Maternal and fetal risk factors for stillbirth: population based study.

0.35 MB·English

by  Gardosi, Jason

BMJ2013;346:f108doi:10.1136/bmj.f108(Published24January2013) Page1of14
Research
RESEARCH
Maternal and fetal risk factors for stillbirth: population
based study
OPENACCESS
Jason Gardosi director1 professor of maternal and perinatal health2, Vichithranie Madurasinghe
epidemiologist1, Mandy Williams research midwife1, Asad Malik data analyst1, André Francis
statistician1
1WestMidlandsPerinatalInstitute,BirminghamB65RQ,UK;2UniversityofWarwickMedicalSchool,CoventryCV47AL,UK
Abstract ConclusionMostnormallyformedsingletonstillbirthsarepotentially
ObjectiveToassessthemainriskfactorsassociatedwithstillbirthina avoidable.Thesinglelargestriskfactorisunrecognisedfetalgrowth
multiethnicEnglishmaternitypopulation. restriction,andpreventivestrategiesneedtofocusonimproving
antenataldetection.
DesignCohortstudy.
SettingNationalHealthServiceregioninEngland. Introduction
Population92218normallyformedsingletonsincluding389stillbirths Stillbirthsrepresentadevastatingpregnancyoutcome,andthe
from24weeksofgestation,deliveredduring2009-11. needforincreasedeffortsinpreventionhasbeenhighlighted
MainoutcomemeasureRiskofstillbirth. bySANDS(StillbirthandNeonatalDeathCharity)1andother
ResultsMultivariableanalysisidentifiedasignificantriskofstillbirthfor parentledcampaigns.StillbirthratesintheUnitedKingdom
areamongthehighestinhighincomecountries2andhaveshown
parity(para0andpara≥3),ethnicity(African,African-Caribbean,Indian,
littleimprovementsincetheearly1990s.3
andPakistani),maternalobesity(bodymassindex≥30),smoking,
pre-existingdiabetes,andhistoryofmentalhealthproblems,antepartum Despitefreeavailabilityofpostmorteminvestigationsinthe
haemorrhage,andfetalgrowthrestriction(birthweightbelow10th EnglishNationalHealthServiceasmanyas50-70%ofstillbirths
customisedbirthweightcentile).Aspotentiallymodifiableriskfactors, haveuntilrecentlybeencategorisedasunclassifiedor
maternalobesity,smokinginpregnancy,andfetalgrowthrestriction unexplained4andare,byimplication,oftenconsidered
togetheraccountedfor56.1%ofthestillbirths.Presenceoffetalgrowth unavoidable.5Furtherinvestigationfoundthatmanystillborn
restrictionconstitutedthehighestrisk,andthisappliedtopregnancies fetuseshadfailedtoreachtheirgrowthpotential,6-8andinclusion
wheremothersdidnotsmoke(adjustedrelativerisk7.8,95%confidence offetalgrowthrestrictionasacategoryinstillbirth
interval6.6to10.9),didsmoke(5.7,3.6to10.9),andwereexposedto classificationsresultedinasubstantialdroptoaround15%in
passivesmokeonly(10.0,6.6to15.8).Fetalgrowthrestrictionalsohad theproportionofcasesconsideredunexplained.89This
thelargestpopulationattributableriskforstillbirthandwasfivefoldgreater encouragedarenewedfocusonunderstandingtheunderlying,
ifitwasnotdetectedantenatallythanwhenitwas(32.0%v6.2%).In mostlyplacentaldiseaserelated,causesoffetalgrowth
total,195ofthe389stillbirthsinthiscohorthadfetalgrowthrestriction, restriction.Recentreportsoflaboratoryinvestigations10and
butin160(82%)ithadnotbeendetectedantenatally.Antenatal postmortemstudies11haveconfirmedthelargecontributionof
recognitionoffetalgrowthrestrictionresultedindelivery10daysearlier placentalfailureinthecauseofstillbirth.
thanwhenitwasnotdetected:median270(interquartilerange261-279) Theclinicalrelevanceofsuchfindingsisthatalthoughthere
daysv280(interquartilerange273-287)days.Theoverallstillbirthrate arelimitedmeansbywhichtotreatfetalgrowthrestrictionin
(per1000births)was4.2,butonly2.4inpregnancieswithoutfetalgrowth utero,recognitionthatthefetusisatriskafterappropriate
restriction,increasingto9.7withantenatallydetectedfetalgrowth maternal-fetalinvestigationscanleadtowelltimeddelivery
restrictionand19.8whenitwasnotdetected. andimprovedperinataloutcome.1213However,thereare
currentlynoestablishedandroutinelyusedmeanstopredict
Correspondence to: J Gardosi [email protected]
Extra material supplied by the author (see http://www.bmj.com/content/346/bmj.f108?tab=related#webextra)
Sensitivity analysis of excluded non-significant risk factors
Sensitivity analysis with variance estimates adjusted for clustering maternity units
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stillbirth,andriskfactorsknownatthebeginningofpregnancy restriction.Weappliedthe10thcentileasthecut-off,asitisin
areconsideredweakpredictorsofoutcome.14 standardclinicaluseandhasbeenvalidatedthroughreceiver
Weinvestigatedtheroleofdemographic,social,andmedical operatorcurvesasbeingclosetooptimalforpredicting
riskfactorsthatcanbeascertainedatthebeginningofpregnancy pathologybycustomisedcentiles.23
togetherwiththosethatbecomeapparentaspregnancy Thecasenoteswerealsoexaminedforanyrecordingoffetal
