandcolleagues(1999),included218womenwithseverepreeclampsia

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between26and34weekswhowererandomlyassignedtobetamethasoneorplaceboadministration.Neonatalcomplications,
includingrespiratorydistress,intraventricularhemorrhage,anddeath,weredecreasedsignificantlywhenbetamethasonewasgiven
comparedwithplacebo.Ontheheavilyweightednegativeside,thereweretwomaternaldeathsand18stillbirths.Weaddthese
findingstobuttressourunenthusiasticacceptanceofattemptstoprolonggestationinmanyofthesewomen(Alexander,2014
Bloom,2003).

CorticosteroidstoAmeliorateHELLPSyndrome

Almost30yearsago,Thiagarajahandassociates(1984)suggestedthatglucocorticoidsmightaidtreatmentofthelaboratory
abnormalitiesassociatedwithHELLPsyndrome.Subsequently,Tompkins(1999)andOBrien(2002)andtheircolleaguesreported
lessthansalutaryeffects.Martinandcoworkers(2003)reviewedobservationaloutcomesofalmost500suchwomentreatedattheir
institutionandreportedsalutaryresultswithtreatment.Unfortunately,theirsubsequentrandomizedtrialcomparedtwo
corticosteroidsanddidnotincludeanontreatedgroup(Isler,2001).

Sincetheseobservationalstudies,atleasttwoprospectiverandomizedtrialshaveaddressedthisquestion.Fonsecaandassociates
(2005)randomlyassigned132womenwithHELLPsyndrometoeitherdexamethasoneorplaceboadministration.Outcomes
assessedincludeddurationofhospitalization,recoverytimeofabnormallaboratorytestresults,resolutionofclinicalparameters,and
complicationsthatincludedacuterenalfailure,pulmonaryedema,eclampsia,anddeath.Noneofthesewassignificantlydifferent
betweenthetwogroups.Inanotherrandomizedstudy,Katzandcoworkers(2008)assigned105postpartumwomenwithHELLP
syndrometotreatmentwithdexamethasoneorplacebo.TheyanalyzedoutcomessimilartotheFonsecastudyandfoundno
advantagetodexamethasone.ShowninFigure4016arerecoverytimesforplateletcountsandserumaspartateaminotransferase
(AST)levels.Thesetimeswerealmostidenticalinthetwogroups.Forthesereasons,the2013TaskForcedoesnotrecommend
corticosteroidtreatmentforthrombocytopeniawithHELLPsyndrome.Acaveatisthatinwomenwithdangerouslylowplatelet
counts,corticosteroidsmightservetoincreaseplatelets.

Figure4016

Recoverytimesforplateletcountsandserumaspartateaminotransferase(AST)levelsinwomenwithHELLPsyndromeassignedto
receivetreatmentwithdexamethasoneorplacebo.(DatafromKatz,2008.)

ExpectantManagmentRisksversusBenefitsRecommendations

Takenintoto,thesestudiesdonotshowoverwhelmingbenefitscomparedwithrisksforexpectantmanagementofsevere
preeclampsiainthosewithgestationsfrom24to32weeks.TheSocietyforMaternalFetalMedicine(2011)hasdeterminedthatsuch
managementisareasonablealternativeinselectedwomenwithseverepreeclampsiabefore34weeks.TheTaskForceofthe
AmericanCollegeofObstetriciansandGynecologists(2013b)supportsthisrecommendation.AsshowninFigure4017,such
managementcallsforinhospitalmaternalandfetalsurveillancewithdeliverypromptedbyevidenceforworseningsevere
preeclampsiaormaternalorfetalcompromise.Althoughattemptsaremadeforvaginaldeliveryinmostcases,thelikelihoodof
cesareandeliveryincreaseswithdecreasinggestationalage.

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Figure4017

Schematicclinicalmanagementalgorithmforsuspectedseverepreeclampsiaat<34weeks.HELLP=hemolysis,elevatedliver
enzymelevels,lowplateletcountL&D=laboranddeliveryMgSO4=magnesiumsulfateUOP=urineoutput.(Adaptedfromthe
SocietyforMaternalFetalMedicine,2011.)

Ourviewismoreconservative.Undoubtedly,theoverridingreasontoterminatepregnancieswithseverepreeclampsiaismaternal
safety.Therearenodatatosuggestthatexpectantmanagementisbeneficialforthemother.Indeed,itseemsobviousthatadelayto
prolonggestationinwomenwithseverepreeclampsiamayhaveseriousmaternalconsequencessuchasthoseshowninTable409.
Notably,placentalabruptiondevelopsinupto20percent,andpulmonaryedemainasmanyas4percent.Moreover,thereare
substantiverisksforeclampsia,cerebrovascularhemorrhage,andespeciallymaternaldeath.Theseobservationsareevenmore
pertinentwhenconsideredwiththeabsenceofconvincingevidencethatperinataloutcomesaremarkedlyimprovedbytheaverage
prolongationofpregnancyofabout1week.Ifundertaken,thecaveatsthatmandatedeliveryshowninTable4010shouldbestrictly
heeded.

TABLE4010IndicationsforDeliveryinWomen<34WeeksGestationManagedExpectantly
CorticosteroidTherapyforLungMaturationaandDeliveryafterMaternalStabilization:
Uncontrolledseverehypertension
Eclampsia
Pulmonaryedema
Placentalabruption
Disseminatedintravascularcoagulation
Nonreassuringfetalstatus
Fetaldemise
CorticosteroidTherapyforLungMaturationDelayDelivery48hrIfPossible:
Pretermrupturedmembranesorlabor
Thrombocytopenia<100,000/L
Hepatictransaminaselevelstwiceupperlimitofnormal
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Fetalgrowthrestriction
Oligohydramnios
ReversedenddiastolicDopplerflowinumbilicalartery
Worseningrenaldysfunction

aInitialdoseonly,donotdelaydelivery.

FromtheSocietyforMaternalFetalMedicine,2011,andtheTaskForceoftheAmericanCollegeofObstetriciansand
Gynecologists,2013b.

Eclampsia

Preeclampsiacomplicatedbygeneralizedtonicclonicconvulsionsappreciablyincreasestherisktobothmotherandfetus.Mattar
andSibai(2000)describedoutcomesin399consecutivewomenwitheclampsiafrom1977through1998.Majormaternal
complicationsincludedplacentalabruption10percent,neurologicaldeficits7percent,aspirationpneumonia7percent,
pulmonaryedema5percent,cardiopulmonaryarrest4percent,andacuterenalfailure4percent.Moreover,1percentofthese
womendied.

Europeanmaternityunitsalsoreportexcessivematernalandperinatalmorbidityandmortalityrateswitheclampsia.Inareportfrom
Scandinavia,Andersgaardandassociates(2006)described232womenwitheclampsia.Althoughtherewasbutasinglematernal
death,athirdofthewomenexperiencedmajorcomplicationsthatincludedHELLPsyndrome,renalfailure,pulmonaryedema,
pulmonaryembolism,andstroke.TheUnitedKingdomObstetricSurveillanceSystem(UKOSS)auditreportedbyKnight(2007)
describednomaternaldeathsin214eclampticwomen,butfivewomenexperiencedcerebralhemorrhage.InTheNetherlands,there
werethreematernaldeathsamong222eclampticwomen(Zwart,2008).FromDublin,Akkawiandcoworkers(2009)reportedfour
maternaldeathsamong247eclampticwomen(Akkawi,2009).DatafromAustraliaaresimilar(Thornton,2013).Thus,indeveloped
countries,thematernalmortalityrateapproximates1percentinwomenwitheclampsia.Inperspective,thisisathousandfold
increaseabovetheoverallmaternaldeathratesforthesecountries.

Almostwithoutexceptionbutattimesunnoticedpreeclampsiaprecedestheonsetofeclampticconvulsions.Dependingon
whetherconvulsionsappearbefore,during,orafterlabor,eclampsiaisdesignatedasantepartum,intrapartum,orpostpartum.
Eclampsiaismostcommoninthelasttrimesterandbecomesincreasinglyfrequentastermapproaches.Inmorerecentyears,the
incidenceofpostpartumeclampsiahasrisen.Thisispresumablyrelatedtoimprovedaccesstoprenatalcare,earlierdetectionof
preeclampsia,andprophylacticuseofmagnesiumsulfate(Chames,2002).Importantly,otherdiagnosesshouldbeconsideredin
womenwithconvulsionsmorethan48hourspostpartumorinwomenwithfocalneurologicaldeficits,prolongedcoma,oratypical
eclampsia(Sibai,2009,2012).

ImmediateManagementofSeizure

Eclampticseizuresmaybeviolent,andthewomanmustbeprotected,especiallyherairway.Soforcefularethemuscularmovements
thatthewomanmaythrowherselfoutofherbed,andifnotprotected,hertongueisbittenbytheviolentactionofthejaws(Fig.40
18).Thisphase,inwhichthemusclesalternatelycontractandrelax,maylastapproximatelyaminute.Gradually,themuscular
movementsbecomesmallerandlessfrequent,andfinallythewomanliesmotionless.Afteraseizure,thewomanispostictal,butin
some,acomaofvariabledurationensues.Whentheconvulsionsareinfrequent,thewomanusuallyrecoverssomedegreeof
consciousnessaftereachattack.Asthewomanarouses,asemiconsciouscombativestatemayensue.Inseverecases,comapersists
fromoneconvulsiontoanother,anddeathmayresult.Inrareinstances,asingleconvulsionmaybefollowedbycomafromwhich
thewomanmayneveremerge.Asarule,however,deathdoesnotoccuruntilafterfrequentconvulsions.Finallyandalsorarely,
convulsionscontinueunabatedstatusepilepticusandrequiredeepsedationandevengeneralanesthesiatoobviateanoxic
encephalopathy.

Figure4018

Hematomaoftonguefromlacerationduringaneclampticconvulsion.Thrombocytopeniamayhavecontributedtothebleeding.

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Respirationsafteraneclampticconvulsionareusuallyincreasedinrateandmayreach50ormoreperminuteinresponseto
hypercarbia,lacticacidemia,andtransienthypoxia.Cyanosismaybeobservedinseverecases.Highfeverisagravesignasitlikely
emanatesfromcerebrovascularhemorrhage.

Proteinuriaisusually,butnotalways,presentasdiscussedonIndicatorsofPreeclampsiaSeverity.Urineoutputmaybediminished
appreciably,andoccasionallyanuriadevelops.Theremaybehemoglobinuria,buthemoglobinemiaisobservedrarely.Often,as
showninFigure4019,peripheralandfacialedemaispronounced,butitmayalsobeabsent.

