OfficialreprintfromUpToDate

www.uptodate.com2017UpToDate

Preeclampsia:Managementandprognosis

Authors: ErrolRNorwitz,MD,PhD,MBA,JohnTRepke,MD
SectionEditor: CharlesJLockwood,MD,MHCM
DeputyEditor: VanessaABarss,MD,FACOG

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Jan2017.|Thistopiclastupdated:Dec02,2016.

INTRODUCTIONPreeclampsiaisamultisystem,progressivedisordercharacterizedbythenewonsetofhypertensionandproteinuriaorhypertensionand
endorgandysfunctionwithorwithoutproteinuriainthelasthalfofpregnancy(table1).Progressionfrommildtosevereonthediseasespectrum(table2)maybe
gradualorrapid.

Akeyfocusofroutineprenatalcareismonitoringpregnanciesforsignsandsymptomsofpreeclampsia.Ifthediagnosisismade,thedefinitivetreatmentis
deliverytopreventdevelopmentofmaternalorfetalcomplicationsfromdiseaseprogression:Deliveryresultsinresolutionofthedisease.Timingofdeliveryis
baseduponacombinationoffactors,includingdiseaseseverity,maternalandfetalcondition,andgestationalage.

Thistopicwilldiscussthemanagementofpregnanciescomplicatedbypreeclampsiaandmaternalprognosis.Otherimportantissuesrelatedtothisdiseaseare
reviewedseparately.

(See"Preeclampsia:Pathogenesis".)
(See"Preeclampsia:Clinicalfeaturesanddiagnosis".)
(See"Earlypregnancypredictionofpreeclampsia".)
(See"Preeclampsia:Prevention".)

PREECLAMPSIAWITHFEATURESOFSEVEREDISEASE

Generalapproach:DeliveryPreeclampsiawithfeaturesofseveredisease(formerlycalledseverepreeclampsia)(table2)isgenerallyregardedasan
indicationfordelivery.Deliveryminimizestheriskofdevelopmentofseriousmaternalandfetalcomplications,suchascerebralhemorrhage,hepaticrupture,renal
failure,pulmonaryedema,seizure,bleedingrelatedtothrombocytopenia,abruptioplacenta,orfetalgrowthrestriction[14].Withtheexceptionoffetalgrowth
restriction,anyoftheselifethreateningcomplicationscanoccursuddenly.(See"Preeclampsia:Clinicalfeaturesanddiagnosis",sectionon'Spectrumofdisease'
and"Preeclampsia:Clinicalfeaturesanddiagnosis",sectionon'Naturalhistory/courseofdisease'.)

Managementofdeliveryisreviewedbelow.(See'Intrapartummanagement'below.)
ConservativemanagementofselectedcasesConservativemanagementratherthandeliveryisreasonableforselectedpretermpregnancieswith
preeclampsiawithfeaturesofseverediseasetoreduceneonatalmorbidityfrompretermbirth,eventhoughthemotherandfetusareatriskfromdisease
progression.Forconsiderationofthisapproach,boththemotherandfetusshouldbestableandshouldbecloselymonitoredinatertiarycarehospitalorin
consultationwithamaternalfetalmedicinespecialist.Wefavorlimitingconservativemanagementtopregnancies24weeksand<34weeksofgestation.
Selectionofappropriatecandidatesforthisapproachandmanagementofthesepregnanciesarediscussedseparately.(See"Expectantmanagementof
preeclampsiawithseverefeatures".)

Pregnanciesinwhichthefetushasnotattainedaviablegestationalage,pregnancies34weeksofgestation,andpregnanciesinwhichthematernaland/orfetal
conditionisunstablearenotcandidatesforconservativemanagement.Attemptingtoprolongpregnancyinthesesettingssubjectsthemotherandfetusto
significantriskswithrelativelysmallpotentialbenefitstherefore,deliveryispreferable.

PREECLAMPSIAWITHOUTFEATURESOFSEVEREDISEASE

Generalapproach

Termpregnancies:DeliveryExpertsconsistentlyrecommenddeliveryofwomenwithpreeclampsiaat37weeksofgestation,evenintheabsenceof
featuresofseveredisease(previouslycalled"mildpreeclampsia")[37].

Thebenefitsoflaborinductionat37weeksofgestationwereillustratedinamulticentertrial(HYPITAT)thatrandomlyassigned756womenwithmild
preeclampsiaorgestationalhypertension>360/7weekstoinductionoflabororconservativemanagementwithmaternal/fetalmonitoring[8].Thistrialshowedthat
preeclampticwomenbenefitedfromearlyintervention,withoutincurringanincreasedriskofoperativedeliveryorneonatalmorbidity.Routineinductionwas
associatedwitha30percentreductioninacompositeofadversematernaloutcomes(31versus44percentrelativerisk[RR]0.71,95%CI0.590.86),whichwas
primarilydrivenbyareductioninpatientswhodevelopedseverehypertensionandwasnotsignificantforwomenat360/7to366/7weeks.Theinducedgroup
delivered,onaverage,1.2weeksearlierthanthecontrolgroupandhadasignificantlylowerrateofcesareandelivery(14versus19percent).Therewereno
significantdifferencesbetweengroupsinneonataloutcome.Thecompositeincludedmaternalmortality,maternalmorbidity(eclampsia,HELLPsyndrome
[Hemolysis,ElevatedLiverenzymes,LowPlateletcount],pulmonaryedema,thromboembolicdisease,placentalabruption),progressiontoseverehypertension
orproteinuria,andmajorpostpartumhemorrhage.Thetrialwasnotlargeenoughtodeterminewhethersmalldifferencesinnewbornoutcomesorinduction
between36and37weeksmightbestatisticallysignificant.

Followupanalysesshowedthatanunfavorablecervixwasnotareasontoavoidinduction[9,10].InasecondaryanalysisofdatafromthistrialandDIGITAT
(pregnanciescomplicatedbyfetalgrowthrestriction),inductionoflaboratterminwomenwithamedianBishopscoreof3(range1to6)wasnotassociatedwitha
higherrateofcesareandeliverythanconservativemanagement,andapproximately85percentofwomeninbothgroupsachievedavaginaldelivery[10].
Prostaglandinsoraballooncatheterwasusedforcervicalripening.

Inaddition,aneconomicanalysisoftheHYPITATtrial(conductedinfromtheNetherlands)concludedinductionwas11percentlesscostlyoverallthanexpectant
managementwithmonitoring[11].

Managementofdeliveryisreviewedbelow.(See'Intrapartummanagement'below.)
 Pretermpregnancies:ConservativemanagementBeforeterm,therisksofserioussequelaefromdiseaseprogressionneedtobebalancedwiththe
risksofpretermbirth.Whenmotherandfetusarestableandwithoutfindingsofseriousendorgandysfunction,aconservativeapproachwithclosemonitoringfor
evidenceofprogressiontothesevereendofthediseasespectrumisreasonabletoachievefurtherfetalgrowthandmaturity.However,atanygestationalage,
evidenceofseverehypertension,seriousmaternalendorgandysfunction(table2),ornonreassuringtestsoffetalwellbeingaregenerallyanindicationfor
promptdelivery.

<34weeksofgestationPriorto340/7weeks,guidelinesfrommajormedicalorganizationsgenerallyrecommendconservativemanagementof
preeclampsiawithoutfeaturesofseveredisease,basedonexpertopinion,giventhehighriskofcomplicationsofprematurity[3,4,7].Weconcurwiththis
approach.

34to36weeksofgestationTheoptimummanagementforwomenwithpreeclampsiawithoutfeaturesofseverediseaseandstablematernalandfetal
conditionat340/7to366/7weeksisuncertain.Althoughthereareseriousmaternalriskswithconservativemanagement,webelieveconservativemanagement
isreasonableinfullyinformedpatientsbecausetheabsolutematernalriskofanadverseoutcomeislowandtheneonatalbenefitsofdeliveryattermare
substantial.

DatafromtherandomizedHYPITATIItrialandobservationalstudiesindicatethatmostpatientswithlateonsetpretermdiseasewillreachtermwithout
developinganadversematernaloutcome(thromboembolicdisease,pulmonaryedema,eclampsia,HELLPsyndrome,placentalabruption,maternaldeath).
InHYPITATII,whichincludedwomenwithnonseverehypertensivedisordersofpregnancybetween34and37weeksofgestation,atleastoneoftheabove
adverseoutcomesoccurredin1.2percent(2/165)oftheimmediatedeliverygroupversus2.5percent(4/159)oftheexpectantmanagementgroup,withno
maternaldeathsorcasesofpulmonaryedema[12].Newbornsbenefitedfromtheextratimeinutero:neonatesintheimmediatedeliverygrouphadahigher
frequencyofrespiratorydistress(5.7versus1.7percentintheconservativemonitoringgroup,relativerisk[RR]3.3,95%CI1.48.2).

Componentsofconservativemanagement

InpatientversusoutpatientcareClosematernalmonitoringupondiagnosisofpreeclampsiaisimportanttoestablishdiseaseseverityandtherateof
progression.Hospitalizationisusefulformakingtheseassessmentsandfacilitatesrapidinterventionintheeventofrapidprogression.Aftertheinitialdiagnostic
evaluation,outpatientcareisacosteffectiveoptionforwomenwithstablepreeclampsiawithoutseverefeatures[1317].Patientsofferedoutpatientmonitoring
shouldbeabletocomplywithfrequentmaternalandfetalevaluations(everyonetothreedays)andshouldhavereadyaccesstomedicalcare.