progresses,andtheirrespectivecontributionstotheincidence growthproblems.Fetalgrowthsurveillanceisusuallydoneby
ofstillbirthsinanNHSregioninEnglandwithamultiethnic aprotocolofmeasuringfundalheightateachantenatalvisitin
population.15Tofocusonpotentiallyavoidablefactorswe thethirdtrimester,withreferralforultrasoundassessmentof
excludedcongenitalanomalies,astheircontributiontostillbirth estimatedfetalweightwhentheseriallyplottedfundalheight
iscontingentonincidenceaswellasculturalchoiceson measurementsdonotfollowthepredictedcurve.Inpregnancies
antenatalscreening,prenataldiagnosis,anddecisionsinresponse whereassessmentoffundalheightisdifficult(forexample,
topositiveresults.Wethereforeexploredtheriskfactorsin maternalobesity)orwheretheriskoffetalgrowthrestriction
pregnancieswithnormallyformedsingletonsandestimatedthe isconsideredincreased(forexample,duetoobstetrichistory)
respectivecontributionofthesefactorstotheoverallburdenof serialestimatedfetalweightmeasurementsaredoneaccording
stillbirthinourpopulation. tolocalprotocolsofvaryingscanfrequency.Antenatal
recognitionoffetalgrowthrestrictioninpregnancieswithbirth
Methods weightsbelowthe10thcustomisedcentilewasdefinedasat
leastoneantenatalentrywiththisdiagnosis,usuallybasedon
Maternity data
oneormoreestimatedfetalweightsbelowthe10thcustomised
Thedatabasewasderivedfromtheregional,NHSnetbased centile,oranabnormalumbilicalarteryDoppler,orboth.This
perinatalepisodeelectronicrecord(PEER)hostedandmanaged assessmentofthematernityrecordispartofroutine
bytheWestMidlandsPerinatalInstitute.16Thiselectronicrecord ascertainment,astheproportionofpregnancieswithantenatally
wasfirstimplementedinApril2009inthe19maternityunits detectedfetalgrowthrestrictionisaregionallyagreedkey
intheWestMidlands.Forthisstudyweusedthedatacollected performanceindicator.
overatwoyearperiod,representingbirthsbetweenJune2009
andMay2011. Linkage to mortality data
Thedataoriginatedfromprospectiverecordscreatedinthe Dataonfetal,neonatal,andinfantdeathsandcongenital
standardisedhandheldmaternitynotesduringpregnancyby anomalieswerenotifiedtothePerinatalInstitutebyanetwork
themidwivesanddoctors.17Traineddataclerksintherespective ofcoordinators,andhadaconsistentlyhighlevelof
hospitalstransferinformationfromthenotesontotheperinatal ascertainment.TheinformationisheldonsecureNHSservers
episodeelectronicrecordattheendofpregnancy.Qualitywas andispseudonymisedbeforeanyfurtheranalysis.Datalinkage
assuredbycentralprojectstaffthroughtrainingworkshopsand wasestablishedwiththeelectronicmaternitydatabase,using
regularon-sitedataqualityaudits.Thedatasetcontained87 theNHSnumberasuniqueidentifier.
regionallyagreedanddefineddataitems,18withinformation Stillbirthwasdefinedasachildbornafterthe24thweekof
aboutmaternalcharacteristics,includingage,parity,ethnic pregnancywhodidnot,atanytimeafterdelivery,breatheor
origin,andmaternalheightandweight(expressedasbodymass showanyothersignsoflife.Alongthelinesofpreviously
index);socialfactors,includingemploymentstatusofthemother appliedmethods,6weadjustedthegestationalageofeach
andherpartner,consanguinitywiththepartner,andindexof stillbornfetusbydeductingtwodaysfromthelengthof
multipledeprivation;historyofmentalhealthproblems, pregnancyatdelivery,tocorrectfortheestimated48hour
pre-existingdiabetesorhypertensivedisease,orprevious averagedelaybetweenintrauterinedeathanddelivery.24
stillbirth;smokingstatus,alcoholconsumption,non-prescription
drugs,folicacidintake,andtimeoffirstvisitinpregnancy(the Confidentiality and consent
informationforallthesepreviousvariableswasusuallyrecorded
attheearlypregnancybookingvisit);complicationsin Maternalconsentwasobtainedbyprovisionofinformationand
pregnancy,includinggestationaldiabetes,antepartum opt-out.Mothersareinformedattheirfirstantenatalvisitabout
haemorrhage,pregnancyinducedhypertension,and theintentionofcollectionandanalysisofsecondarydata,and
pre-eclampsia(definedaspregnancyinducedhypertensionwith thisisalsoexplainedintextprintedintheirstandardised,hand
proteinuria);andfetalorneonatalcharacteristics,includingsex, heldpregnancynotes.Thatthisinformationhasbeengivenand
gestationalageandweightatbirth,andestimatedweightduring explainedisrecordedinthenotesandsignedbythemidwife.
pregnancy.Gestationalagewasdeterminedonthebasisof Amothercanoptoutatanytimefromherdatabeingused,in
routinelyoffereddatingscans,whichwerecarriedoutinthe whichcaseherNHSnumberisaddedtoan“opt-outregister”
firstorsecondtrimester(<22weeks)in96.5%ofpregnancies andfurtheranalysisisblocked.ThePerinatalInstitute’s
inthispopulation,withtheremainingpregnanciesdatedbythe confidentialityandconsentprotocolhasbeenreviewedand
lastmenstrualperiod. passedasappropriatebyUKConnectingforHealth,theNHS,
andtheInformationCommissioner.
