ContentslistsavailableatScienceDirect
Vaccine
jo u rn al h om ep a g e :w w w . e l s e v i e r . c o m / l o c a t e / v a c c i n e
Stillbirth:
Case
definition
and
guidelines
for
data
collection,
analysis,
and
presentation
of
maternal
immunization
safety
data
夽
Fernanda
Tavares
Da
Silva
a,
Bernard
Gonik
b,
Mark
McMillan
c,
Cheryl
Keech
d,
Stephanie
Dellicour
e,
Shraddha
Bhange
f,
Mihaela
Tila
g,
Diana
M.
Harper
h,
Charles
Woods
h,
Alison
Tse
Kawai
i,
Sonali
Kochhar
j,
Flor
M.
Munoz
k,∗,
The
Brighton
Collaboration
Stillbirth
Working
Group
1 aGlaxoSmithKlineBiologicals,Wavre,BelgiumbWayneStateUniversitySchoolofMedicine,Detroit,MI,USA cTheUniversityofAdelaide,NorthAdelaide,SouthAustralia,Australia dPATH,Seattle,WA,USA
eLiverpoolSchoolofTropicalMedicine,Liverpool,UnitedKingdom fNovartisHealthcare,Hyderabad,India
gSanofiPasteur,Lyon,France
hUniversityofLouisvilleSchoolofMedicine,Louisville,KY,USA
iHarvardMedicalSchoolandHarvardPilgrimHealthCareInstitute,MA,USA jGlobalHealthcareConsulting,India
kBaylorCollegeofMedicine,Houston,TX,USA
a
r
t
i
c
l
e
i
n
f
o
Articlehistory:
Keywords: Stillbirth Fetaldeath Adverseevent Immunization Guidelines Casedefinition
1. Preamble
1.1. Needfordevelopingcasedefinitionsandguidelinesfordata collection,analysis,andpresentationforstillbirthasanadverse eventfollowingimmunizationduringpregnancy
Oneofthemostcommonadversepregnancyoutcomesisthe
deathof thefetus. Fetaldeathhas a great number ofdifferent
夽 Disclaimer:Thefindings,opinionsandassertionscontainedinthisconsensus documentarethoseoftheindividualscientificprofessionalmembersoftheworking group.Theydonotnecessarilyrepresenttheofficialpositionsofeachparticipant’s organization.Specifically,thefindingsandconclusionsinthispaperarethoseofthe authorsanddonotnecessarilyrepresenttheviewsoftheirrespectiveinstitutions.
∗Correspondingauthor.Tel.:+17137985248/8328244371. E-mailaddresses:contact@brightoncollaboration.org, secretariat@brightoncollaboration.org(F.M.Munoz).
1 BrightonCollaborationhomepage:http://www.brightoncollaboration.org.
andlegallymandateddefinitionsandparticularly,different
repor-ting requirementsamong different countriesand states, which
sometimesusedifferentparameters,includingbirthweight,body
lengthand/ortheclinicalestimateofgestationalagethresholds[1]. Miscarriage(spontaneousabortion)andstillbirtharetwogeneral termsdescribingthedeathofthefetus,buttheyrefertolossesthat occuratdifferenttimesduringpregnancy.Thedistinctionofthese
definitions affects the prospects for theiraccuraterecording in
vitalregistrationsystemsornationalstillbirthregistries, commu-nityandhospitalsurveys,clinicalresearchstudies,togetherwith
thoseformeasurementsandcomparisons.Thereisnouniversally
accepteddefinitionwhenafetaldeathiscalledastillbirthvs. spon-taneousabortion;thereportingpoliciesinthedifferentcountries andwithinthestatesofasamecountryarenotuniformlyfollowed andtherearealsodifferencesintermsofhowthegestationalage isassessedandinterpreted[1–4].
Thevariousdefinitions usedthereforeposeamethodological
difficultywhenattemptingtointerpret andaccuratelycompare
http://dx.doi.org/10.1016/j.vaccine.2016.03.044
Table1
ExistingconventionaldefinitionsforStillbirth.
Source GestationalAge (weeks)
Birth weight(g)
Heightcriteria (crown-heel length)
Definition
USA(CDC) ≥200/7 ≥350 TheUSfederalguidelinesrecommendreportingthosefetaldeathswhosebirth weightisof350gormore,orifweightisunknown,of20completedweeks gestationormore,calculatedfromthedatelastnormalmenstrualperiod;the deathshallbereportedwithin5daysafterdeliverytotheOfficeofVital StatisticsorasotherwisedirectedbytheStateRegistrar.Forty-oneareasusea definitionverysimilartothefederaldefinition,thirteenareasuseashortened definitionoffetaldeath,andthreeareashavenoformaldefinitionoffetal death.Only11areasspecificallyusetheterm‘stillbirth’,oftensynonymously withlatefetaldeath;howevertheyaresplitbetweenwhetherstillbirthsare irrespectiveofthedurationofpregnancy,andwhethersomeageorweight constraintisapplied[92].
WHO/ICD(usefor generalstatisticsand registration)
≥220/7 ≥500 ≥25 TheInternationalClassificationofDiseases,10threvision(ICD-10)definesa fetaldeathas:“deathpriortothecompleteexpulsionorextractionfromits motherofaproductofconception,irrespectiveofthedurationofpregnancy;the deathisindicatedbythefactthataftersuchseparationthefetusdoesnotbreathe orshowanyotherevidenceoflife,suchasbeatingoftheheart,pulsationofthe umbilicalcord,ordefinitemovementofvoluntarymuscleswithoutspecificationof thedurationofpregnancy”.WHO/ICDdefinesstillbirthsasthedeathofafetus thathasreachedabirthweightof500g,orifbirthweightisunavailable, gestationalageof22weeksorcrown-to-heellengthof25cm.Withinthis category,ICDclassifieslatefetaldeaths(greaterthan1000gorafter28weeks) andearlyfetaldeaths(500–1000gor22–28weeks).Thelegalrequirements forregistrationoffetaldeathsvarybetweenandevenwithincountries.WHO recommendsthat,ifpossible,allfetusesandinfantsweighingatleast500gat birth,whetheraliveordead,shouldbeincludedinthestatistics.Theinclusion innationalstatisticsoffetusesandinfantsweighingbetween500gand1000g isrecommendedbothbecauseofitsinherentvalueandbecauseitimproves thecoverageofreportingat1000gandover[5,7].
WHO/ICD(for International comparisonand reporting)
≥280/7 ≥1000 ≥35 TheWHOrecommendsusingthehigherlimit(1000g/28weeks/35cm)of third-trimesterstillbirthsforinternationalcomparisonsandreporting[5,7].
EMA ≥220/7 TheEuropeanMedicinesAgency(EMA)usesthetermstillbirthasthe
synonymoflatefetaldeath,whichisthedeathafter22completedweeksof gestation[102]
NICHD–SCRNUS, VPDCAustralia
≥200/7 ≥400 TheStillbirthCollaborativeResearchNetwork(SCRN)definesstillbirthasFetal deathat≥20completedweeksofgestationor≥400gbirthweight.In Australia,stillbirthisalsodefinedasfetaldeath(nosignsoflife),whether antepartumorintrapartum,at≥20weeksofgestationor≥400gbirthweight, ifgestationalageisunknown,anditmustberegistered[103,104].
ACOG(US) ≥200/7 ≥350 TheAmericanCollegeofObstetriciansandGynecologists(ACOG)defines
stillbirthasdeliveryoffetuswhichshowsnosignsoflifee.g.absenceof breathing,heartbeats,pulsationsinumbilicalcordareabsent,novoluntary movementofmuscle.Thesuggestedrequirementistoreportfetaldeathsat20 weeksorgreaterofgestation(ifthegestationalageisknown)oraweight greaterthanorequalto350gifthegestationalageisnotknown.Thecut-offof 350gisthe50thpercentileforweightat20weeksgestation[2].
UK ≥240/7 TheUnitedKingdomdefinesstillbirthasfetaldeathat24ormorecompleted
weeksofgestation[105,106].
stillbirthratesandassociatedriskfactors.Itisthereforenecessary
toreachaconsensusonthedefinitionandclassificationforthe
adverseeventsinpregnancydatatobecomparableaswellassteps towardamorecomprehensiveevaluationofstillbirth.
BasedontheWHOdefinitionofthird-trimesterstillbirthused
forinternationalcomparability,i.e.deadfetusof1000gormoreat birth,orafter28completedweeksofgestation,orattainmentof atleast35cmcrown-heellength(seeTable1),atleast2.65million casesofannualstillbirthswerecalculatedworldwidein2008,with 1.2millionofthesefetaldeathsoccurringintrapartum[5–7].
Thereportedincidenceofstillbirthvariessignificantlybetween
studiesfromdifferentcountriesanddependingonthedefinitions
used,butgenerallyrangesfrom3.1to6.2/1000birthsor1in160 deliveries[2,8,9]. The largemajorityof stillbirths (∼98%)occur
inlow/middle-incomecountries[1,6,7,10–12].Withimprovement
in prenatal care, some of these deaths can be preventable. It
is a fact that the overall incidence of stillbirth has declined
overtime in developed countries by implementing appropriate
healthcarepoliciesforhandlinghigh-riskpregnantwomen.Inlow/
middle-incomecountries,prevalenceratescanbehowever
inaccu-rateduetounderreportinganddocumentation(e.g.homedelivery) andreliabledataareoftendifficulttoobtain[10,13–17].
1.1.1. Causesandriskfactorsofstillbirth
Thecauseofthedeathofafetusisoftenunknown,butcanbe attributabletovariousorigins[2,18–26].Itisimportantto
recog-nizethatthereisadistinction betweentheunderlyingcauseof
thedeath(thediseaseprocess),themodeofdeath(forexample
asphyxia)andtheclassificationofthedeath(e.g.growth restric-tion).Causesofstillbirthmayalsodifferatdifferentgestational ages.
