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Transcript of How to Assess Stillbirths and Miscarriages · Toxoplosmosis gondii Toxoplasmosis Rare Severe...
HowtoAssessStillbirthsandMiscarriages
DeborahKrakow,MDProfessorandChair
DepartmentsofObstetricsandGynecology,HumanGeneticandOrthopaedicSurgery
DavidGeffenSchoolofMedicine
Objectivesformanagementofmiscarriageorstillborn
• Closureforthefamily• Identifytheconditionsthathavebeenbestdemonstratedtocausemiscarriageorstillbirth• Evaluatebothadverseeventsusingthemosteffectiveworkup• Accuratelyformulateanetiologyfortheeventwhenpossible• Conferwithexpertstoemploythebestrecommendedhospitalpoliciesformanagementofstillbirth
Definitions
Spontaneousabortion• Miscarriage• <20weeksgestationor<500g
Intrauterinefetaldemise• “Stillbirth”• >20weeksgestationor>350g—statedependent• 350gis50%ilefor20weeksgestation• Illinois:>20weeksgestation
• “Deliveryofafetusshowingnosignsoflifeasindicatedbytheabsenceofbreathing,heartbeats,pulsationoftheumbilicalcord,ordefinitemovementsofvoluntarymuscles”• DoesnotincludeterminationsofpregnancyorIOLforpreviable PPROM
Causesofstillbirth
• >30classificationsystemsexist• Importanttodistinguishbetween• Underlyingcauseofdeath• Mechanismofdeath• Riskfactors
TheNationalInstituteofChildHealthandHumanDevelopment
Classificationofstillbirth
Classificationofstillbirth
ClassificationofStillbirth
• EuniceKennedyShriverworkshop2007• NationalInstituteofChildHealthandHumanDevelopment• “Anoptimalclassificationsystemwouldidentifythepathophysiologicalentityinitiatingthechainofeventsthatirreversiblyleadtodeath”
Criteriafor“cause”
• Epidemiologicdatademonstrateanexcessofstillbirthassociatedwiththatcondition• Biologicplausibilitythattheconditioncausesstillbirth• Eitherrarelyseeninassociationwithlivebirths or,whenseeninlivebirths,resultsinasignificantincreaseinneonataldeath• Adose-responserelationshipexists• Thegreaterthe“dose”ofthecondition,thegreatertheriskoffetaldeath
• Associatedwithevidenceoffetalcompromise• Thestillbirthlikelywouldnothaveoccurredifthatconditionhadnotbeenpresent
Causesofstillbirth
Reddy,UMetal.“StillbirthClassification—DevelopinganInternationalConsensusforResearch.”ObstetricsandGynecology,Vol 114,No4,October2009.
• Associatedwith10-20% ofstillbirthsindevelopedcountries• Higherassociationwithpretermbirth• Sometimesdifficulttoprovecausality
Infection Causesofstillbirth—NIHCHDworkshopconsensus
Ascendinginfectionàamniotic fluidorfetusàfetalpneumonitisHematogenous spreadàvillitis
Mechanismoffetaldeath
• Severematernalillness• Placentalinfectionthatpreventsoxygen/nutrientsfromcrossingtothefetus• Fetalinfectionthatcausesalethalcongenitaldeformity
• Fetalinfectionthatdamagesavitalorgan• Precipitationofpretermlabor,withintrapartumfetaldeath
InfectionsShoule BeProven• Signsofinfectioninthefetus• Evidenceonautopsyofextensiveorganinvolvement
• Positivefetalcultures• Positivematernalculturespluschorioamnionitis/funisitis
Kumar:Robbinspathologicbasisofdisease,8th edition.2009
CausesofIUFD:SpirochetesOrganism Maternaldisease CommentTreponemapalladium Syphilis Major causeofstillbirthwhen
maternal prevalenceishighBorreliaburgdorferi Lymedisease Tickborne;nota commoncause
ofstillbirthBorreliarecurrentis Relapsingfever Tick borne;commoninthe
WesternUS;rarecauseofstillbirth
Borrelia duttonii Relapsingfever Tick borne;sub-SaharanAfrica;importantcauseofstillbirth