Thepresenceofintrauterinegrowthrestrictionwasestablished
onthebasisofabirthweightbelowthe10thweightfor
Statistical analyses
gestationalagecentile,usingthegestationrelatedoptimalweight
standard(GROW),19withcoefficientsderivedfromtheWest Afterinitialexploratoryanalysis,weassessedtheindependent
Midlandspopulation.Thismethoddefinesthefetalgrowth andmultiplevariableeffectsofexplanatoryvariableson
potentialbyexcludingpathologicalfactorssuchassmoking stillbirthsinPoissonregressionmodels.Variablesenteredin
anddiabetes,andindividualadjustmentor“customisation”for themultivariableanalysisarethoseofknownclinicalrelevance
thebaby’ssexandthemother’sheight,weight,ethnicorigin, andfrompreviouspublications214andincludedmaternalage,
andparity.2021Aweightthatissmallforgestationalageafter parity,ethnicorigin,placeofbirth,bodymassindex,historyof
suchadjustmentbygrowthpotentialhasbeenshowntorepresent mentalhealthproblems,pre-existinghypertension,pre-existing
pathologicalsmallness22andisreferredtoasfetalgrowth diabetes,cardiacdisease,previousstillbirths,smokingin
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pregnancy,alcoholconsumption,antenatalfolicacidintake, riskofstillbirth.Ahistoryofmentalhealthproblems,diabetes,
latebooking(≥13weeks),gestationaldiabetes,pregnancy andstillbirthincreasedtherisk.Inthecurrentpregnancy,
inducedhypertension,pre-eclampsia,antepartumhaemorrhage, pre-eclampsiaandantepartumhaemorrhagewerestrongly
andfetalgrowthrestriction.Inadditiontotheindexofmultiple associated,whereasgestationaldiabeteswasnot.
deprivation,weincludedmaternalandpaternalemployment Thestrongestfactorwasfetalgrowthrestriction,witharelative
statusassocialfactorsinthemultivariableanalysis.Weentered riskof4.0(95%confidenceinterval2.8to5.7)whenfetal
variablesusingthemanualstepwise(forward-backward) growthrestrictionwasdetectedantenatally,doublingto8.0(6.5
method.Toreducetheover-relianceintheestimatesandthe to9.9)whenitwasnotdetected.Theoverallstillbirthrate(per
selectionmechanismthatmayariseduetorarityofstillbirths, 1000births)was4.2,whichwasacompositeofarateof2.4
weusedthebootstrappingapproachtocalculatestandarderrors. (185/76356)inpregnancieswithoutfetalgrowthrestriction
Inthemultivariableanalysisallvariablesreachinga0.05 and16.7(195/11697)inpregnancieswithfetalgrowth
significancelevelwereretainedinthemodel.Wealso restriction(table1).Ofpregnancieswithfetalgrowthrestriction,
consideredalltwofactorinteractionsbetweentheexplanatory thestillbirthrateforcasesdetectedantenatallywas9.7
variablesandusedempiricalprobabilityplotstocheckthefinal (35/3601),whereastherateincreasedto19.8(160/8096)when
modeltoassesswhetherthemodellingassumptionsweremet. caseswerenotdetected(fig1⇓).
Wecarriedoutsensitivityanalysestoassesstheinfluenceof
Becauseofthestronginteractionbetweensmokingandfetal
factorsexcludedbecauseofP>0.05,potentialclusteringby
growthrestriction,stillbirthratesforpregnancieswithmaternal
maternityunit,andtheeffectofrepeatpregnanciesfromthe
smokingarealsopresentedforsubgroupsoffetalgrowth
samemother.
restriction(table2⇓).Theoverallstillbirthrate(per1000births)
Toassesstheproportionofstillbirthsthatcouldbepotentially washigherinmotherswhosmoked(5.8v3.8),butthiswas
preventedifriskfactorswereremoved,wecalculatedadjusted onlythecaseforpregnancieswithfetalgrowthrestriction(13.0),
populationattributableriskestimatesusingstandardmethods25: whereastheriskofstillbirthinpregnancieswithoutfetalgrowth
populationattributablerisk=expectednumberofcasesinthe restriction(3.7)wassimilartothatwherethemotherdidnot
population−expectednumberofcasesifnobodyinthe smoke(3.8).Thehighestriskofstillbirthwasinpregnancies
populationhastheriskfactorofinterest/expectednumberof withfetalgrowthrestrictionwherethemotherdidnotsmoke.
casesinthepopulation×100 Antenataldetectionoffetalgrowthrestrictionduringthestudy
TheanalysesweredoneusingstatisticalpackageSTATA periodwas31%overall(table1)andhigherinpregnancies
version11. wherethemothersmoked(1451/4012,36.2%)thanwhereshe
didnot(1480/5280,28.0%).
Results Fig2⇓showscumulativefrequencygraphsforpregnancieswith
andwithoutfetalgrowthrestrictionforstillbirthsandlivebirths.
Atotalof105476caseswereenteredduringthetwoyear
Forbothoutcomes,pregnancieswithfetalgrowthrestriction
collectionperiod.Ofthese,13258wereexcludedbecauseof
tendedtobedeliveredearlier.Themediangestationalagefor
congenitalanomalyormultiplepregnancy,whichleft92218
stillbirthswithfetalgrowthrestrictionwas32weeksandthree
normallyformedsingletonpregnanciesleadingto91829live
dayscomparedwith36weeksandsixdaysforstillbirthswithout
birthsand389stillbirths.Thisrepresentedastillbirthrateof
fetalgrowthrestriction.
4.2/1000birthsandcompareswithnationallyreportedstillbirth
ratesofnormallyformedsingletonsof3.9-4.1/1000overthe
Multivariable analysis
sameperiod.26Theanalysisincluded841(0.9%)repeat
pregnanciesduringthetwoyearperiodofthe92218mothers Table3⇓liststheresultsofthePoissonregressionmodel,which
inthecohort. includedallsignificantfactorsshownintheunivariateanalysis.
