Download Autoimmune Disorders in Pregnancy

AutoimmuneDisordersin
Pregnancy
FrancisMartinez,D.O.
MaternalFetalMedicine,Harrisburg,PA
PresenterDisclosure
• ThereisnoConflictofInteresttodisclose
• TherearenoFinancialorScientific
disclosures
• TherearenoOff-Labeldisclosures.
LearningObjectives
• Reviewthenormalchangesoftheimmunesystemin
pregnancyandcomparetothepathophysiologyof
autoimmunedisorders
• Discussthematernalmanagementofthemorecommon
autoimmunedisordersinpregnancy
• Discusstheantenatalmonitoringstrategiestooptimize
perinataloutcomedependingonthetypeofautoimmune
disorderpresent
AutoimmuneDisordersinPregnancy
• Autoimmunityvs.autoimmunedisease
• Autoimmunity- immuneresponseagainstself
• Mayshowautoantibodieswithoutclinicaldisease(e.g.positiveANAbutnosignsofSLE)
• PositiveANAcanbepositiveyearspriortoclinicaldxofSLE
• Autoimmunedz- pathogenicautoimmunitythatleadstoovert
pathologyoforgansororgan-systems.
• Difficulttoassignspecificdiagnosis
• Maytake12monthsoffollow-up
• Explainsthecategoryof“undifferentiated”disease
• Femaleandnon-Caucasianpreponderance
• 8:1to10:1dependingonthedisease(Sjogren’s- 10:1)
• SLEhigherincidenceinAfricanAmericanwomen(4:1)
AutoimmuneDisordersinPregnancy
TypesofAutoimmuneDisorders
• Organ-Specific
• Singletissueororganistargeted
• Canhavemultipleorgan-specificautoimmune
disease
• E.g.- Type1DM,autoimmunehepatitis,thyroiditis
• System-specific(oldername- collagenvasculardisease
• Multipleorgansofthesameordifferentsystemsare
affectedbythesameautoantibodies
• E.g.- SLE,Sjogren’sSyndrome,Scleroderma
MaternalImmuneSystem
Concepts
• Medawartheory(1952)
• Addressestheuniqueimmunologyofmaternal-fetal
interfaceforfirsttime
• Describedthefetalallograftanalogywhereinthefetusis
viewedassemi-allogeneicbecauseitispartlymadeupof
paternalantigensandthereforeforeigntomaternal
immunesystemyetevadesrejectionofthematernal
immunesystem
MaternalImmuneSystem
Concepts
• Maternal-placentaltolerance
• Embryodividesintoinnercellmass(fetus)andexternal
trophoectoderm(placenta)
• Trophoblastsdirectlyinteractwithmaternaluterine
cells/immunesystem
• Somehowthetrophoblastscanavoidimmunerejection
• Fetushaspaternalmajorhistocompatibilitycomplex
(MHC)antigensexpressed
• Notontrophoblasts
TypesofImmuneResponse
InnateImmunity
• Involvesphagocyticcells
• Macrophagesandgranulocytes
• Expresspatternrecognitionreceptors(PRR)
• Detectconservedpathogen-derivedsequenceson
microbes
• Severalactions
• Produceinflammatorycytokines,releasedegradative
enzymes,inducephagocytosis
• Primerfortheadaptiveimmuneresponse
TypesofImmuneResponse
AdaptiveImmunity
• Receivesphagocyticmaterialfrominnatesystem
• HumoralandCellularresponses
•
•
•
•
Antibodyproduction(humoral)
CelllysiswithTlymphocytes
Releasecytokines
Memoryattribute
• Willremembertheforeignantigenicmaterialsothat
canrespondevenmorevigorouslytosubsequent
exposure
TypesofImmuneResponse
AdaptiveImmunity
• CYTOKINES
• Canbeproinflammatoryoranti-inflammatory
• Thelpercelldifferentiation
• Bothtypes- counter-regulatoryeffects
• Th1cellsproinflammatory
• IL-2,interferon-Ύ whichinduceacytotoxicresponse