Leptospira interrogans Leptospirosis Uncommon
Severeplacentaldysfunction
Protozoa
Organism Maternaldisease CommentTrypanosomabrucei Trypanasomiasis TsetseflyTrypanosomacruzi Chagas disease KissingbugPlasmodiumfalciparum Malaria CommoninendemicareasPlasmodium vivax Malaria MosquitoesToxoplosmosisgondii Toxoplasmosis Rare
Severeplacentaldysfunction
Severeplacentaldysfunction
VirusesOrganism Maternal disease CommentParvovirusB19 Erythemainfectiosum Likelythemostcommonviral
etiologicagentCoxsackie AandB Various May beimportantEchovirus Various ImportanceunknownEnterovirus Various Importance unknownHepatitsEvirus Fulminanthepaticfailure EspeciallyinendemicareasPoliovirus Polio HistoriccauseVaricellazoster Chickenpox RarecauseRubella Germanmeasles Rare indevelopedcountriesMumps Parotitis Rareindeveloped countriesRubeola Measles Rareindeveloped countriesCytomegalovirus Asymptomatic CasereportsHIV AIDS NotlikelycausativeInfluenza Respiratory tractinfection Severematernalillness
Causeslethalfetalanomalies
Bacteria
Organism Maternaldisease CommentE.Coli Asymptomatic Probablythemostcommon
organismassoc withstillbirthGBS Asymptomatic Commoncause ofstillbirthKlebsiella Asymptomatic Common causeofstillbirthEnterococcus AsymptomaticUreaplasma,mycoplasma AsymptomaticListeriamonocytogenes Listeriosis TransmittedtransplacentallyChlamydiatrachomatis Pelvicinfection Suggestedcause—casereportsNeisseria gonorrhoeae Pelvicinfection Suggestedcause—casereportsCandidaalbicans Thrush; vaginitis Confirmed incasereports
GoldenbergRL,ThompsonC.Theinfectiousoriginsofstillbirth.AmJObstetGynecol2003;189:861–73
Severeplacentaldysfunction
MaternalmedicalconditionsCausesofstillbirth—NICHHDworkshopconsensus
Condition Estimated stillbirthrateper1000birthsinpatientswiththecondition
Allpregnancies 6-7Chronichypertension 5-25Superimposed preeclampsia 52Gestational hypertensionandmildpreeclampsia 9Severepreeclampsia 21Eclampsia 18-48HELLP syndrome 51
Simpson,LL.Maternalmedicaldisease:RiskofAntepartumFetalDeath.Semin Perinatol,2002,26,47.
Hypertensivedisorders
Hypertensivedisorders
Mechanismoffetaldemise:• Placentalinsufficiency• IUGR• Abruption
Toconsidercauseofdeath:• Ifitprogressestoeclampsia• Ifitisassociatedwithplacentalabruptionorfetalgrowthrestriction
Condition Estimated stillbirthrateper1000birthsinpatientswiththecondition
Allpregnancies 6-7Gestationaldiabetes 5-10Type1diabetes 6-10Type2 diabetes 35
Simpson,LL.Maternalmedicaldisease:RiskofAntepartumFetalDeath.Semin Perinatol,2002,26,47.
Diabetes
DiabetesMechanismoffetaldemise:• Congenitalabnormality• Placentaldysfunction• Obstructedlaborandintrapartumdeath• Macrosomia• Fetalhyperglycemiaàfetal insulinproductionàexcessive fetalgrowthàmetabolic acidosis
Toconsidercauseofdeath:• Signsofintrauterineorintrapartum asphyxia• LGAfetus• SGAfetus• Severemalformation• Placentademonstratescharacteristichistologic findings• Largeedematousvilli• Increasedprominenceofcytotrophoblasts
Condition Estimated stillbirthrateper1000birthsinpatientswiththecondition
Allpregnancies 6-7Stabletreatedhyperthyroidism 0-36Uncontrolled thyrotoxicosis 100-156Subclinicalhypothyroidism 0-15Overthypothyrodism 15-125SLE 40-150Mildchronicrenaldisease 15Moderateandseverechronic renaldisease 32-200Cholestasis ofpregnancy 12-30
Simpson,LL.Maternalmedicaldisease:RiskofAntepartumFetalDeath.Semin Perinatol,2002,26,47.