Overall,25021births,including103stillbirths,wereexcluded
Univariate analysis becauseofincompletedata.Thisrepresentedarateof4.1/1000
births,whichwassimilartotheoverallrateofstillbirth
Table1⇓liststhevariables,groupedaccordingtomaternaland
(4.2/1000,table1).Sensitivityanalysesoftheexcludedfactors
fetalcharacteristics,socialfactors,medicalhistory,and
(P>0.05inunivariateanalysis),ofclusteringofbirthswithin
complicationsduringpregnancy.Analysiswasforcomplete
maternityunits(seesupplementaryappendices1and2),andof
casesonly.Thestillbirthrateispresentedforsubgroups,together
repeatpregnanciesbythesamemother(resultsnotshown)
withrelativerisksand95%confidenceintervalsinrelationto
indicatedonlyminordifferencesinconfidenceintervalsand
therespectivereferencevalues.
resultedinnochangesinrelativerisks.
Formaternalcharacteristics,stillbirthrateswereincreasedin
First,third,andhigherorderpregnanciesweresignificantly
firstaswellasthirdandsubsequentpregnanciescomparedwith
associatedwithstillbirthaswerepregnanciesinAfrican,
secondpregnancies,andinmothersofAfrican,
African-Caribbean,andIndianmothersandfirstgeneration
African-Caribbean,andSouthAsianethnicorigincompared
migrantsfromPakistan.Obesity(bodymassindex>30),
withtheirEuropeancounterparts.Firstgenerationmigrantshad
pre-existingdiabetes,historyofmentalhealthproblems,and
anoverallhigherriskofstillbirth.Maternalageindicateda
antepartumhaemorrhageintheindexpregnancywereassociated
slightincreaseinyounger(<25)andolder(≥35)mothers,
withanincreasedriskofstillbirth.
suggestingaU-shapeddistribution,butthistrenddidnotreach
significance. Interactionsbetweenallvariablesweretestedandwerefound
tobenon-significant,withtheexceptionofastronginteraction
Socialfactorswithsignificantassociationsincludeddeprivation
betweensmokingandfetalgrowthrestriction.Thereforethe
andunemploymentofthemotherorherpartner.Pregnancies
resultsarepresentedseparatelyforsmokerswithpregnancies
inwhichtheparentswerebloodrelationswerenotat
thatdidordidnothavefetalgrowthrestriction.Activesmoking
significantlyincreasedrisk.Obesity(bodymassindex≥30),
wasassociatedwithanincreasedriskofstillbirth(adjusted
activeaswellaspassivesmoking,lackofantenatalfolicacid,
relativerisk2.5,95%confidenceinterval1.7to3.6),butthe
andbookingafter13weekswereallassociatedwithanincreased
associationbecamesubstantiallystronger(5.7,3.6to8.9)for
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pregnancieswherethefetuswasalsogrowthrestricted.There reportwhichfoundthattheassociationbetweenstillbirthand
wasnoassociationbetweenpassivesmokingandstillbirthunless maternalagedisappearswhencongenitalanomaliesare
fetalgrowthrestrictionwasalsopresent,inwhichcasethe excluded.14
relativeriskwasevenhigherthanwithactivesmoking(10.0, Motherslivinginthemostdeprivedareashadanincreasedrisk
6.6to15.8).Theriskofstillbirthwasincreasedforall ofstillbirth,asdidwomenwhowereorhadapartnerwhowas
pregnancieswithfetalgrowthrestriction,butwashighestwhen unemployed.Ethnicorracialdisparitiesinstillbirthrateshave
themotherdidnotsmoke(7.8,5.6to10.9). beenhighlighted1430andwerealsoindependentriskfactorsin
Table3alsoliststhepopulationattributableriskderivedfrom ourstudy.Eachofthemainethnicminoritygroupsinour
prevalenceandrelativeriskofeachsignificantfactor.Themodel populationhadanincreasedriskofstillbirth(table3).Further
wasabletoattributeriskfactorsto80.6%ofthestillbirthsin workisrequiredtohelpunderstandthereasonsfortheincreased
thiscohort.Thehighestpopulationattributableriskswere riskinthesegroups.Alimitationofourstudyisthatconsent
associatedwithfetalgrowthrestriction,primiparity,and ratesforpostmortemexaminationsarelowinsomeethnic
antepartumhaemorrhage. groups,asaresultofwhichsomecaseswithundiagnosed
Inpregnancieswithfetalgrowthrestriction,theadjustedrisk congenitalanomaliesmayhavebeeninadvertentlyincludedin
ofstillbirthwas3.4(2.2to5.2)iffetalgrowthrestrictionwas ourcohort.
detectedantenatally.Theriskincreasedto6.5(4.9to8.4)if Amongpre-existingconditions,diabetesisaknownriskfactor31
fetalgrowthrestrictionwasnotdetected,and32%ofthe andhadahigherrisk(adjustedrelativerisk3.9,1.7to8.9),but
stillbirthscouldbeattributedtothisgroup.Pregnancieswith apopulationattributableriskofonly2.0%becauseofthelow
fetalgrowthrestrictiondetectedantenatallyweredeliveredon prevalenceinthiscohort.Ahistoryofmentalhealthproblems
average10daysearlierthanthosenotdetectedantenatally(table wasalsoasignificantriskfactor(adjustedrelativerisk1.4,1.0
4⇓). to1.9),reportedby11.7%ofmothers.Ithasbeensuggested
Justoverhalfofthestillbirths(203/389,52%)occurredafter thatthelinkbetweenmentalillnessandadverseoutcomecould
34weeksofgestation.Table5⇓presentsthesignificant bemediatedthroughgeneralfactorssuchasinsufficient
pathologicalfactorsofthemodel,adjustedformaternal attendanceatantenatalclinicsorunhealthylifestyles.32Antenatal
characteristics,forstillbirthsbeforeandafter34weeksof haemorrhageincludingplacentalabruptionhasaknown
gestation.Forstillbirthsbetween24and33weeksofgestation, associationwithstillbirth28;ourresultsconfirmthislinkand
theonlysignificantfactorwasfetalgrowthrestriction(adjusted emphasisetheneedforimmediate,thoroughinvestigationof
relativerisk4.0,2.9to5.6),whichaccountedforjustunderhalf anyantepartumbleeding.