Astillbirthofunknowncauseisonethatcannotbeexplainedby anyidentifiablecause.Theprevalenceofstillbirthsduetounknown causesvariesfrom25to60%ofallfetaldeaths,dependingonthe
classificationsystemsand evaluationofthedeadbornfetus,e.g.
thecauseofdeathof thefetus whoissmallforgestationalage
canbeattributedtothefetalgrowthrestrictioninsomesystems, butothersconsideritinexplicableiftheunderlyingcauseofthe F.T. Da Silva et al. / Vaccine 34 (2016) 6057–6068
growthrestrictionisunknown[26,27].Theproportionof unclassi-fiedstillbirthscanbesignificantlyreducedwithsystemsthatuse customizedweight-for-gestational-agecharts,suchastherelevant conditionatdeath(ReCoDe)system[22],orwithsystemsthat cap-turemultipleand/orsequentialcontributingfactors,suchasTulip,
PerinatalSocietyofAustraliaandNewZealand–PerinatalDeath
Classification(PSANZ-PDC)orCausesOfDeathandAssociated
Con-ditions(CODAC)[28];moreover,stillbirthratesmaydifferwhen thereisassociationwithunderlyingdeterminants,forexample,a lowerriskofstillbirthisobservedinasmallforgestationalagefetus ifthemotherisofshortstatureandhasamultiplegestation[29].
Traditionally,thecausesofstillbirthhavebeendifferentiatedin maternal,fetal,placentalandexternalfactors.Themostcommonly quotedcausesintheliteratureareasfollows:
-Maternalcauses:Maternalinfectionisoneofthemostimportant causesforstillbirth[20].Commonascendinginfections(withor withoutmembranerupture)areduetoEscherichiacoli,Klebsiella, Group B Streptococcus, Enterococcus, Mycoplasma/Ureaplasma, Haemophilus influenzae and Chlamydia [30,31]. In developing
countries, otherinfectious agents can alsobe considered,e.g.
malaria,syphilis andHIV [5].Onedatabasecohortstudy
con-ductedinEnglandassessingviralinfectionsasacauseoffetalloss
indatafrom1988to2008concludedthatmorethanone-third
(37%)oftheviral-attributedfetal deathsoccurredantepartum,
fromparvovirus(63%)orcytomegalovirus(33%)[32].Diabetes
mellitus,thyroidabnormalities,hypertensivedisorders,systemic lupuserythematosus,cholestasisofthepregnancy,renaldisease, sickle-celldiseaseandothermaternalmedicalconditionsarealso causesfor stillbirth[2].Anemiaandnutritionaldeficienciesin
themother,commoninlow/middle-incomecountries,havebeen
longdebatedtobealsoacauseof stillbirthsorotheradverse
pregnancyoutcomes[5].Incontrast,ahighfirsthemoglobin
mea-surementinearlypregnancyhasbeenshowntobeassociated
withanalmost2-foldincreaseinriskofstillbirth[33].
-Fetalcauses:Amongthese,poorfetalgrowthorintrauterinefetal growthrestriction(IUGR)isconsideredoneofthemostfrequent causesofstillbirth.Presumably,thegrowthrestrictionisduetoa
placentaldysfunctionwhichmayberelatedtonumerous
mater-naldiseasesorinfectionsdescribedabove[34–36].Othercited
causes are: multiple gestation, congenital anomalies, genetic
abnormalities,fetal infection,and postmaturity [19,20,37,38]. Themostcommongeneticetiologyforstillbirthisdueto
karyo-typeabnormalities,howevermanystillbornfetuseswithnormal
karyotypesalsohavegeneticabnormalities[39].
-Placentalcausesincludeplacentalabruption,prematurerupture
ofmembranes,vasaprevia,chorioamnionitis,vascular
malfor-mationsandumbilicalcordaccidentssuchasknotsorabnormal
placement[21,40].
-Externalcauses: Some common examples are: antepartum
mother’sinjuries/traumaordelivery/laborincidentssuchasbirth
asphyxiaandobstetrictrauma.Wheremodernobstetriccareis
notavailable,deathscanbefrequent.Itisestimatedthatin
devel-opingcountriesasphyxiacausesaroundsevendeathsper1000
births,whereasindevelopedcountriesthisproportionislessthan onedeathper1000births(5,20).Availabilityofgooddelivery facilitiesalsoaffectsthepregnancyoutcomes,asitwasobserved inastudythatavailabilityofskilledattendantduringdelivery (oneofthefactorsindeliveryprocess)leadtodeclinein still-birthrate,howevertheauthorsconcludedthatthisneedsfurther analysis[41].
Therearemanyknownepidemiologicalriskfactorsforstillbirth.
Systematicreviewshaveconfirmedveryearlyoradvanced
mater-nalageasriskfactors.Moreover,nulliparouswomenhaveahigher riskofstillbirththanmultiparouswomenacrossallages.Ofthese,
nulliparouswomenaged35yearsandolderhavebeenshownto
havea3.3-foldincreaseintheriskofunexplainedfetaldeath com-paredwithwomenyoungerthan35yearsofage.Theoddsratiofor maternalage40yearsandolderis3.7[42,43].
Otherfactorsassociated withincreasedrisk ofstillbirthare:
bodymassindex(BMI)≥30,smoking(whichincludesactiveand
passive smoking),substanceabuse (especially cocaine, but also
cannabisandalcohol),andmultifetalgestation,withsignificantly higherratesofstillbirthobservedinmonochorionictwinsthanin dichorionic[2,44–48].Onestudyshowedthatmaternaloverweight (i.e.BodyMassIndex≥25)increasestheriskofantepartum still-birth,especiallytermantepartumstillbirth,whereasweightgain perseduringpregnancywasnotassociatedwiththeriskoffetal death[49].Womenwithapreviousstillbirtharewellknowntobe at5-to10-foldincreasedriskofrecurrenceforstillbirth.AlsoAB bloodgroupappearedtobepreferentiallyassociatedwithstillbirth before24completedweeksofgestation[50].
Globally,blackwomenhave2.2foldincreasedriskofstillbirth comparedtowhitewomen[51].Theblack/whitedisparityin
still-birthhazardat20–23weeksis2.75,decreasingto1.57at39–40
weeks.Medical,pregnancyandlaborcomplicationsaccountfor30% oftheriskofstillbirthinBlacksand20%inWhitesandHispanics. Trendshavealsoshowthatstillbirthratesareslightlyhigheramong malecomparedtofemalefetuses[51].Worldwide,67%ofstillbirths occurinruralfamilies,whereskilledbirthattendanceandcesarean sectionsaremuchlowerthanthatforurbanbirths[52].
1.1.2. Diagnosisofstillbirth
Therearediverseexistingmethods/criteriaforidentifying still-births:
-Clinicalsigns:Theyarethosethatreflectabsenceoffetalvitality,
eitherantepartumorbydirectexaminationpostpartum:
a.Antepartum:motherdoesnot feelfetal activity;the
mater-nalweightismaintainedordecreased,thefundalheightstops
increasing or even decreases if the reabsorption of
amni-otic fluid occurs. At the medical examination, intrauterine
ascertainmentofdeathisconfirmedbytheabsenceoffetal
heart tones before delivery by auscultation methods (e.g.
usingPinardhorn,handheldDoppler,fetoscopy,doptoneor
stethoscope)or afterelectronicfetal heart
monitoring/non-stress test. Auscultation of the fetal heart tones by Pinard
horn,stethoscopeorevenhandheldDopplerisinsufficiently
sensitiveforaconfirmatorydiagnosis.Ina seriesof70late
pregnancies in which fetal heart tones were inaudible on
auscultation,22werefoundtohaveviablefetuses[53]. Aus-cultationoffetalhearttonesormisinterpretedexperiencesof fetalmovementscanalsogivefalsereassurance[54];
mater-nalpelvicbloodflowcanresultinanapparentlynormal,but
low,fetalheartratepatternwithhandheldDoppler.Thesign
ofBoeroistheclearauscultationofmaternalaorticbeatsdue totheeventualabsorptionofamnioticfluid.Thefetusbecomes lessperceptibletopalpationasmacerationprogresses.Thesign ofNegriisthecracklingorcrepitationofthefetalheadduring itspalpation.Sometimesvaginaldarkbloodlossisnoted,there
mightbeincreasedconsistencyofcervixbecauseofthe
hor-monaldeclineandalso,appearanceofsecretionofcolostrum
inthemammaryglands,althoughthesesignsarenotspecific.
b.Postpartum ascertainment of death is confirmed by Apgar
scoresof0at1and5min,absenceofvitalsignsincludingthe
documentationofnoheartrateandrespirations,absenceof
pulsationoftheumbilicalcord,andnodefinitivemovement
of voluntary muscles. Heartbeats are to be distinguished
from transient cardiac contractions; respirations are to be
distinguished from transient fleeting respiratory efforts or
ofmacerationandthelevelofmacerationcandeterminetime ofdeath.Theearliestsignofmacerationsareseenintheskin
4–6hafterintrauterinedeath;desquamatedskinmeasuring
1cmormoreindiameterandredorbrowndiscolorationof
theumbilicalcordcorrelatewithfetaldeath6ormorehours beforebirth;desquamationinvolvingtheskinofface,backor
abdomenwith12ormorehours;desquamationof5%ormore
ofthebodysurfacewith18ormorehours;moderatetosevere
desquamation,brownskindiscolorationoftheabdomenwith
24ormorehoursandmummificationisseeninfetuseswho
died2ormoreweeksbeforebirth[55].
-Radiologicstudies:Inadditiontotheaboveclinicalsigns,other
secondaryfeaturesmightbeseenantepartumifeventually
imag-ingtechniquessuchasX-rayradiographyareused:collapseof
thefetalskullwithoverlappingbonesduetoliquefactionofthe
brain,hydrops,flatteningof thecranialcavity,head
asymme-try,fallofthemandible(signofopenmouth),orfetalbunching duetoalossofthenormalcurvatureofthespinedueto
macer-atingspinalligaments,whichmayappearcompletelycollapsed
resultinginunrecognizablefetalmass.Inaddition,theremightbe alsointra-fetalgaswithintheheart,bloodvesselsandjointsora translucentperi-cranialhaloduetoaccumulationoffluidinthe
subcutaneoustissue;whentheimageiscompletegivesdouble
cranialhalocalled“holycrown”[56–60].