Figure4019

Severeedemainayoungnulliparawithantepartumpreeclampsia.(PhotographcontributedbyDr.NidhiShah.)

Aswithseverepreeclampsia,anincreaseinurinaryoutputafterdeliveryisusuallyanearlysignofimprovement.Ifthereisrenal
dysfunction,serumcreatininelevelsshouldbemonitored.Proteinuriaandedemaordinarilydisappearwithinaweekpostpartum.In
mostcases,bloodpressurereturnstonormalwithinafewdaysto2weeksafterdelivery(Berks,2009).Assubsequentlydiscussed,
thelongerhypertensionpersistspostpartumandthemoresevereitis,themorelikelyitisthatthewomanalsohaschronicvascular
disease(Podymow,2010).

Inantepartumeclampsia,labormaybeginspontaneouslyshortlyafterconvulsionsensueandmayprogressrapidly.Iftheconvulsions
occurduringlabor,contractionsmayincreaseinfrequencyandintensity,andthedurationoflabormaybeshortened.Becauseof
maternalhypoxemiaandlacticacidemiacausedbyconvulsions,itisnotunusualforfetalbradycardiatofollowaseizure(Fig.40
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20).Bradycardiausuallyrecoverswithin3to5minutes.Ifitpersistsmorethanabout10minutes,however,thenanothercausesuch
asplacentalabruptionorimminentdeliverymustbeconsidered.

Figure4020

Fetalheartratetracingshowsfetalbradycardiafollowinganintrapartumeclampticconvulsion.Bradycardiaresolvedandbeatto
beatvariabilityreturnedapproximately5minutesfollowingtheseizure.

Pulmonaryedemamayfollowshortlyaftereclampticconvulsionsoruptoseveralhourslater.Thisusuallyiscausedbyaspiration
pneumonitisfromgastriccontentinhalationduringvomitingthatfrequentlyaccompaniesconvulsions.Insomewomen,pulmonary
edemamaybecausedbyventricularfailurefromincreasedafterloadthatmayresultfromseverehypertensionandfurtheraggravated
byvigorousintravenousfluidadministration(Dennis,2012b).Suchpulmonaryedemafromventricularfailureismorecommonin
morbidlyobesewomenandinthosewithpreviouslyunappreciatedchronichypertension.

Occasionally,suddendeathoccurssynchronouslywithaneclampticconvulsion,oritfollowsshortlythereafter.Mostofteninthese
cases,deathresultsfromamassivecerebralhemorrhage(seeFig.4011).Hemiplegiamayresultfromsublethalhemorrhage.
CerebralhemorrhagesaremorelikelyinolderwomenwithunderlyingchronichypertensionasdiscussedonManagementofSevere
Hypertension.Rarely,theymaybeduetoarupturedcerebralberryaneurysmorarteriovenousmalformation(Witlin,1997a).

Inapproximately10percentofwomen,somedegreeofblindnessfollowsaseizure.Thecausesofblindnessorimpairedvisionare
discussedonNeuroimagingStudies.Blindnesswithseverepreeclampsiawithoutconvulsionsisusuallyduetoretinaldetachment
(VigilDeGracia,2011).Conversely,blindnesswitheclampsiaisalmostalwaysduetooccipitallobeedema(Cunningham,1995).In
bothinstances,however,theprognosisforreturntonormalfunctionisgoodandisusuallycompletewithin1to2weekspostpartum.

Upto5percentofwomenwitheclampsiahavesubstantivelyalteredconsciousness,includingpersistentcoma,followingaseizure.
Thisisduetoextensivecerebraledema,andtranstentorialherniationmaycausedeathasdiscussedonNeuroimagingStudies
(Cunningham,2000).

Rarely,eclampsiaisfollowedbypsychosis,andthewomanbecomesviolent.Thismaylastforseveraldaysto2weeks,butthe
prognosisforreturntonormalfunctionisgood,providedtherewasnopreexistingmentalillness.Itispresumedtobesimilarto
postpartumpsychosisdiscussedindetailinChapter61(AnxietyDisorders).Antipsychoticmedicationshaveprovedeffectiveinthe
fewcasesofposteclampsiapsychosistreatedatParklandHospital.

DifferentialDiagnosis

Generally,eclampsiaismorelikelytobediagnosedtoofrequentlyratherthanoverlooked.Epilepsy,encephalitis,meningitis,brain
tumor,neurocysticercosis,amnionicfluidembolism,postduralpuncturecephalgia,andrupturedcerebralaneurysmduringlate
pregnancyandthepuerperiummaysimulateeclampsia.Untilothersuchcausesareexcluded,however,allpregnantwomenwith
convulsionsshouldbeconsideredtohaveeclampsia.

ManagementofEclampsia

Ithasbeenlongrecognizedthatmagnesiumsulfateishighlyeffectiveinpreventingconvulsionsinwomenwithpreeclampsiaandin
stoppingtheminthosewitheclampsia.Inhisreview,Chesley(1978)citedobservationaldatabyPritchardandcolleagues(1955,
1975)fromParklandHospitalandfromhisowninstitution,KingsCountyHospitalinBrooklyn.Atthattime,mosteclampsia
regimensusedintheUnitedStatesadheredtoasimilarphilosophystillinusetoday,thetenetsofwhichincludethefollowing:

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1.Controlofconvulsionsusinganintravenouslyadministeredloadingdoseofmagnesiumsulfatethatisfollowedbya
maintenancedose,usuallyintravenous,ofmagnesiumsulfate

2.Intermittentadministrationofanantihypertensivemedicationtolowerbloodpressurewheneveritisconsidereddangerously
high

3.Avoidanceofdiureticsunlessthereisobviouspulmonaryedema,limitationofintravenousfluidadministrationunlessfluid
lossisexcessive,andavoidanceofhyperosmoticagents

4.Deliveryofthefetustoachievearemissionofpreeclampsia.

MagnesiumSulfatetoControlConvulsions

Inmoreseverecasesofpreeclampsiaandineclampsia,magnesiumsulfateadministeredparenterallyisaneffectiveanticonvulsant
thatavoidsproducingcentralnervoussystemdepressionineitherthemotherortheinfant.Itmaybegivenintravenouslyby
continuousinfusionorintramuscularlybyintermittentinjection(Table4011).Thedosagesforseverepreeclampsiaarethesameas
foreclampsia.Becauselaboranddeliveryisamorelikelytimeforconvulsionstodevelop,womenwithpreeclampsiaeclampsia
usuallyaregivenmagnesiumsulfateduringlaborandfor24hourspostpartum.

TABLE4011MagnesiumSulfateDosageScheduleforSeverePreeclampsiaandEclampsia
ContinuousIntravenous(IV)Infusion
Give4to6gloadingdoseofmagnesiumsulfatedilutedin100mLofIVfluidadministeredover1520min
Begin2g/hrin100mLofIVmaintenanceinfusion.Somerecommend1g/hr
Monitorformagnesiumtoxicity:
Assessdeeptendonreflexesperiodically
Somemeasureserummagnesiumlevelat46hrandadjustinfusiontomaintainlevelsbetween4and7mEq/L(4.8to8.4mg/dL)
Measureserummagnesiumlevelsifserumcreatinine1.0mg/dL
Magnesiumsulfateisdiscontinued24hrafterdelivery
IntermittentIntramuscularInjections
Give4gofmagnesiumsulfate(MgSO47H2OUSP)asa20%solutionintravenouslyataratenottoexceed1g/min
Followpromptlywith10gof50%magnesiumsulfatesolution,onehalf(5g)injecteddeeplyintheupperouterquadrantofeach
buttockthrougha3inchlong20gaugeneedle.(Additionof1.0mLof2%lidocaineminimizesdiscomfort.)Ifconvulsionspersist
after15min,giveupto2gmoreintravenouslyasa20%solutionataratenottoexceed1g/min.Ifthewomanislarge,upto4g
maybegivenslowly
Every4hrthereafter,give5gofa50%solutionofmagnesiumsulfateinjecteddeeplyintheupperouterquadrantofalternate
buttocks,butonlyafterensuringthat:
Thepatellarreflexispresent,
Respirationsarenotdepressed,and
Urineoutputtheprevious4hrexceeded100mL
Magnesiumsulfateisdiscontinued24hrafterdelivery

Magnesiumsulfateisalmostuniversallyadministeredintravenously.Inmostunits,theintramuscularroutehasbeenabandoned.Of
concern,magnesiumsulfatesolutions,althoughinexpensivetoprepare,arenotreadilyavailableinallpartsofthedevelopingworld.
Andevenwhenthesolutionsareavailable,thetechnologytoinfusethemmaynotbe.Therefore,itshouldnotbeoverlookedthatthe
drugcanbeadministeredintramuscularlyandthatthisrouteisaseffectiveasintravenousadministration(Salinger,2013).Intwo
reportsfromIndia,intramuscularregimenswerenearlyequivalentinpreventingrecurrentconvulsionsandmaternaldeathsinwomen
witheclampsia(Chowdhury,2009Jana,2013).TheseobservationscomportwithearlieronesfromParklandHospitalasdescribed
byPritchardandcolleagues(1975,1984).

Magnesiumsulfateisnotgiventotreathypertension.Basedonseveralstudiescitedsubsequentlyandextensiveclinicalobservations,
magnesiummostlikelyexertsaspecificanticonvulsantactiononthecerebralcortex.Typically,themotherstopsconvulsingafterthe
initial4gloadingdose.Byanhourortwo,sheregainsconsciousnesssufficientlytobeorientedtoplaceandtime.

ThemagnesiumsulfatedosagespresentedinTable4011usuallyresultinplasmamagnesiumlevelsillustratedinFigure4021.
Whenmagnesiumsulfateisgiventoarresteclampticseizures,10to15percentofwomenwillhaveasubsequentconvulsion.Ifso,
anadditional2gdoseofmagnesiumsulfateina20percentsolutionisslowlyadministeredintravenously.Inasmallwoman,this
additional2gdosemaybeusedonce,butitcanbegiventwiceifneededinalargerwoman.Inonly5of245womenwitheclampsia
atParklandHospitalwasitnecessarytousesupplementaryanticonvulsantmedicationtocontrolconvulsions(Pritchard,1984).For
these,anintravenousbarbiturateisgivenslowly.Midazolamorlorazepammaybegiveninasmallsingledose,butprolongeduseis
avoidedbecauseitisassociatedwithahighermortalityrate(RoyalCollegeofObstetriciansandGynaecologists,2006).