ofthestillbirths(populationattributablerisk49.5%).Atthe Bodymassindexcategoriesof30-34.9and35ormore
sametime,pre-eclampsiaemergedasasignificantprotective representeda40%and60%increasedriskofstillbirth,
factor.From34weeksofgestation,fetalgrowthrestrictionagain respectively,andtogetherwereprevalentinjustunder20%of
representedthestrongestrisk,andwashighestinpregnancies thiscohort,resultinginapopulationattributableriskof8.7%.
wherethemotherdidnotsmoke. Contrarytosomereports,14wefoundnoincreaseinriskof
stillbirthassociatedwithoverweightmothers(bodymassindex
Discussion 25-29.9)inourpopulation.
Ourstudyshowsthatwhilethereareseveralriskfactorsfor Active and passive smoking
stillbirththatcanbeascertainedfromtheoutsetofpregnancy,
Maternalsmokinginearlypregnancyisassociatedwith
thesinglelargestfactorisfetalgrowthrestriction,whichis
stillbirth,withanaverageriskof1.36basedonfourstudies.28
currentlynotwellpredictedandnotrecognisedantenatallyin
Wefoundtherisktobehigher(relativerisk1.8,95%confidence
mostpregnancies.Consideringthatmostinstancesaremissed,
interval1.4to2.3,table1),possiblyasaresultofhighlevels
aretrospectivedefinitionoffetalgrowthrestrictionusinggrowth
potential19appliedtobirthweightwasimportanttobeableto ofsocialdeprivationinourpopulation,whichisstronglylinked
tosmoking.33
quantifythelinkwithstillbirth.Thefindingsindicatethe
importanceofimprovingcurrentstrategiesandprotocolsfor However,thedatabasealsoallowedustoexaminetheinteraction
improvedsurveillanceoffetalgrowththroughouttheantenatal betweensmokingandfetalgrowth,andtheeffectonstillbirth
period.13 riskwhenfetalgrowthrestrictionisdetectedantenatally.The
increasedriskofsmokingworksmostlythroughfetalgrowth
Early pregnancy risk factors restriction,andtherateofstillbirthinpregnanciesofmothers
whosmokedbuthadnofetalgrowthrestrictionwassimilar
ThepopulationbaseddataderivedfromawholeNHSregion
(3.7)tothatofmotherswhowerenon-smokers(3.8,table2).
allowedustoassessseveralknownaswellasnewriskfactors
Thishighlightstheimportanceofearlypregnancysmoking
thatwillrequirefurtherinvestigationinfuturestudies.These
cessationprogrammes,whichhavebeenfoundtoreduce
factorshavevaryingclinicalimplications.
smallnessforgestationalageandprematurity.34Interestingly,
Parity,ethnicity,andpreviousmentalhealthproblemsare thehigheststillbirthratewasinnon-smokingpregnantwomen
indicatorsofriskelicitedatthebeginningofpregnancy.The withfetalgrowthrestriction,whichcouldbebecausethese
associationbetweennulliparityandstillbirthreflectsother pregnanciesareconsideredlowriskandfetalgrowthrestriction
reports,14butwealsoobserveda60%increaseinriskfor islesslikelytobedetectedantenatally.
motherswithaparityof3orhigher,suggestingaU-shaped
Wewerealsoabletoquantifytheeffectofpassiveor
relationbetweenparityandriskofstillbirth(table2),as
environmentalsmoking,andfoundittobeassociatedwithan
previouslyreported.27Contrarytoasystematicreview,28we
increaseinriskofstillbirthby30%(table1)—aneffect
foundnosignificantincreaseinriskofstillbirthwitholder
correspondingtothe23%reportedinarecentmetaanalysisof
maternalage(table1).Thismaybebecauseweexcluded
fourtrials.35Howeverinthemultivariablemodelthisfactorwas
congenitalanomaliesfromourcohort,whichareknowntobe
significantonlywhentherewasfetalgrowthrestriction,inwhich
increasedinoldermothers.29Thisisconsistentwitharecent
casetheriskevenexceededthatassociatedwiththemother
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beingasmoker(adjustedrelativerisk10.0,95%confidence (median270v280days;table4).Basedontheprevalenceof
interval6.6to15.8;table3).Thisobservationneeds undetectedfetalgrowthrestriction(9.2%,table4)andthelower
confirmationinfuturestudiesbutcouldhaveseveralplausible riskofstillbirthwhenitisdetected(adjustedrelativerisk3.4),
explanations.Passivesmoking,resultingfromthe“sidestream” 18.2%or71stillbirthsinourcohortcouldhavebeenavoided
effectofsmokeproducedbetweenpuffs,hasbeenshownin throughimprovedantenataldetection.ExtrapolatedtotheUK
animalstudiestobefourtimesastoxicas“mainstream”smoke,36 population,thiswouldrepresent600fewerstillbirthsperyear.