-Ultrasound(US):real-timeultrasonographyisthegoldstandard fortheaccuratediagnosisofstillbirthantepartum.Theadvantage ofthismethodliesintheprecocitywithwhichthediagnosiscan bemade,becauserealtimeultrasoundallowsdirectvisualization ofthefetalheartandtheabsenceofcardiacactivity,absenceof aorticactivityandtheabsenceofmovementsofthebodyorlimbs ofthefetus(tobedistinguishedfromperiodsoffetal physiolog-icalrest).Imagingcanbetechnicallydifficult,particularlyinthe
presenceofmaternalobesity,abdominalscarsand
oligohydram-nios,butviewscanoftenbeimprovedwithnewgenerationUS
orwithcolorDopplerofthefetalheartandumbilicalcord.Other
secondarysignsthatcanbeseenatUSare:theaccumulationof
fluidinthesubcutaneoustissue(anasarca),pleuralandperitoneal effusion,andthelossofthedefinitionoffetalstructures,which
oftenreflectmaceration.
1.1.3. Stillbirthfollowingimmunization
Decadesof vaccineuseand evidence fromclinicaltrialdata
and observational studieshave shown thesafety of traditional
non-live vaccines (e.g. tetanus, pertussis or influenza) during
pregnancy.Currentlyinactivatedinfluenzavirus,andpertussis
vac-cinesarerecommendedforuseduringpregnancyinmanyparts
of theworld. Pertussis vaccines are generally availableas part
ofcombined vaccinessuchas tetanustoxoid,reduced
diphthe-riatoxoid,andacellularpertussis(Tdap) vaccines,orTdapwith
inactivated poliomyelitis virus vaccines (Tdap-IPV). Systematic
reviewsforinactivatedinfluenzavirusvaccines haveconcluded
thatthevaccineisnotassociatedwithanincreasedriskof
still-birth [61,65,67,70]. One review paper describes that influenza
vaccinationmight decrease the incidence of adverse outcomes
ofpregnancy suchasstillbirth, asa result oftheprevention of
influenzainfectionrelatedinflammation[61].Thesefindingswere
generalizabletomonovalentinfluenzaA(H1N1)vaccines,withthe
majorityofevidenceobtainedforwomenimmunizedduringtheir
2ndor3rdtrimesterofpregnancy[61–75].
FewerstudieshaveexaminedstillbirthfollowingTdap adminis-trationduringpregnancy,includingtwolargeretrospectivestudies
completedintheUSandtheUKwherestillbirthrateswere
com-paredtomatchedunvaccinatedpregnantwomenandtheauthors
concludedthat thevaccine is not associatedwith anincreased
risk ofstillbirth [76–78].Remaining stillbirth dataonpertussis
containingvaccinescomesfromadverseeventregistriesandsmall studieshavingsimilarfindings[79–81].Tetanustoxoid(TT)
mono-valentand tetanustoxoid reduceddiphtheria (Td)vaccines are
recommendedforuseinpregnancyinsomecountrieswhere
elim-inationofmaternalandneonataltetanusremainsapriority[82].
Mostlivevaccines are contraindicated ornot recommended
foruseduringpregnancy[83].Manyoftheliveattenuated
vac-cinesalsocomewitharecommendationtoavoidpregnancyfor
themonthfollowing immunization.Thisisdue tothe
theoreti-calriskoftransmissionofthevirusthroughtheplacentatothe fetus[82,83].Stillbirthdataonmanyofthesevaccinesisderived
fromthefollow up ofwomen inadvertently immunizedduring
earlypregnancy.Rubellaandvaricellaareofspecificinterestdue
tothepotentiallysevereconsequencesofwild-typeinfectionin
susceptiblepregnantwomen,whichcanleadtocongenitalrubella
syndrome(CRS),andcongenitalvaricellasyndrome.Muchofthe
researchinvestigatingthesafetyoftheMMRandvaricellavaccine
hasthereforelookedatcongenitalanomaliesoutcomes.However,
thereissomedataavailableonstillbirthratesfollowing
immu-nizationshowingnosafetyconcerns[84–86].Ameta-analysisof
elevenstudiesreporteddataonstillbirth(definedasfetal death
≥20weeksofgestation)andfoundthatthesmallpoxvaccination
isnotassociatedwithanincreasedriskofstillbirth,pooledRR1.03
(95%CI:0.75–1.40)[87].AstudyconductedinFinlandduringa
massoralpoliovirusimmunizationcampaignconductedbetween
1984and1986reportedstillbirthratesamongwomenwhowere
pregnantduringtheperiodofvaccinationandwhoseinfantswere
deliveredatthethreemajorhospitalsintheHelsinkiareabetween 0.4%and0.6%,dependingontheirtrimesterofexposure,compared with0.45%inthereferencecohort[88].
1.2. Methodsforthedevelopmentofthecasedefinitionand guidelinesfordatacollection,analysis,andpresentationfor stillbirthasanadverseeventsfollowingimmunizationduring pregnancy
Followingthe process described in theoverview paper [89]
as well as on theBrighton Collaboration Website http://www.
brightoncollaboration.org/internet/en/index/process.html, the
Brighton Collaboration Stillbirth Working Group was formed
in 2015 and included members of clinical, academic, public
health, research and industry background. The composition of
theworkingand referencegroupaswellasresultsofthe
web-basedsurveycompletedbythereferencegroupwithsubsequent
discussionsintheworkinggroupcanbeviewedat:http://www.
brightoncollaboration.org/internet/en/index/workinggroups.
html.
Toguidethedecision-makingforthecasedefinitionand
guide-lines,a literaturesearchwasperformedusingMedline,Embase
andtheCochraneLibraries,includingthetermsstillbirth,stillborn, intrauterinedeath,fetaldemise,fetalmortality,fetaldeath,
dead-born,fetal loss,intrapartumdeath, antepartumdeath, perinatal
audit,perinataldeath,perinatalmortality,pregnancylossand
vac-cine,immunizationandvaccination.Exhaustivesearchstrategies
wereimplementedusingappropriatekeywords,acceptedMeSH
words,andcombinationsthereof.Allabstractswerescreenedfor
possible reports of stillbirth following immunization. Searches
wererestrictedtoreferencesinEnglish,publishedsince1970and involvingonlyhumansubjects.Multiplegeneralmedical,pediatric, obstetricsandinfectiousdiseasetextbookswerealsosearched.
Thesearchandscreeningresultedintheidentificationofarticles withpotentiallyrelevantmaterialforfurtherevaluation.This lit-eratureprovidedseveraldifferentgeneraldefinitionsforstillbirth, itsepidemiology,numerousdescriptionsforstillbirthcausesand/or riskfactorsandthediagnosticcriteriaputforth.Mostpublications addressingstillbirthfollowingimmunizationwerecasereportsof F.T. Da Silva et al. / Vaccine 34 (2016) 6057–6068
singlecasesorcaseseriesdescribingvariouspregnancyoutcomes,
forwhichterminologywasveryinconsistentandveryfewused
casedefinitions.
1.3. Rationaleforselecteddecisionsaboutthecasedefinitionof stillbirthasanadverseeventfollowingimmunizationduring pregnancy
1.3.1. Thetermstillbirth
Ingeneral,stillbirthisdefinedasafetuswithnosignsoflifeprior tothecompleteexpulsionorextractionfromitsmother,andafter apre-defineddurationofgestation;afterdelivery,itisconfirmed
thatthefetusdoesnotshowanyevidenceoflife,andcannotbe
resuscitated.
The basic WHO definition for “stillbirth” is the intrauterine
deathofthefetusatanytimeduringpregnancy[90].However,
forpracticalpurposes,legaldefinitionsusuallyrequirereportable fetaldeathstoattainagestationalage(forstillbirththeGA
gen-erallyconsideredisbetween20and28weeks)orabirthweight
(generallybetween 350and 1000g). The minimum gestational
agecut-offdefiningstillbirthvs.miscarriagegenerallyvariesfrom
20 to28 weeksof gestationbased onstandardsof fetal
viabil-ityacrosscountries, basedonavailablemedical careand health
infrastructure[6].Inmosthighincomeandsomemiddleincome
countries, thresholds vary from 18 to 22 weeks while in low
income areas/countries thresholds are higher, up to 28 weeks
[18].Thedefinitionandascertainmentcouldbetherefore
differ-entindeveloping/low-middleincomevs.developed/highincome
countries.Forinternationalcomparability,theWHOrecommends
usingthecut-offof1000gormoreatbirth(ifavailable),orafter
28completedweeksofgestation,orattainmentofatleast35cm
crown-heellength[5].IntheUnitedStates,thereareeightdifferent
definitionsbycombinationsofgestationalageandweight,andat
leastasmanyinEurope[91,92].
Ingeneral,stillbirthsareclassifiedaccordingtothegestational age,andaretypicallydividedintoearlystillbirths(from20to28 weeksgestation) and late stillbirths(after 28 weeks gestation). Thisdivisionisbasedonthosestillbirthsthataredifficultto pre-ventcomparedwiththosethatarepotentiallypreventable(i.e.late stillbirths).Stillbirthsarealsoclassifiedbywhetherdeathoccurred beforeoraftertheonsetoflabor,referredasantepartumstillbirth andintrapartumstillbirth,respectively.
Despiteall thesesubclassifications,theprimary methodfor
classificationofstillbirthisaccordingtothepresumedcause[93].In addition,thereareover35classificationsystemstodefinestillbirth
orperinataldeathusedin differentcountriesaroundtheworld
[18,42,94–97],themostrecentarethesuggestedReCoDe[98],the
modifiedWhitfield-Australia/NewZealandClassifications[99],and
theWorldHealthOrganization’sInternationalClassificationof Dis-ease(ICD-10)systems[90](seeTable1).
Inthisarticle,wewillusethegeneraltermstillbirth,toreferto fetaldeathsoccurringafterapre-defineddurationofgestation,in
accordancewithselected/preferreddefinitionsusedtofulfillthe
researchneedsin a given setting ortofit a reporting purpose,
regardlessofwhetherthedeathofthefetuscouldhaveoccurredin utero(antepartum)oratthetimeofdelivery(intrapartum).