Figure4021

ComparisonofserummagnesiumlevelsinmEq/Lfollowinga4gintravenousloadingdoseofmagnesiumsulfateandthen
maintainedbyeitheranintramuscularorcontinuinginfusion.Multiplyby1.2toconvertmEq/Ltomg/dL.(DatafromSibai,1984.)

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Maintenancemagnesiumsulfatetherapyiscontinuedfor24hoursafterdelivery.Foreclampsiathatdevelopspostpartum,
magnesiumsulfateisadministeredfor24hoursaftertheonsetofconvulsions.EhrenbergandMercer(2006)studiedabbreviated
postpartummagnesiumadministrationin200womenwithmildpreeclampsia.Of101womenrandomizedto12hourtreatment,
sevenhadworseningpreeclampsia,andtreatmentwasextendedto24hours.Noneofthese101womenandnoneoftheothercohort
of95giventhe24hourmagnesiuminfusiondevelopedeclampsia.Thisabbreviatedregimenneedsfurtherstudybeforebeing
routinelyadministeredforseverepreeclampsiaoreclampsia.

PharmacologyandToxicology

MagnesiumsulfateUSPisMgSO47H2OandnotsimpleMgSO4.Itcontains8.12mEqper1g.Parenterallyadministered
magnesiumisclearedalmosttotallybyrenalexcretion,andmagnesiumintoxicationisunusualwhentheglomerularfiltrationrateis
normaloronlyslightlydecreased.Adequateurineoutputusuallycorrelateswithpreservedglomerularfiltrationrates.Thatsaid,
magnesiumexcretionisnoturineflowdependent,andurinaryvolumeperunittimedoesnot,perse,predictrenalfunction.Thus,
serumcreatininelevelsmustbemeasuredtodetectadecreasedglomerularfiltrationrate.

Eclampticconvulsionsarealmostalwayspreventedorarrestedbyplasmamagnesiumlevelsmaintainedat4to7mEq/L,4.8to8.4
mg/dL,or2.0to3.5mmol/L.Althoughlaboratoriestypicallyreporttotalmagnesiumlevels,freeorionizedmagnesiumistheactive
moietyforsuppressingneuronalexcitability.Taberandassociates(2002)foundpoorcorrelationbetweentotalandionizedlevels.
Furtherstudiesarenecessarytodetermineifeithermeasurementprovidesasuperiormethodforsurveillance.

Aftera4gintravenousloadingdoseinnonobesewomen,magnesiumlevelsobservedwiththeintramuscularregimenandthose
observedwiththemaintenanceinfusionof2g/hraresimilar(seeFig.4021).Theobesityepidemichasaffectedtheseobservations.
Tudelaandcolleagues(2013)reportedourobservationsfromParklandHospitalwithmagnesiumadministrationtoobesewomen.
Morethan60percentofwomenwhosebodymassindex(BMI)exceeded30kg/m2andwhowerereceivingthe2g/hrdosehad
subtherapeuticlevelsat4hours.Thus,40percentofobesewomenwouldrequire3g/hrtomaintaineffectiveplasmalevels.That
said,currentlymostdonotrecommendroutinemagnesiumlevelmeasurements(AmericanCollegeofObstetriciansand
Gynecologists,2013bRoyalCollegeofObstetriciansandGynaecologists,2006).

Patellarreflexesdisappearwhentheplasmamagnesiumlevelreaches10mEq/Labout12mg/dLpresumablybecauseofa
curariformaction.Thissignservestowarnofimpendingmagnesiumtoxicity.Whenplasmalevelsriseabove10mEq/L,breathing
becomesweakened.At12mEq/Lorhigherlevels,respiratoryparalysisandrespiratoryarrestfollow.Somjenandcoworkers(1966)
inducedmarkedhypermagnesemiainthemselvesbyintravenousinfusionandachievedplasmalevelsupto15mEq/L.Predictably,at
suchhighplasmalevels,respiratorydepressiondevelopedthatnecessitatedmechanicalventilation,butdepressionofthesensorium
wasnotdramaticaslongashypoxiawasprevented.

Treatmentwithcalciumgluconateorcalciumchloride,1gintravenously,alongwithwithholdingfurthermagnesiumsulfate,usually
reversesmildtomoderaterespiratorydepression.Oneoftheseagentsshouldbereadilyavailablewhenevermagnesiumisbeing
infused.Unfortunately,theeffectsofintravenouslyadministeredcalciummaybeshortlivedifthereisasteadystatetoxiclevel.For
severerespiratorydepressionandarrest,prompttrachealintubationandmechanicalventilationarelifesaving.Directtoxiceffectson
themyocardiumfromhighlevelsofmagnesiumareuncommon.Itappearsthatcardiacdysfunctionassociatedwithmagnesiumis

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duetorespiratoryarrestandhypoxia.Withappropriateventilation,cardiacactionissatisfactoryevenwhenplasmamagnesiumlevels
areexceedinglyhigh(McCubbin,1981Morisaki,2000).

Becausemagnesiumisclearedalmostexclusivelybyrenalexcretion,thedosagesdescribedwillbecomeexcessiveifglomerular
filtrationissubstantiallydecreased.Theinitial4gloadingdoseofmagnesiumsulfatecanbesafelyadministeredregardlessofrenal
function.Itisimportanttoadministerthestandardloadingdoseandnottoreduceitunderthemistakenconceptionthatdiminished
renalfunctionrequiresit.Thisisbecauseafterdistribution,aloadingdoseachievesthedesiredtherapeuticlevel,andtheinfusion
maintainsthesteadystatelevel.Thus,onlythemaintenanceinfusionrateshouldbealteredwithdiminishedglomerularfiltration
rate.Renalfunctionisestimatedbymeasuringplasmacreatinine.Wheneverplasmacreatininelevelsare>1.0mg/mL,serum
magnesiumlevelsaremeasuredtoguidetheinfusionrate.Withsevererenaldysfunction,onlytheloadingdoseofmagnesiumsulfate
isrequiredtoproduceasteadystatetherapeuticlevel.

Acutecardiovasculareffectsofparenteralmagnesiuminwomenwithseverepreeclampsiahavebeenstudiedusingdataobtainedby
pulmonaryandradialarterycatheterization.Aftera4gintravenousdoseadministeredover15minutes,meanarterialpressurefell
slightly,accompaniedbya13percentincreaseincardiacindex(Cotton,1986b).Thus,magnesiumdecreasedsystemicvascular
resistanceandmeanarterialpressure.Atthesametime,itincreasedcardiacoutputwithoutevidenceofmyocardialdepression.These
findingswerecoincidentalwithtransientnauseaandflushing,andthecardiovasculareffectspersistedforonly15minutesdespite
continuedmagnesiuminfusion.

Thurnauandassociates(1987)showedthattherewasasmallbuthighlysignificantincreaseintotalmagnesiumconcentrationinthe
cerebrospinalfluidwithmagnesiumtherapy.Themagnitudeoftheincreasewasdirectlyproportionaltothecorrespondingserum
concentration.

Magnesiumisanticonvulsantandneuroprotectiveinseveralanimalmodels.Someproposedmechanismsofactioninclude:(1)
reducedpresynapticreleaseoftheneurotransmitterglutamate,(2)blockadeofglutamatergicNmethyldaspartate(NMDA)
receptors,(3)potentiationofadenosineaction,(4)improvedcalciumbufferingbymitochondria,and(5)blockageofcalciumentry
viavoltagegatedchannels(Arango,2006Wang,2012a).

UterineEffects

Relativelyhighserummagnesiumconcentrationsdepressmyometrialcontractilitybothinvivoandinvitro.Withtheregimen
describedandtheplasmalevelsthatresult,noevidenceofmyometrialdepressionhasbeenobservedbeyondatransientdecreasein
activityduringandimmediatelyaftertheinitialintravenousloadingdose.Levenoandassociates(1998)comparedoutcomesin480
nulliparouswomengivenphenytoinforpreeclampsiawithoutcomesin425preeclampticwomengivenmagnesiumsulfate.
Magnesiumdidnotsignificantlyaltertheneedforoxytocinstimulationoflabor,admissiontodeliveryintervals,orrouteofdelivery.
Similarresultshavebeenreportedbyothers(Atkinson,1995Szal,1999Witlin,1997b).

Themechanismsbywhichmagnesiummightinhibituterinecontractilityarenotestablished.Itisgenerallyassumed,however,that
thesedependonitseffectsonintracellularcalciumasdiscussedindetailinChapter21(Phase4ofParturition:ThePuerperium).
Inhibitionofuterinecontractilityismagnesiumdosedependent,andserumlevelsofatleast8to10mEq/Larenecessarytoinhibit
uterinecontractions(WattMorse,1995).Thislikelyexplainswhytherearefewifanyuterineeffectsseenclinicallywhen
magnesiumsulfateisgivenforpreeclampsia.AndasdiscussedinChapter42(Ritodrine),magnesiumisalsonotconsideredtobean
effectivetocolyticagent.

FetalandNeonatalEffects

Magnesiumadministeredparenterallypromptlycrossestheplacentatoachieveequilibriuminfetalserumandlesssoinamnionic
fluid(Hallak,1993).Levelsinamnionicfluidincreasewithdurationofmaternalinfusion(GortzakUzen,2005).Currentevidence
supportstheviewthatmagnesiumsulfatehassmallbutsignificanteffectsonthefetalheartratepatternspecificallybeattobeat
variability.Hallakandcoworkers(1999)comparedaninfusionofmagnesiumsulfatewithasalineinfusion.Theseinvestigators
reportedthatmagnesiumwasassociatedwithasmallandclinicallyinsignificantdecreaseinvariability.Similarly,inaretrospective
study,Duffyandassociates(2012)reportedalowerheartratebaselinethatwaswithinthenormalrangedecreasedvariabilityand
fewerprolongeddecelerations.Theynotednoadverseoutcomes.

Overall,maternalmagnesiumtherapyappearssafeforperinates.Forexample,arecentMFMUNetworkstudyofmorethan1500
exposedpretermneonatesfoundnoassociationbetweentheneedforneonatalresuscitationandcordbloodmagnesiumlevels
(Johnson,2012).Still,thereareafewneonataladverseeventsassociatedwithitsuse.InaParklandHospitalstudyof6654mostly
termexposednewborns,6percenthadhypotonia(AbbassiGhanavati,2012).Inaddition,exposedneonateshadlower1and5
minuteApgarscores,ahigherintubationrate,andmoreadmissionstothespecialcarenursery.Thestudyshowedthatneonatal
depressionoccursonlyifthereisseverehypermagnesemiaatdelivery.