• Th2cellsanti-inflammatory
• IL-4,IL-6,IL-10involvedinantibodyproduction
REASONSFORIMMUNEPROTECTION
OFTHEPREGNANCY
• Placentaasmechanicalbarrier
• Suppressionofmaternalimmunesystem
• AbsenceofMHCclassImoleculesontrophoblasts
• Localandsystemiccytokineshifts
• LocalimmunesuppressionmediatedbyFas/Fasligand
(FasL)system
REASONSFORIMMUNEPROTECTION
OFTHEPREGNANCY
• Placenta- mechanicalbarrier(upto1980s)
• Physicalbarriertomaternalimmunecells
• Studiesshowedbidirectionalityofcellsbetween
placentaanduterus
• Fetalcellsshowninmaternaltissueyearsafterpregnancy
• Suppressionofmaternalimmunesystem
• Pregnancysomehowreducesmaternalimmune
response
• Studiesshownoeffectonantiviralimmunity
• Alsonotsupportedbywoman’ssurvivalinhostile
environmentsinsomecultures
REASONSFORIMMUNEPROTECTION
OFTHEPREGNANCY
CytokineShift
• Relatestothedifferentphasesof
implantation/placentation
• Dividedinto3phases
•
•
•
•
Correlatewiththetrimestersofpregnancy
First- proinflammatory
Second- anti-inflammatory
Third- proinflammatory
REASONSFORIMMUNEPROTECTION
OFTHEPREGNANCY
CytokineShift
• Firstphase
• Trophoblastsbreakthroughendometriumcausingtissue
damageandstimulating immuneresponse
• Removalofdamagedcellsandcellularrepairneeded
• Maternalsymptomsinfirsttrimesterpartiallyduetothis
immuneresponse
REASONSFORIMMUNEPROTECTION
OFTHEPREGNANCY
CytokineShift
• Secondphase
• Periodoffetalgrowth/development
• Proinflammatorystatereplacedbyanti-inflammatory
state
• Maternalsymptomsdecrease
• ThirdPhase
• Occursnearendofthirdtrimester
• Influxofimmunecellsintomyometriumrestartingthe
proinflammatorystate
• Promotescontractions,expulsionofbabyandplacenta
MaternalImmuneSystem
RethinkingitsRole
(RedefiningMedawarHypothesis)
• Immunesystemfunctionsdifferentlytowards
pregnancycomparedtotypicalconcernsin
transplantation
• Muchofmaternalimmunesystemworksinconcert
withpregnancy,notagainstit
• Involvedinsupportiverolestowardsthepregnancy
• Probablyrelatedtosemi-allografttissuewithchangesto
protectagainstanimmuneresponsetowardsthepaternalderivedfetalcells
MaternalImmuneSystem
Concepts
• Muchmoretothestorythangraft-hostinteraction
• Maternalimmunesystemcanhave
protective/nurturingeffectonpregnancy
• Fetoplacentalunitnotapassiveentity
• Trophoblastresponse,FIRS
• Maternalinflammationcanhavelong-termeffecton
fetaldevelopment
SystemicLupusErythematosus
(SLE)inPregnancy
• Occursinapprox.1per1000pregnancies
• Multisystemautoimmunedisease
• Skin,kidneys,liver,CNS,immunesystem,hematologic
• Resultofimmune-mediatedtissuedamage
• Involvementofpathologicactivationofcomplementsystem
• MaternalComplications- usuallyinvolvesflare
• Lupusflare- increasedsymptoms,decreasedcomplement
• Riskdependentonpresenceofflarewithin6monthsof
conception
• Noflare- 8%risk,flarewithin6mos– 58%risk
• Developingactiveflare– Riskofpregnancyloss– 40%
SLEinPregnancy
MaternalEffects
• Activeflare- Lupusnephritis
• Strongpredictorofpregnancyoutcome
• Activenephritisinpregnancy- 2-3xincreasedriskfor
pregnancylossorpretermbirth
• Pretermbirthsecondarytoseverepre-eclampsia
• Thrombocytopenia
• CanbeSLE-inducedorsecondarytoantiphospholipid