Thecasedefinitionpresentedinthisdocumentdoesnot
pre-scribetheuseofaspecificgestationalagecutofforcombination
ofgestationalageand/orweightandsizeassessmentsto
differ-entiatebetweenmiscarriage andstillbirth, but rather considers
thecurrentlyutilizeddefinitionsofstillbirthworldwideandthe importanceofhavingadefinitionthatisapplicableindifferent clin-icalsettingsandenvironments.Thevariabilityinthedefinitionof stillbirthstemsfromvariabilityinviabilitycutoffsindifferent sett-ings,availableresources,localpractices,culturalinfluences,legal implications,andlocalandinternationalreportingrequirements.
TheWHOdefinitionstaketheseelementsinconsiderationandare
widelyused[5].
Theworkinggroupemphasizestheimportanceofconsistently
andsystematicallycapturingallcasesofstillbirthinclinicaltrials assessingthesafetyofvaccinesgivenduringpregnancy.Thestudy protocolshouldclearlydescribetheselecteddefinitionofacase ofstillbirthandutilizeitconsistentlythroughoutallstudysitesfor datacollectionandanalysistoensuredatacomparabilityanda
bet-terunderstandingofthisadversepregnancyoutcome.Theworking
grouprecommendstomakeexplicitaworkingdefinitionof
still-birthtocaptureallevents,forexample“deadbornfetusatorafter
22completedweeksofgestation”andtoconsidercategorization
intoothersubgroupsbasedonthegoalsofthestudyandrelevant analyses,forexample“early(after22weeks)”vs.“late(after28 weeks)”stillbirth.
Theworkinggroupsuggeststhatdifferentiationofantepartum
andintrapartumstillbirthisrelevant,wheneverpossible,to
under-standpotentialunderlyingetiologiesandmechanismsleadingto
theevent.However,whenthisdifferentiationisnotpossible,the outcomewillberecordedasastillbirth,definedasthedeliveryof afetuswithnosignsoflifeandassessedbytheattendantand/or investigatortobewithinthegestationalageconsistentwiththe selectedcutoffinthedefinition.
1.3.2. Relatedterm(s)ofstillbirth
Therearedifferenttermsusedwithinthiscontext.Thoseterms are:stillborn,intrauterinedeath,fetal/fetaldemise,fetal/fetal mor-tality,fetal/fetaldeath,dead-bornandfetal/fetalloss.Otherless
specific terms are sometimesused as well: intrapartum death,
antepartumdeath,perinatalaudit,perinataldeath,perinatal mor-tality,pregnancyloss.
1.3.3. Formulatingacasedefinitionthatreflectsdiagnostic certainty:weighingspecificityvs.sensitivity
Itneedstobere-emphasizedthatthegradingofdefinition lev-elsisentirelyaboutdiagnosticcertainty,notclinicalseverityor causalityofanevent.Detailedinformationabouttheseverityof
theeventshouldadditionallyalwaysberecorded,asspecifiedby
thedatacollectionguidelines.
Thenumberofsymptomsand/orsignsthatwillbedocumented
foreachcasemayvaryconsiderably.Thecasedefinitionhasbeen
formulatedsuchthattheLevel1definitionishighlyspecificfor
thecondition.Asmaximumspecificitynormallyimpliesalossof
sensitivity,twoadditionaldiagnosticlevelshavebeenincludedin thedefinition,offeringastepwiseincreaseofsensitivityfromLevel OnetoLevelThree,whileretaininganacceptablelevelofspecificity atalllevels.Inthiswayitishopedthatallpossiblecasesofstillbirth
canbecaptured.
1.3.4. Rationaleforindividualcriteriaordecisionmaderelatedto thecasedefinition
Thereis a need toconsider data sources and availability of
existingdatawhendefiningpregnancyoutcomesinresearch.The
interpretationofdataisdifficultwhencut-offvaluesofthe defini-tionsdiffer,anditisalsoproblematicinmultiplegestationswith bothliveanddeadsiblings.Flexibilityandalignmentwithexisting definitionswherestudies/surveillanceareperformedarenecessary toensurecomparabilityandinterpretationofdata.Another consid-erationforcaseinclusioncriteriaaredeliveriesthatoccuroutsideof thehospitalsetting(e.g.homedelivery),intheabsenceofmedical personnel,andthenarepresentedtothehospitalasadeath. Some-timesthesedataarenotmadeavailable.Inaddition,underthese circumstances,itisnotalwayspossibletodeterminewhetherthe fetuswasstillborn,orifthefetuslivedforanylengthoftime.
Althoughveryfewdatamaybeavailabletodetermineacause
examinationofthefetusforcongenitalmalformations,andif
avail-able,autopsyandkaryotype;cordandplacentalexaminationand
pathology,documentingantepartumeventssuchasmaternal
fac-tors,fetal factors (e.g.intrauterine growthrestriction), external factors(e.g.trauma),andperi-partumeventssuchaspreterm
pre-matureruptureofmembranes(PPROM),infection,abruption,cord
events,laboratoryfindings,etc.Thesedata(i.e.pathologyand
lab-oratoryfindings) maynot beincludedin thecase definition of
stillbirth,butarerecommendedtobeobtainedinthedataanalysis toascertainthepossiblecause.
1.3.5. Determinationofthegestationalageatdeath
Thegestational age(GA)seems tobethemost widelyused
criteriontodefinestillbirth.Severalalgorithmsareavailablefor
assessmentofgestational ageat deathbasedonavailable
clini-caldataandsimpleexaminationoftheinfantafterdelivery[100].
Thesemaybeusedwhenothermeansofdetermininggestational
ageareunavailable.
Themostcommonmethodfortheascertainmentofestimated
GestationalAge(GA)attimeoffetaldeathisbasedontheLast
Men-strualPeriod(LMP):Thedurationofgestationismeasuredfrom
thefirstdayofthelastnormalmenstrualperiod.Gestationalageis
expressedinweeks.Othermethodsincludemeasurementoffundal
height,biometricparametersofthefetuswhichcanbedetermined
antepartumbyUSorbyotherlessaccuratemeasurement
meth-odspost-partum,suchasfetalcrown-to-heellengthorfootlength
[100,101],orthedirectobservationofthefetalmaturation,ifno
measurementmethodsareavailable.Differentscoringsystemsare
alsousedtoestimatethegestationalageafterbirthbutallinvolve neurologicreflexesand/orphysicalcharacteristicssuchasskinand
cartilagechanges,howeveralltheseneurologicmeasuresarenot
possibleforstillbirthsandskinandcartilagechangesareunreliable ifthereismaceration.
AproposedalgorithmforestimatingGAforstudiesinvarious
communitysettingsispresentedinarelatedmanuscript(Preterm
BirthDefinitionandGAassessmentalgorithm–availableathttp://
www.brightoncollaboration.org).Thisalgorithmpresentscriteria
basedondifferentparameters thatcouldbeavailable,including
LMPand differentmeasurement methods including ultrasound
scan, or stillborn assessment immediately after birth. In obese
women,orwhenuterineanatomyisotherwisecompromised(e.g.
multiplefibroids),cliniciandeterminationofGAby“best
assess-ment” is to be used. Although GA is determined antepartum,
findingsmustbeconsistentwithimmediateandsimple
exami-nationofthestillbornfetusafterdelivery,otherwise aposthoc determinationisneeded.Assessmentofgestationalageofthefetus isakeycomponentofthecasedefinitionofstillbirth.The
work-inggrouprecommendstheuseoftheGAassessmentalgorithmin
the“PretermBirth”BrightonCollaborationCaseDefinitionforthe assessmentofgestationalageinthemotherorfetus.
1.3.6. Timingpostimmunizationinpregnancy
Wepostulatethatadefinitiondesignedtobeasuitabletoolfor testingcausalrelationshipsrequiresascertainmentoftheoutcome
(e.g.stillbirth) independent fromthe exposure(e.g.
immuniza-tions).
Further,stillbirthoftenoccursoutsidethecontrolledsettingof aclinicaltrialorhospital.Insomesettingsitmaybeimpossibleto obtainacleartimelineoftheevent,particularlyinlessdeveloped orruralsettingsandintheobservationalresearchsettingvia retro-spectivemedicalrecordreviews.Inordertoavoidselectingagainst suchcases,theBrightonCollaborationcasedefinitionavoidssetting
arbitrarytimeframes.Anexacttime-frameshouldnotbeoffered
sinceitwouldhavetorefertoawiderangeofsignsandsymptoms withoutascientificevidencebase.Usinganarbitrarilyrestrictive setpointmightbiasfuturedatacollectionunnecessarily.Therefore,
toavoidselectionbias,arestrictivetimeintervalfrom immuniza-tiontoonsetofstillbirthshouldnotbeanintegralpartofsucha
definition,butisrecommendedtobeusedinthedataanalysisto
examinefactorssuchastemporalclusters.Wherefeasible,details ofthisintervalshouldbeassessedandreportedasdescribedinthe datacollectionguidelines(seeguideline34,section3.2).
1.4. Guidelinesfordatacollection,analysisandpresentation
As mentioned in the overview paper, the case definition is
accompaniedbyguidelineswhicharestructuredaccordingtothe
stepsofconductingaclinicaltrial,i.e.datacollection,analysisand presentation.Neithercasedefinitionnorguidelinesareintendedto guideorestablishcriteriaformanagementofillinfants,children,
oradults.Bothweredevelopedtoimprovedatacomparability.
1.5. Periodicreview
SimilartoallBrightonCollaborationcasedefinitionsand guide-lines,reviewofthedefinitionwithitsguidelinesisplannedona regularbasis(i.e.everythreetofiveyears)ormoreoftenifneeded.