Observationalstudieshavesuggestedaprotectiveeffectofmagnesiumagainstthedevelopmentofcerebralpalsyinverylow
birthweightinfants(Nelson,1995Schendel,1996).Atleastfiverandomizedtrialshavealsoassessedneuroprotectiveeffectsin
pretermnewborns.ThesefindingsarediscussedindetailinChapter42(MagnesiumSulfateforFetalNeuroprotection).Nguyenand
colleagues(2013)expandedthispossibilitytoincludetermnewbornneuroprotection.TheyperformedaCochraneDatabasereview
tocomparetermneonataloutcomeswithandwithoutexposuretoperipartummagnesiumtherapyandreportedthattherewere
insufficientdatatodrawconclusions.

Finally,asdiscussedinChapter42(Ritodrine),longtermuseofmagnesium,givenforseveraldaysfortocolysis,hasbeenassociated
withneonatalosteopenia(AmericanCollegeofObstetriciansandGynecologists,2013c).

MaternalSafetyandEfficacyofMagnesiumSulfate
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ThemultinationalEclampsiaTrialCollaborativeGroupstudy(1995)involved1687womenwitheclampsiarandomlyallocatedto
differentanticonvulsantregimens.Inonecohort,453womenwererandomlyassignedtobegivenmagnesiumsulfateandcompared
with452givendiazepam.Inasecondcohort,388eclampticwomenwererandomlyassignedtobegivenmagnesiumsulfateand
comparedwith387womengivenphenytoin.Theresultsoftheseandothercomparativestudiesthateachenrolledatleast50women
aresummarizedinTable4012.Inaggregate,magnesiumsulfatetherapywasassociatedwithasignificantlylowerincidenceof
recurrentseizurescomparedwithwomengivenanalternativeanticonvulsant9.7versus23percent.Importantly,thematernaldeath
rateof3.1percentwithmagnesiumsulfatewassignificantlylowerthanthatof4.9percentfortheotherregimens.

TABLE4012RandomizedComparativeTrialsofMagnesiumSulfatewithAnotherAnticonvulsanttoPreventRecurrentEclamptic
Convulsions
RecurrentSeizures MaternalDeaths
Comparison MgSO 4 OtherDrug RR(95% MgSO4 OtherDrug RR(95%
Study
Drug (%) (%) CI) (%) (%) CI)
0.80
Crowther(1990) Diazepam 5/24 7/27 1/24 0/27
(0.292.2)
0.09
Bhalla(1994) Lyticcocktail 1/45 11/45 0/45 2/45
(0.10.68)
0.48 0.5
EclampsiaTrialCollaborativeGroup Phenytoin 60/453 126/452 (0.360.63) 10/388 20/387 (0.241.00)
(1995) Diazepam 22/388 66/387 0.33 17/453 24/452 0.74
(0.210.53) (0.401.36)
88/910 210/911 0.41 28/910 45/911 0.62
Totals
(9.7) (23) (0.320.51) (3.1) (4.9) (0.390.99)

DataadaptedfromAlexander,2014.

MagnesiumsafetyandtoxicitywasrecentlyreviewedbySmithandcoworkers(2013).Inmorethan9500treatedwomen,theoverall
rateofabsentpatellartendonreflexeswas1.6percentrespiratorydepression1.3percentandcalciumgluconateadministration0.2
percent.Theyreportedonlyonematernaldeathduetomagnesiumtoxicity.Ouranecdotalexperiencesaresimilarintheestimated
50yearsofitsuseinmorethan40,000women,therehasbeenonlyonematernaldeathfromanoverdose(Pritchard,1984).

ManagementofSevereHypertension

Dangeroushypertensioncancausecerebrovascularhemorrhageandhypertensiveencephalopathy,anditcantriggereclamptic
convulsionsinwomenwithpreeclampsia.Othercomplicationsincludehypertensiveafterloadcongestiveheartfailureandplacental
abruption(Clark,2012).

Becauseofthesesequelae,theNationalHighBloodPressureEducationProgramWorkingGroup(2000)andthe2013TaskForce
recommendtreatmenttolowersystolicpressurestoorbelow160mmHganddiastolicpressurestoorbelow110mmHg.Martinand
associates(2005)reportedprovocativeobservationsthathighlighttheimportanceoftreatingsystolichypertension.Theydescribed
28selectedwomenwithseverepreeclampsiawhosufferedanassociatedstroke.Mostofthesewerehemorrhagicstrokes93percent
andallwomenhadsystolicpressures>160mmHgbeforesufferingtheirstroke.Bycontrast,only20percentofthesesame
womenhaddiastolicpressures>110mmHg.Itseemslikelythatatleasthalfofserioushemorrhagicstrokesassociatedwith
preeclampsiaareinwomenwithchronichypertension(Cunningham,2005).Longstandinghypertensionresultsindevelopmentof
CharcotBouchardaneurysmsinthedeeppenetratingarteriesofthelenticulostriatebranchofthemiddlecerebralarteries.These
vesselssupplythebasalganglia,putamen,thalamus,andadjacentdeepwhitematter,aswellastheponsanddeepcerebellum.These
uniqueaneurysmalweakeningspredisposethesesmallarteriestoruptureduringsuddenhypertensiveepisodes(Chap.50,Pregnancy
AggravatedHypertensionorSuperimposedPreeclampsia).

AntihypertensiveAgents

Severaldrugsareavailabletorapidlylowerdangerouslyelevatedbloodpressureinwomenwiththegestationalhypertensive
disorders.Thethreemostcommonlyemployedarehydralazine,labetalol,andnifedipine.Foryears,parenteralhydralazinewasthe
onlyoneofthesethreeavailable.Butwhenparenterallabetalolwaslaterintroduced,itwasconsideredtobeequallyeffectivefor
obstetricaluse.Orallyadministerednifedipinehassincethengainedsomepopularityasfirstlinetreatmentforseveregestational
hypertension.

Hydralazine

ThisisprobablystillthemostcommonlyusedantihypertensiveagentintheUnitedStatesfortreatmentofwomenwithsevere
gestationalhypertension.Hydralazineisadministeredintravenouslywitha5mginitialdose,andthisisfollowedby5to10mg
dosesat15to20minuteintervalsuntilasatisfactoryresponseisachieved(AmericanCollegeofObstetriciansandGynecologists,
2012b).Somelimitthetotaldoseto30mgpertreatmentcycle(Sibai,2003).Thetargetresponseantepartumorintrapartumisa
decreaseindiastolicbloodpressureto90to110mmHg.Lowerdiastolicpressuresriskcompromisedplacentalperfusion.
Hydralazinehasprovenremarkablyeffectivetopreventcerebralhemorrhage.Itsonsetofactioncanbeasrapidas10minutes.
Althoughrepeatedadministrationevery15to20minutesmaytheoreticallyleadtoundesirablehypotension,thishasnotbeenour
experiencewhengiveninthese5to10mgincrements.

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AtParklandHospital,between5and10percentofallwomenwithintrapartumhypertensivedisordersaregivenaparenteral
antihypertensiveagent.Mostoften,weusehydralazineasdescribed.Wedonotlimitthetotaldose,andseldomhasasecond
antihypertensiveagentbeenneeded.Weestimatethatnearly6000womenhavebeensotreatedatParklandduringthepast50years.
AlthoughlesspopularinEurope,hydralazineisusedinsomecenters,accordingtotheRoyalCollegeofObstetriciansand
Gynaecologists(2006).AdissentingopinionforfirstlineintrapartumuseofhydralazinewasvoicedbytheVancouvergroupaftera
systematicreview(Magee,2009).Atthesametime,however,Umansandcoworkers(2014)concludedthatobjectiveoutcomedata
didnotsupporttheuseofonedrugoveranother.

Aswithanyantihypertensiveagent,thetendencytogivealargerinitialdoseofhydralazineifthebloodpressureishighermustbe
avoided.Theresponsetoeven5to10mgdosescannotbepredictedbyhypertensionseverity.Thus,ourprotocolistoalways
administer5mgastheinitialdose.AnadverseresponsetoexceedingthisinitialdoseisshowninFigure4022.Thiswomanhad
chronichypertensioncomplicatedbyseveresuperimposedpreeclampsia,andhydralazinewasinjectedmorefrequentlythan
recommended.Herbloodpressuredecreasedinlessthan1hourfrom240270/130150mmHgto110/80mmHg,andfetalheart
ratedecelerationscharacteristicofuteroplacentalinsufficiencybecameevident.Decelerationspersisteduntilherbloodpressurewas
increasedwithrapidcrystalloidinfusion.Insomecases,thisfetalresponsetodiminisheduterineperfusionmaybeconfusedwith
placentalabruptionandmayresultinunnecessaryandpotentiallydangerousemergentcesareandelivery.

Figure4022

Hydralazinewasgivenat5minuteintervalsinsteadof15minuteintervals.Themeanarterialpressuredecreasedfrom180to90mm
Hgwithin1hourandwasassociatedwithfetalbradycardia.Rapidcrystalloidinfusionraisedthemeanpressureto115mmHg,and
thefetusrecovered.

Labetalol

Thiseffectiveintravenousantihypertensiveagentisan1andnonselectiveblocker.Somepreferitsuseoverhydralazinebecause
offewersideeffects(Sibai,2003).AtParklandHospital,wegive10mgintravenouslyinitially.Ifthebloodpressurehasnot
decreasedtothedesirablelevelin10minutes,then20mgisgiven.Thenext10minuteincrementaldoseis40mgandisfollowedby
another40mgifneeded.Ifasalutaryresponseisnotachieved,thenan80mgdoseisgiven.Sibai(2003)recommends20to40mg
every10to15minutesasneededandamaximumdoseof220mgpertreatmentcycle.TheAmericanCollegeofObstetriciansand
Gynecologists(2012b)recommendsstartingwitha20mgintravenousbolus.Ifnoteffectivewithin10minutes,thisisfollowedby
40mg,then80mgevery10minutes.Administrationshouldnotexceeda220mgtotaldosepertreatmentcycle.

HydralazineversusLabetalol

Comparativestudiesofthesetwoantihypertensiveagentsshowequivalentresults(Umans,2014).Inanoldertrial,Mabieand
colleagues(1987)comparedintravenoushydralazinewithlabetalolforbloodpressurecontrolin60peripartumwomen.Labetalol
loweredbloodpressuremorerapidly,andassociatedtachycardiawasminimal.However,hydralazineloweredmeanarterialpressures
tosafelevelsmoreeffectively.Inalatertrial,VigilDeGraciaandassociates(2007)randomlyassigned200severelyhypertensive
womenintrapartumtobegiveneither:(1)intravenoushydralazine5mg,whichcouldbegivenevery20minutesandrepeatedtoa
maximumoffivedoses,or(2)intravenouslabetalol20mginitially,followedby40mgin20minutesandthen80mgevery20
minutesifneededuptoamaximum300mgdose.Maternalandneonataloutcomesweresimilar.Hydralazinecausedsignificantly
morematernaltachycardiaandpalpitations,whereaslabetalolmorefrequentlycausedmaternalhypotensionandbradycardia.Both
drugshavebeenassociatedwithareducedfrequencyoffetalheartrateaccelerations(Cahill,2013).

