AutoimmuneDisordersinPregnancyFrancisMartinez,D.O.

MaternalFetalMedicine,Harrisburg,PA

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LearningObjectives Reviewthenormalchangesoftheimmunesysteminpregnancyandcomparetothepathophysiologyofautoimmunedisorders Discussthematernalmanagementofthemorecommonautoimmunedisordersinpregnancy Discusstheantenatalmonitoringstrategiestooptimizeperinataloutcomedependingonthetypeofautoimmunedisorderpresent

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)

AutoimmuneDisordersinPregnancyTypesofAutoimmuneDisorders

Organ-Specific Singletissueororganistargeted Canhavemultipleorgan-specificautoimmunedisease E.g.- Type1DM,autoimmunehepatitis,thyroiditis

System-specific(oldername- collagenvasculardisease Multipleorgansofthesameordifferentsystemsareaffectedbythesameautoantibodies E.g.- SLE,SjogrensSyndrome,Scleroderma

MaternalImmuneSystemConcepts

Medawartheory(1952) Addressestheuniqueimmunologyofmaternal-fetalinterfaceforfirsttime Describedthefetalallograftanalogywhereinthefetusisviewedassemi-allogeneicbecauseitispartlymadeupofpaternalantigensandthereforeforeigntomaternalimmunesystemyetevadesrejectionofthematernalimmunesystem

MaternalImmuneSystemConcepts

Maternal-placentaltolerance Embryodividesintoinnercellmass(fetus)andexternaltrophoectoderm(placenta) Trophoblastsdirectlyinteractwithmaternaluterinecells/immunesystem Somehowthetrophoblastscanavoidimmunerejection Fetushaspaternalmajorhistocompatibilitycomplex(MHC)antigensexpressed Notontrophoblasts

TypesofImmuneResponseInnateImmunity

Involvesphagocyticcells Macrophagesandgranulocytes

Expresspatternrecognitionreceptors(PRR) Detectconservedpathogen-derivedsequencesonmicrobes

Severalactions Produceinflammatorycytokines,releasedegradativeenzymes,inducephagocytosis

Primerfortheadaptiveimmuneresponse

TypesofImmuneResponseAdaptiveImmunity

Receivesphagocyticmaterialfrominnatesystem HumoralandCellularresponses

Antibodyproduction(humoral) CelllysiswithTlymphocytes Releasecytokines Memoryattribute Willremembertheforeignantigenicmaterialsothatcanrespondevenmorevigorouslytosubsequentexposure

TypesofImmuneResponseAdaptiveImmunity

CYTOKINES Canbeproinflammatoryoranti-inflammatory Thelpercelldifferentiation Bothtypes- counter-regulatoryeffects Th1cellsproinflammatory

IL-2,interferon- whichinduceacytotoxicresponse Th2cellsanti-inflammatory

IL-4,IL-6,IL-10involvedinantibodyproduction

REASONSFORIMMUNEPROTECTIONOFTHEPREGNANCY

Placentaasmechanicalbarrier Suppressionofmaternalimmunesystem AbsenceofMHCclassImoleculesontrophoblasts Localandsystemiccytokineshifts LocalimmunesuppressionmediatedbyFas/Fasligand(FasL)system

REASONSFORIMMUNEPROTECTIONOFTHEPREGNANCY

Placenta- mechanicalbarrier(upto1980s) Physicalbarriertomaternalimmunecells Studiesshowedbidirectionalityofcellsbetweenplacentaanduterus Fetalcellsshowninmaternaltissueyearsafterpregnancy

Suppressionofmaternalimmunesystem Pregnancysomehowreducesmaternalimmuneresponse Studiesshownoeffectonantiviralimmunity Alsonotsupportedbywomanssurvivalinhostileenvironmentsinsomecultures

REASONSFORIMMUNEPROTECTIONOFTHEPREGNANCY

CytokineShift Relatestothedifferentphasesofimplantation/placentation

Dividedinto3phases Correlatewiththetrimestersofpregnancy First- proinflammatory Second- anti-inflammatory Third- proinflammatory

REASONSFORIMMUNEPROTECTIONOFTHEPREGNANCY

CytokineShift Firstphase Trophoblastsbreakthroughendometriumcausingtissuedamageandstimulating immuneresponse Removalofdamagedcellsandcellularrepairneeded Maternalsymptomsinfirsttrimesterpartiallyduetothisimmuneresponse

REASONSFORIMMUNEPROTECTIONOFTHEPREGNANCY

CytokineShift Secondphase

Periodoffetalgrowth/development Proinflammatorystatereplacedbyanti-inflammatorystate Maternalsymptomsdecrease

ThirdPhase Occursnearendofthirdtrimester Influxofimmunecellsintomyometriumrestartingtheproinflammatorystate Promotescontractions,expulsionofbabyandplacenta

MaternalImmuneSystemRethinkingitsRole

(RedefiningMedawarHypothesis) Immunesystemfunctionsdifferentlytowardspregnancycomparedtotypicalconcernsintransplantation Muchofmaternalimmunesystemworksinconcertwithpregnancy,notagainstit Involvedinsupportiverolestowardsthepregnancy Probablyrelatedtosemi-allografttissuewithchangestoprotectagainstanimmuneresponsetowardsthepaternal-derivedfetalcells

MaternalImmuneSystemConcepts

Muchmoretothestorythangraft-hostinteraction Maternalimmunesystemcanhaveprotective/nurturingeffectonpregnancy Fetoplacentalunitnotapassiveentity Trophoblastresponse,FIRS

Maternalinflammationcanhavelong-termeffectonfetaldevelopment

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%

SLEinPregnancyMaternalEffects

Activeflare- Lupusnephritis Strongpredictorofpregnancyoutcome Activenephritisinpregnancy- 2-3xincreasedriskforpregnancylossorpretermbirth Pretermbirthsecondarytoseverepre-eclampsia

Thrombocytopenia CanbeSLE-inducedorsecondarytoantiphospholipidsyndrome(APS) NoteasilydistinguishedeveninthepresenceofAPS-antibodies IfAPSrelatedthenalsoincreasedriskforthrombosis

SLEinPregnancyAntiphospholipidSyndrome

Labcriteria:atleastonemustbepresent Lupusanticoagulant- positive AnticardiolipinAb- IgMandIgGmedium/highpositive Beta-2glycoprotein-1Ab- IgMandIgG>99th percentile(usuallymedium/highpositive)

Clinicalcriteria:atleastonemustbepresent Vascularthrombosis- arterialorvenous,anysizevessel Unexplainedfetaldeathatorbeyond10wks Unexplainedfetallossesx3