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AutoimmuneDisordersinPregnancyFrancisMartinez,D.O.
MaternalFetalMedicine,Harrisburg,PA
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PresenterDisclosure
ThereisnoConflictofInteresttodisclose
TherearenoFinancialorScientificdisclosures
TherearenoOff-Labeldisclosures.
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LearningObjectives Reviewthenormalchangesoftheimmunesysteminpregnancyandcomparetothepathophysiologyofautoimmunedisorders Discussthematernalmanagementofthemorecommonautoimmunedisordersinpregnancy Discusstheantenatalmonitoringstrategiestooptimizeperinataloutcomedependingonthetypeofautoimmunedisorderpresent
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AutoimmuneDisordersinPregnancy Autoimmunityvs.autoimmunedisease
Autoimmunity- immuneresponseagainstself Mayshowautoantibodieswithoutclinicaldisease(e.g.-positiveANAbutnosignsofSLE) PositiveANAcanbepositiveyearspriortoclinicaldxofSLE
Autoimmunedz- pathogenicautoimmunitythatleadstoovertpathologyoforgansororgan-systems.
Difficulttoassignspecificdiagnosis Maytake12monthsoffollow-up Explainsthecategoryofundifferentiateddisease
Femaleandnon-Caucasianpreponderance 8:1to10:1dependingonthedisease(Sjogrens- 10:1) SLEhigherincidenceinAfricanAmericanwomen(4:1)
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AutoimmuneDisordersinPregnancyTypesofAutoimmuneDisorders
Organ-Specific Singletissueororganistargeted Canhavemultipleorgan-specificautoimmunedisease E.g.- Type1DM,autoimmunehepatitis,thyroiditis
System-specific(oldername- collagenvasculardisease Multipleorgansofthesameordifferentsystemsareaffectedbythesameautoantibodies E.g.- SLE,SjogrensSyndrome,Scleroderma
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MaternalImmuneSystemConcepts
Medawartheory(1952) Addressestheuniqueimmunologyofmaternal-fetalinterfaceforfirsttime Describedthefetalallograftanalogywhereinthefetusisviewedassemi-allogeneicbecauseitispartlymadeupofpaternalantigensandthereforeforeigntomaternalimmunesystemyetevadesrejectionofthematernalimmunesystem
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MaternalImmuneSystemConcepts
Maternal-placentaltolerance Embryodividesintoinnercellmass(fetus)andexternaltrophoectoderm(placenta) Trophoblastsdirectlyinteractwithmaternaluterinecells/immunesystem Somehowthetrophoblastscanavoidimmunerejection Fetushaspaternalmajorhistocompatibilitycomplex(MHC)antigensexpressed Notontrophoblasts
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TypesofImmuneResponseInnateImmunity
Involvesphagocyticcells Macrophagesandgranulocytes
Expresspatternrecognitionreceptors(PRR) Detectconservedpathogen-derivedsequencesonmicrobes
Severalactions Produceinflammatorycytokines,releasedegradativeenzymes,inducephagocytosis
Primerfortheadaptiveimmuneresponse
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TypesofImmuneResponseAdaptiveImmunity
Receivesphagocyticmaterialfrominnatesystem HumoralandCellularresponses
Antibodyproduction(humoral) CelllysiswithTlymphocytes Releasecytokines Memoryattribute Willremembertheforeignantigenicmaterialsothatcanrespondevenmorevigorouslytosubsequentexposure
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TypesofImmuneResponseAdaptiveImmunity
CYTOKINES Canbeproinflammatoryoranti-inflammatory Thelpercelldifferentiation Bothtypes- counter-regulatoryeffects Th1cellsproinflammatory
IL-2,interferon- whichinduceacytotoxicresponse Th2cellsanti-inflammatory
IL-4,IL-6,IL-10involvedinantibodyproduction
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REASONSFORIMMUNEPROTECTIONOFTHEPREGNANCY
Placentaasmechanicalbarrier Suppressionofmaternalimmunesystem AbsenceofMHCclassImoleculesontrophoblasts Localandsystemiccytokineshifts LocalimmunesuppressionmediatedbyFas/Fasligand(FasL)system