Nifedipine

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Thiscalciumchannelblockingagenthasbecomepopularbecauseofitsefficacyforcontrolofacutepregnancyrelatedhypertension.
TheNHBPEPWorkingGroup(2000)andtheRoyalCollegeofObstetriciansandGynaecologists(2006)recommenda10mginitial
oraldosetoberepeatedin30minutesifnecessary.Nifedipinegivensublinguallyisnolongerrecommended.Randomizedtrialsthat
comparednifedipinewithlabetalolfoundneitherdrugdefinitivelysuperiortotheother.However,nifedipineloweredbloodpressure
morequickly(Scardo,1999Shekhar,2013Vermillion,1999).

OtherAntihypertensiveAgents

Afewothergenerallyavailableantihypertensiveagentshavebeentestedinclinicaltrialsbutarenotwidelyused(Umans,2014).
Belfortandassociates(1990)administeredthecalciumantagonistverapamilbyintravenousinfusionat5to10mgperhour.Mean
arterialpressurewasloweredby20percent.Belfortandcoworkers(1996,2003)reportedthatnimodipinegiveneitherbycontinuous
infusionororallywaseffectivetolowerbloodpressureinwomenwithseverepreeclampsia.Bolteandcolleagues(1998,2001)
reportedgoodresultsinpreeclampticwomengivenintravenousketanserin,aselectiveserotonergic(5HT2A)receptorblocker.
Nitroprussideornitroglycerineisrecommendedbysomeifthereisnotoptimalresponsetofirstlineagents.Withtheselattertwo
agents,fetalcyanidetoxicitymaydevelopafter4hours.Wehavenothadtheneedforeitherduetoourconsistentsuccesswithfirst
linetreatmentusinghydralazine,labetalol,oracombinationofthetwogiveninsuccession,butneversimultaneously.

Thereareexperimentalantihypertensivedrugsthatmaybecomeusefulforpreeclampsiatreatment.Oneiscalcitoningenerelated
peptide(CGRP),a37aminoacidpotentvasodilator.AnotherisantidigoxinantibodyFab(DIF)directedagainstendogenous
digitalislikefactors,alsocalledcardiotonicsteroids(Bagrov,2008Lam,2013).

Diuretics

Potentloopdiureticscanfurthercompromiseplacentalperfusion.Immediateeffectsincludedepletionofintravascularvolume,which
mostoftenisalreadyreducedcomparedwiththatofnormalpregnancy(BloodVolume).Therefore,beforedelivery,diureticsarenot
usedtolowerbloodpressure(Zeeman,2009Zondervan,1988).Welimitantepartumuseoffurosemideorsimilardrugssolelyto
treatmentofpulmonaryedema.

FluidTherapy

LactatedRingersolutionisadministeredroutinelyattherateof60mLtonomorethan125mLperhourunlessthereisunusualfluid
lossfromvomiting,diarrhea,ordiaphoresis,or,morelikely,excessivebloodlosswithdelivery.Oliguriaiscommonwithsevere
preeclampsia.Thus,coupledwiththeknowledgethatmaternalbloodvolumeislikelyconstrictedcomparedwiththatofnormal
pregnancy,itistemptingtoadministerintravenousfluidsmorevigorously.Butcontrolled,conservativefluidadministrationis
preferredforthetypicalwomanwithseverepreeclampsiawhoalreadyhasexcessiveextracellularfluidthatisinappropriately
distributedbetweenintravascularandextravascularspaces.AsdiscussedonBloodVolume,infusionoflargefluidvolumesenhances
themaldistributionofextravascularfluidandtherebyappreciablyincreasestheriskofpulmonaryandcerebraledema(Dennis,
2012aSciscione,2003Zinaman,1985).Forlaboranalgesiawithneuraxialanalgesia,crystalloidsolutionsareinfusedslowlyin
gradedamounts(Chap.25,TimingofEpiduralPlacement).

PulmonaryEdema

Womenwithseverepreeclampsiaeclampsiawhodeveloppulmonaryedemamostoftendosopostpartum(Cunningham,1986,2012
Zinaman,1985).Withpulmonaryedemaintheeclampticwoman,aspirationofgastriccontents,whichmaybetheresultof
convulsions,anesthesia,oroversedation,shouldbeexcluded.AsdiscussedinChapter47(AcutePulmonaryEdema),therearethree
commoncausesofpulmonaryedemainwomenwithseverepreeclampsiasyndromepulmonarycapillarypermeabilityedema,
cardiogenicedema,oracombinationofthetwo.

Somewomenwithseverepreeclampsiaespeciallyifgivenvigorousfluidreplacementwillhavemildpulmonarycongestionfrom
permeabilityedema(seeFig.406).Thisiscausedbynormalpregnancychangesmagnifiedbythepreeclampsiasyndromeas
discussedinChapter4(CardiovascularSystem).Importantly,plasmaoncoticpressuredecreasesappreciablyinnormalterm
pregnancybecauseofdecreasedserumalbuminconcentration,andoncoticpressurefallsevenmorewithpreeclampsia(Zinaman,
1985).Andbothincreasedextravascularfluidoncoticpressureandincreasedcapillarypermeabilityhavebeendescribedinwomen
withpreeclampsia(Brown,1989ian,1986).

InvasiveHemodynamicMonitoring

Knowledgeconcerningcardiovascularandhemodynamicpathophysiologicalalterationsassociatedwithseverepreeclampsia
eclampsiahasaccruedfromstudiesdoneusinginvasivemonitoringandaflowdirectedpulmonaryarterycatheter(seeFigs.405
and406).ClarkandDildy(2010)havereviewedsuchmonitoringinobstetrics.Twoconditionsfrequentlycitedasindicationsare
preeclampsiaassociatedwitheitheroliguriaorpulmonaryedema.Somewhatironically,itisusuallyvigoroustreatmentoftheformer
thatresultsinmostcasesofthelatter.TheAmericanCollegeofObstetriciansandGynecologists(2013a)recommendsagainst
routineinvasivemonitoring.TheCollegenotesthatsuchmonitoringshouldbereservedforseverelypreeclampticwomenwith
accompanyingseverecardiacdisease,renaldisease,orbothorincasesofrefractoryhypertension,oliguria,andpulmonaryedema.
Analternativenoninvasivehemodynamicmonitoringstrategyhasbeenevaluatedinpreliminarystudies(Moroz,2013).

PlasmaVolumeExpansion

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Becausethepreeclampsiasyndromeisassociatedwithhemoconcentration,attemptstoexpandbloodvolumeseemintuitively
reasonable(Ganzevoort,2004).Thishasledsometoinfusevariousfluids,starchpolymers,albuminconcentrates,orcombinations
thereoftoexpandbloodvolume.Thereare,however,olderobservationalstudiesthatdescribeseriouscomplicationsespecially
pulmonaryedemawithvolumeexpansion(Benedetti,1985LpezLlera,1982Sibai,1987b).Ingeneral,thesestudieswerenot
controlledorevencomparative(Habek,2006).

TheAmsterdamrandomizedstudyreportedbyGanzevoortandcoworkers(2005a,b)wasawelldesignedinvestigationdoneto
evaluatevolumeexpansion.Atotalof216womenwithseverepreeclampsiawereenrolledbetween24and34weeksgestation.The
studyincludedwomenwhosepreeclampsiawascomplicatedbyHELLPsyndrome,eclampsia,orfetalgrowthrestriction.Allwomen
weregivenmagnesiumsulfatetopreventeclampsia,betamethasonetopromotefetalpulmonarymaturity,ketanserinetocontrol
dangeroushypertension,andnormalsalineinfusionsrestrictedonlytodelivermedications.Inthegrouprandomlyassignedto
volumeexpansion,eachwomanwasgiven250mLof6percenthydroxyethylstarchinfusedover4hourstwicedaily.Theirmaternal
andperinataloutcomeswerecomparedwithacontrolgroupandareshowninTable4013.Noneoftheseoutcomeswassignificantly
differentbetweenthetwogroups.Importantly,seriousmaternalmorbidityandasubstantiveperinatalmortalityrateaccompanied
theirexpectantmanagement(seeTable409).

TABLE4013MaternalandPerinatalOutcomesinaRandomizedTrialofPlasmaVolumeExpansionversusSalineInfusionin216
WomenwithSeverePreeclampsiabetween24and34Weeks
Outcomes ControlGroupa(n=105) TreatmentGroupa(n=111)
MaternalOutcomes(%)
Eclampsia(afterenrollment) 1.9 1.8
HELLP(afterenrollment) 19.0 17.0
Pulmonaryedema 2.9 4.5
Placentalabruption 3.8 1.0
PerinatalOutcomes
Fetaldeaths(%) 7 12
Prolongationofpregnancy(mean) 11.6d 6.7d
EGAatdeath(mean) 26.7wk 26.3wk
Birthweight(mean) 625g 640g
Livebirths(%) 93 88
Prolongationofpregnancy(mean) 10.5d 7.4d
EGAatdelivery(mean) 31.6wk 31.4wk
RDS(%) 30 35
Neonataldeath(%) 7.6 8.1
Perinatalmortalityrate(nper1000) 142/1000 207/1000

aAllcomparisonsp>0.05.

EGA=estimatedgestationalageHELLP=hemolysis,elevatedliverenzymelevels,lowplateletcountRDS=respiratorydistress
syndrome.

DatafromGanzevoort,2005a,b.

NeuroprophylaxisPreventionofSeizures

Therehavebeenseveralrandomizedtrialsdesignedtotesttheefficacyofseizureprophylaxisforwomenwithgestational
hypertension,withorwithoutproteinuria.Inmostofthese,magnesiumsulfatewascomparedwithanotheranticonvulsantorwitha
placebo.Inallstudies,magnesiumsulfatewasreportedtobesuperiortothecomparatoragenttopreventeclampsia.Fourofthe
largerstudiesaresummarizedinTable4014.InthestudyfromParklandHospital,Lucasandcolleagues(1995)reportedthat
magnesiumsulfatetherapywassuperiortophenytointopreventeclampticseizuresinwomenwithgestationalhypertensionand
preeclampsia.Belfortandcoworkers(2003)comparedmagnesiumsulfateandnimodipineacalciumchannelblockerwithspecific
cerebralvasodilatoractivityforeclampsiaprevention.Inthisunblindedrandomizedtrialinvolving1650womenwithsevere
preeclampsia,therateofeclampsiawasmorethanthreefoldhigherforwomenallocatedtothenimodipinegroup2.6versus0.8
percent.