2. Casedefinitionofstillbirth2
2.1. Stillbirth
Is a fetal deathoccurring beforebirth after a selected, pre-defineddurationofgestation(seeTable1).Thedeathofthefetus
couldhaveoccurredbeforetheonsetoflabor3 (antepartum)or
atthetimeofdelivery(intrapartum).Foralllevelsofdiagnostic certainty,thedefinitionofstillbirthmustinclude:
-Determinationofabsenceofsignsoflife4inthefetusornewborn AND
-Determinationoffetal/newborngestationalagethrough
mater-nal information or through fetal/newborn evaluation (see
PretermBirthDefinition–AssessmentofGestationalAge)
2.1.1. Antepartumstillbirth
Antepartumstillbirthisdefinedasfetaldeathoccurring
dur-ingpregnancyandpriortodelivery,beforetheonsetoflabor.Itis usuallydiagnosedpriortodelivery,butmaynotbediagnoseduntil aftertheinfantisdelivered.Theinfantisbornwithoutsignsoflife.3
2.1.2. Intrapartumstillbirth
Intrapartumstillbirthisdefinedasfetaldeathoccurringafter theonsetoflaborandpriortodelivery.Theinfantisbornwithout signsoflife.3Documentationofalivefetuspriortoorattheonset
oflaborexists.
Additionalfindingsthatmightbehelpfultodifferentiatebetween AntepartumandIntrapartumStillbirthatthetimeofdelivery:
•PhysicalExamination:Fetuseswhodiedantepartumcanhave
skinchangesconsistentwithmaceration,tissueinjury,
meco-niumstaining,andedema.
•Laboratory/pathology:Autopsyexaminationofthefetusand/or
theplacenta.
2Thecasedefinitionshouldbeappliedwhenthereisnoclearalternativediagnosis
forthereportedeventtoaccountforthecombinationofsymptoms.
3Theonsetoflaborisdefinedasregular,painfuluterinecontractionsresultingin
progressivecervicaleffacementanddilatation.
4Signsoflifeinclude:spontaneousmovements,spontaneousrespirations,and
spontaneouscardiacactivity.
F.T. Da Silva et al. / Vaccine 34 (2016) 6057–6068
2.2. Stillbirthascertainmentoflevelsofcertainty
2.2.1. AntepartumStillbirth
Fetaldeathoccurspriortotheevidenceoflabor.
Level1
•Deliveryofaninfantwithnoofsignsoflifeatbirth(No
spon-taneousmovements,noumbilicalcordpulse,noheartbeat,no
respirations,Apgarscoreof0 at1and 5min)determinedby
physicalexaminationafterdelivery(withorwithoutelectronic monitoringofheartrate,respiratoryrate,andpulseoximetry).
AND
•Prenatalultrasoundexaminationdocumentinglackoffetal
car-diacactivityormovementbeforetheonsetoflabor.
OR
•Auscultationforfetalhearttones (usingelectronicdevicesor non-electronicdevices)documentinglackoffetalheartbeat.
AND
•Maternalreportoflackoffetalmovementfor24hormore.
OR
•Maternalphysicalexaminationconfirminglackoffetal
move-ment.
OR
•Radiologyfindingsconsistentwithintrauterinefetaldeath.
AND
•Attendeddeliveryfollowedbyfetalphysicalexaminationafter
birthconsistentwithantepartumdeath,byobstetrician,
neona-tologist, pediatrician, maternal-fetal medicine specialist, or
pathologist.In thesetting whereaccesstoa specialistis not feasible,diagnosisbyahealthcareprovidertrainedor experi-encedtomakethediagnosisisacceptable(e.g.generalpractice physician,mid-wife,nursepractitioner,aphysician’sassistant orotherqualifiedtrainedpractitioner).
OR
•Fetal/placental pathology report consistent withantepartum
death.
AND
•Gestationalagewithinpre-definedrangeforselectedstillbirth definitionasassessedbymaternaland/orfetalparameters(Level 1or2inGAassessmentalgorithm).
Level2
•Deliveryofaninfantwithnoofsignsoflifeatbirth(No
spon-taneousmovements,noumbilicalcordpulse,noheartbeat,no
respirations,Apgarscoreof0at1and5min)determined phys-icalexaminationafterdelivery.
AND
•Maternalreportoflackoffetalmovementfor24hormore.
OR
•Maternalphysicalexaminationconfirminglackoffetal
move-ment.
OR
•Auscultation for fetal heart tones (using electronic or
non-electronicdevices)documentinglackoffetalheartbeat.
AND
•Attendeddeliveryfollowedbyphysicalexaminationafterbirth
consistent withantepartum death, by specialist or qualified
trainedpractitionerappropriatetothehealthcaresetting.
OR
•Fetal/placental pathology report consistent withantepartum
death.
AND
•Gestationalagewithinpre-definedrangeforselectedstillbirth definitionasassessedbymaternaland/orfetalparameters(Level
1–2inGAassessmentalgorithm).
Level3
•Deliveryofaninfantreportedtohavenoofsignsoflifeatbirth
(Nospontaneousmovements,noumbilicalcordpulse,no
heart-beat,nocryorspontaneousrespirations,nochestmovement,
andwholebodycyanosis).
AND
•Maternalreportoflackoffetalmovementfor24hormoreprior todelivery.
OR
•Reportofauscultationforfetalhearttones(usingelectronicor non-electronicdevices)documentinglackoffetalheartbeat.
AND
•Non-attendeddeliveryfollowedbyphysicalexaminationofthe
fetusafterbirthconsistentwithantepartumdeathbyahealth
careprofessionalappropriatetothelevelofstandardofcarein thehealthcaresetting.
OR
•Verbalhistorybya trainedhealthcareprovider,non-medical
witnessorthemotherofafetusbornwithnosignsoflifeor
unresponsivetoresuscitationeffortsimmediatelyafterbirthand
withphysicalfeaturesconsistentwithantepartumdeath.
AND
•Gestationalagewithinpre-definedrangeforselectedstillbirth definitionasassessedbymaternaland/orfetalparameters(Level
2–3inGAassessmentalgorithm).
Level4
•Reportofstillbirthbutfetusisnotavailableforphysical exami-nationafterbirth(noobjectiveassessmentcanbemade).
•Maternalinformationinsufficienttoassessgestationalage.
2.2.2. Intrapartumstillbirth
Fetaldeathoccursduringlaborandbeforedelivery
Level1
•Deliveryofaninfantwithnoofsignsoflifeatbirth,including:No
spontaneousmovements,noumbilicalcordpulse,noheartbeat,
norespirations,andApgarscoreof0at1and5min.
•Determinationoftheabsenceofsignsoflifeismadebyphysical examinationafterdelivery,withorwithoutelectronic monitor-ingofheartrate,respiratoryrate,andpulseoximetry.
AND
•Evidenceoflivefetuspriortoonsetoflabor(documentationof
fetalmovementandoffetalhearttonesbyultrasoundpriorto
onsetoflabor)(Note:intheabsenceofevidenceofalivefetus priortotheonsetoflabor,thefetaldeathshouldbereportedas astillbirthoranantepartumstillbirth).
AND
•Attended delivery followed by physical examination after
birth consistent with intrapartum death by obstetrician,
neonatologist,pediatrician,maternal-fetalmedicinespecialist, pathologist.Inthesettingwhereaccesstoaspecialistisnot feasi-ble,diagnosisbyahealthcareprovidertrainedorexperiencedto makethediagnosisisacceptable(e.g.generalpracticephysician, mid-wife,orotherqualifiedtrainedpractitioner).
AND
•Gestationalagewithinpre-definedrangeforselectedstillbirth
definitionasassessedbymaternaland/orfetal-neonatal
param-eters(Level1inGAassessmentalgorithm)
Level2
•Deliveryofaninfantwithnoofsignsoflifeatbirth,including:No
spontaneousmovements,noumbilicalcordpulse,noheartbeat,
•Determinationoftheabsenceofsignsoflifeismadebyphysical
examination afterdelivery, withorwithoutelectronic
moni-toring ofheart rate,respiratory rate,and pulse oximetryOR
documentationoflackofresponsetoresuscitationefforts.
AND
•Evidenceoflivefetuspriortoonsetoflabor(maternalreport
offetalmovementpriortoonsetoflaboranddocumentationof
fetalhearttonesbyauscultationorhandheldDoppler)(Note:in theabsenceofevidenceofalivefetuspriortotheonsetoflabor, thefetaldeathshouldbereportedasastillbirthoranantepartum stillbirth).
AND
•Attendeddeliveryfollowedbyphysicalexaminationafterbirth
consistentwithintrapartumdeathbyahealthcareprofessional appropriatetothelevelofstandardofcareinthehealthcare setting.
AND
•Gestationalagewithinpre-definedrangeforselectedstillbirth definitionasassessedbymaternaland/orfetalparameters(Level
1–2inGAassessmentalgorithm).
Level3
•Deliveryofaninfantreportedtohavenoofsignsoflifeatbirth,
including:Nospontaneousmovements,noumbilicalcordpulse,
noheartbeat,nocry,nospontaneousrespirationsorchest
move-ment,andwholebodycyanosis.
AND
•Evidenceoflivefetuspriortoonsetoflabor(maternalreportof fetalmovementpriortoonsetoflaborORauscultationoffetal hearttones)(Note:intheabsenceofevidenceofalivefetusprior
totheonsetoflabor,thefetaldeathshouldbereportedasa
stillbirthoranantepartumstillbirth).
AND
•Non-attendeddeliveryfollowedbyphysicalexaminationofthe
fetusafterbirthconsistentwithintrapartumdeathbyahealth careprofessionalappropriatetothelevelofstandardofcarein thehealthcaresettingORverbalhistorybyatrainedhealthcare provider,non-medicalwitnessorthemotherofafetusbornwith nosignsoflifeorunresponsivetoresuscitationefforts immedi-atelyafterbirth.
AND
•Gestationalagewithinpre-definedrangeforselectedstillbirth definitionasassessedbymaternaland/orfetalparameters(Level
2–3inGAassessmentalgorithm).
Level4
•Reportofstillbirthbutfetusisnotavailableforphysical exami-nationafterbirth(noobjectiveassessmentcanbemade).
•Maternalinformationinsufficienttoassessgestationalage.
3. Guidelinesfordatacollection,analysisandpresentation ofstillbirth
Itwas theconsensusofthe BrightonCollaborationStillbirth
WorkingGrouptorecommendthefollowingguidelinestoenable
meaningfuland standardized collection,analysis,and
presenta-tionofinformationaboutstillbirth.However,implementationof
allguidelinesmightnotbepossibleinallsettings.Theavailability
ofinformationmayvarydependinguponresources,geographical
region,andwhetherthesourceofinformationisaprospective clin-icaltrial,apost-marketingsurveillanceorepidemiologicalstudy, oranindividualreportofstillbirth.Also,theseguidelineshavebeen developedbythisworkinggroupforguidanceonly,andarenotto beconsideredamandatoryrequirementfordatacollection, analy-sis,orpresentation.