andthismayextendtofetusesduringpregnancy.Also,thata Thesubanalysisofthemultivariablemodelbyearlyandlate
non-smokingmotherlivesinasmokingenvironmentmaybe gestationalagecategories(table5)showedfetalgrowth
missed,resultinginthepregnancynotbeingaffordedthesame restrictionagaintobethestrongestfactorforriskofstillbirth
clinicalattention,includingconcernaboutfetalgrowth. after34weeksofgestation,withthehighestriskinpregnancies
wherethemotherdidnotsmoke.Before34weeksofgestation,
Modifiable factors
fetalgrowthrestrictionwasthesinglesignificantfactorand
Overall,thelargestpopulationattributablerisk(37.4%)was accountedforclosetohalfofallstillbirths(population
associatedwithfetalgrowthrestrictionwithandwithout attributablerisk49.5%).Theseresultssupportthenotionof
smoking,followedbymaternalsmokingwithoutfetalgrowth differingpatternsofplacentaldiseaseinearlyandlateonset
restriction(9.4%)andobesity(bodymassindex≥30;population fetalgrowthrestriction.1013Theprotectiveeffectof
attributablerisk8.7%,table3).Thesethreevariablescouldbe pre-eclampsia(table5)isinterestingbutnotsurprising:the
consideredasthepotentiallymostmodifiablefactorsand, diseaseisoftenassociatedwithfetalgrowthrestriction,butas
allowingforoverlap,togetheraccountedfor55.5%ofstillbirths thesepregnanciesareoftendeliveredearlyformaternalreasons,
inourcohort.Howevertheyhavedifferentimplicationsfor thebabyisremovedfromahighriskintrauterineenvironment.
prevention.Reductionofsmokingandobesityrequireconcerted
publichealtheffortsandeducationprogrammesforwomenof Implicationsforcliniciansandcommissioners
childbearingage,aswellasthemothers’cooperationwith Theincreasedriskofstillbirthafterundetectedfetalgrowth
smokingcessationprogrammesduringpregnancy.The problemsisconsistentwithanineyearreviewofdeliveriesin
effectivenessofsuchprogrammesisnotalwaysclear.Onthe asingleunitinMalmö40andarecentcase-controlstudyfrom
otherhand,theriskofstillbirthasaresultoffetalgrowth Auckland.41InourdatabasefromalargeNHSregion,wewere
restrictioncanbereducedbyearlyidentificationofthecondition abletoquantifytheimportanceofthisriskfactorandestablish
andreferralforinvestigationsbyultrasoundandDoppler itspre-eminentassociationwithstillbirthevenafteradjustment
imaging.12 formedical,social,anddemographicriskfactorsthatcanbe
ascertainedinearlypregnancy.Mostcasesoffetalgrowth
Fetal growth restriction and antenatal
restrictiondonotmanifestuntilthethirdtrimesterofpregnancy,
detection
andintheabsenceofeffectivescreeningtests,prevention
Theoveralldetectionrateoffetalgrowthrestrictionwasonly strategiesneedtoincludeanenhancedlevelofsurveillance
31%,lowerthanthatachievedinourcontrolledstudyin throughoutpregnancy.Ourfindingssuggestthatearlydetection
Nottinghamusingcustomisedcharts(48%)37andarecentreport offetalgrowthproblemscansubstantiallyreducetheriskof
fromAustralia(51%).38However,wefoundthatthedetection stillbirth,andneedstobecomeacornerstoneandkeyindicator
rateinourpopulationrangedwidelybetweenmaternityunits ofsafetyandeffectivenessinantenatalcare.
(12.5-50.0%),39varyingwiththeamountofstafftrainingand
adherencetoprotocols.Thishighlightstheimportanceofa Wethankourregionalnetworkofbereavementmidwiveswhosubmit
standardisedandqualityassuredapproachtotheantenatal notificationsonallperinataldeaths;AnnTonks,CatherineFranklin,and
surveillanceoffetalgrowthinroutineclinicalpractice.Among RobynCaleywhoruntheregionalperinatalmortalityregistersfor
thecohortof389stillbirths,thedetectionratewasevenlower: ensuringhighqualityascertainment;thenetworkofunitbaseddata
195(50.1%)ofthecaseshadfetalgrowthrestrictionandin160 clerkswhoentertheregionalmaternitydatasetforeachpregnancyon
(82.1%)fetalgrowthrestrictionwasnotdetectedantenatally thePEERelectronicrecord(www.pi.nhs.uk/peer);andMichelleSoutham
(table1). andLorraineEcclestoneforensuringdataqualitythrougharolling
programmeoftrainingandaccuracyaudits.
Thepotentialpreventabilityofstillbirthsassociatedwithfetal
growthrestrictionisillustratedbythereducedriskafterantenatal Contributors:Allauthorshadfullaccesstothedata,assistedwithits
detection(fig1andtable1).Althoughpregnancieswithfetal analysisandinterpretationoftheresults,andreviewedandapproved
growthrestrictionhaveaneighttimeshigherrateofstillbirth thefinalmanuscript.JGdevelopedthestudydesign,assistedwiththe
(16.7v2.1,fig1),thisriskisreducedwhenfetalgrowth analysisandinterpretation,andwrotethepaper.Hehasfinal
restrictionisdetected(9.7),althoughnottothesamelevelsas responsibilitytosubmitforpublication,andistheguarantor.
innon-fetalgrowthrestrictedpregnancies.Thisislikelytobe Funding:Datacollectionandanalyticalstaffwerefinanciallysupported
becausethebabyisoftennotdeliveredimmediately,eitherdue byNHSWestMidlandsStrategicHealthAuthorityandallprimarycare
toinappropriatedelaysorbecauseofconcernsaboutneonatal trusts.Thefundershadnoinfluenceonthestudydesign,analysis,
immaturity.Conversely,theriskishigherstilliffetalgrowth interpretation,writingupofthemanuscript,orthedecisiontosubmitfor
restrictionispresentbutnotdetected. publication.