TABLE4014RandomizedComparativeTrialsofProphylaxiswithMagnesiumSulfateandPlaceboorAnotherAnticonvulsantin
WomenwithGestationalHypertension
No.withSeizures/TotalNo.Treated(%)
Study/Inclusions MagnesiumSulfate Control Comparisona
Lucasetal(1995) Phenytoin
Gestationalhypertensionb 0/1049(0) 10/1089(0.9) p<0.001
Coetzeeetal(1998) Placebo
RR=0.09
Severepreeclampsia 1/345(0.3) 11/340(3.2)
(0.10.69)

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No.withSeizures/TotalNo.Treated(%)
Study/Inclusions MagnesiumSulfate Control Comparisona
MagpieTrial(2002)c Placebo
RR=0.42
Severepreeclampsia 40/5055(0.8) 96/5055(1.9)
(0.260.60)
Belfortetal(2003) Nimodipine
RR=0.33
Severepreeclampsia 7/831(0.8) 21/819(2.6)
(0.140.77)

aAllcomparisonssignificantp<0.05.

bIncludedwomenwithandwithoutproteinuriaandthosewithallseveritiesofpreeclampsia.

cMagpieTrialCollaborationGroup,2002.

ThelargestcomparativestudywastheentitledMAGnesiumSulfateforPreventionofEclampsiaandreportedbytheMagpieTrial
CollaborationGroup(2002).Morethan10,000womenwithseverepreeclampsiafrom33countrieswererandomlyallocatedto
treatmentwithmagnesiumsulfateorplacebo.Womengivenmagnesiumhada58percentsignificantlylowerriskofeclampsiathan
thosegivenplacebo.Smythandassociates(2009)providedfollowupdataofinfantsborntothesemothersgivenmagnesiumsulfate.
Atapproximately18months,childbehaviordidnotdifferinthoseexposedcomparedwiththosenotexposedtomagnesiumsulfate.

WhoShouldBeGivenMagnesiumSulfate?

Magnesiumwillpreventproportionatelymoreseizuresinwomenwithcorrespondinglyworsedisease.Aspreviouslydiscussed,
however,severityisdifficulttoquantify,andthusitisdifficulttodecidewhichindividualwomanmightbenefitmostfrom
neuroprophylaxis.The2013TaskForcerecommendsthatwomenwitheithereclampsiaorseverepreeclampsiashouldbegiven
magnesiumsulfateprophylaxis.Again,criteriathatestablishseverityarenottotallyuniform(seeTable402).Atthesametime,
however,the2013TaskForcesuggeststhatallwomenwithmildpreeclampsiadonotneedmagnesiumsulfateneuroprophylaxis.
Theconundrumiswhetherornottogiveneuroprophylaxistoanyofthesewomenwithnonseveregestationalhypertensionor
preeclampsia(Alexander,2006).

Inmanyothercountries,andprincipallyfollowingdisseminationoftheMagpieTrialCollaborationGroup(2002)studyresults,
magnesiumsulfateisnowrecommendedforwomenwithseverepreeclampsia.Insome,however,debatecontinuesconcerning
whethertherapyshouldbereservedforwomenwhohaveaneclampticseizure.Weareoftheopinionthateclampticseizuresare
dangerousforreasonsdiscussedonHELLPSyndrome.Maternalmortalityratesofupto5percenthavebeenreportedeveninrecent
studies(Andersgaard,2006Benhamou,2009Moodley,2010Schutte,2008Zwart,2008).Moreover,therearesubstantially
increasedperinatalmortalityratesinbothindustrializedcountriesandunderdevelopedones(AbdElAal,2012Knight,2007
Ndaboine,2012Schutte,2008vonDadelszen,2012).Finally,thepossibilityofadverselongtermneuropsychologicalandvision
relatedsequelaeofeclampsiadescribedbyAukes(2009,2012),Postma(2009),Wiegman(2012),andtheircoworkers,whichare
discussedonRenalSequelae,haveraisedadditionalconcernsthateclampticseizuresarenotbenign.

SelectiveversusUniversalMagnesiumSulfateProphylaxis

Thereisuncertaintyaroundwhichwomenwithnonseveregestationalhypertensionshouldbegivenmagnesiumsulfate
neuroprophylaxis.Anopportunitytoaddressthesequestionswasaffordedbyachangeinourprophylaxisprotocolforwomen
deliveringatParklandHospital.Beforethistime,Lucasandassociates(1995)hadfoundthattheriskofeclampsiawithout
magnesiumprophylaxiswasapproximately1in100forwomenwithmildpreeclampsia.Upuntil2000,allwomenwithgestational
hypertensionweregivenmagnesiumprophylaxisintramuscularlyasfirstdescribedbyPritchardin1955.After2000,weinstituteda
standardizedprotocolforintravenouslyadministeredmagnesiumsulfate(Alexander,2006).Atthesametime,wealsochangedour
practiceofuniversalseizureprophylaxisforallwomenwithgestationalhypertensiontooneofselectiveprophylaxisgivenonlyto
womenwhometourcriteriaforseveregestationalhypertension.Thesecriteria,showninTable4015,includedwomenwith2+
proteinuriameasuredbydipstickinacatheterizedurinespecimen.

TABLE4015SelectiveversusUniversalMagnesiumSulfateProphylaxis:ParklandHospitalCriteriatoDefineSeverityof
GestationalHypertension
Inawomanwithnewonsetproteinurichypertension,atleastoneofthefollowingcriteriaisrequired:
SystolicBP160ordiastolicBP110mmHg
Proteinuria2+bydipstickinacatheterizedurinespecimen
Serumcreatinine>1.2mg/dL
Plateletcount<100,000/L
Aspartateaminotransferase(AST)elevatedtwotimesaboveupperlimitofnormalrange
Persistentheadacheorscotomata
Persistentmidepigastricorrightupperquadrantpain

BP=bloodpressure.

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CriteriabasedonthosefromNationalHighBloodPressureEducationProgramWorkingGroup,2000AmericanCollegeof
ObstetriciansandGynecologists,2012bcitedbyAlexander,2006.

Followingthisprotocolchange,60percentof6518womenwithgestationalhypertensionduringa4yearperiodweregiven
magnesiumsulfateneuroprophylaxis(Table4016).Theremaining40percentwithnonseverehypertensionwerenottreated,andof
these,27womendevelopedeclampticseizures1in92.Theseizureratewasonly1in358for3935womenwithcriteriaforsevere
diseasewhoweregivenmagnesiumsulfate,andthusthesecasesweretreatmentfailures.Toassessmorbidity,outcomesin87
eclampticwomenwerecomparedwithoutcomesinall6431noneclamptichypertensivewomen.Althoughmostmaternaloutcomes
weresimilar,almostafourthofwomenwitheclampsiawhounderwentemergentcesareandeliveryrequiredgeneralanesthesia.This
isagreatconcernbecauseeclampticwomenhavelaryngotrachealedemaandareatahigherriskforfailedintubation,gastricacid
aspiration,anddeath(AmericanCollegeofObstetriciansandGynecologists,2013d).Neonataloutcomeswerealsoaconcern
becausethecompositemorbiditydefinedinTable4016wassignificantlyincreasedtenfoldineclampticcomparedwith
noneclampticwomen12versus1percent,respectively.

TABLE4016SelectedPregnancyOutcomesin6518WomenwithGestationalHypertensionAccordingtoWhetherThey
DevelopedEclampsia
PregnancyOutcomes EclampsiaNo.(%) Gest.HTNaNo.(%) pvalue
Number 87 6431
Maternal
Cesareandelivery 32(37) 2423(38) 0.86
Placentalabruption 1(1) 72(1) 0.98
Generalanesthesiab 20(23) 270(4) <0.001
Neonatal
Compositemorbidityc 10(12) 240(1) 0.04

aIncludeswomenwhohadpreeclampsia.

bEmergentcesareandelivery.

cOneormore:cordarterypH<7.05minuteApgarscore<4perinataldeathorunanticipatedadmissionofterminfanttoan
intensivecarenursery.

Gest.HTN=gestationalhypertension.

DatafromAlexander,2006.

Thus,ifoneusestheParklandcriteriafornonseveregestationalhypertension,about1of100suchwomenwhoarenotgiven
magnesiumsulfateprophylaxiscanbeexpectedtohaveaneclampticseizure.Afourthofthesewomenlikelywillrequireemergent
cesareandeliverywithattendantmaternalandperinatalmorbidityandmortalityfromgeneralanesthesia.Fromthis,themajor
questionregardingmanagementofnonseveregestationalhypertensionremainswhetheritisacceptabletoavoidunnecessary
treatmentof99womentoriskeclampsiainone?Theanswerappearstobeyesassuggestedbythe2013TaskForce.

Delivery

Toavoidmaternalrisksfromcesareandelivery,stepstoeffectvaginaldeliveryareusedinitiallyinwomenwitheclampsia.
Followingaseizure,laboroftenensuesspontaneouslyorcanbeinducedsuccessfullyeveninwomenremotefromterm(Alanis,
2008).Animmediatecuredoesnotpromptlyfollowdeliverybyanyroute,butseriousmorbidityislesscommonduringthe
puerperiuminwomendeliveredvaginally.

BloodLossatDelivery

Hemoconcentrationorlackofnormalpregnancyinducedhypervolemiaisanalmostpredictablefeatureofseverepreeclampsia
eclampsiaasquantifiedbyZeemanandassociates(2009)andshowninFigure407.Thesewomen,whoconsequentlylacknormal
pregnancyhypervolemia,aremuchlesstolerantofevennormalbloodlossthanarenormotensivepregnantwomen.Itisofgreat
importancetorecognizethatanappreciablefallinbloodpressuresoonafterdeliverymostoftenmeansexcessivebloodlossandnot
suddenresolutionofvasospasmandendothelialdamage.Whenoliguriafollowsdelivery,thehematocritshouldbeevaluated
frequentlytohelpdetectexcessivebloodloss.Ifidentified,hemorrhageshouldbetreatedappropriatelybycarefulcrystalloidand
bloodtransfusion.