3.1. Datacollection
Theseguidelinesrepresentadesirablestandardforthe
collec-tionofavailablepregnancyoutcomedatafollowingimmunization
toallowcomparability.Theguidelinesarenotintendedtoguidethe primaryreportingofstillbirthstoasurveillancesystem. Investiga-torsdevelopingadatacollectiontoolbasedonthesedatacollection guidelinesalsoneedtorefertothecriteriainthecasedefinition.
Guidelines1–43belowhavebeendevelopedtoaddressdata ele-mentsforthecollectionofadverseeventinformationasspecified ingeneraldrugsafetyguidelinesbytheInternationalConference
onHarmonizationofTechnical RequirementsforRegistrationof
PharmaceuticalsforHumanUse[107],andtheformforreporting
ofdrugadverseeventsbytheCouncilforInternational
Organiza-tionsofMedicalSciences [108].Thesedataelementsincludean
identifiablereporterandpatient,oneormorepriorimmunizations, andadetaileddescriptionoftheadverseevent,inthiscase,of still-birthfollowingimmunization.Theadditionalguidelineshavebeen developedasguidanceforthecollectionofadditionalinformation toallowforamorecomprehensiveunderstandingofstillbirth
fol-lowingimmunization.
3.1.1. Sourceofinformation/reporter
Forallcasesand/orallstudyparticipants,asappropriate,the
followinginformationshouldberecorded:
(1)Dateofreport.
(2)Name and contact information of person reporting5 and/or
diagnosingthestillbirthasspecifiedbycountry-specificdata
protectionlaw.
(3)Nameandcontactinformationoftheinvestigatorresponsible
forthesubject,asapplicable.
(4)Relationtothepatient(e.g.immunizer[clinician,nurse],family member[indicaterelationship],other).
3.1.2. Vaccinee/control
3.1.2.1. Demographics. Forallcasesand/orallstudyparticipants
(i.e.pregnantwomenandnewborn),asappropriate,thefollowing
informationshouldberecorded:
(5)Case/studyparticipantidentifiers(e.g.participant’sfirstname initialfollowedbylastnameinitial)orcode(orinaccordance withcountry-specificdataprotectionlaws).
(6)Participant’sageatenrolment,race/ethnicityandgestational ageatthetimeofenrolment.
(7)Fordeadnewborn:Gestationalageandbirthweight/height.
3.1.2.2. Clinical and immunization history. For all cases and/or allstudyparticipants,asappropriate,thefollowing information
shouldberecorded:
(8)Pastmedical history,includinghospitalizations, underlying
diseases/disorders, pre-immunization signs and symptoms
includingidentificationofindicatorsfor,ortheabsenceof,a historyofallergytovaccines,vaccinecomponentsor medica-tions;foodallergy;allergicrhinitis;eczema;asthma.
(9)Anymedicationhistory (including treatmentfor theevent
described)prior to,during,andafterimmunization
includ-ing prescription and non-prescription medication as well
as medication or treatment with long half-life or long
term effect (e.g. immunoglobulins, blood transfusion and
5Ifthereportingcenterisdifferentfromthevaccinatingcenter,appropriateand
timelycommunicationoftheadverseeventshouldoccur.
F.T. Da Silva et al. / Vaccine 34 (2016) 6057–6068
immune-suppressants)orsubstanceabuse(e.g.narcoticsor otherrecreationaldrug,alcoholorsmoking).
(10)Immunizationhistory(i.e.previousimmunizationsandany
adverse eventfollowing immunization (AEFI), inparticular
occurrenceofstillbirthafterapreviousimmunization.
(11)Medicalconfirmationoflivefetuspriortomaternal
immuni-zation.
3.1.3. Detailsoftheimmunization
Forallcasesand/orallstudyparticipants,asappropriate,the
followinginformationshouldberecorded:
(12)Dateandtimeofmaternalimmunization(s).
(13)Descriptionofvaccine(s)(nameofvaccine,manufacturer,lot number,dose(e.g.0.25mL,0.5mL,multi-dosevial,etc.),
num-berofdoseifpartofaseriesofimmunizationsagainstthe
samediseaseandvaccinediluentifseparatefromthevaccine containeritself).
(14)Theanatomicalsites(includingleftorrightside)ofall immun-izations(e.g.vaccineAinproximalleftlateralthigh,vaccineB inleftdeltoid).
(15)Routeandmethodofadministration(e.g.intramuscular,
intra-dermal,subcutaneous,and needle-free(includingtype and
size),otherinjectiondevices).
(16)Needlelengthandgauge.
(17)Gestationalageofthepregnancyatthetimeofimmunization
3.1.4. Theadverseevent
(18)For all cases at any level of diagnostic certainty and for
reportedeventswithinsufficientevidence,thecriteria
ful-filledtomeetthecasedefinitionshouldberecorded. Specificallydocument(ifavailable):
(19)Clinicaldescriptionofsignsandsymptomsofstillbirth,andif therewasmedicalconfirmationoftheevent(i.e.patientseen byphysician).
(20)Date/timeofonset,6firstobservation7anddiagnosis8;aswell
asendofepisode9andfinaloutcome,10ifappropriate(e.g.if
theeventnolongermeetsthecasedefinitionofstillbirthat thelowestlevelofthedefinition).Foraneventthatmeetsthe casedefinitionofstillbirth,theendofepisodeisthesameas date/timeofonset,andtheoutcomeisfatal(i.e.itresultsin deathofthefetus).
(21)Concurrentsigns,symptoms,anddiseases.
(22)Pregnancy,laboranddeliverydetails:
•Pregnancy details: dateof last normal menstrualperiod,
ultrasoundexaminations,antenatalcarevisits,
pregnancy-relatedillnessesandcomplications.
•Labor and delivery details: for intrapartum fetal death
specificallydocument(if available)modeofdeliveryand
complications (e.g.fetal distress, antepartum/postpartum
hemorrhage,assisteddelivery,etc.).
(23)Measurement/testing
•Values and units of routinelymeasuredparameters (e.g.
temperature,bloodpressure)–inparticularthoseindicating theseverityoftheevent;
6Thedateand/ortimeofonsetisdefinedasthetimepostimmunization,when
thefirstsignorsymptomindicativeforstillbirthoccurred.Thismayonlybepossible todetermineinretrospect.
7Thedateand/ortimeoffirstobservationofthefirstsignorsymptomindicative
forstillbirthcanbeusedifdate/timeofonsetisnotknown.
8Thedateofdiagnosisofanepisodeisthedaypostimmunizationwhentheevent
metthecasedefinitionatanylevel.
9Theendofanepisodeisdefinedasthetimetheeventnolongermeetsthecase
definitionatthelowestlevelofthedefinition.
10Example:recoverytopre-immunizationhealthstatus,spontaneousresolution,
therapeuticintervention,persistenceoftheevent,sequelae,death.
•Methodofmeasurement(e.g.typeofthermometer,oralor
otherroute,durationofmeasurement,etc.);
•Resultsoflaboratoryexaminations,surgicaland/or patho-logicalfindingsanddiagnosesifpresent.
(24)Treatmentgivenforstillbirth,especiallyspecifywhat medi-cationsanddosing,aswellasotherinterventions.
(25)Outcome9atlastobservation(e.g.foraneventthatmeetsthe
casedefinitionofstillbirth,itresultsindeathofthefetus).Add
descriptionsifantepartum/intrapartumorpostpartum
mater-naldeathoccurred.Also,formultiplegestation,ifconcomitant
twindeathoccurred.
(26)Objective clinical evidence supportingclassification of the
eventas“serious”11(i.e.resultsindeathofthefetus).
(27)Exposures other than the immunization before and after
immunization(e.g.food,environmental)considered
poten-tiallyrelevanttothereportedevent.
3.1.5. Miscellaneous/general
(28)Thedurationoffollow-up reportedduringthesurveillance
periodshouldbepredefinedlikewise (inthis case,birthor
delivery).Itshouldaimtocontinuetoresolutionoftheevent (i.e.theoutcomeofthepregnancyiscaptured).
(29)Methodsofdatacollectionshouldbeconsistentwithinand
betweenstudygroups,ifapplicable.
(30)Follow-upofcasesshouldattempttoverifyandcompletethe informationcollectedasoutlinedindatacollectionguidelines 1–27.
(31)Investigatorsofpatientswithstillbirthshouldprovide guid-ancetoreporterstooptimizethequalityandcompletenessof
informationprovided.
(32)ReportsofStillbirthshouldbecollectedthroughoutthestudy
periodregardlessofthetimeelapsedbetweenimmunization
andtheadverseevent.Ifthisisnotfeasibleduetothestudy
design,thestudyperiodsduringwhichsafetydataarebeing
collectedshouldbeclearlydefined.
3.2. Dataanalysis
Thefollowingguidelinesrepresentadesirablestandardfor anal-ysisofdataonStillbirthtoallowforcomparabilityofdata,andare recommendedasanadditiontodataanalyzedforthespecificstudy questionandsetting.
(33)Reportedeventsshouldbeclassifiedinoneofthefollowing
fivecategoriesincludingthethree levelsof diagnostic
cer-tainty.Eventsthatmeetthecasedefinitionshouldbeclassified accordingtothelevelsofdiagnosticcertaintyasspecifiedin thecasedefinition.Eventsthatdonotmeetthecasedefinition shouldbeclassifiedintheadditionalcategoriesforanalysis.
Eventclassificationin5categories12
•Eventmeetscasedefinition
11AnAEFIisdefinedasseriousbyinternationalstandardsifitmeetsoneor
moreofthefollowingcriteria:(1)itresultsindeath,(2)islife-threatening,(3)it requiresinpatienthospitalizationorresultsinprolongationofexisting hospitaliza-tion,(4)resultsinpersistentorsignificantdisability/incapacity,(5)isacongenital anomaly/birthdefect,(6)isamedicallyimportanteventorreaction.Forstillbirth, theeventmeetsthedefinitionofserious(i.e.itresultsindeathofthefetus).