Outpatientcarecanbeprovidedinthepatientshomeor,whereavailable,atanantenataldaycareunit,whichisacommonapproachintheUnitedKingdom[18].
Ifsignsorsymptomsofdiseaseprogressionarenoted,hospitalizationformoreintensivemonitoringandpossibledeliveryisindicated.

Therearelimiteddataonoutcomeofoutpatientmanagementofpreeclampticwomen.Anobservationalstudyandarandomizedtrialreportedgoodoutcomes,
butthesestudieshadtoofewsubjectstodetectclinicallysignificantdifferencesinoutcomebetweeninpatientandoutpatientmanagement[14,15].Asystematic
reviewofthreetrialswithatotalof504womenwithvariouscomplicationsofpregnancyobservednomajordifferencesinclinicaloutcomesformothersorinfants
betweenantenataldayunitsorhospitaladmission[18].
 PatienteducationAllwomenwithpreeclampsiashouldbeawareofthesignsandsymptomsatthesevereendofthediseasespectrumandshould
monitorfetalmovementsdaily[4].Ifawomandevelopssevereorpersistentheadache,visualchanges,shortnessofbreath,orrightupperquadrantorepigastric
pain,sheshouldcallherhealthcareproviderimmediately.Aswithanypregnancy,decreasedfetalmovement,vaginalbleeding,abdominalpain,ruptureof
membranes,oruterinecontractionsshouldbereportedimmediately,aswell.

ActivityStrictbedrestisunnecessaryasthereisnoevidencethatbedrestimprovespregnancyoutcomeordelaysprogressionofthedisease[19].
Furthermore,bedrestinhospitalizedpregnantwomenhasbeenassociatedwithanincreasedriskofvenousthromboembolism[20].

Restrictedactivityisoftenrecommendedsincebloodpressureislowerinrestedpatients.Restingintheleftlateraldecubituspositioncanaugmentuteroplacental
flow,whichmaybenefitpregnanciesinwhichthisisaconcern.Inallpregnantwomen,avoidingthesupinesleeppositioncanhavefavorablefetaleffectsand
appearsprudent[21].

LaboratoryfollowupTheminimumlaboratoryevaluationshouldincludeplateletcount,serumcreatinine,andliverenzymes.Thesetestsshouldbe
repeatedatleastweeklyinwomenwithpreeclampsiawithoutseverefeaturestoassessfordiseaseprogression,andmoreoftenifclinicalsignsandsymptoms
suggestworseningdisease[4].

Althoughotherlaboratoryabnormalitiesmayoccur(see"Preeclampsia:Clinicalfeaturesanddiagnosis",sectionon'Laboratoryfindings'),thevalueofmonitoring
additionallaboratorytestsislessclear.Arisinghematocritcanbeusefultolookforhemoconcentration,whichsuggestscontractionofintravascularvolumeand
progressiontomoreseveredisease,whileafallinghematocritmaybeasignofhemolysis.Anelevatedserumindirectbilirubinand/orLDHconcentrationisa
bettermarkerforhemolysis.Hemolysiscanbeconfirmedbyobservationofschistocytesandhelmetcellsonabloodsmear(picture1AB).(See"HELLP
syndrome".)

Sinceseveralclinicalstudieshaveshownthatneithertherateofincreasenortheamountofproteinuriaaffectsmaternalorperinataloutcomeinthesettingof
preeclampsia[2225],repeatedurinaryproteinestimationsarenotusefuloncethethresholdof300mg/24hoursorrandomurineprotein/creatinineratio0.3
mg/dLforthediagnosisofpreeclampsiahasbeenexceeded.Atthatpoint,serumcreatininealonecanbeusedtomonitorrenalfunction.Itisthepracticeofsome
providers,includingtheauthors,toconfirmalowpositiveproteincreatinineratio(0.3to0.6)witha24hourcollection.(See"Proteinuriainpregnancy:Evaluation
andmanagement"and"Expectantmanagementofpreeclampsiawithseverefeatures".)

TreatmentofhypertensionBloodpressureshouldbemeasuredatleasttwiceweeklyinoutpatients.Theuseofantihypertensivedrugstocontrolmild
hypertension(systolicbloodpressure<160mmHganddiastolicbloodpressure<110mmHg)inthesettingofpreeclampsiadoesnotalterthecourseofthe
diseaseordiminishperinatalmorbidityormortality,andshouldbeavoidedinmostpatients.Itdoes,however,reducetheoccurrenceofprogressiontosevere
hypertension.Theindicationsforstartingantihypertensivetherapy,thechoiceofdrug,andbloodpressuregoalsarediscussedindetailseparately.(See
"Managementofhypertensioninpregnantandpostpartumwomen",sectionon'Preeclampsia'.)

Sodiumrestrictionbelowtherecommendeddailyintakeanddiureticshavenoroleinroutinetherapy[2628].Althoughintravascularvascularvolumeisreduced,a
randomizedtrialshowedthatplasmavolumeexpansiondidnotimprovematernalorfetaloutcome[29].Diureticsareonlyindicatedfortreatmentofpulmonary
edema.
 AssessmentoffetalgrowthEarlyfetalgrowthrestrictionmaybethefirstmanifestationofpreeclampsiaandisasignofsevereuteroplacental
insufficiency.Weperformsonographicestimationoffetalweighttoevaluateforgrowthrestrictionandoligohydramniosatthetimeofdiagnosisofpreeclampsia.If
theinitialexaminationisnormal,werepeattheultrasoundexaminationeverythreeweeks.Managementofthegrowthrestrictedfetusisreviewedseparately.(See
"Fetalgrowthrestriction:Evaluationandmanagement".)

AssessmentoffetalwellbeingTherearenodatafromrandomizedtrialsonwhichtobaserecommendationsfortheoptimaltypeandfrequencyof
antepartumfetalmonitoring.Wesuggestdailyfetalmovementcountsandtwiceweeklynonstresstestingwithassessmentofamnioticfluidvolume,ortwice
weeklybiophysicalprofiles,beginningatthetimeofdiagnosisofpreeclampsia.Fetaltestingisrepeatedpromptlyifthereisanabruptchangeinmaternal
condition.(See"Nonstresstestandcontractionstresstest"and"Thefetalbiophysicalprofile".)

EvaluationofumbilicalarteryDopplerindicesisusefuliffetalgrowthrestrictionissuspected,astheresultshelpinoptimaltimingofdelivery.Inametaanalysisof
16randomizedtrialsinhighriskpregnancies(n=10,225infants),knowledgeofumbilicalarteryDopplervelocimetryresultsresultedina29percentreductionin
perinataldeath(RR0.71,95%CI0.520.981.2versus1.7percentnumberneededtotreat203,95%CI1034352),primarilyinpregnanciescomplicatedby
preeclampsiaand/orgrowthrestriction[30].ThefrequencyofassessmentdependsonthefindingsweeklyassessmentisreasonablewhenDopplerindicesare
normal.(See"Dopplerultrasoundoftheumbilicalarteryforfetalsurveillance".)

AntenatalcorticosteroidsAlthoughpreeclampsiamayacceleratefetallungmaturation,neonatalrespiratorydistressremainscommoninpremature
neonatesofpreeclampticpregnancies[31,32].Antenatalcorticosteroids(betamethasone)topromotefetallungmaturityshouldbeadministeredtowomen<34
weeksofgestationsincetheyareatincreasedriskofprogressiontoseverediseaseandpretermdelivery.Acourseofsteroidsisadministeredwhentheclinician
believesdeliverywithinthenextsevendaysislikelyandneonatalresuscitationisplanned.Useofsteroidsafter34weeksismorecomplicatedanddiscussed
separately.(See"Antenatalcorticosteroidtherapyforreductionofneonatalmorbidityandmortalityfrompretermdelivery",sectionon'Gestationalageat
administration'.)

TimingofdeliveryForpatientsmanagedconservatively,deliveryisindicatedat37weeksofgestationorassoonastheydeveloppreeclampsiawith
severefeatures(table2)oreclampsia,whetherornotthecervixisfavorable.

INTRAPARTUMMANAGEMENT

RouteofdeliveryTherouteofdeliveryisbasedonstandardobstetricalindications.Observationaldatasuggestthatthedecisiontoexpeditedeliveryinthe
settingofpreeclampsiawithfeaturesofseverediseasedoesnotmandateimmediatecesareanbirth[4,33,34].Cervicalripeningagentscanbeusedpriorto
inductionifthecervixisnotfavorable[35].(See"Techniquesforripeningtheunfavorablecervixpriortoinduction".)

However,webelievethataprolongedinductionandinductionswithalowlikelihoodofsuccessarebestavoided.Forexample,cesareandeliveryisreasonablefor
womenwithpreeclampsiawithseverefeatureswhoarelessthanabout32weeksofgestationandhavealowBishopscore,giventhehighfrequencyofabnormal
fetalheartratetracingsandfailureofthecervixtodilateinthissetting[3537].Lessthanonethirdofpreterminductionsinthissettingresultinvaginalbirth.