AnalgesiaandAnesthesia

Duringthepast20years,theuseofconductionanalgesiaforwomenwithpreeclampsiasyndromehasprovenideal.Initialproblems
withthismethodincludedhypotensionanddiminisheduterineperfusioncausedbysympatheticblockadeinthesewomenwith
attenuatedhypervolemia.Butpulmonaryedemawasmitigatedbytechniquesthatusedslowinductionofepiduralanalgesiawith
dilutesolutionsofanestheticagentstocountertheneedforrapidinfusionoflargevolumesofcrystalloidorcolloidtocorrect
maternalhypotension(Hogg,1999Wallace,1995).Moreover,epiduralblockadeavoidsgeneralanesthesia,inwhichthestimulation
oftrachealintubationmaycausesuddenseverehypertension.Suchbloodpressureincreases,inturn,cancausepulmonaryedema,
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cerebraledema,orintracranialhemorrhage.Finally,trachealintubationmaybeparticularlydifficultandthushazardousinwomen
withairwayedemaduetopreeclampsia(AmericanCollegeofObstetriciansandGynecologists,2013d).

Atleastthreerandomizedstudieshavebeenperformedtoevaluatethesemethodsofanalgesiaandanesthesia.Wallaceand
colleagues(1995)studied80womenatParklandHospitalwithseverepreeclampsiawhoweretoundergocesareandelivery.They
hadnotbeengivenlaborepiduralanalgesiaandwererandomizedtoreceivegeneralanesthesia,epiduralanalgesia,orcombined
spinalepiduralanalgesia.Theiraveragepreoperativebloodpressuresapproximated170/110mmHg,andallhadproteinuria.
Anestheticandobstetricalmanagementincludedantihypertensivedrugtherapyandlimitedintravenousfluidsaspreviously
described.Perinataloutcomesineachgroupweresimilar.Maternalhypotensionresultingfromregionalanalgesiawasmanagedwith
judiciousintravenousfluidadministration.Inwomenundergoinggeneralanesthesia,maternalbloodpressurewasmanagedtoavoid
severehypertension(Fig.4023).Therewerenoseriousmaternalorfetalcomplicationsattributabletoanyofthethreeanesthetic
methods.Itwasconcludedthatallthreeareacceptableforuseinwomenwithpregnanciescomplicatedbyseverepreeclampsiaif
stepsaretakentoensureacarefulapproachtotheselectedmethod.

Figure4023

Bloodpressureeffectsofgeneralanesthesiaversusepiduralorspinalepiduralanalgesiaforcesareandeliveryin80womenwith
severepreeclampsia.MAP=meanarterialpressure.Timeposts(T):OR=operatingroomIN=inductionofanesthesiaT=tracheal
intubationIN5=induction+5minIN10=induction+10minIN20=induction+20minSKI=skinincisionD=deliverySKC
=skinclosureO=extubation.(FromWallace,1995,withpermission.)

Anotherrandomizedstudyincluded70womenwithseverepreeclampsiareceivingspinalanalgesiaversusgeneralanesthesia(Dyer,
2003).Allhadanonreassuringfetalheartratetracingastheindicationforcesareandelivery,andoutcomeswereequivalent.Dyer
andcoworkers(2008)latershowedthatdecreasedmeanarterialbloodpressureinducedbyepiduralblockadecouldbeeffectively
counteractedbyphenylephrineinfusiontomaintaincardiacoutput.

InastudyfromtheUniversityofAlabamaatBirmingham,Headandcolleagues(2002)randomlyassigned116womenwithsevere
preeclampsiatoreceiveeitherepiduralorpatientcontrolledintravenousmeperidineanalgesiaduringlabor.Astandardizedprotocol
limitedintravenousfluidsto100mL/hr.Morewomen9percentfromthegroupassignedtoepiduralanalgesiarequiredephedrine
forhypotension.Asexpected,painreliefwassuperiorintheepiduralgroup,butmaternalandneonatalcomplicationsweresimilar
betweengroups.Onewomanineachgroupdevelopedpulmonaryedema.

Itisimportanttoemphasizethatepiduralanalgesiaisnottobeconsideredtreatmentofpreeclampsia.Lucasandassociates(2001)
studied738laboringwomenatParklandHospitalwhowere36weeksormoreandwhohadgestationalhypertensionofvarying
severity.Patientswererandomlyassignedtoreceiveeitherepiduralanalgesiaorpatientcontrolledintravenousmeperidineanalgesia.
Maternalandneonataloutcomesweresimilarinthetwostudygroups.However,asshowninTable4017,epiduralanalgesiaresulted
inagreaterdecrementofmeanmaternalarterialpressurecomparedwithmeperidine,butitwasnotsuperiorinpreventingrecurrent
severehypertensionlaterinlabor.

TABLE4017ComparisonofCardiovascularEffectsofEpiduralversusPatientControlledMeperidineAnalgesiaDuringLaborin
WomenwithGestationalHypertension
LaborAnalgesia
HemodynamicChange Epidural(n=372) Meperidine(n=366) pvalue
Meanarterialpressurechange(mean) 25mmHg 15mmHg <0.001
Ephedrineforhypotension(%) 11% 0 <0.001
Severehypertensionafteranalgesia(%)(BP160/110mmHg) <1% 1% NS

NS=notsignificant.

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DatafromLucas,2001.

Forthesereasons,judiciousfluidadministrationisessentialinseverelypreeclampticwomenwhoreceiveregionalanalgesia.
Newsomeandcoworkers(1986)showedthatvigorouscrystalloidinfusionwithepiduralblockadeinwomenwithsevere
preeclampsiacausedelevationofpulmonarycapillarywedgepressures(seeFig.406).Aggressivevolumereplacementinthese
womenincreasestheirriskforpulmonaryedema,especiallyinthefirst72hourspostpartum(Clark,1985Cotton,1986a).When
pulmonaryedemadevelops,thereisalsoconcernfordevelopmentofcerebraledema.Finally,Hellerandassociates(1983)
demonstratedthatmostcasesofpharyngolaryngealedemawererelatedtoaggressivevolumetherapy.

PersistentSeverePostpartumHypertension

Thepotentialproblemofantihypertensiveagentscausingseriouscompromiseofuteroplacentalperfusionandthusoffetalwellbeing
isobviatedbydelivery.Postpartum,ifdifficultyarisesincontrollingseverehypertensionorifintravenoushydralazineorlabetalol
arebeingusedrepeatedly,thenoralregimenscanbegiven.Examplesincludelabetaloloranotherblocker,nifedipineoranother
calciumchannelblocker,andpossibleadditionofathiazidediuretic.Persistentorrefractoryhypertensionislikelydueto
mobilizationofpathologicalinterstitialfluidandredistributionintotheintravenouscompartment,underlyingchronichypertension,
orusuallyboth(Sibai,2012Tan,2002).Inwomenwithchronichypertensionandleftventricularhypertrophy,severepostpartum
hypertensioncancausepulmonaryedemafromcardiacfailure(Cunningham,1986,2012Sibai,1987a).

Furosemide

Becausepersistenceofseverehypertensioncorrespondstotheonsetandlengthofdiuresisandextracellularfluidmobilization,it
seemslogicalthatfurosemideaugmenteddiuresismightservetohastenbloodpressurecontrol.Tostudythis,Ascarelliand
coworkers(2005)designedarandomizedtrialthatincluded264postpartumpreeclampticwomen.Afteronsetofspontaneous
diuresis,patientswereassignedto20mgoralfurosemidegivendailyornotherapy.Womenwithmilddiseasehadsimilarblood
pressurecontrolregardlessofwhethertheyreceivedtreatmentorplacebo.However,womenwithseverepreeclampsiawhowere
treated,comparedwiththosereceivingplacebo,hadalowermeansystolicbloodpressureat2days142versus153mmHg.They
alsorequiredlessfrequentlyadministeredantihypertensivetherapyduringtheremainderofhospitalization14versus26percent,
respectively.

Wehaveusedasimplemethodtoestimateexcessiveextracellular/interstitialfluid.Thepostpartumweightiscomparedwiththemost
recentprenatalweight,eitherfromthelastclinicvisitoronadmissionfordelivery.Onaverage,soonafterdelivery,maternalweight
shouldbereducedbyatleast10to15poundsdependingoninfantandplacentalweight,amnionicfluidvolume,andbloodloss.
Becauseofvariousinterventions,especiallyintravenouscrystalloidinfusionsgivenduringoperativevaginalorcesareandelivery,
womenwithseverepreeclampsiaoftenhaveanimmediatepostpartumweightinexcessoftheirlastprenatalweight.Ifthisweight
increaseisassociatedwithseverepersistentpostpartumhypertension,thendiuresiswithintravenousfurosemideisusuallyhelpfulin
controllingbloodpressure.

PlasmaExchange

Martinandcolleagues(1995)havedescribedanatypicalsyndromeinwhichseverepreeclampsiaeclampsiapersistsdespitedelivery.
Theseinvestigatorsdescribed18suchwomenwhomtheyencounteredduringa10yearperiod.Theyadvocatesingleormultiple
plasmaexchangeforthesewomen.Insomecases,3Lofplasmawasexchangedthreetimesa36to45donorunitexposurefor
eachpatientbeforearesponsewasforthcoming.Othershavedescribedplasmaexchangeperformedinpostpartumwomenwith
HELLPsyndrome(Frster,2002Obeidat,2002).Inallofthesecases,however,thedistinctionbetweenHELLPsyndromeand
thromboticthrombocytopenicpurpuraorhemolyticuremicsyndromewasnotclear.AsfurtherdiscussedinChapter56(Thrombotic
Microangiopathies),inourexperienceswithmorethan50,000womenwithgestationalhypertensionamongnearly450,000
pregnanciescaredforatParklandHospitalthrough2012,wehaveencounteredveryfewwomenwithpersistentpostpartum
hypertension,thrombocytopenia,andrenaldysfunctionwhowerediagnosedashavingathromboticmicroangiopathy(Dashe,1998).
TheselattersyndromescomplicatingpregnancywerereviewedbyMartin(2008)andGeorge(2013)andtheircolleagues,who
concludethatarapiddiagnostictestforADAMTS13enzymeactivitymightbehelpfultodifferentiatemostofthesesyndromes.

ReversibleCerebralVasoconstrictionSyndrome

Thisisanothercauseofpersistenthypertension,thunderclapheadaches,seizures,andcentralnervoussystemfindings.Itisaform
ofpostpartumangiopathy.AsshowninFigure4024,itischaracterizedbydiffusesegmentalconstrictionofcerebralarteriesand
maybeassociatedwithischemicandhemorrhagicstrokes.Thereversiblecerebralvasoconstrictionsyndromehasseveralinciting
causesthatincludepregnancy,andparticularlypreeclampsia(Ducros,2012).Itismorecommoninwomen,andinsomecases,
vasoconstrictionmaybesosevereastocausecerebralischemiaandinfarction.Theappropriatemanagementisnotknownatthis
time(Edlow,2013).

