Stillbirth: Case definition and guidelines for data collection, analysis, and presentation of maternal immunization safety data.

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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

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,Belgium

bWayneStateUniversitySchoolofMedicine,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

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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

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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

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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

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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

(6)

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

(7)

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,

(8)

•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

(9)

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

(10)

(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

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References

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