Thyroid/renaldisorders
Thyroid/renaldisordersThyroiddisorders• Gravesdisease,wherethyroid-stimulatinghormonereceptorantibodycausesfetaltoxicosis• Untreatedthyroiddisorders
Renaldisorders• Linearrelationshipbetweenmaternalcreatinine andriskoffetaldemise
Systemic LupusErythematosus� Stillbirth ratesarehigherinthepresenceofHTN,nephritis,orAPL� Circulating auto-antibodies,anti-Ro,anti-La
� Congenitalheartblock,hydrops
Maternalmedicalconditions• Riskisacontinuum
Reddy,UMetal,2009
ThrombophiliasAntiphospholipid syndrome• Inflammation,thrombosis,andinfarctionintheplacenta• Clearhistopathologicalorclinicalevidenceofplacentalinsufficiency
Inheritedthrombophilias• FactorVLeidenmutation,antithrombinIIIdeficincy,prothrombingenemutation,proteinCdeficiency,proteinSdeficiency• Placentalinfarctionandthrombosis
TwolargeprospectivecohortstudiesfoundnoassociationbetweenfactorVLeidenmutationandpregnancylossorplacentalinsufficiency
Thrombophilias arecommoninhealthywomenwithnormaloutcomes
Thrombophiliasshouldonlybeconsideredasthecauseofstillbirthwith:•Evidenceofplacentalinsufficiencysuchasfetalgrowthrestrictionorinfarctionand•Recurrentfetalloss
Causesofstillbirth—NIHCHDworkshopconsensus
Alloimmunization Causesofstillbirth—NIHCHDworkshopconsensusRedcellalloimmunization• Anti-RhesusD,anti-RhesusC,anti-Kell• MusthaveapositiveindirectCoombstest• Antibodytitersmorethan1:16(or1:8foranti-Kell)• Evidenceoffetalanemiawithhydrops• Evidenceoffetalextramedullaryhematopoeisis
Plateletalloimmunization• HPA-1a,HPA-5a,HPA-4• Maternalantibodiesagainstpaternalandfetalplateletantigens• Parentalplateletincompatibilityforthepertinentantigen• Fetalthrombocytopenia• Massiveintracranialhemorrhage
CongenitalmalformationschromosomalabnormalitiesCausesofstillbirth—NIHCDworkshopconsensus
Criteria
• Epidemiologicdatademonstratinganexcessofintrauterinemortality• Seenrarelyinliveborn neonates• Whenseeninliveborn neonates,itfrequentlyresultsinneonataldeath• Biologicplausibilitythatitcanresultindeath
Causeofdeath Stillbirthcases,%(out oftotal2211assessed)
Trisomy 21 1.53Jugulolymphatic obstruction 1.45Turnersyndrome 1.09Twin-twintransfusionsyndrome 1.09Anencephaly 1.0Trisomy 18 0.81Amniondisruptionsequence 0.59Lower mesodermal defects 0.50Idiopathic nonimmune fetalhydrops 0.50Trisomy 13 0.41
Congenitalmalformations
Reddy,UMetal.“StillbirthClassification—DevelopinganInternationalConsensusforResearch.”ObstetricsandGynecology,Vol 114,No4,October2009.