IntrapartummonitoringContinuousmaternalfetalmonitoringisindicatedintrapartumtoidentifyworseninghypertensiondeterioratingmaternalhepatic,
renal,cardiopulmonary,neurologic,orhematologicfunctionabruptioplacentaoranabnormalfetalheartratetracing.Therearenoevidencebasedstandardsfor
theoptimalapproach.

Routineinvasivematernalhemodynamicmonitoring(arterialcatheterization,centralvenouscatheterplacement)isnotrecommended,eveninthesettingof
severepreeclampsia[4].Mostwomencanbemanagedwithouttheseinvasivetoolsandshouldnotbeexposedtotherisksassociatedwiththem.

However,informationfromanarterialorcentralvenouscathetercanbeusefulinselectedcomplicatedpatients,suchasthosewithseverecardiacdisease,
severerenaldisease,severeoliguria,refractoryhypertension,orpulmonaryedema.Randomizedtrialshavenotbeenperformed[38].(See"Anesthesiaforthe
patientwithpreeclampsia",sectionon'Hemodynamicmonitoring'.)

FluidsFluidbalanceshouldbemonitoredcloselytoavoidexcessiveadministration,sincewomenwithpreeclampsiaareatriskofpulmonaryedemaand
significantthirdspacing,especiallyatthesevereendofthediseasespectrum.Amaintenanceinfusionofabalancedsaltorisotonicsalinesolutionatabout80
mL/hourisoftenadequateforapatientwhoisnilbymouthandhasnoongoingabnormalfluidlosses,suchasbleeding[39].

Oliguriathatdoesnotrespondtoamodesttrialofincreasedfluids(eg,a300mLfluidchallenge)suggestsrenalinsufficiencyandshouldbetoleratedtoreduce
thepotentialforiatrogenicpulmonaryedema[39].Inpatientswithrenalinsufficiency,itisimportanttorevisethemaintenanceinfusionratetoaccountforthe
volumeoffluidusedtoinfuseintravenousmedications.

ManagementofhypertensionSeverehypertensioninlaborshouldbetreatedwithintravenouslabetalolorhydralazineororalnifedipinetopreventstroke
(table3).Antihypertensivemedicationsdonotpreventeclampsia.Drugsanddosesarereviewedindetailseparately.(See"Managementofhypertensionin
pregnantandpostpartumwomen",sectionon'Acutetherapy'.)

Seizureprophylaxis

CandidatesforseizureprophylaxisWeadministerintrapartumandpostpartumseizureprophylaxistoallwomenwithpreeclampsia,basedondatafrom
randomizedtrialsthatdemonstratedthatmagnesiumsulfatetreatmentreducedtheriskofeclampsia(see'Drugofchoice:Magnesiumsulfate'below).Although
seizureisaninfrequentoutcomeinwomenwithoutseverefeaturesofpreeclampsiawhodonotreceiveseizureprophylaxis,wefeelthebenefitoftreatmentis
justifiablegiventhelowcostandtoxicityofthetreatmentofchoice:magnesiumsulfate,andtherelativelysmallnumberofpatientsthatneedtobetreatedto
preventoneseizure.IntheMAGPIEtrial(magnesiumsulfateforpreventionofeclampsiatrial),whichincluded10,000patientsandisthelargestrandomized
placebocontrolledtrialthatevaluatedoutcomesbyseverityofdisease,thefrequencyofeclampsiainwomenwithpreeclampsiawithoutseverefeatureswas1.6
percentwithoutprophylaxisversus0.7percentwithprophylaxisabout100womenwithpreeclampsiawithoutseverefeaturesandabout60womenwith
preeclampsiawithseverefeatureswouldneedtobetreatedtopreventoneseizure[40].Althoughnotstatisticallysignificant,prophylaxisalsoreducedtheriskof
maternaldeathinwomenwithoutseverefeaturesofpreeclampsia(RR0.54,95%CI0.201.456/3758[0.16percent]versus11/3710[0.30percent]without
treatment).

Ourrecommendationisincontrasttothe2013AmericanCollegeofObstetriciansandGynecologists'recommendations,whichstatethat"forwomenwith
preeclampsiawithsystolicbloodpressureoflessthan160mmHgandadiastolicbloodpressurelessthan110mmHgandnomaternalsymptoms,itissuggested
thatmagnesiumsulfatenotbeadministereduniversallyforthepreventionofeclampsia"[4].
Itisimportanttoemphasizethatseizureprophylaxisdoesnotpreventprogressionofdiseaseunrelatedtoconvulsions.Approximately10to15percentofwomen
inlaborwithpreeclampsiawithoutseverefeatureswilldevelopsigns\symptomsofpreeclampsiawithseverefeatures(eg,severehypertension,severeheadache,
visualdisturbance,epigastricpain,laboratoryabnormalities)orabruptioplacenta,whetherornottheyreceivemagnesiumtherapy[41,42].

Wedonotadministerseizureprophylaxistowomenwithonlygestationalhypertension(pregnancyrelatedhypertensionwithoutproteinuriaorendorgan
dysfunction),astheseizureriskinthelattergroupislessthan0.1percent[43].(See"Gestationalhypertension".)

Drugofchoice:MagnesiumsulfateMajormedicalorganizationsworldwideconsistentlyrecommendmagnesiumsulfateasthedrugofchoiceforthe
preventionofeclampsia[4,7,44].Inametaanalysisofrandomizedtrialsofwomenwithpreeclampsia(anyseverity),magnesiumsulfatewasmoreeffectivefor
preventionofafirstseizurethanplacebo/notreatment(RR0.41,95%CI0.290.58sixtrials,11,444women),phenytoin(RR0.08,95%CI0.010.60threetrials,
2291women),oranantihypertensivedrugalone(nimodipine,RR0.33,95%CI0.140.77onetrial,1650women)[45].Comparedwithplacebo/notreatment,
magnesiumsulfateresultedinanonstatisticalbutpotentialclinicallyimportantreductioninmaternaldeath(RR0.54,95%CI0.261.10)andaslightincreasein
cesareandeliveries(RR1.05,95%CI1.011.10),withnocleardifferenceinstillbirthorneonataldeath(RR1.04,95%CI0.93to1.15)orseriousmaternal
morbidity(RR1.08,95%CI0.891.32).

Inmetaanalysesofrandomizedtrialsinvolvingeclampticwomen,magnesiumsulfatewassaferandmoreeffectiveforpreventionofrecurrentseizuresthan
phenytoin,diazepam,orlyticcocktail(ie,chlorpromazine,promethazine,andpethidine).Thesedataprovideadditionalindirectevidenceofitseffectivenessin
preeclampsia[4648].(See"Eclampsia",sectionon'Preventionofrecurrentseizures'.)

Themechanismfortheanticonvulsanteffectsofmagnesiumsulfatehasnotbeenclearlydefined.Theprimaryeffectisthoughttobecentral.Hypothesesinclude
raisingtheseizurethresholdbyitsactionatthenmethyldaspartate(NMDA)receptor,membranestabilizationinthecentralnervoussystemsecondarytoits
actionsasanonspecificcalciumchannelblocker,aswellasdecreasingacetylcholineinmotornerveterminals[49,50].Anothertheoryisthatitpromotes
vasodilatationofconstrictedcerebralvesselsbyopposingcalciumdependentarterialvasospasm,therebyreducingcerebralbarotrauma[51].

ContraindicationsMagnesiumsulfateiscontraindicatedinwomenwithmyastheniagravissinceitcanprecipitateaseveremyastheniccrisis.Alternative
anticonvulsantdrugsshouldbeused.(See"Managementofmyastheniagravisinpregnancy",sectionon'Treatmentissues'.)

Althoughatleastoneguidelineconsiderspulmonaryedemaacontraindicationtouseofmagnesiumsulfate[52],theauthorsadministerthedrugcautiouslyto
affectedpatients,withattentiontofluidrestriction,diuresis,andoxygensupplementation.(See"Acuterespiratoryfailureduringpregnancyandtheperipartum
period",sectionon'Pulmonaryedema'.)

RegimenThereisnoconsensusontheoptimalmagnesiumregimen,whenitshouldbestartedandterminated,orrouteofadministration[53].

TimingMagnesiumsulfateforseizureprophylaxisisusuallyinitiatedattheonsetoflabororinduction,orpriortoacesareandelivery[4,54,55].Itis
usuallynotadministeredtostableantepartumpatientsoffthelaborunit,butissometimesgiventowomenwithpreeclampsiawithseverefeatureswhiletheyare
beingconsideredforconservativemanagement.Prolongedantepartumtherapy(morethanfivetosevendays)shouldbeavoidedasithasbeenassociatedwith
adverseeffectsonfetalboneswhenitwasadministeredfortocolysis[56].(See"Expectantmanagementofpreeclampsiawithseverefeatures".)
 DosingThemostcommonmagnesiumsulfateregimen,andtheonethatweuse,isaloadingdoseof6gofa10percentsolutionintravenouslyover15
to20minutesfollowedby2g/hourasacontinuousinfusion[4,42,55,57].Analternativeregimenis5gofa50percentsolutionintramuscularlyintoeachbuttock
(totalof10g)followedby5gintramuscularlyeveryfourhours.Theseregimensgenerallyresultinsimilarmagnesiumlevelshowever,intramuscular
administrationresultsinmorefluctuationandisassociatedwithmoresideeffects,particularlypainattheinjectionsite[58].Publisheddosageregimensfor
magnesiumsulfatevarywidely,withloadingdosesof4to6gintravenouslyandmaintenancedosesof1to3g/hour.