syndrome(APS)
• NoteasilydistinguishedeveninthepresenceofAPSantibodies
• IfAPSrelatedthenalsoincreasedriskforthrombosis
SLEinPregnancy
AntiphospholipidSyndrome
• Labcriteria:atleastonemustbepresent
• Lupusanticoagulant- positive
• AnticardiolipinAb- IgMandIgGmedium/highpositive
• Beta-2glycoprotein-1Ab- IgMandIgG>99th percentile
(usuallymedium/highpositive)
• Clinicalcriteria:atleastonemustbepresent
• Vascularthrombosis- arterialorvenous,anysizevessel
• Unexplainedfetaldeathatorbeyond10wks
• Unexplainedfetallossesx3<10wkswithchromosomal
abnormalitiesexcluded
• Pretermdelivery<34wksduetopre-eclampsiaor
placentalinsufficiency(IUGR)
SLEinPregnancy
AntiphospholipidSyndrome
• Thrombosis- 40%riskwithSLEandAPSpresent
• Pregnancymorbidity- mechanismnotwellunderstood
• Pregnancyloss,pre-eclampsia,placentalinsufficiency,preterm
birth
• Managementdependsonhistoryofthrombosisorthetypeof
pregnancycomplication
• HxofthrombosisandAPS- Heparin(prophylactic+aspirin
(81mg)
• Anyoftheco-morbiditiespresentwithantibodies- prophylactic
heparinindicatedantepartumandpostpartum
• Tx:Lowmolecularweightheparinpreferred- lesssideeffects
• Antibodieswithoutanyclinicalhistory- anticoagulationmaynot
beindicated
SLEinPregnancy
NeonatalEffects
• NeonatalLupusSyndrome- alwaystransient
• Photosensitiverash,thrombocytopenia,hepatitis,
hemolyticanemia
• UsuallywithhighmaternalSSAorSSBtiters
• Typesofanti-nuclearantibodies
• Long-termrisks
• SomestudiessuggestchildrenofSLEmomsmaybeat
increasedriskforSLElaterinlife
• Probablygeneticcomponentinvolved
• Congenitalheartblock- usuallypermanentwhendevelops
• InpresenceofmaternalSSAorSSBantibodies
SLEinPregnancy
CongenitalHeartBlock
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1/3patientswithSLEhaveSSAorSSBantibodies
Approx.1-3%riskforaffectedchildwithnohistory
Increasesto25-30%riskofCHBwithoneaffectedchild
Highestriskbetween18-28weeksgestation
DexamethasonegivenifsignsofCHB- poorlyeffective
Latestrecommendation:weeklymonitoringoffetalPRInterval
withultrasoundifSSAorSSBpositive
• Suggestedtomonitoruntil28weeks
• Inourpractice- monitorfrom17weeksuntildelivery
• Reason:onceinCHB- willnotreverseinmostcases
• PRintervalabnormallyincreased- suggest1st deg.heartblock
• Dexamethasoneisrecommendedtopreventprogression
tocompleteheartblock
Sjogren’sSyndrome(SS)inPregnancy
• Lymphocyticinfiltrationofepithelialcellsofvarious
tissuesleadingtoimmunecomplexesorB-cell
hyperactivity
• Femalepredominance
• PrimarySS- immunecomplexesinsalivaryandtear
glands- leadstooral/oculardryness
• SecondarySS- systemicorfoundwithother
autoimmunediseases(e.g.- SLE)
• Canleadtoimmunecomplexdepositionwithintissues
• Nephritis,obstructivebronchiolitis,cholangitis
• CanleadtoB-cellhyperactivity
• Glomerulonephritis,neuropathy,B-celllymphoma
Sjogren’sSyndrome(SS)inPregnancy
• Maternalmorbidity- usuallyuncomplicated
• Dependsonunderlyingdiseasestate- primaryvs.secondary
• Fetal/neonatalmorbidity
• MainlysecondarytopresenceofSSAandSSBantibodies
• SSA- 60-80%ofpts,SSB- 30-40%ofpts.
• SSBisneverpresentunlessSSAispresentinSjogren’sSynd.