ChromosomalabnormalitiesIncidence
• Cytogeneticabnormalitiesaccountfor6-13%ofallstillbirths• Thismaybehigherbecause40-50%attemptedkaryotypesfailtogrow• 23%monosomy X,23%trisomy 21,21%trisomy 18,8%trisomy 13
Fetomaternal hemorrhage
• Thecause4%ofallstillbirths• Riskfactors:• Placentalabruption• Abdominaltrauma• Multiplegestation• Abnormalfetaltesting
Causesofstillbirth—NIHCDworkshopconsensus
Fetomaternal hemorrhage
• Riskofstillbirthdependson• Amountofhemorrhage• Acute/chronic• Gestationalage
• Athresholdof20mL/kgoffetalbleedingisassociatedwithincreasedriskofstillbirth• Autopsyconfirmationoffetalanemiaandhypoxia
PlacentalcausesCausesofstillbirth—NIHCHDworkshopconsensus
• Placentaprevia,vasa previa,neoplasms• Placentalabruptionhas8.9relativeriskofstillbirth• Maybeconsideredthecauseofdeathif>30%oftheplacentashowssignsofabruption
Reddy,UMetal,2009
Placentalcauses
• AnydiseasethatcausesanSGAplacentamayresultinstillbirth• <5%expectedweightforgestationalage• Preeclampsia,DM,HTN,renal,chronicinfections
• AnydiseasethatcausesanLGAplacentamayresultinstillbirth• >95%expectedweightforgestationalage• Hydrops fetalis,DM,syphilis
Umbilicalcordpathology
• Accountfor3.4-15%ofstillbirths• Velamentous insertion• Ifitleadstoavasa previa orbleedingduringlabor
• Umbilicalcordprolapse• Associatedwithprematurity,malpresentation,mutiparity,obstetricmanipulation
• Umbilicalcordocclusion• Cordprolapse,entanglement(mono-monotwins)• Torsion• Rupture,strictures,hematomas
Causesofstillbirth—NIHCHDworkshopconsensus
Umbilicalcordpathology
• Nuchal cord• Occursinupto30%ofnormalpregnancies• Notassociatedwithanincreasedriskofstillbirthinstudyof14,000deliveries
• Trueknot• Alsocommoninlivebirths• Groovingofthecord,constrictionoftheumbilicalvessels,edema,congestion,thrombosisàrequired toclaimitistheetiology
Isolatedfindingofanuchalcordoratrueknotatthetime
ofdeliveryisinsufficientevidencethatcordaccidentis
thecauseofstillbirth
•Excludeotherrelevantcausesofstillbirth•Findevidenceofhypoxiaandcordocclusion onpostmortemexamination
Complicationsofmultifetal gestation• Monochorionicplacentation• Twin-twintransfusionsyndromeoccursin9%ofmono-di twins• Mortalitycanbe90%inuntreatedcases
Complicationsofmultifetal gestation• Mono-monotwins• Cordentanglement,pretermbirth,growthimpairment,malformations,geneticabnormalities,vascularanastomoses
Gabbe:Obstetrics:normalandproblempregnancies,6th ed.Saunders2012
Uterinecomplications
• Uterinerupture• Evidenceofobstructedcirculation
• Uterineabnormalities• Thereisanincreasedriskofuterineabnormalitiesinwomenwithrecurrentpregnancyloss/stillbirth• Possiblyduetopoorlyvascularized uterinetissueorspaceconstraints• IncreasedriskofPPROM,cervicalinsufficiency,pretermlabor• Septate uterushashighestriskofstillbirthandplacentalabruption
Importanceofastillbirthevaluation
• Counselingforriskofrecurrence• Possibleintervention toreducerecurrencerisk• Facilitateemotionalclosureandhealing
Moststillbirthsremainunexplained
• Incompleteevaluation• Lackofclinicianawareness• Concernsofthefamily
• Lackofsingleuniversallyacceptedclassificationscheme• Difficulttoassignadefinitivecause
• Unknowncause• Sometimesdespitethoroughevaluation
Overview