Itisnotnecessarytocheckforatherapeuticdruglevelastheredoesnotappeartobeaclearthresholdconcentrationforensuringthepreventionofconvulsions.
Atherapeuticrangeof4.8to8.4mg/dL(2.0to3.5mmol/L)hasbeenrecommendedbasedonretrospectivedata[59].Loadingdoseslessthan6garemorelikely
toresultinsubtherapeuticmagnesiumlevels(lessthan4.5mg/dL)[57,60].Highermaternalweightincreasesthetimerequiredtoreachsteadystatelevels[61],
whichshouldbeconsideredifthepatienthasaseizureshortlyafterreceivingtheloadingdose.

Clinicalassessmentformagnesiumtoxicityshouldbeperformedeveryonetotwohours.Themaintenancedoseisonlygivenwhenapatellarreflexispresent
(lossofreflexesisthefirstmanifestationofsymptomatichypermagnesemia),respirationsexceed12breaths/minute,andurineoutputexceeds100mLoverfour
hours.

Ifmagnesiumtoxicityissuspected,themaintenancedoseshouldbedecreasedoreliminatedandthemagnesiumlevelshouldbechecked.(See'Toxicity'below.)

RenalinsufficiencyMagnesiumsulfateisexcretedbythekidneys.Womenwithrenalinsufficiencyshouldreceiveastandardloadingdosesincetheir
volumeofdistributionisnotaltered,butareducedmaintenancedose.Wesuggest1g/houriftheserumcreatinineis>1.2and<2.5mg/dL(106to221
micromol/L)andnomaintenancedoseiftheserumcreatinineis2.5mg/dL(221micromol/L)ormagnesiumtoxicityissuspected.

Clinicalassessmentformagnesiumtoxicityshouldbeperformedeveryonetotwohours,andthemaintenancedoseisonlyadministeredwhentherearenosigns
suggestiveoftoxicity,asdescribedabove(see'Dosing'above).Wealsoobtainserummagnesiumlevelseverysixhoursasanadjuncttoclinicalassessmentin
womenwithcompromisedrenalfunction.(See'Toxicity'below.)

SideeffectsRapidinfusionofmagnesiumsulfatecausesdiaphoresis,flushing,andwarmth,probablyrelatedtoperipheralvasodilationandadropinblood
pressure.Nausea,vomiting,headache,muscleweakness,visualdisturbances,andpalpitationscanalsooccur.Dyspneaorchestpainmaybesymptomsof
pulmonaryedema,whichisararesideeffect.(See"Symptomsofhypermagnesemia".)

Althoughmagnesiumsulfateisaweaktocolytic,labordurationdoesnotappeartobeaffectedbyitsadministration[62].Theriskofpostpartumhemorrhage,
possiblyrelatedtouterineatonyfrommagnesium'stocolyticeffects,wasslightlyincreasedinonetrial[63].

Magnesiumtherapyresultsinatransientreductionoftotalandionizedserumcalciumconcentrationduetorapidsuppressionofparathyroidhormonerelease
[64].Rarely,hypocalcemiabecomessymptomatic(myoclonus,delirium,electrocardiogramabnormalities).Cessationofmagnesiumtherapywillrestorenormal
serumcalciumlevels.However,calciumgluconateadministrationmayberequiredforpatientswithsignificantsymptoms(calciumgluconate10to20mLofa10
percentsolution).(See"Symptomsofhypermagnesemia",sectionon'Hypocalcemia'and"Causesandtreatmentofhypermagnesemia".)
 ToxicityMagnesiumtoxicityisuncommoninwomenwithgoodrenalfunction[65].Toxicitycorrelateswiththeserummagnesiumconcentration:lossofdeep
tendonreflexesoccursat7to10mEq/L(8.5to12mg/dLor3.5to5.0mmol/L),respiratoryparalysisat10to13mEq/L(12to16mg/dLor5.0to6.5mmol/L),
cardiacconductionisalteredat>15mEq/L(>18mg/dLor>7.5mmol/L),andcardiacarrestoccursat>25mEq/L(>30mg/dLor>12.5mmol/L)[66].

WhentocheckmagnesiumlevelsWeobtainserummagnesiumlevelseverysixhoursasanadjuncttoclinicalassessmentinpatientswhohave:

Aseizurewhilereceivingmagnesiumsulfate
Clinicalsigns/symptomssuggestiveofmagnesiumtoxicity(eg,absentpatellarreflex,respiratoryrate12breaths/minute)
Renalinsufficiency(creatinine>1.2mg/dL[106micromol/L)

Followingserummagnesiumlevelsisnotrequiredifthewoman'sclinicalstatusiscloselymonitoredeveryonetotwohoursforsignsandsymptomsofpotential
magnesiumtoxicityandnoabnormalitiesarenoted.

AntidoteCalciumgluconate15to30mLofa10percentsolution(1500to3000mg)intravenouslyover2to5minutesisadministeredtopatientsin
cardiacarrestorwithseverecardiactoxicityrelatedtohypermagnesemia[67].Astartingdoseof10mLofa10percentsolution(1000mg)isusedforpatients
withlesssevere,butlifethreateningcardiorespiratorycompromise.

Calciumchloride5to10mLofa10percentsolution(500to1000mg)intravenouslyovertwotofiveminutesisanacceptablealternativebutismoreirritatingand
morelikelytocausetissuenecrosiswithextravasation.

FetaleffectsMagnesiumfreelycrossestheplacentaasaresult,thecordbloodconcentrationapproximatesthematernalserumconcentration.Maternal
therapycausesadecreaseinbaselinefetalheartrate,whichgenerallyremainswithinthenormalrange,andadecreaseinfetalheartratevariability,whichmay
beabsentorminimal[68].Antenatalfetalassessmenttestresults(eg,biophysicalprofilescoreandnonstresstestreactivity)arenotsignificantlyaltered[69].

DruginteractionsNeuromuscularblockadeandhypotensionduetoconcurrentuseofmagnesiumsulfateandcalciumchannelblockershavebeen
describedincasereports,buttheriskappearstobeminimal[70].Postpartumpatientsreceivingbothmagnesiumsulfateandopioidsareatahigherriskfor
cardiopulmonarydepression.(See'Generalpostpartumcare'below.)

DurationoftherapyMagnesiumsulfateisusuallycontinuedfor24hourspostpartum[55].Timingofdrugdiscontinuationhasbeenarbitrarythereareno
highqualitydatatoguidetherapy.Inmostwomenwhohavepreeclampsiawithoutseverefeatures,therapycanbesafelydiscontinuedafter12hours[71].In
womenwithpreeclampsiawithseverefeaturesoreclampsia,seizureprophylaxisisgenerallycontinuedfor24to48hourspostpartum,afterwhichtheriskof
recurrentseizuresislow.

Itisprobablyreasonabletoextendthedurationofmagnesiumsulfatetherapyinwomenwhosediseasehasnotbeguntoimprovepostpartumandshortenthe
durationoftherapyinwomenwhoareclearlyimprovingclinically(eg,diuresisof100mL/hourfortwoconsecutivehours,absenceofsymptoms[headache,visual
changes,epigastricpain],andabsenceofseverehypertension)[7275].Diuresis(greaterthan4L/day)isbelievedtobethemostaccurateclinicalindicatorof
resolutionofpreeclampsia/eclampsia,butisnotaguaranteeagainstthedevelopmentofseizures[76].Inwomenwithpersistentrenalimpairmentpostpartum,itis
importanttobecautiouswhenprolongingthemagnesiumsulfateinfusionsincethesepatientsareatincreasedriskformagnesiumtoxicity.
ManagementofthrombocytopeniaTheriskofbleedingduetothrombocytopeniaisgenerallyconsideredtoincreaseonlywhentheplateletcountisbelow
100,000/microL,andtheriskincreasessubstantiallyonlywithplateletcountsbelow50,000/microL.Platelettransfusionshouldnotbeusedtonormalizethe
plateletcountinnonbleedingpatients,aslongastheplateletcountisabove10,000to20,000/microL.However,plateletsshouldnotbewithheldfromapatient
withpotentiallylifethreateningbleedingoronewhorequiresahigherplateletcounttopreventbleedinginahighrisksetting,suchassurgery.(See
"Thrombocytopeniainpregnancy".)

Althoughaplateletcount>50,000/microLisgenerallyconsideredsafefordelivery(vaginalorcesarean)[77,78],achievementofaspecificplateletthresholddoes
notsubstituteforclinicaljudgmentinpreparationforandmanagementofdelivery.Forseverelythrombocytopenicpatients(plateletcount<20,000/microL),both
authorsnotifythebloodbankandhaveplateletsreadilyavailableinthedeliveryroomfortransfusionincaseexcessivebleedingdevelopsatvaginaldeliveryor
excessiveoozingisobservedatthetimeoftheskinincisionatcesarean.Excessivelybleedingpatientsaretransfused.

Thedecisionforprophylacticplatelettransfusioninwomenwithseverepreeclampsiarelatedthrombocytopeniabutnoexcessivebleedingdependsonpatient
specificfactorsconsultationwiththehematologyservicemaybehelpful.Patientspecificfactorsthatmayinfluencetheauthors'decisiontoinitiateprophylactic
platelettransfusionincludearapidlyfallingplateletcount,recentuseoflowdoseaspirin,coexistentabruption,andseverehypertension,becauseallofthese
factorsmayimpacttheriskofclinicalbleedingorcerebrovascularaccident.