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REASONSFORIMMUNEPROTECTIONOFTHEPREGNANCY
Placenta- mechanicalbarrier(upto1980s) Physicalbarriertomaternalimmunecells Studiesshowedbidirectionalityofcellsbetweenplacentaanduterus Fetalcellsshowninmaternaltissueyearsafterpregnancy
Suppressionofmaternalimmunesystem Pregnancysomehowreducesmaternalimmuneresponse Studiesshownoeffectonantiviralimmunity Alsonotsupportedbywomanssurvivalinhostileenvironmentsinsomecultures
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REASONSFORIMMUNEPROTECTIONOFTHEPREGNANCY
CytokineShift Relatestothedifferentphasesofimplantation/placentation
Dividedinto3phases Correlatewiththetrimestersofpregnancy First- proinflammatory Second- anti-inflammatory Third- proinflammatory
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REASONSFORIMMUNEPROTECTIONOFTHEPREGNANCY
CytokineShift Firstphase Trophoblastsbreakthroughendometriumcausingtissuedamageandstimulating immuneresponse Removalofdamagedcellsandcellularrepairneeded Maternalsymptomsinfirsttrimesterpartiallyduetothisimmuneresponse
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REASONSFORIMMUNEPROTECTIONOFTHEPREGNANCY
CytokineShift Secondphase
Periodoffetalgrowth/development Proinflammatorystatereplacedbyanti-inflammatorystate Maternalsymptomsdecrease
ThirdPhase Occursnearendofthirdtrimester Influxofimmunecellsintomyometriumrestartingtheproinflammatorystate Promotescontractions,expulsionofbabyandplacenta
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MaternalImmuneSystemRethinkingitsRole
(RedefiningMedawarHypothesis) Immunesystemfunctionsdifferentlytowardspregnancycomparedtotypicalconcernsintransplantation Muchofmaternalimmunesystemworksinconcertwithpregnancy,notagainstit Involvedinsupportiverolestowardsthepregnancy Probablyrelatedtosemi-allografttissuewithchangestoprotectagainstanimmuneresponsetowardsthepaternal-derivedfetalcells
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MaternalImmuneSystemConcepts
Muchmoretothestorythangraft-hostinteraction Maternalimmunesystemcanhaveprotective/nurturingeffectonpregnancy Fetoplacentalunitnotapassiveentity Trophoblastresponse,FIRS
Maternalinflammationcanhavelong-termeffectonfetaldevelopment
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SystemicLupusErythematosus(SLE)inPregnancy
Occursinapprox.1per1000pregnancies Multisystemautoimmunedisease Skin,kidneys,liver,CNS,immunesystem,hematologic Resultofimmune-mediatedtissuedamage Involvementofpathologicactivationofcomplementsystem
MaternalComplications- usuallyinvolvesflare Lupusflare- increasedsymptoms,decreasedcomplement Riskdependentonpresenceofflarewithin6monthsofconception Noflare- 8%risk,flarewithin6mos 58%risk
Developingactiveflare Riskofpregnancyloss 40%
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SLEinPregnancyMaternalEffects
Activeflare- Lupusnephritis Strongpredictorofpregnancyoutcome Activenephritisinpregnancy- 2-3xincreasedriskforpregnancylossorpretermbirth Pretermbirthsecondarytoseverepre-eclampsia
Thrombocytopenia CanbeSLE-inducedorsecondarytoantiphospholipidsyndrome(APS) NoteasilydistinguishedeveninthepresenceofAPS-antibodies IfAPSrelatedthenalsoincreasedriskforthrombosis
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SLEinPregnancyAntiphospholipidSyndrome
Labcriteria:atleastonemustbepresent Lupusanticoagulant- positive AnticardiolipinAb- IgMandIgGmedium/highpositive Beta-2glycoprotein-1Ab- IgMandIgG>99th percentile(usuallymedium/highpositive)
Clinicalcriteria:atleastonemustbepresent Vascularthrombosis- arterialorvenous,anysizevessel Unexplainedfetaldeathatorbeyond10wks Unexplainedfetallossesx3