Recommended studies Sometimeshelpful Notgenerallyuseful•Autopsy•Placental pathology•Karyotype– Chromosomalmicroarray•Kliehauer-Betke•IndirectCoombs•Acquiredthrombophilia panel•AntiB2-glycoproteinab•Toxicologyscreen
•Syphilisserology•Inherited thrombophilia panel•Glucosescreening•TSH•CMV,toxoplasmosis,otherinfectious•Bileacids•Sonohysterogram
•Routine TORCHtiters•ANAtesting•Culturesofplacentalmembranes
Silveretal,2010
Physician’sexam
• Weight,headcircumference,length• Photographs• Frontalandprofie• Wholebody,face,extremeties,palms,abnormalities
Kumar:Robbinspathologicbasisofdisease,8th edition.2009
Finding Time ofdemiseBrownorreddiscoloration ofthecordstumpDesquamation >1cm
>6hoursago
Desquamation offace,back,abdomen >12hoursagoDesquamation >5%ofthebodyor>2bodyzones >18hoursagoSkincolor brownortan >24hoursagoMummification(reducedsoft tissue,leatheryskin,darkbrown)
>2weeks ago
Timeofdemise
“Estimatingthetimeofdeathinstillbornfetuses:III.Externalfetalexamination;astudyof86stillborns.”GenestDR,SingerDB.ObstetandGynecol,1992;80(4),593
Autopsy
• Newinformationthatinfluencescounselingin26-51% ofcases• ValuableHowever,itisperformedin<50%ofcases• Clinicianhesitationtorecommendautopsy• Patientreservations
Alternativestoautopsy
• MRI• Radiographsforskeletaldysplasias• Partialautopsy• Head-sparingautopsy(maymissCNSpathology)
• Externalexaminationbyatrainedpathologist• Canidentifysyndromes,congenitalanomalies,timingofdeath,growthanomalies• Willlikelymissfetalinfectionsandinternalanomalies
• Externalexaminationwithselectedbiopsies• Morelikelytoidentifyfetalinfection
Alternativestoautopsy:MRI
• VerygoodforCNSpathology• Sometimesbetterthanautopsy,becausefetalbrainhashighwatercontentandliquefies
• Fluidcollectionsandeffusionsinthebody
◦ Maymiss cardiacanomalies,bowelanomalies◦ Cannotdiagnoseinfectionsormetabolicdisease
Advantages Disadvantages
Examinationoftheplacenta
• Themostvaluablediagnostictestinmoststudies• Dutchstudyshowedittobevaluablein95%ofcases
• Providesadditionalinformationin30%ofcases
Examinationoftheplacenta
• Weightinrelationtonormsforgestationalage• Evidenceofabruption,infarction,thrombophilias• Hemosiderin depositsàchronic abruption• Perivillious andmarginalfibrindeposition• Decidual necrosis• Evidenceofinfarction
Examinationoftheplacenta
• Multiples:chorionicity,vascularanastomoses inmultifetal gestations• Cord:thrombosis,velamentous cordinsertion,vasa previa• Evidenceofinfections• Morecommoninpretermstillbirth• Viralnuclic acidamplification• Bacterialcultures
Karyotype/Chromosomalmicroarray
• Abnormalfetalkaryotype notedin8-13%ofallstillbirthsandin>20%ofthosewithmorphologicabnormalitiesorIUGR• Dutchstudy:11.9%prevalenceofachromosomalabnormalityinthe362IUFDswhounderwentkaryotyping• 37%trisomy 21,16%monosomy X,4%trisomy 13
• Karyotypewasvaluablein29%ofcases• FISHcanalsobeperformed
Iflivecellsarenotavailable:Microarray
• Screensthegenomeforcopynumbervariations(CNPs)• BACarraysprovideoverviewofgenome• SNParraysprovidemoredetailedcoveragewithprobesonevery100-1000basepairs• Detectsdeletions,duplications,aneuploidies,unbalancedtranslocationswithagain/lossofsequences
• Goodforsmalldeletionsorcrypticchanges• Cytogenetics resolutionisonly5-10Mb
Microarrayversuskaryotyping