TheAmericanCollegeofObstetriciansandGynecologistshasnotmadeaspecificrecommendation[79]butcitesanAABBguidelinethatrecommendsplatelet
transfusiontoincreasethematernalplateletcountto>50,000/microLbeforemajorelectivenonneuraxialsurgery(weakrecommendationbasedonverylow
qualityevidence)[80].

Theminimumplateletcountbeforeplacementofneuraxialanesthesiaiscontroversial,dependsonfactorsinadditiontoplateletconcentration,andisinstitution
dependent.(See"Adverseeffectsofneuraxialanalgesiaandanesthesiaforobstetrics",sectionon'Neuraxialanalgesiaandlowplatelets'.)

Glucocorticoidtherapydoesnotappeartobeeffectiveforsignificantlyraisingtheplateletcountinwomenwithpreeclampsia[81],butavailabledatainwomenwith
preeclampsiaorHELLPsyndrome[82]arelimitedbythesmallnumberofsubjectsinthetrials.Wedonotadministersteroidstoraisetheplateletcountinpatients
withthesedisorders.(See"HELLPsyndrome",sectionon'RoleofdexamethasonefortreatmentofHELLP'.)

AnalgesiaandanesthesiaNeuraxialtechniquesaregenerallysafeandeffectiveinpreeclampticwomen[4,83].Inpreeclampsia,thetwomajoranesthesia
relatedconcernswithuseofneuraxialtechniquesare(1)thepotentialforalargedropinbloodpressureduetothecombinationofdepletedintravascularvolume
andsympatheticblockadeand(2)periduralhematomainwomenwithseverethrombocytopenia.Theformercanbeminimizedbyappropriateadjustmentsinpre
hydration,drugchoice,drugdosing,anddrugdeliverybytheanesthesiologisthowever,asdiscussedabove,alowplateletcountmayprecludeneuraxial
anesthesia.Theplateletcountnecessarytosafelyperformneuraxialanesthesiaisunknown[84],andpracticevaries.(See"Anesthesiaforthepatientwith
preeclampsia".)

Themajorconcernsassociatedwithgeneralanesthesia(forcesareandelivery)aredifficultorfailedintubationbecauseoforopharyngealedema,atransientspike
inbloodpressureduringintubationasaresponsetonoxiousstimuli,andhypotensionfromanestheticinducedreductionincardiacoutputandsystemicvascular
resistance.Giventheseissues,earlypatientassessmentbytheanesthesiateamisdesirable.(See"Anesthesiaforthepatientwithpreeclampsia".)
CranialimagingMostpatientswithsymptomsassociatedwiththeseverespectrumofthediseaserespondtotreatmentwithantihypertensiveandanalgesic
medications.Forthosewitheitherunremittingheadacheorneurologicsigns/symptoms,weconsulttheneurologyserviceandleavedecisionsforfurther
evaluation,suchascranialimaging,tothem.

POSTPARTUMCARE

GeneralpostpartumcareTherearenoevidencebasedstandardsfortheoptimalapproachtopostpartummaternalmonitoringandfollowup.Wemonitor
vitalsignseverytwohourswhilethepatientremainsonmagnesiumsulfate,andwerepeatlaboratorytests(eg,plateletcount,creatinine,liverfunctiontests)until
twoconsecutivesetsofdataarenormal.

Postpartumpatientsreceivingbothmagnesiumandopioidsareatahigherriskforcardiopulmonarydepression.Painshouldbecontrolledwiththeminimally
effectivedoseofopioidwhilerecognizingthepossiblesynergybetweenthetwodrugswithrespecttorespiratorydepression.Vitalsignsarecloselymonitored,
ideallyinassociationwithpulseoximetry.Itmaybenecessarytoreducethedoseofoneorbothdrugs,andpatientswithserioustoxicitymayrequireanantidote
(calciumgluconate,naloxone).(See"Paincontrolinthecriticallyilladultpatient",sectionon'Typeandmanagementofsideeffects'.)

Nonsteroidalantiinflammatorydrugs(NSAIDs)forpaincontrolshouldbeavoidedinwomenwithpoorlycontrolledhypertension,oliguria,orrenalinsufficiency,
sinceNSAIDscanhaveanadverseeffectontheseconditions.(See"NonselectiveNSAIDs:Overviewofadverseeffects".)

Severehypertensionshouldbetreatedsomepatientswillhavetobedischargedonantihypertensivemedications,whicharediscontinuedwhenbloodpressure
returnstonormal.(See"Managementofhypertensioninpregnantandpostpartumwomen",sectionon'Postpartumhypertension'.)

TheAmericanCollegeofObstetriciansandGynecologistssuggestsmonitoringbloodpressureinhospitalorathomeforthefirst72hourspostpartumandagain7
to10dayspostdelivery[4].Somepatientswillrequirelongermonitoringcontinuedfollowupisneededuntilallofthesignsandsymptomsofpreeclampsiahave
resolved.Alternativediagnosesshouldbesoughtinthosewithpersistentabnormalfindingsafterthreetosixmonths[85].(See"Overviewofhypertensionin
adults".)

WomenwithpostpartumonsetofpreeclampsiaSomewomenareinitiallydiagnosedwithpreeclampsiaafterdelivery.TheAmericanCollegeof
ObstetriciansandGynecologistssuggestsadministrationofmagnesiumsulfatetothosewith(1)newonsethypertensionandheadacheorblurredvision,or(2)
severehypertension[4].Antihypertensivetherapyshouldbeadministeredtowomenwithsystolicbloodpressure150mmHgordiastolicbloodpressure100
mmHgontwooccasionsfourtosixhoursapart,butwithinonehourifsystolicbloodpressureis160mmHgordiastolicbloodpressureis110mmHg.(See
"Managementofhypertensioninpregnantandpostpartumwomen",sectionon'Acutetherapy'.)

PROGNOSISPrognosticissuesincludetheriskofrecurrentpreeclampsiaandrelatedcomplicationsinsubsequentpregnanciesandlongtermmaternalhealth
risks.

RecurrenceA2015metaanalysisofindividualpatientdatafromover75,000womenwithpreeclampsiawhobecamepregnantagainfoundthat16percent
developedrecurrentpreeclampsiaand20percentdevelopedhypertensionaloneinasubsequentpregnancy[86].
Therecurrenceriskvarieswiththeseverityandtimeofonsetoftheinitialepisode[87].Womenwithearlyonset,severepreeclampsiaareatgreatestriskof
recurrence(ashighas25to65percent)[8890].Theriskofpreeclampsiainasecondpregnancyismuchlower(5to7percent)forwomenwhohad
preeclampsiawithoutseverefeaturesintheirfirstpregnancyandlessthan1percentinwomenwhohadanormotensivefirstpregnancy(doesnotapplyto
abortions)[88,9196].Theserelationshipswereillustratedbyaseriesof125womenwithseveresecondtrimesterpreeclampsiafollowedforfiveyears:65percent
developedrecurrentpreeclampsiaand35percentwerenormotensiveintheirsubsequentpregnancy[88].Ofthepreeclampticgroup,approximatelyonethird
developedthediseaseat27weeks,onethirdat28to36weeks,andonethirdat37weeks.Thus,21percentofsubsequentpregnancieswerecomplicatedby
severepreeclampsiainthesecondtrimester.

Recurrentpreeclampsiaismorelikelyfollowingapreeclampticsingletonpregnancythanapreeclamptictwinpregnancy[97].Therecurrenceriskinwomenwith
HELLPsyndrome(whomaydevelopeitherHELLPorpreeclampsiainasubsequentpregnancy)isdiscussedseparately.(See"HELLPsyndrome",sectionon
'Recurrenceinsubsequentpregnancies'.)

PreventionofrecurrenceLowdoseaspirintherapyduringpregnancymodestlyreducestheriskofpreeclampsiainwomenathighriskfordevelopingthe
disease.Selectionofcandidatesforprophylaxis,drugdosing,andevidenceofefficacyarereviewedindetailseparately.Anticoagulationdoesnotprevent
recurrence[98].(See"Preeclampsia:Prevention".)

RiskofrelatedobstetricalcomplicationsPreeclampsia,growthrestriction,pretermdelivery,abruptioplacenta,andstillbirthcanallbesequelaeofischemic
placentaldisease.Womenwithpregnanciescomplicatedbyoneofthesedisordersareatincreasedriskofdevelopingoneoftheotherdisordersinfuture
pregnancies[99,100].Earlyonsetpreeclampsiaismorelikelytobeassociatedwithoneoftheseadverseeventsinasubsequentpregnancy,evenif
normotensive,thanlateonsetpreeclampsia[101,102].

Longtermmaternalrisksofpregnancyassociatedhypertension

CardiovasculardiseaseTheAmericanHeartAssociationconsidersahistoryofpreeclampsiaorpregnancyinducedhypertensionamajorriskfactorfor
developmentofcardiovasculardisease[103].Thisconclusionisbasedonconsistentfindingsfromcasecontrolandcohortstudies.Thefutureriskof
cardiovascularmorbidityandmortalityappearstoberelatedtotheseverityofpreeclampsia,thegestationalagewhendeliverywasrequired,andthenumberof
diseaserecurrences[104].Womenwithearlyonset/severepreeclampsiawithpretermdeliveryareathighestriskofcardiovasculardiseaselaterinlife,including
duringthepremenopausalperiod(table4).