• SSAandSSBantibodieshaveaffinityforspecificfetal
myocardialantigensandepitopes
• IfSSAORSSBpositivethenshouldfollowrecommendations
discussedpreviouslyconcerningfetalmonitoringofheart
rhythm
Scleroderma(SystemicSclerosis)
inPregnancy
• Uncommondiseaseofunknowncauseandvariable
presentation
• Hallmarks:autoimmunity,inflammation,pathologic
alterationofsmallbloodvessels,interstitialandvascular
fibrosisintheskinandinternalorgans
• Connectivetissuediseaseaffectingskinandinternal
organs
• Chronicinflammationwithvariabledegreesofcollagen
accumulation(fibrosis)
• Obliterativevasculopathyofvariousorgans
• Treatment- organ-specificbutnotherapyavailableforthe
diseasesystemically
SystemicSclerosisinPregnancy
• DatalimitedsinceSystemicSclerosisusuallydevelopsafter
childbearingyears
• Coursedependsondiseasepresentpriortopregnancy
• Basedonamountofsmall-vesseldiseasepresent
• Sclerodermarenalcrisis
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•
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2-3%ofSclerodermapregnancies
Canbeindistinguishablefromseverepre-eclampsia/HELLP
Deliverysometimesindicatedduetoacuterenalfailure
ACEinhibitorsindicatedpostpartumbuthasfetaleffects
antepartum
• IncreasedriskforIUGR/placentalinsufficiency
• Low-doseASAshouldbeconsidered,antenatalmonitoringof
growthandweeklyantenataltestinginthethirdtrimester
RheumatoidArthritisinPregnancy
• Systemicautoimmunediseasewithchronicinflammation
ofjointsandotherstructures
• Femalepredominant- 3:1
• Pregnancymorbidity
• Antepartum- usualimprovementofarthriticsymptoms- approx.
75%ofpatients
• Postpartum- higherriskforflare
• Glucocorticoidscanbeusedeitherantepartumorpostpartumfor
flares
• Smallamountofmedicationwillcrossplacenta
• SmallincreasedriskforIUGR
• Considermonitoringfetalgrowth
• Weeklytestingbasedongrowthpattern
TakayasuArteritisinPregnancy
• Immunearteritiscausinginflammationoftheaorta,
majorbranchesandpulmonaryarteries
• Femalepredominance- 6-8:1
• Earlyageonset(<30y/o),morecommonAsianwomen(1in
3000inJapan),2.6/millionintheU.S.
• Organinvolvement- cardiac,lungs,aorta,kidneys
• Cardiac- 6-16%withcoronaryarterydisease,heartfailure
• Aorta- increasedriskforaneurysms
• Lungs- pulmonaryhypertension
• Pregnancymorbidity- basedonmaternaldisease
• Comarmond(2015)- studied142pregnancies- pre- andpost-dx
• Pre-eclampsia(24%),pretermdelivery(8%),IUGR/fetaldemise
(5%)
AntenatalFetalMonitoringStrategies
• Considerfetalgrowthassessmentthroughoutpregnancy
regardlessofthetypeofdisorder
• FirstTrimester
• AntiphospholipidAb,SSA/SSBtiters,anti-dsDNA,complement(C3,
C4,CH50),ANAtiter
• SerialANAtitersnotnecessaryunlessconcernforflare
• ConsiderSSAandSSBwithANApositiveregardlessofSLEdx
• 24-urineforproteinandcreatinineclearanceifunderlyingriskfor
vasculopathy(i.e.notnecessaryforRA)
• ThirdTrimester- dependsonwhetherriskincreasedfor
vasculopathy(i.e.canaffectplacentalfunction)
• WeeklyNSTstartingat32-34weeksuntildelivery
• Modeofdeliverybasedonobstetricalindications
• Timingofdelivery- variablebasedonmaternal/fetalstatus
AutoimmuneDisordersinPregnancy
Summary
• Maternalimmunesysteminhealthystateisvery
adaptiveandsupportivetotheallogeneicfetus
• Importanttobeawareofthevariousautoimmune
disordersduetothepredominanceinwomen
• SLEinpregnancyshouldbemonitoredcloselyasany
flarecanimpactthepregnancyintermsofplacental
functionanddeliverytiming
• SSAandSSBshouldbecheckedwithcertaindisorders
(SLE,Sjogren’s,Scleroderma)duetoriskofCHB
• Antenatalmonitoringimportanttooptimizefetal
outcome