• ReddyUMetal,2012:Prospectivepopulation-basedstudyof532stillbirthsover2years• PatientswithIUFDunderwent:• Interview,chartabstraction,postpartumexamination,placentalpathology,karyotype analysis,andspecimencollection
• DNAanalyzedwithanSNPmicroarraywithdataalignedtoHumanGenomerelease18
Microarrayversuskaryotyping
• Microarrayanalysisyieldedaresultin87.4%stillbirthscomparedto70.5% forkaryotype• 85.2%ofthesewerebenign,toosmall,orprobablybenign• 2.6%werepathogenic,6.9%wereaneuploid• MicroarraydetectedCNVconsistentwithDiGeorge syndromenotdetectedbykaryotypein3cases
ReddyUMetal,2012
MaternalWorkupLaboratories(Recommended)• CBC• Kliehauer-Betke• HumanparvovirusB-19IgG andIgM• Lupusanticoagulant,anticardiolipin antibodies• IndirectCoombs• Ifnotalreadydoneantepartum
• Toxicologyscreen
Kliehauer Betke
• Recommendedtodobeforeinductionoflabor• However,giventhatonlymassivehemorrhageislikelytocausefetaldeath,canalsobedoneupto2-3weeksafterdelivery• Inonestudy,FMHwasacontributingfactorin10.6%ofthetotalcohort
Kliehauer Betke
Reddyetal2009
Antiphospholipid antibodies
• Onefetaldeathsatisfiescriteriafortesting• Confirmwithrepeattestingin6-12weeks• MorelikelypositiveifstillbirthwasaccompaniedbyIUGRorseverepreeclampsia• Twodutch studies(750fetaldeathsinKorteweg etal2010,1025fetaldeathsinKorteweg etal2012)showedthatneithertestingforacquirednorinheritedthrombophilia isvaluable• Unlessthepatienthasafamilyorpersonalhistoryofthrombophilia
Laboratories(Sometimesuseful)• Syphilis• TSH• Inheritedthrombophilia workup• FactorVLeiden,prothrombin genemutation,antithrombin III,fastinghomocysteine
• Glucosescreening• Sonohysterogram• Especiallyiflossassociatedwithpretermlabor,PPROM,cervicalinsufficiency,previable gestations,fetalmalpresentation
Guidedbymaternalhistoryandriskfactors
Inheritedthrombophilia
• Korteweg etal2010.Multicenter,prospectivestudy.750singletonfetaldeaths>=20wks,excludingterminations• TestedforvWF,antithrombin,proteinC,totalandfreeproteinS,prothrombin genemutation,factorVLeiden• Causeofdeathclassifiedbyapanel• “ExceptforvWF andpaternalfreeproteinS,acquiredandthrombophilic defectswerenotmoreprevalentafterfetaldeath.”• However,manycase-controlstudiesshowanassociation
Laboratories(unprovenbenefit)
• Toxoplasmosis,rubella,CMV,HSV,otherinfections• Virusesforwhichvaccinesareprevalentareuncommonindevelopedcountries• However,ifautopsy,pathology,orhistoryissuggestive,takematernal/neonatalserology,specialtissuestaines,testingfornucleicacids
• ANA
Considerations
• Parentsbenefitfromseeing/holding theinfant• Warnthemabouthowthebabywillappear
• Usetheterm“baby”• Encourageparentstoname theinfant• Knowingthesex isimportant
• Fetallosscanbedevastationatanygestationalage• Differentcultures grieveindifferentways
Conclusions
• Thecauseofastillbirthistheinitialpathophysiologic entity thatirreversiblyledtofetaldeath• Causemustbeprovenwithevidenceoffetalharm• Therearemanybenefits tofindingacause• Encouragepatientstoallowanevaluationwithintheboundariesoftheirpersonalandculturalvalues
Conclusions
• RecommendedlaboratoriesareCBC,Kliehauer-Betke,parvovirus B-19IgG andIgM,lupusanticoagulant,anticardiolipin antibodies,andtoxicologyscreen• Onlyperformotherlabsasindicatedbymaternalhistory• Encouragepatientstoreceiveanautopsy