Therelationshipbetweenpreeclampsiaandcardiovasculardiseasewasillustratedintwosystematicreviewsofcontrolledstudiesthatevaluatedtheriskoflate
cardiovasculareventsinwomenwithandwithoutahistoryofpreeclampsia[105,106]:

Comparedwithwomenwithnohistoryofthedisease,womenwithpreeclampsiawereatincreasedriskofdevelopinghypertension(RR3.70,95%CI2.70
5.05atmeanfollowupof14years),ischemicheartdisease(RR2.16,95%CI1.862.52atmeanfollowupof11.7years),stroke(RR1.81,95%CI1.452.27
atmeanfollowupof10.4years),andvenousthromboembolism(RR1.79,95%CI1.372.33atmeanfollowupof4.7years)[105].Theabsoluteriskthata
womanwithorwithoutahistoryofpreeclampsiawoulddeveloponeofthesecardiovasculareventsatage50to59yearswasestimatedtobe17.8and8.3
percent,respectively.
 Agradedrelationshipwasobservedbetweenseverityofpreeclampsiaandriskoffuturecardiacdisease(mildpreeclampsiaRR2.00,95%CI1.832.19
moderatepreeclampsiaRR2.99,95%CI2.513.58severepreeclampsiaRR5.36,95%CI3.967.27),aswellasacorrelationbetweenpreeclampsiaand
futureperipheralarterydisease(RR1.87,95%CI0.943.73)[106].Theauthorsdefinedpreeclampsiaas"mild"ifthepregnancyhadanuncomplicated
course,"moderate"ifpreeclampsiawascomplicatedbyfetalgrowthrestrictionormaternalseizures,and"severe"ifpreeclampsiawascomplicatedby
pretermdeliveryorfetaldemise.

Prospectivecohortstudiespublishedafterthesereviewshavereportedsimilarfindings[107110].Oneofthesestudieshad30yearsoffollowupandnotedthat,
comparedwithwomenwithnohistoryofpreeclampsia,theriskofdeathfromcardiovasculardiseasewasincreasedtwofoldinwomenwithpreeclampsiaonset
>34weeksofgestationandincreased9to10foldinwomenwithpreeclampsiaonset<34weeks[109].

Inaddition,preeclampsiaisaknownriskfactorforcardiomyopathy,bothperipartum(see"Peripartumcardiomyopathy:Etiology,clinicalmanifestations,and
diagnosis")andyearsafterdelivery.Inaretrospectivepopulationbasedcohortstudy,womenwithahistoryofpreeclampsiaorgestationalhypertensionwereat
increasedriskofcardiomyopathyfor>5yearsafterdeliverycomparedwithwomenwithoutsuchahistory[111].Elevenpercentofallcardiomyopathyeventsinthe
cohortoccurredamongwomenwithahistoryofpreeclampsiaorgestationalhypertensionandabout50percentoftheassociationwasrelatedtopostpregnancy
chronichypertension.However,theabsoluteriskofcardiomyopathywassmall:14.6to17.3cases/100,000personyears.

Someepidemiologicdatasuggestthattheincreasedriskoflatecardiovascularmorbidity/mortalityinapreviouslypreeclampticwomancanbeattributedto
underlyinggeneticfactorsandriskfactorsthatarecommontobothdisorders[112115].Itisalsopossiblethatpreeclampsiainducedphysiologicandmetabolic
changesassociatedwithcardiovasculardisease,suchasendothelialdysfunction[116119],insulinresistance,sympatheticoveractivity,proinflammatoryactivity,
andabnormallipidprofile[120],remainafterdelivery,leadingtolatecardiovasculardisease[121125]andotherdisordersassociatedwiththeseabnormalities.In
onestudy,20percentofwomenwithbothpreeclampsiaandagrowthrestrictednewbornmetcriteriaformetabolicsyndromewhenevaluatedseveralmonths
postpartum[126].

Itisestimatedthatlifestyleinterventionsafterpreeclampsiawoulddecreaseawoman'scardiovasculardiseaseriskby4to13percent[127].Assessmentof
cardiovascularriskfactors,typeandfrequencyofpatientmonitoring,andriskreductionstrategiesarereviewedseparately.(See"Overviewofprimaryprevention
ofcoronaryheartdiseaseandstroke".)

DiabetesmellitusWomenwithahistoryofpreeclampsiaorgestationalhypertensionmaybeatincreasedriskofdevelopingdiabetes[128131]however,
theavailableevidencedoesnotsupportachangeinstandardscreeningguidelines.(See"Screeningfortype2diabetesmellitus",sectionon'Screening
recommendationsbyexpertgroups'.)

Inapopulationbasedretrospectivecohortstudyincludingoveronemillionwomen,preeclampsiaorgestationalhypertensionintheabsenceofgestational
diabetesmellitus(GDM)wasassociatedwithatwofoldincreaseintheincidenceofdiabetesduring16.5yearsofpostdeliveryfollowup,aftercontrollingfor
severalconfoundingvariables(buttheauthorsdidnotcontrolforobesity)[128].InwomenwhohadpreeclampsiaorgestationalhypertensionandGDM,therisk
offuturediabeteswasincreased16to18fold,whichwasabovethealreadyelevated13foldincreaseinriskassociatedwithGDMalone.Previousstudieshave
reportedsimilarfindings[129131].
 EndstagerenaldiseaseWomenwithpreeclampsiamaybeatincreasedriskofdevelopingendstagerenaldisease(ESRD)laterinlife,buttheabsolute
riskissmall,andevaluationofasymptomaticwomenisnotwarranted.AstudythatlinkedfourdecadesofdatafromtheNorwegiannationalbirthandESRD
registriesfoundthatwomenwithpreeclampsiaintheirfirstpregnancyhadafourfoldincreaseinriskofESRDcomparedwithwomenwithoutpreeclampsia(RR
4.7,95%CI3.66.1)afteradjustingforknownconfounders,buttheabsoluteriskofESRDwaslessthan1percentwithin20years[132].Similarly,astudyusing
claimsdatafromtheTaiwanNationalHealthInsuranceProgramnotedthatwomenwithpreeclampsia/eclampsiawereatsignificantlyhigherriskofdeveloping
ESRDovertimethanwomenwithouthypertensivedisordersduringpregnancy(incidence5.33versus0.34per10,000personyears)[133].

AlthoughwomenwhowentontodevelopESRDmayhavehadsubclinicalrenaldiseaseduringpregnancy,itisalsopossiblethatasyetundefinedriskfactors
predisposedthesewomentobothpreeclampsiaandESRD.Itislesslikelythatpreeclampsiadamagesthekidney,therebyinitiatingaprocessofchronic
deterioration.

SubclinicalhypothyroidismInanestedcasecontrolstudy,nulliparouswomenwhodevelopedpreeclampsiaweretwiceaslikelytodevelopsubclinical
hypothyroidismduringpregnancyandlongafterdeliverycomparedwithmatchednormotensivecontrols[134].Theriskwashighestinwomenwithrecurrent
preeclampsiaandwithoutthyroidperoxidaseantibodies,suggestinganautoimmunemediatedmechanismofhypothyroidismwasnotinvolved.Inastudy
including25,000pregnantwomen,womenwithsubclinicalhypothyroidismidentifiedduringpregnancywereatincreasedriskofdevelopingseverepreeclampsia
comparedwitheuthyroidwomen(oddsratio1.6,95%CI1.12.4),afteradjustmentforriskfactorsforpreeclampsia[135].Abnormallevelsofthyroidhormones
appeartodamageendothelialcells,potentiallyleadingtopreeclampsiaandlongtermcardiovascularsequelae.

Allpatientswithsymptomsofhypothyroidism(table5)shouldbeevaluatedforhypothyroidism.Screeningofasymptomaticindividualsiscontroversial.(See
"Diagnosisofandscreeningforhypothyroidisminnonpregnantadults",sectionon'Candidatesforscreening'.)

CancerAntiangiogenesisisakeycharacteristicofpreeclampsia.Becauseantiangiogenesisisalsoimportantforrestrictingtumorgrowth,ithasbeen
hypothesizedthatwomenwithpreeclampsiamaybeatreducedriskoffuturedevelopmentofsolidcancers.However,asystematicreviewofprospectiveand
retrospectivecohortstudiesfoundnosignificantassociationbetweenpreeclampsiaandlaterdevelopmentofcancer[105].

INFORMATIONFORPATIENTSUpToDateofferstwotypesofpatienteducationmaterials,"TheBasics"and"BeyondtheBasics."TheBasicspatient
educationpiecesarewritteninplainlanguage,atthe5thto6thgradereadinglevel,andtheyanswerthefourorfivekeyquestionsapatientmighthaveabouta
givencondition.Thesearticlesarebestforpatientswhowantageneraloverviewandwhoprefershort,easytoreadmaterials.BeyondtheBasicspatient
educationpiecesarelonger,moresophisticated,andmoredetailed.Thesearticlesarewrittenatthe10thto12thgradereadinglevelandarebestforpatientswho
wantindepthinformationandarecomfortablewithsomemedicaljargon.