12Todeterminetheappropriatecategory,theusershouldfirstestablish,whether
areportedeventmeetsthecriteriaforthelowestapplicablelevelofdiagnostic certainty,e.g.Levelthree.Ifthelowestapplicablelevelofdiagnosticcertaintyof thedefinitionismet,andthereisevidencethatthecriteriaofthenexthigherlevel ofdiagnosticcertaintyaremet,theeventshouldbeclassifiedinthenextcategory. Thisapproachshouldbecontinueduntilthehighestlevelofdiagnosticcertainty foragiveneventcouldbedetermined.Majorcriteriacanbeusedtosatisfythe requirementofminorcriteria.Ifthelowestlevelofthecasedefinitionisnotmet,it
(1)Level1:CriteriaasspecifiedintheStillbirthcase defini-tion
(2)Level2:CriteriaasspecifiedintheStillbirthcase defini-tion
(3)Level3:CriteriaasspecifiedintheStillbirthcase defini-tion
•Eventdoesnotmeetcasedefinition
Additionalcategoriesforanalysis
(4)Reportedstillbirthwithinsufficientevidencetomeetthe casedefinition13
(5)Notacaseofstillbirth14
(34)Theinterval betweenimmunization andreportedstillbirth
couldbedefinedasthedate/timeofimmunization(last
vac-cination)tothedate/timeofonset8oftheevent,consistent
withthedefinition.Iffewcases arereported,theconcrete
timecoursecouldbeanalyzedforeach;foralargenumber
ofcases,datacanbeanalyzedinthefollowingincrementsfor identificationoftemporalclusters:
SubjectswithStillbirthbyIntervaltoPresentation.
Interval* Number(Percentage)
≤24hafterimmunization 2–≤7daysafterimmunization 8–≤42daysafterimmunization >42daysafterimmunization Weeklyunitincrementsthereafter Total
(35)Ifmorethanonemeasurementofaparticularcriterionistaken andrecorded,thevaluecorrespondingtothegreatest magni-tudeoftheadverseexperiencecouldbeusedasthebasisfor analysis.Analysismayalsoincludeothercharacteristicslike qualitativepatternsofcriteriadefiningtheevent.
(36)Thedistributionofdata(asnumeratoranddenominatordata) couldbeanalyzedinpredefinedincrements(e.g.measured values,times),whereapplicable.Incrementsspecifiedabove shouldbeused.Whenonlyasmallnumberofcasesis pre-sented,therespectivevaluesortimecoursecanbepresented individually.
(37)Data on stillbirthobtained from subjects receiving a vac-cine should be compared with those obtained from an appropriatelyselectedanddocumentedcontrolgroup(s)and wheneverpossiblewithbackgroundratesoftheeventin non-exposedpopulations.Datashouldbeanalyzedbystudyarm anddosewherepossible,e.g.inprospectiveclinicaltrials.
3.3. Datapresentation
Theseguidelinesrepresentadesirablestandardforthe presen-tationandpublicationofdataonstillbirthfollowingimmunization toallowforcomparabilityofdata,andarerecommendedasan addi-tiontodatapresentedforthespecificstudyquestionandsetting. Additionally,itisrecommendedtorefertoexistinggeneral guide-linesforthepresentationandpublicationofrandomizedcontrolled trials,systematicreviews,andmeta-analysesofobservational stud-iesinepidemiology(e.g.statementsofConsolidatedStandardsof ReportingTrials(CONSORT),ofImprovingthequalityofreportsof
shouldberuledoutthatanyofthehigherlevelsofdiagnosticcertaintyaremetand theeventshouldbeclassifiedinadditionalcategoriesfourorfive.
13 Iftheevidenceavailableforaneventisinsufficientbecauseinformationis miss-ing,suchaneventshouldbecategorizedas“Reportedstillbirthwithinsufficient evidencetomeetthecasedefinition”.
14 Aneventdoesnotmeetthecasedefinitionifinvestigationrevealsanegative findingofanecessarycriterion(necessarycondition)fordiagnosis.Suchanevent shouldberejectedandclassifiedas“Notacaseofstillbirth”.
meta-analysesofrandomizedcontrolledtrials(QUORUM),andof Meta-analysisOfObservationalStudiesinEpidemiology(MOOSE), respectively)[109–111].
(38)Allreportedeventsofstillbirthshouldbepresentedaccording tothecategorieslistedinguideline33.
(39)Dataonpossiblestillbirtheventsshouldbepresentedin
accor-dancewithdatacollectionguidelines1–32anddataanalysis
guidelines33–37.
(40)Data shouldbe presented withnumerator and
denomina-tor(n/N)(andnotonlyinpercentages),ifavailable.Although
immunizationsafetysurveillancesystemsdenominatordata
areusuallynotreadilyavailable,attemptsshouldbemadeto
identifyapproximatedenominators.Thesourceofthe
denom-inatordatashouldbereportedandcalculationsofestimatesbe described(e.g.manufacturerdataliketotaldosesdistributed,
reporting through Ministry of Health, coverage/population
baseddata,etc.).
(41)Theincidenceofcasesinthestudypopulationshouldbe presentedandclearlyidentifiedassuchinthetext.
(42)If the distribution of data is skewed, median and
inter-quartilerangeareusuallythemoreappropriate
sta-tisticaldescriptorsthanamean.However,themeanand
standarddeviationshouldalsobeprovided.
(43)Anypublication ofdata onstillbirthshould include a
detaileddescriptionofthemethods usedfor data
col-lectionandanalysisaspossible.Itisessentialtospecify:
•Thestudydesign;
•Themethod,frequencyanddurationofmonitoringfor
stillbirth;
•Thetrialprofile,indicating participantflowduringa
studyincluding drop-outsand withdrawalsto
indi-catethesizeandnatureoftherespectivegroupsunder investigation;
•Thetypeofsurveillance(e.g.passiveoractive surveil-lance);
•Thecharacteristicsofthesurveillancesystem(e.g. pop-ulationserved,modeofreportsolicitation);
•Thesearchstrategyinsurveillancedatabases;
•Comparisongroup(s),ifusedforanalysis;
•Theinstrument of data collection(e.g. standardized
questionnaire,diarycard,reportform);
•Whetherthedayofimmunizationwasconsidered“day
one”or“dayzero”intheanalysis;
•Whetherthe dateof onset8 and/orthe dateof first
observation9 and/orthedateofdiagnosis10wasused
foranalysis;and
•Useofthiscasedefinitionforstillbirth,intheabstract ormethodssectionofapublication.15
Acknowledgements
The authors are grateful for the support and helpful
comments provided by the Brighton Collaboration (Jan
Bon-hoeffer, JorgenBauwens) and the reference group(see https://
brightoncollaboration.org/public/what-we-do/setting-standards/
case-definitions/groups.html for reviewers), as well as other
expertsconsultedaspartoftheprocess.Theauthorsarealso
grate-fultotheBrightonCollaborationSecretariatandtothemembers
oftheISPESpecialInterestGroupinVaccines(VAXSIG)fortheir
reviewandconstructivecommentsonthisdocument.Finally,we
15Useofthisdocumentshouldpreferablybereferencedbyreferringtothe
respec-tivelinkontheBrightonCollaborationwebsite(http://www.brightoncollaboration. org).
F.T. Da Silva et al. / Vaccine 34 (2016) 6057–6068
wouldliketoacknowledgetheGlobalAlignmentofImmunization SafetyAssessmentinPregnancy(GAIA)project,fundedbytheBill
andMelindaGatesFoundation.
AppendixA. Supplementarydata
Supplementarydataassociatedwiththisarticlecanbefound,in theonlineversion,atdoi:10.1016/j.vaccine.2016.03.044.
References
[1]BarfieldW.Clinicalreports—standardterminologyforfetal,infant,and peri-nataldeaths.Pediatrics2011;128(July(1)).
[2]AmericanCollegeofObstetriciansandGynecologists.Managementof still-birth.ACOGPracticeBulletinNumber102.ObstetGynecol2009;113:748–61. [3]GraafmansWC, Richardus JH, MacFarlane A, Rebagliato M, Blondel B, Verloove-VanhorickSP,etal.Comparabilityofpublishedperinatalmortality ratesinWesternEurope:thequantitativeimpactofdifferencesingestational ageandbirthweightcriteria.BJOG2001;108(12):1237–45.
[4]HowellEM,BlondelB.Internationalinfantmortalityrates:biasfromreporting differences.AmJPublicHealth1994;84(5):850–2.
[5]World Health Organization. Neonatal and perinatal mortality country, regionalandglobalestimates.Geneva:WorldHealthOrganization;2006. Accessedat:http://whqlibdoc.who.int/publications/2006/9241563206eng. pdf.
[6]LawnJE,YakoobMY,HawsRA,SoomroT,DarmstadtGL,BhuttaZA.3.2million stillbirths:epidemiologyandoverviewoftheevidencereview.BMC Preg-nancyChildbirth2009;9(Suppl.1):S2.
[7]LawnJ,GravettM,NunesT,RubensC,StantonC,theGAPPSReviewGroup. Globalreportonpretermbirthandstillbirth(1of7):definitions,description oftheburdenandopportunitiestoimprovedata.BMCPregnancyChildbirth 2010;10(Suppl.1):S1.
[8]OstermanMJ,KochanekKD,MacDormanMF,StrobinoDM,GuyerB.Annual summaryofvitalstatistics:2012–2013.Pediatrics2015, pii: peds.2015-0434.Accessedat:http://pediatrics.aappublications.org/content/early/2015/ 04/28/peds.2015-0434.long.
[9]CousensS,BlencoweH,StantonC,ChouD,AhmedS,SteinhardtL,etal. National,regional,andworldwideestimatesofstillbirthratesin2009with trendssince1995:asystematicanalysis.Lancet2011;377:1319.
[10]McClureEM,Nalubamba-PhiriM,GoldenbergRL.Stillbirthindeveloping countries.IntJGynaecolObstet2006;94(August(2)):82–90.