Theseassociationsarealsoshownwhenallotherfactorsare Competinginterests:AllauthorshavecompletedtheICMJEuniform
adjustedforinthemultivariableanalysis(table4):the disclosureformatwww.icmje.org/coi_disclosure.pdf(availableon
populationattributableriskof32.0%indicatesthatfivetimes requestfromthecorrespondingauthor)anddeclare:nosupportfrom
asmanystillbirthsareassociatedwithundetectedantenatalfetal anyorganisationforthesubmittedwork;nofinancialrelationshipswith
growthrestrictionthanwithdetectedfetalgrowthrestriction anyorganisationsthatmighthaveaninterestinthesubmittedworkin
(6.2).Pregnancieswithfetalgrowthrestrictionweredelivered thepreviousthreeyears,andnootherrelationshipsoractivitiesthat
onaverage10daysearlierthanthosewithout,butstillat couldappeartohaveinfluencedthesubmittedwork.
relativelymaturegestationswhendetectedthanwhennot
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RESEARCH
Whatisalreadyknownonthistopic
StillbirthrateshavechangedlittleintheEnglishNationalHealthServiceoverthepasttwodecades
Manyhaveconventionallybeenconsideredunexplainedandunavoidable
Riskfactorshavegenerallybeenconsideredweakpredictorsofstillbirth
Whatthisstudyadds
Maternalobesity,smoking,andfetalgrowthrestriction,potentiallymodifiableriskfactors,togetheraccountforthemajorityofnormally
formedstillbirths
Comparedwithpregnancieswithnormalgrowth,thestillbirthrateinthosewithfetalgrowthrestrictionincreasedfourfold,andincreased
furthertoeightfoldifgrowthrestrictionwasnotdetectedantenatally
Fetalgrowthrestrictioniscurrentlymissedinmostpregnancies,andbetterantenataldetectionneedstobecomeacornerstoneandkey
indicatorofsafetyandeffectivenessinmaternitycare
Ethicalapproval:Notrequired;datawerecollectedwithpatientconsent 24 GenestDR,WilliamsMA,GreeneMF.Estimatingthetimeofdeathinstillbornfetuses:I.
Histologicevaluationoffetalorgans;anautopsystudyof150stillborns.ObstetGynecol
andwerepseudonymisedbeforeanalysis. 1992;80:575-84.
Datasharing:Noadditionaldataavailable. 25 KooperbergC,PetittiDB.Usinglogisticregressiontoestimatetheadjustedattributable
riskoflowbirthweightinanunmatchedcase-controlstudy.Epidemiology1991;2:363-6.
26 ConfidentialEnquiryintoMaternalandChildHealth.Perinatalmortality2007.CEMACH,
1 SavingBabiesLivesReport.StillbirthandNeonatalDeathCharity(SANDS),2009.2012. 2009:21.
www.why17.org/fileadmin/content/About_Sands/03520_Saving_babies_lives_watermarked. 27 BaiJ,WongFW,BaumanA,MohsinM.Parityandpregnancyoutcomes.AmJObstet
pdf. Gynecol 2002;186:274-8.
2 FlenadyV,MiddletonP,SmithGC,DukeW,ErwichJJ,YeeKhongT,etal.Stillbirths: 28 FlenadyV,KoopmansL,MiddletonP,FrøenF,SmithGC,GibbonsK,etal.Majorrisk
thewayforwardinhigh-incomecountries.Lancet2011;377:1703-17. factorsforstillbirthinhigh-incomecountries:asystematicreviewandmeta-analysis.
3 OfficeforNationalStatistics(2011).Deathregistrationsummarytables,England&Wales, Lancet2011;377:1331-40.
2010.2012.www.ons.gov.uk/ons/publications/re-reference-tables.html?edition=tcm% 29 HollierLM,LevenoKJ,KellyMA,McIntireDD,CunninghamFG.Maternalageand
3A77-230730. malformationsinsingletonbirths.ObstetGynecol2000;96:701-6.
4 ConfidentialEnquiryintoMaternalandChildHealth(CEMACH).Perinatalmortality2006: 30 ReeskeA,KutschmannM,RazumO,SpallekJ.Stillbirthdifferencesaccordingtoregions
England,WalesandNorthernIreland.CEMACH,2008.(Table4.2). oforigin:ananalysisoftheGermanperinataldatabase,2004-2007.BMCPregnancy
5 GardosiJ.Clinicalimplicationsof‘unexplained’stillbirths.In:MaternalandChildHealth Childbirth2011;11:63.
ResearchConsortium,ed:CESDI8thannualreport.ConfidentialEnquiryintoStillbirths 31 PerssonM,NormanM,HansonU.Obstetricandperinataloutcomesintype1diabetic
andDeathsinInfancy,2001:40-7. pregnancies:alarge,population-basedstudy.DiabetesCare2009;32:2005-9.
6 GardosiJ,MulT,MongelliM,FaganD.Analysisofbirthweightandgestationalagein 32 King-HeleS,WebbRT,MortensenPB,ApplebyL,PicklesA,AbelKM.Riskofstillbirth
antepartumstillbirths.BJOG1998;105:524-30. andneonataldeathlinkedwithmaternalmentalillness:anationalKing-Helecohortstudy.