Herearethepatienteducationarticlesthatarerelevanttothistopic.Weencourageyoutoprintoremailthesetopicstoyourpatients.(Youcanalsolocate
patienteducationarticlesonavarietyofsubjectsbysearchingon"patientinfo"andthekeyword(s)ofinterest.)

Basicstopics(see"Patienteducation:Preeclampsia(TheBasics)"and"Patienteducation:Highbloodpressureandpregnancy(TheBasics)"and"Patient
education:HELLPsyndrome(TheBasics)")

BeyondtheBasicstopics(see"Patienteducation:Preeclampsia(BeyondtheBasics)")
SUMMARYANDRECOMMENDATIONS

Thedefinitivetreatmentofpreeclampsiaisdeliverytopreventdevelopmentofmaternalorfetalcomplicationsfromdiseaseprogression.Timingofdeliveryis
basedupongestationalage,theseverityofpreeclampsia,andmaternalandfetalcondition.(See'Introduction'above.)

Preeclampsiawithfeaturesofseveredisease(table2)isgenerallyregardedasanindicationfordelivery,regardlessofgestationalage,giventhehighriskof
seriousmaternalmorbidity.However,prolongedantepartummanagementinatertiarycaresettingorinconsultationwithamaternalfetalmedicinespecialist
isanoptionforselectedwomenremotefromterm(<34weeksofgestation).(See'Preeclampsiawithfeaturesofseveredisease'above.)

Antihypertensivetherapyisindicatedfortreatmentofseverehypertension(systolicbloodpressure160mmHganddiastolicbloodpressure110mmHg)to
preventstroke(table3)itdoesnotpreventeclampsia.Antihypertensivetherapytocontrolmildhypertensiondoesnotalterthecourseofpreeclampsiaor
diminishperinatalmorbidityormortality,andshouldbeavoidedinmostpatients.(See"Managementofhypertensioninpregnantandpostpartumwomen",
sectionon'Preeclampsia'.)

Forwomenwithpreeclampsiawithoutfeaturesofseveredisease,wesuggestconservativemanagementwithdeliverywhenthepregnancyhasreached37
weeksofgestation(Grade2B).(See'Preeclampsiawithoutfeaturesofseveredisease'above.)

Expectantmanagementofwomenwithpreeclampsiawithoutfeaturesofseverediseaseconsistsoffrequentlaboratorymonitoring(plateletcount,liverand
renalfunctiontests),assessmentofmaternalbloodpressureandsymptoms,andevaluationoffetalgrowthandwellbeing.Inmostpatients,antihypertensive
therapyisnotindicatedforsystolicbloodpressure<160mmHgordiastolicbloodpressure<110mmHg.(See'Componentsofconservativemanagement'
above.)

Forwomenwithaviablefetusandpreeclampsia<34weeksofgestation,werecommendacourseofantenatalglucocorticoids(betamethasone)(Grade1A).
Useofsteroidsat34to36weeksiscontroversial.(See"Antenatalcorticosteroidtherapyforreductionofneonatalmorbidityandmortalityfrompreterm
delivery",sectionon'23to34weeks'and"Antenatalcorticosteroidtherapyforreductionofneonatalmorbidityandmortalityfrompretermdelivery",sectionon
'After34weeks'.)

Forwomenwithpreeclampsiaandfeaturesofseveredisease,werecommendintrapartumandpostpartumseizureprophylaxis(Grade1A).Thebenefitof
seizureprophylaxisislessclearinwomenwithoutseverehypertensionorpreeclampsiasymptomshowever,wealsosuggestintrapartumandpostpartum
prophylaxisforthesewomen(Grade2B).Werecommendtheuseofmagnesiumsulfateasafirstlineagentforseizureprophylaxisinpreeclampsia(Grade
1A).(See'Seizureprophylaxis'above.)

Wegivealoadingdoseof6gmagnesiumsulfateintravenouslyover15to20minutesfollowedby2g/hourasacontinuousinfusion.Themaintenancedose
isonlygivenwhenapatellarreflexispresent(lossofreflexesisthefirstmanifestationofsymptomatichypermagnesemia),respirationsexceed12
breaths/minute,andurineoutputexceeds100mLoverfourhours.(See'Dosing'above.)

Themaintenancedose(butnottheloadingdose)shouldbeadjustedinwomenwithrenalinsufficiency.Weuse1g/houriftheserumcreatinineis>1.2and
<2.5mg/dL(106to221micromol/L)andnomaintenancedoseiftheserumcreatinineis2.5mg/dL(221micromol/L).(See'Renalinsufficiency'above.)
 Magnesiumtoxicityisuncommoninwomenwithgoodrenalfunction.Toxicityisrelatedtoserummagnesiumconcentration:lossofdeeptendonreflexes
occursat7to10mEq/L(8.5to12mg/dLor3.5to5.0mmol/L),respiratoryparalysisat10to13mEq/L(12to16mg/dLor5.0to6.5mmol/L),cardiac
conductionisalteredat>15mEq/L(>18mg/dLor>7.5mmol/L),andcardiacarrestoccursat>25mEq/L(>30mg/dLor>12.5mmol/L).(See'Toxicity'
above.)

Clinicalassessmentformagnesiumtoxicityshouldbeperformedeveryonetotwohours.Weobtainserummagnesiumlevelseverysixhoursasanadjunctto
clinicalassessmentinpatientswhohaveaseizurewhilereceivingmagnesiumsulfate,clinicalsigns/symptomssuggestiveofmagnesiumtoxicity,orrenal
insufficiency.(See'Whentocheckmagnesiumlevels'above.)

Calciumgluconate15to30mLofa10percentsolutionintravenouslyover2to5minutesisadministeredtowomenwithcardiacarrestorseverecardiac
toxicityrelatedtohypermagnesemia.Astartingdoseof10mLofa10percentsolutionisusedforpatientswithlessseverebutlifethreatening
cardiorespiratorycompromise.(See'Antidote'above.)

Forseverelythrombocytopenicpatients,wenotifythebloodbankandhaveplateletsreadilyavailablefortransfusionincaseexcessivebleedingdevelopsat
vaginaldeliveryorexcessiveoozingisobservedatthetimeofskinincisionatcesarean.Thedecisionforprophylacticplatelettransfusioninwomenwith
severepreeclampsiarelatedthrombocytopeniabutnoexcessivebleedingdependsonpatientspecificfactorsconsultationwiththehematologyservicemay
behelpful.(See'Managementofthrombocytopenia'above.)

Fluidbalanceshouldbemonitoredcloselytoavoidexcessiveadministration,whichcanleadtopulmonaryedema.Amaintenanceinfusionofabalancedsalt
orisotonicsalinesolutionatabout80mL/hourisoftenadequate.Oliguriathatdoesnotrespondtoamodesttrialofincreasedfluids(eg,a300mLfluid
challenge)suggestsrenalinsufficiencyandshouldbetoleratedtoreducethepotentialforiatrogenicpulmonaryedema.(See'Fluids'above.)

Thereisanincreasedriskofpreeclampsiarecurrenceinsubsequentpregnancies.Earlyonsetpreeclampsiawithseverefeatureshasahigherriskof
recurrencethanmilderdiseasewithonsetatterm.(See'Prognosis'above.)

TheAmericanHeartAssociationconsidersahistoryofpreeclampsiaorpregnancyinducedhypertensionamajorriskfactorfordevelopmentof
cardiovasculardisease(see'Cardiovasculardisease'above).Routinewellwomancareshouldincludeassessmentofcardiovascularriskfactors,with
appropriatepatientmonitoringandriskreductioninterventions,whenindicated.(See"Overviewofprimarypreventionofcoronaryheartdiseaseandstroke".)

UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.

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Topic6825Version77.0
GRAPHICS

Criteriaforthediagnosisofpreeclampsia

Systolicbloodpressure140mmHgordiastolicbloodpressure90mmHgontwooccasionsatleastfourhoursapartafter20weeksofgestationina
previouslynormotensivepatient

Ifsystolicbloodpressureis160mmHgordiastolicbloodpressureis110mmHg,confirmationwithinminutesissufficient

and

Proteinuria0.3gina24hoururinespecimenorprotein/creatinineratio0.3(mg/mg)(30mg/mmol)

Dipstick1+ifaquantitativemeasurementisunavailable

OR

Newonsethypertensionwiththenewonsetofanyofthefollowing(withorwithoutproteinuria):

Plateletcount<100,000/microL

Serumcreatinine>1.1mg/dL(97.2micromol/L)

Livertransaminasesatleasttwicetheupperlimitofthenormalconcentrationsforthelocallaboratory

Pulmonaryedema

Cerebralorvisualsymptoms(eg,newonsetandpersistentheadachesnotrespondingtousualdosesofanalgesicsblurredvision,flashinglightsorsparks,scotomata)

*Eachmeasuredasmg/dL.

Datafrom:AmericanCollegeofObstetriciansandGynecologists,TaskForceonHypertensioninPregnancy.Hypertensioninpregnancy.ReportoftheAmericanCollegeof
ObstetriciansandGynecologists'TaskForceonHypertensioninPregnancy.ObstetGynecol2013122:1122.

