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.