• PartialautopsyandMRIarealternatives• Alwayssendtheplacenta topathology
Causesofmiscarriage
• PUBMEDsearch– “causesofmiscarrriage,”24,817articlesfrom1873to2017• Originalreference“OnthecausesofUnavoidableHaemorrhageduringMiscarriageorLabour whenthePlacentaisPrevia,”Duncan,JM.BritishMedicalJournal22;2(673):597-599,1873
CausesofMiscarriage
• ANEUPLOIDY• Historicdatasuggeststhat50%offirsttrimestermiscarriagesareduetoaneupolidy• Recentdataisconfirmatory(QuSetal.,2017)• 468productsofconceptionwereevaluatedbysinglenucleotidepolymorphism(SNParray)orkaryotypeanalysis• Meangestationalageatmiscarriage9.4weeks(4to13weeks)• Meanageofpregnantwomenwas19-47yearsold
CausesofMiscarriages(Quetal.,2017)
CausesofMiscarriages(Quetal.,2017)
CausesofMiscarriages(Quetal.,2017)MaternalAge
CausesofMiscarriages(Quetal.,2017)ChromosomalAnomaly/GestationalAge
CausesofMiscarriage(Quetal.,2017)UniparentalIsodisomy CauseofMiscarriages
• Endometriosis– increasesrisk,particularlymildendometriosisassociatedwithpro-inflammatorystate(adjustedrisk1.97(CI1.41-2.75)
Miscarriageandtreatments• Lowdoseaspirinandrecurrentpregnancyloss• Schisterman etal.,2014– Lowdoseaspirindoesnotappeartobeaneffectivetreatmentforpatientswithpriorpregnancylosses
• IVIGinrecurrentpregnancyloss• Christiansenetal.,2014– inasmallstudyIVIGdoesnotappeartobeeffectiveforwomenwithsecondaryrecurrentpregnancyloss
• Obesityandweightgainbeforepregnancy• Gaskinetal.,2014-IndatafromtheNurses’HealthStudyshowedthatobesityandweightgainbeforepregnancyisassociatedwithpregnancyloss
• IVFforrecurrentpregnancyloss• Murugappan etal.,2016–ExpectantmanagementinunexplainedrecurrentpregnancylossisassuccessfulatIVFpreimplantationgenetictestingandhadalowermediantimetopregnancy
• Chronicendometriosis• Bouet etal.,2016- Chronicendometritisisassociatedwithrecurrentpregnancyloss.Officehysteroscopycouldaidindiagnosisbyimmunohistochemistryforsyndecan 1.
• ACOGPracticeBulletinNumber102.“ManagementofStillbirth.”AmericanCollegeofObstetriciansandGynecologists.March2009.acog.org
• Fligner CL,Dighe M.“FetalandPerinatal DeathInvestigation:RedefiningtheAutopsyandtheRoleofRadiologicImaging.”UltrasoundClin 6,2011(105-117).
• IllinoisMasonicMedicalCenterPerinatal LossPolicy.Policy20.118.044• Korteweg FJ,Erwich JJHM,Timmer A,etal.“Evaluationof1025fetaldeaths:proposeddiagnosticworkup.”AmJObstet Gynecol 2012;206:53.e1-12.Korteweg FJ,Erwich JJHM,etal.“PrevalenceofParentalThrombophilic DefectsafterFetalDeathandRelationtoCause.”Obstet andGynecol.August2010,Vol 116,No2,part1.
• Kumar:RobbinsandColtran PathologicBasisofDisease,ProfessionalEdition,8th ed.2009Saunders,animprintofElsevier.
• ReddyUM,Goldenburg R,etal.“StillbirthClassification—DevelopinganInternationalConsensusforResearch.”Obstet andGynecol.Oct2009,Vol 114,No4.
• ReddyUM,PageGP,Saade GR.“Karyotype versusMicroarraytestingforGeneticAbnormalitiesafterStillbirth.”NEngl Jmed367;23,December2012
• SilverR,Heuser C.“StillbirthWorkupandDeliveryManagement.”Clin Obstet andGynecol 2010;53,3.
• Stein,CK.“Applicationsofcytogenetics inModernPathology.”McPherson:Henry’sClinicalDiagnosisandManagementbyLaboratoryMethods,22nd ed.2011Saunders,animprintofElsevier.