Graphic79977Version21.0
Inapatientwithpreeclampsia,thepresenceofoneormoreofthefollowingindicatesadiagnosisof"preeclampsiawith
severefeatures"

Symptomsofcentralnervoussystemdysfunction:
Newonsetcerebralorvisualdisturbance,suchas:
Photopsia,scotomata,corticalblindness,retinalvasospasm
Severeheadache(ie,incapacitating,"theworstheadacheI'veeverhad")orheadachethatpersistsandprogressesdespiteanalgesictherapy
Alteredmentalstatus

Hepaticabnormality:
Severepersistentrightupperquadrantorepigastricpainunresponsivetomedicationandnotaccountedforbyanalternativediagnosisorserumtransaminaseconcentration2timestheupper
limitofthenormalrange,orboth

Severebloodpressureelevation:
Systolicbloodpressure160mmHgordiastolicbloodpressure110mmHgontwooccasionsatleastfourhoursapartwhilethepatientisonbedrest(antihypertensivetherapymaybeinitiated
uponconfirmationofseverehypertension,inwhichcasecriteriaforseverebloodpressureelevationcanbesatisfiedwithoutwaitinguntilfourhourshaveelapsed)

Thrombocytopenia:
<100,000platelets/microL

Renalabnormality:
Progressiverenalinsufficiency(serumcreatinine>1.1mg/dL[97.2micromol/L]oradoublingoftheserumcreatinineconcentrationintheabsenceofotherrenaldisease)

Pulmonaryedema

Incontrasttooldercriteria,the2013criteriadonotincludeproteinuria>5g/24hoursandfetalgrowthrestrictionasfeaturesofseveredisease.

Adaptedfrom:Hypertensioninpregnancy:ReportoftheAmericanCollegeofObstetriciansandGynecologists'TaskForceonHypertensioninPregnancy.ObstetGynecol2013
122:1122.

Graphic76975Version18.0
Peripheralsmearinmicroangiopathichemolyticanemia
showingpresenceofschistocytes

Peripheralbloodsmearfromapatientwithamicroangiopathichemolyticanemia
withmarkedredcellfragmentation.Thesmearshowsmultiplehelmetcells
(arrows)andotherfragmentedredcells(smallarrowhead)microspherocytes
arealsoseen(largearrowheads).Theplateletnumberisreducedthelarge
plateletinthecenter(dashedarrow)suggeststhatthethrombocytopeniaisdue
toenhanceddestruction.

CourtesyofCarolavonKapff,SH(ASCP).

Graphic70851Version8.0

Normalperipheralbloodsmear
Highpowerviewofanormalperipheralbloodsmear.Severalplatelets
(arrows)andanormallymphocyte(arrowhead)canalsobeseen.Thered
cellsareofrelativelyuniformsizeandshape.Thediameterofthenormalred
cellshouldapproximatethatofthenucleusofthesmalllymphocytecentral
pallor(dashedarrow)shouldequalonethirdofitsdiameter.

CourtesyofCarolavonKapff,SH(ASCP).

Graphic59683Version4.0
Helmetcellsinmicroangiopathichemolyticanemia

Peripheralsmearsfromtwopatientswithmicroangiopathichemolyticanemia,
showinganumberofredcellfragments(ie,schistocytes),someofwhichtakethe
formofcombat(arrow),bicycle(arrowhead),orfootball(shortarrow)"helmets."
Microspherocytesarealsoseen(dashedarrows),alongwithanucleatedredcell
(thickarrow).

CourtesyofCarolavonKapff,SH(ASCP).

Graphic50715Version4.0
Treatmentofacuteseverehypertensioninpregnancy
Drug
Labetalol
Hydralazine
Nifedipineimmediaterelease
Nifedipineextendedrelease
Nicardipine(parenteral)
Initialdose
20mgIVover2minutes.
AcontinuousIVinfusionof1to2mg/minutecanbeusedinstead
ofintermittenttherapyorstartedafter20mgIVdose.
Requiresuseofprogrammableinfusionpumpandcontinuous
noninvasivemonitoringofbloodpressureandheartrate.
5mgIVover1to2minutes.*
HypotensiveresponseislesspredictablethanwithIVlabetalol.
10mgorally.
MaybeassociatedwithprecipitousdropsinBPinsomewomen.
UpToDateauthorsthereforecautionagainstuse.Ifused,fetalheart
rateshouldbemonitoredwhileadministeringshortacting
nifedipine.
30mgorally.
AcontinuousIVinfusionof3to9mg/hour.
Onsetofactionisdelayedby5to15minutesingeneral,rapid
titrationisavoidedtominimizeriskofovershootingdose.
Followup
RepeatBPmeasurementat10minuteintervals:
IfBPremainsabovetargetlevelat10minutes,give40mgIV
over2minutes.
IfBPremainsabovetargetlevelat20minutes,give80mgIV
over2minutes.
IfBPremainsabovetargetlevelat30minutes,give80mgIV
over2minutes.
IfBPremainsabovetargetlevelat40minutes,give80mgIV
over2minutes.
Cumulativemaximumdoseis300mg.IftargetBPisnotachieved,
switchtoanotheragent.
Adjustdosewithinthisrangetoachievetargetbloodpressure.
Cumulativemaximumdoseis300mg.IftargetBPisnotachieved,
switchtoanotheragent.
RepeatBPmeasurementat20minuteintervals:
IfBPremainsabovetargetlevelat20minutes,give5or10mg
IVover2minutes,dependingontheinitialresponse.
IfBPremainsabovetargetlevelat40minutes,give10mgIV
over2minutes,dependingonthepreviousresponse.
Cumulativemaximumdoseis20mg.IftargetBPisnotachieved,
switchtoanotheragent.
RepeatBPmeasurementat20minuteintervals:
IfBPremainsabovetargetat20minutes,give10or20mg
orally ,dependingontheinitialresponse.
IfBPremainsabovetargetat40minutes,give10or20mg
orally ,dependingonthepreviousresponse.
IftargetBPisnotachieved,switchtoanotherclassofagent.
IftargetBPisnotachievedin1to2hours,anotherdosecanbe
administered.
IftargetBPisnotachieved,switchtoanotherclassofagent.
AdjustdosewithinthisrangetoachievetargetBP.
 Requiresuseofaprogrammableinfusionpumpandcontinuous
noninvasivemonitoringofbloodpressureandheartrate.

IV:intravenousBP:bloodpressure.
*IfIVaccessisnotimmediatelyavailable,hydralazinemaybegivenintramuscularly(IM)atadoseof10mg.
Capsulesshouldbeswallowedwholeandnotpuncturedorotherwisegivensublingually.

Datafrom:AmericanCollegeofObstetriciansandGynecologistsCommitteeonObstetricPractice.CommitteeOpinionNo.623:Emergenttherapyforacuteonset,severe
hypertensionduringpregnancyandthepostpartumperiod.ObstetGynecol2015125:521.

Graphic110261Version1.0
Deathsfromcardiovascularcauses

Population Relativehazardrate(95%CI)

Nonpreeclamptic,termdelivery 1

Nonpreeclamptic,pretermdelivery 2.95(2.124.11)

Preeclamptic,termdelivery 1.65(1.012.70)

Preeclamptic,pretermdelivery 8.12(4.3115.33)

Datafrom:IrgensHU,ReisaeterL,IrgensLM,LieRT.Longtermmortalityofmothersandfathersafterpreeclampsia:populationbasedcohortstudy.BMJ2001323:1213.

Graphic76674Version3.0
Majorsymptomsandsignsofhypothyroidism

Mechanism Symptoms Signs

Slowingofmetabolicprocesses Fatigueandweakness Slowmovementandslowspeech

Coldintolerance Delayedrelaxationoftendonreflexes
Dyspneaonexertion Bradycardia
Weightgain Carotenemia
Cognitivedysfunction
Mentalretardation(infantileonset)
Constipation
Growthfailure

Accumulationofmatrixsubstances Dryskin Coarseskin

Hoarseness Puffyfaciesandlossofeyebrows
Edema Periorbitaledema
Enlargementofthetongue

Other Decreasedhearing Diastolichypertension

Myalgiaandparesthesia Pleuralandpericardialeffusions
Depression Ascites
Menorrhagia Galactorrhea
Arthralgia
Pubertaldelay

Graphic62676Version4.0
ContributorDisclosures
ErrolRNorwitz,MD,PhD,MBA Grant/Research/ClinicalTrialSupport:Illumina[Preeclampsia(primaryinvestigatoronaprospectivecohortstudytocollect
samplesfrompatientswithpreeclampsiatofacilitatedevelopmentofabiomarkertesttopredict/diagnosethisdisorder)].Consultant/AdvisoryBoards:Hologic
[Pretermbirth(Fetalfibronectintesttopredictpretermbirth)]Natera[Fetalaneuploidytesting(NIPTasascreeningtestforfetalaneuploidy)]Seracare[Fetal
aneuploidytesting(DevelopingcontrolsforNIPTscreeningtestforfetalaneuploidy)].Bayer[Predictiontestforpreeclampsia(Useofurinaryangiogenicfactorsto
predictpreeclampsia)]. JohnTRepke,MD Nothingtodisclose CharlesJLockwood,MD,MHCM Consultant/AdvisoryBoards:Celula[Aneuploidyscreening
(NocurrentproductsordrugsintheUS)]. VanessaABarss,MD,FACOG Nothingtodisclose

Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseareaddressedbyvettingthroughamultilevelreview
process,andthroughrequirementsforreferencestobeprovidedtosupportthecontent.Appropriatelyreferencedcontentisrequiredofallauthorsandmust
conformtoUpToDatestandardsofevidence.

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