Figure4024

Reversiblecerebralvasoconstrictionsyndrome.Magneticresonanceangiographyshowsgeneralizedvasoconstrictionoftheanterior
andposteriorcerebralcirculation(arrows).(FromGarciaReitboeck,2013,withpermission.)

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CounselingforFuturePregnancies
AsdiscussedonEtiology,defectiveremodelingofthespiralarteriesinsomeplacentationshasbeenpositedasthecauseofatleast
onepreeclampsiaphenotype.Lackofdeepplacentationhasbeenassociatedwithpreeclampsia,placentalabruption,fetalgrowth
restriction,andpretermbirth(Wikstrm,2011).Withthistypeofoverlapsyndrome,hypertensivedisordersmayserveasmarkers
forsubsequentpretermlaborandfetalgrowthrestriction.Forexample,eveninsubsequentnonhypertensivepregnancies,women
whohadpretermpreeclampsiaareatincreasedriskforpretermbirth(Connealy,2013.)

Inaddition,womenwhohavehadeithergestationalhypertensionorpreeclampsiaareathigherrisktodevelophypertensioninfuture
pregnancies.Generally,theearlierpreeclampsiaisdiagnosedduringtheindexpregnancy,thegreaterthelikelihoodofrecurrence.
Sibaiandcolleagues(1986,1991)foundthatnulliparasdiagnosedwithpreeclampsiabefore30weekshavearecurrenceriskashigh
as40percentduringasubsequentpregnancy.Inaprospectivestudyof500womenpreviouslydeliveredforpreeclampsiaat37
weeks,therecurrencerateinasubsequentgestationwas23percent(Bramham,2011).Theseinvestigatorsalsofoundanincreased
riskduringsubsequentpregnanciesforpretermdeliveryandfetalgrowthrestrictionevenifthesewomenremainednormotensive.

InastudyfromtheDenmarkBirthRegistry,Lykkeandcoworkers(2009b)analyzedsingletonbirthsinmorethan535,000women
whohadafirstandseconddelivery.Womenwhosefirstpregnancywascomplicatedbypreeclampsiabetween32and36weekshada
significanttwofoldincreasedincidenceofpreeclampsiaintheirsecondpregnancy25versus14percentcomparedwithwomen
whowerenormotensiveduringthefirstpregnancy.Analyzedfromanotherview,theyalsofoundthatpretermdeliveryandfetal
growthrestrictioninthefirstpregnancysignificantlyincreasedtheriskforpreeclampsiainthesecondpregnancy.

Asprobablyexpected,womenwithHELLPsyndromehaveasubstantiveriskforrecurrenceinsubsequentpregnancies.Intwo
studiestheriskrangedfrom5to26percent,butthetruerecurrencerisklikelyliesbetweenthesetwoextremes(Habli,2009Sibai,
1995).EvenifHELLPsyndromedoesnotrecurwithsubsequentpregnancies,thereisahighincidenceofpretermdelivery,fetal
growthrestriction,placentalabruption,andcesareandelivery(Habli,2009Hnat,2002).

LongTermConsequences
Overthepast20years,evidencehasaccruedthatpreeclampsia,likefetalgrowthdisordersandpretermbirth,isamarkerfor
subsequentcardiovascularmorbidityandmortality.Thus,womenwithhypertensionidentifiedduringpregnancyshouldbeevaluated
duringthefirstseveralmonthspostpartumandcounseledregardinglongtermrisks.TheWorkingGroupconcludedthathypertension
attributabletopregnancyshouldresolvewithin12weeksofdelivery(NationalHighBloodPressureEducationProgram,2000).
Persistencebeyondthistimeisconsideredtobechronichypertension(Chap.50,GeneralConsiderations).TheMagpieTrialFollow
UpCollaborativeGroup(2007)reportedthat20percentof3375preeclampticwomenseenatamedianof26monthspostpartumhad
hypertension.Importantly,evenifhypertensiondoesnotpersistintheshortterm,convincingevidencesuggeststhattheriskforlong
termcardiovascularmorbidityissignificantlyincreasedinpreeclampticwomen.

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Withtheadventofnationaldatabases,severalstudiesconfirmthatanyhypertensionduringpregnancyisamarkerforanincreased
riskformorbidityandmortalityinlaterlife(AmericanCollegeofObstetriciansandGynecologists,2013c).Inacasecontrolstudy
fromIceland,Arnadottirandassociates(2005)analyzedoutcomesfor325womenwhohadhypertensioncomplicatingpregnancy
andwhoweredeliveredfrom1931through1947.Atamedianfollowupof50years,60percentofwomenwithpregnancyrelated
hypertensioncomparedwithonly53percentofcontrolshaddied.Comparedwith629normotensivepregnantcontrols,the
prevalencesofischemicheartdisease24versus15percent,andstroke9.5versus6.5percent,weresignificantlyincreasedinthe
womenwhohadgestationalhypertension.InaSwedishpopulationstudyofmorethan400,000nulliparasdeliveredbetween1973
and1982,Wikstrmandcoworkers(2005)alsofoundanincreasedincidenceofischemicheartdiseaseinwomenwithprior
pregnancyassociatedhypertension.

Lykkeandassociates(2009a)citedfindingsfromaDanishregistryofmorethan780,000nulliparouswomen.Afterameanfollow
upofalmost15years,theincidenceofchronichypertensionwassignificantlyincreased5.2foldinthosewhohadgestational
hypertension,3.5foldaftermildpreeclampsia,and6.4foldafterseverepreeclampsia.Aftertwohypertensivepregnancies,therewas
a5.9foldincreaseintheincidence.Importantly,theseinvestigatorsalsoreportedasignificant3.5foldincreasedriskfortype2
diabetes.

Bellamyandcoworkers(2007)performedasystematicreviewandmetaanalysisoflongtermrisksforcardiovasculardiseasein
womenwithpreeclampsia.AsshowninFigure4025,therisksinlaterlifewereincreasedforhypertension,ischemicheartdisease,
stroke,venousthromboembolism,andallcausemortality.Asemphasizedbyseveralinvestigators,othercofactorsorcomorbidities
arerelatedtoacquisitionoftheselongtermadverseoutcomes(Gastrich,2012Harskamp,2007Hermes,2012Spaan,2012b).
Theseincludebutarenotlimitedtothemetabolicsyndrome,diabetes,obesity,dyslipidemia,andatherosclerosis.Theseconclusions
areunderscoredbythefindingsofBerendsandcolleagues(2008),whoconfirmedsharedconstitutionalrisksforlongtermvascular
relateddisordersinpreeclampticwomenandintheirparents.SimilarpreliminaryobservationswerereportedbySmith(2009,2012)
andStekkinger(2013)andtheirassociates.

Figure4025

Longtermcardiovascularconsequencesofpreeclampsia.Alldifferencesp.001.(DatafromBellamy,2007.)

Atleastinsomeofthesewomen,theirhypertensivecardiovascularpathologiesappeartohavebegunnearthetimeoftheirown
births.Forexample,individualswhoarebornpretermhaveincreasedventricularmasslaterinlife(Lewandowski,2013).Women
whohavepreeclampsiaandwhodevelopchronichypertensionlaterinlifehaveanincreasedventricularmassindexbeforethey
becomehypertensive(GhosseinDoha,2013).Asimilarphenomenonisassociatedwithpretermbirthandwithfetalgrowth
disorders.

RenalSequelae

Preeclampsiaappearstoalsobeamarkerforsubsequentrenaldisease.Inapreliminarystudy,thepossibilitywasraisedthat
persistentpodocyturiamightbeamarkerforsuchdisease(Garrett,2013).Ina40yearstudyofNorwegianbirthandendstagerenal
diseaselinkedregistries,althoughtheabsoluteriskofrenalfailurewassmall,preeclampsiawasassociatedwithafourfoldincreased
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risk(Vikse,2008).Womenwithrecurrentpreeclampsiahadanevengreaterrisk.Thesedataneedtobeconsideredinlightofthe
findingsthat15to20percentofwomenwithpreeclampsiawhoundergorenalbiopsyhaveevidenceofchronicrenaldisease
(Chesley,1978).Inanotherlongtermfollowupstudy,Spaanandcoworkers(2009)comparedformerlypreeclampticwomenwitha
cohortofwomenwhowerenormotensiveatdelivery.At20yearsfollowingdelivery,preeclampticwomenweresignificantlymore
likelytobechronicallyhypertensive55versus7percentcomparedwithcontrolwomen.Theyalsohadhigherperipheralvascular
andrenovascularresistanceanddecreasedrenalbloodflow.Thesedatadonotpermitconclusionsastocauseversuseffect.

NeurologicalSequelae

Untilrecently,eclampticseizureswerebelievedtohavenosignificantlongtermsequelae.Findingshavenowaccrued,however,that
thisisnotalwaysthecase.Recallthatalmostalleclampticwomenhavemultifocalareasofperivascularedema,andaboutafourth
alsohaveareasofcerebralinfarction(Zeeman,2004a).

ADutchgrouphasreportedseverallongtermfollowupstudiesinwomenwithseverepreeclampsiaandeclampsia(Aukes,2007,
2009,2012).Theseinvestigatorsfoundlongtermpersistenceofbrainwhitematterlesionsthatwereincurredduringeclamptic
convulsions(Aukes,2009).WhenstudiedwithMRimagingatameanof7years,40percentofformerlyeclampticwomenhadmore
numerousandlargeraggregatewhitematterlesionscomparedwith17percentofnormotensivecontrolwomen.Theseinvestigators
lateralsoobservedthesewhitematterlesionsinpreeclampticwomenwithoutconvulsions(Aukes,2012).Instudiesdesignedto
assessclinicalrelevance,Aukesandcolleagues(2007)reportedthatformerlyeclampticwomenhadsubjectivelyimpairedcognitive
functioning.Theyalsoreportedthatwomenwithmultipleseizureshadimpairedsustainedattentioncomparedwithnormotensive
controls(Postma,2009).Andrecently,Wiegmanandassociates(2012)describedthatformerlyeclampticwomenatapproximately
10yearshadlowervisionrelatedqualityoflifecomparedwithcontrolsubjects.Becausetherewerenostudiesdonebeforethese
womensufferedfrompreeclampsiaoreclampsia,theinvestigatorsappropriatelyconcludedthatcauseversuseffectofthesewhite
matterlesionsremainsunknown.

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