[11]McClureEM,WrightLL,GoldenbergRL,GoudarSS,ParidaSN,JehanI,etal. Theglobalnetwork:aprospectivestudyofstillbirthsindevelopingcountries. AmJObstetGynecol2007;197:247.e1.
[12]McClureEM,PashaO,GoudarSS,ChombaE,GarcesA,TshefuA,etal. Epidemi-ologyofstillbirthinlow-middleincomecountries:aGlobalNetworkStudy. ActaObstetGynecolScand2011;90(December(12)):1379–85.
[13]GisslerM,MohangooAD,BlondelB,ChalmersJ,MacfarlaneA,GaizauskieneA, etal.PerinatalhealthmonitoringinEurope:resultsfromtheEURO-PERISTAT project.InformHealthSocCare2010;35(2):64–79.
[14]GregoryEC,MacDormanMF,MartinJA.Trendsinfetalandperinatal mor-talityintheUnitedStates,2006–2012.NCHSDataBrief2014;(November (169)):1–8.
[15]KramerMS,LiuS,LuoZ,YuanH,PlattRW,JosephKS.Analysisof peri-natalmortalityanditscomponents:timeforachange?AmJEpidemiol 2002;156(6):493–7.
[16]SayL,DonnerA,GülmezogluAM,TaljaardM,PiaggioG.Theprevalenceof stillbirths:asystematicreview.ReprodHealth2006;3:1.
[17]Stanton C, Lawn JE, Rahman H, Wilczynska-Ketende K, Hill K. Still-birthrates:deliveringestimates in190countries.Lancet2006;367(May (9521)):1487–94.
[18]AminuM,UnkelsR,MdegelaM,UtzB,AdajiS,vandenBroekN.Causesof andfactorsassociatedwithstillbirthinlow-andmiddle-incomecountries:a systematicliteraturereview.BJOG2014;121(September(Suppl.4)):141–53. [19]BalchinI,WhittakerJC,PatelRR,LamontRF,SteerPJ.Racialvariationin theassociationbetweengestationalageandperinatalmortality:prospective study.BMJ2007;334:833.
[20]BellR,GlinianaiaSV,RankinJ,WrightC,PearceMS,ParkerL.Changing pat-ternsofperinataldeath,1982–2000:aretrospectivecohortstudy.ArchDis ChildFetalNeonatalEd2004;89:F531.
[21]BlackwellS,RomeroR,ChaiworapongsaT,KimYM,BujoldE,EspinozaJ, etal.Maternalandfetalinflammatoryresponsesinunexplainedfetaldeath. JMaternFetalNeonatalMed2003;14:151.
[22]GardosiJ,MadurasingheV,WilliamsM,MalikA,FrancisA.Maternalandfetal riskfactorsforstillbirth:populationbasedstudy.BMJ2013;346:f108. [23]Getahun D, Ananth CV, Kinzler WL. Risk factors for antepartum and
intrapartum stillbirth: a population-based study. Am J Obstet Gynecol 2007;196:499.
[24]SinghA,ToppoA.Re.Co.De:abetterclassificationfordeterminationofstill births.JObstetGynaecolIndia2011;61(December(6)):656–8.
[25]StormdalBringH,HulthénVarliIA,KublickasM,PapadogiannakisN, Pet-terssonK.Causes ofstillbirthatdifferent gestational agesin singleton pregnancies.ActaObstetGynecolScand2014;93(January(1)):86–92.
[26]VerganiP,CozzolinoS,PozziE,CuttinMS,GrecoM,OrnaghiS,etal. Identify-ingthecausesofstillbirth:acomparisonoffourclassificationsystems.AmJ ObstetGynecol2008;199:319.e1.
[27]GardosiJ,KadySM,McGeownP,FrancisA,TonksA.Classificationofstillbirth byrelevantconditionatdeath(ReCoDe):populationbasedcohortstudy.BMJ 2005;331:1113.
[28]FlenadyV,FrøenJF,PinarH,TorabiR,SaastadE,GuyonG,etal.Anevaluation ofclassificationsystemsforstillbirth.BMCPregnancyChildbirth2009;9:24. [29]CnattingiusS,HaglundB,KramerMS.Differencesinlatefetaldeathratesin associationwithdeterminantsofsmallforgestationalagefetuses:population basedcohortstudy.BMJ1998;316:1483.
[30]MoyoSR,HägerstrandI,NyströmL,TswanaSA,BlombergJ,BergströmS, etal.Stillbirthsandintrauterineinfection,histologicchorioamnionitisand microbiologicalfindings.IntJGynaecolObstet1996;54:115–23.
[31]OsmanNB,FolgosaE,GonzalesC,BergströmS.Genitalinfectionsinthe aetiologyoflatefetaldeath:anincidentcasereferentstudy.JTropPediatr 1995;41:258–66.
[32]WilliamsEJ,EmbletonND,ClarkJE,BythellM,WardPlattMP,etal.Viral infec-tions:contributionstolatefetaldeath,stillbirth,andinfantdeath.JPediatr 2013;163:424.
[33]Stephansson O, Dickman PW, Johansson A, Cnattingius S. Maternal hemoglobinconcentrationduringpregnancyandriskofstillbirth.JAMA 2000;284:2611.
[34]BukowskiR,HansenNI,WillingerM,ReddyUM,ParkerCB,PinarH,etal. Fetalgrowthandriskofstillbirth:apopulation-basedcase–controlstudy. PLoSMed2014;11:e1001633.
[35]FrøenJF,GardosiJO,ThurmannA,FrancisA,Stray-PedersenB.Restrictedfetal growthinsuddenintrauterineunexplaineddeath.ActaObstetGynecolScand 2004;83:801.
[36]ZhangJ,KlebanoffMA.Small-for-gestational-ageinfantsandriskoffetal deathinsubsequentpregnancies.NEnglJMed2004;350:754.
[37]GoldenbergRL,McClureEM,SaleemS,ReddyUM.Infection-relatedstillbirths. Lancet2010;375:1482.
[38]StillbirthCollaborativeResearchNetworkWritingGroup.Causesofdeath amongstillbirths.JAMA2011;306:2459.
[39]SilverRM,VarnerMW,ReddyU,GoldenbergR,PinarH,ConwayD,etal. Work-upofstillbirth:areviewoftheevidence.AmJObstetGynecol2007;196:433. [40]CareyJC,RayburnWF.Nuchalcordencirclementsandriskofstillbirth.IntJ
GynaecolObstet2000;69:173.
[41]WoodsR.Long-termtrendsinfetalmortality:implicationsfordeveloping countries.BullWorldHealthOrgan2008;86(6):460–6.
[42]ReddyUM,GoldenbergR,SilverR,SmithGC,PauliRM,WapnerRJ,etal. Stillbirthclassification–developinganinternationalconsensusforresearch: executivesummaryof aNationalInstitute ofChildHealthand Human Developmentworkshop.ObstetGynecol2009;114:901[Erratumin:Obstet Gynecol.2010Jan;115(1):191].
[43]ReddyUM,LaughonSK,SunL,TroendleJ,WillingerM,ZhangJ.Pregnancy riskfactorsforantepartumstillbirthintheUnitedStates.ObstetGynecol 2010;116:1119.
[44]DiMarioS,SayL,LincettoO.Riskfactorsforstillbirthindevelopingcountries: asystematicreviewoftheliterature.SexTransmDis2007;34:S11. [45]FlenadyV,KoopmansL,MiddletonP,FrøenJF,SmithGC,GibbonsK,etal.
Majorriskfactorsforstillbirthinhigh-incomecountries:asystematicreview andmeta-analysis.Lancet2011;377:1331.
[46]FrøenJF,ArnestadM,FreyK,VegeA,SaugstadOD,Stray-PedersenB.Risk factorsforsuddenintrauterineunexplaineddeath:epidemiologic character-isticsofsingletoncasesinOslo,Norway,1986–1995.AmJObstetGynecol 2001;184:694.
[47]LiuLC,WangYC,YuMH,SuHY.Majorriskfactorsforstillbirthin differ-enttrimestersofpregnancy–asystematicreview.TaiwanJObstetGynecol 2014;53(June(2)):141–5.
[48]VarnerMW,SilverRM,RowlandHogueCJ,WillingerM,ParkerCB,Thorsten VR,etal.Associationbetweenstillbirthandillicitdruguseandsmoking dur-ingpregnancy.ObstetGynecol2014;123:113.
[49]StephanssonO,DickmanPW,JohanssonA,CnattingiusS.Maternalweight, pregnancyweightgain,andtheriskofantepartumstillbirth.AmJObstet Gynecol2001;184:463.
[50]Stillbirth Collaborative Research Network Writing Group. Association betweenstillbirthandriskfactorsknownatpregnancyconfirmation.JAMA 2011;306:2469.
[51]WillingerM,KoCW,ReddyUM.Racialdisparitiesinstillbirthriskacross gestationintheUnitedStates.AmJObstetGynecol2009;201:469.e1. [52]LawnJE,BlencoweH,PattinsonR,CousensS,KumarR,IbiebeleI,etal.
Stillbirths:Where? When?Why?Howtomakethedatacount? Lancet 2011;377:1448–63.
[53]HarbourR,MillerJ.Anewsystemforgradingrecommendationsinevidence basedguidelines.BMJ2001;323:334–6.
[54]LindeA,PetterssonK,RådestadI.Women’sexperiencesoffetalmovements beforetheconfirmationoffetaldeath-contractionsmisinterpretedasfetal movement.Birth2015;42:2.
[55]Langley FA. The perinatal postmortem examination. J Clin Pathol 1971;24:159–69.
[56]McCullyJG.Gasinthefetaljoints:asignofintrauterinedeath.ObstetGynecol 1970;36:433–6.
[57]ShaffMI.Anevaluationofradiologicalsignsoffetaldeath.SAfrMedJ 1975;49:736.
[58]SooYS.Threecommonradiologicalsignsofintrauterinefetaldeath.JAsian FedObstetGynecol1971;2:20.
[59]WeinsteinBJ,PlattLD.Theultrasonicappearanceofintravasculargasinfetal death.JUltrasoundMed1983;2:451–4.