7 FroenJF,GardosiJ,ThurmannA,FrancisA,Stray-PedersenB.Restrictedfetalgrowth ArchDisChildFetalNeonatalEd.2009;94:F105-10.
insuddenintrauterineunexplaineddeath.ActaObstetGynecolScand2004;83:81-7. 33 GoyaJ,DoddL,RosenbergMWKingaWDHealth-riskbehaviours:examiningsocial
8 GardosiJ,KadySM,McGeownP,FrancisA,TonksA.Classificationofstillbirthbyrelevant disparitiesintheoccurrenceofstillbirthPaediatrPerinatalEpidemiol2008;22:314-20.
conditionatdeath(ReCoDe):populationbasedcohortstudy.BMJ2005;331:1113-7. 34 McCowanLM,DekkerGA,ChanE,StewartA,ChappellLC,HunterM,etal.Spontaneous
9 VerganiP,CozzolinoS,PozziE,CuttinMS,GrecoM,OrnaghiS,etal.Identifyingthe pretermbirthandsmallforgestationalageinfantsinwomenwhostopsmokingearlyin
causesofstillbirth:acomparisonoffourclassificationsystems.AmJObstetGynecol pregnancy:prospectivecohortstudy.BMJ2009;26;338:b1081.Erratumin:BMJ2009;338.
2008;199:319.e1-4. doi:10.1136/bmj.b1558.
10 KortewegFJGordijnSJ,TimmerA,HolmJP,RaviseJM,ErwichJJ.Aplacentalcause 35 Leonardi-BeeJ,BrittonJ,VennA.Secondhandsmokeandadversefetaloutcomesin
ofintra-uterinefetaldeathdependsontheperinatalmortalityclassificationsystemused. nonsmokingpregnantwomen:ameta-analysis.Pediatrics2011;127:734-41.
Placenta2008;29:71-8. 36 SchickS,GlantzS.PhilipMorristoxicologicalexperimentswithfreshsidestreamsmoke:
11 StillbirthCollaborativeResearchNetworkWritingGroup.Causesofdeathamongstillbirths. moretoxicthanmainstreamsmoke.TobControl2005;14:396-404.
JAMA2011;306:2459-68. 37 GardosiJ,FrancisA.Controlledtrialoffundalheightmeasurementplottedoncustomised
12 AlfirevicZ,NielsonJP.Dopplerultrasonographyinhighriskpregnancies:systematic antenatalgrowthcharts.BJOG1999;106:309-17.
reviewwithmeta-analysis.AmJObstetGynecol 1995;172:1379-87. 38 RoexA,NikpoorP,vanEerdE,HodylN,DekkerG.Serialplottingoncustomisedfundal
13 FiguerasF,GardosiJ:Intrauterinegrowthrestriction:newconceptsinantenatal heightchartsresultsindoublingoftheantenataldetectionofsmallforgestationalage
surveillance,diagnosis,andmanagement.AmJObstetGynecol 2010;doi:10.1016/j. fetusesinnulliparouswomen.AustNZJObstetGynaecol2012;52:78-82.doi:10.1111/
ajog.2010.08.055 j.1479-828X.2011.01408.x.
14 StillbirthCollaborativeResearchNetworkWritingGroup.Associationbetweenstillbirth 39 WestMidlandsPerinatalKPIReport,Q22010/11.PerinatalInstitute,2011.2012.www.
andriskfactorsknownatpregnancyconfirmation.JAMA2011;306:2469-79. pi.nhs.uk/pnm/maternitydata/Q2_2010-11_Perinatal_KPI_report.pdf.
15 KeyHealthDatafortheWestMidlands—2009.NHSPerinatalInstitute.2012.www.pi. 40 LindqvistPG,MolinJ.Doesantenatalidentificationofsmall-for-gestationalagefetuses
nhs.uk/pnm. significantlyimprovetheiroutcome?UltrasoundObstetGynecol2005;25:258-64.
16 PerinatalEpisodeElectronicRecord(PEER).NHSPerinatalInstitute.2012.www.pi.nhs. 41 StaceyT,ThompsonJM,MitchellEA,ZuccolloJM,EkeromaAJ,McCowanLM.Antenatal
uk/peer. care,identificationofsuboptimalfetalgrowthandriskoflatestillbirth:findingsfromthe
17 Pregnancynotes.NHSPerinatalInstitute.2012.www.preg.info. AucklandStillbirthStudy.AustNZJObstetGynaecol2012.doi:10.1111/j.1479-828X.
18 WestMidlandsCoreMaternityDatasetv1.7,2009.NHSPerinatalInstitute.2012.www. 2011.01406.
pi.nhs.uk/peer/WM_Maternity_Dataset_v1.7.pdf. Accepted:18December2012
19 GROW(GestationRelatedOptimalWeight)softwareversion6.5(UK).GestationNetwork.
2012.www.gestation.net.
20 GardosiJ,ChangA,KalyanB,SahotaD,SymondsEM.Customisedantenatalgrowth Citethisas:BMJ2013;346:f108
charts.Lancet1992;339:283-7.
21 GardosiJ,MongelliM,WilcoxM,ChangA.Anadjustablefetalweightstandard.Ultrasound Thisisanopen-accessarticledistributedunderthetermsoftheCreativeCommons
ObstetGynecol1995;6:168-74. AttributionNon-commercialLicense,whichpermitsuse,distribution,andreproductionin
22 GardosiJ.Customisedassessmentoffetalgrowthpotential:implicationsforperinatal
anymedium,providedtheoriginalworkisproperlycited,theuseisnoncommercialand
care.ArchDisChildFetalNeonatalEd2012;doi:10.1136/fetalneonatal-2012-301708.
23 DeJongCL,FrancisA,VanGeijnHP,GardosiJ.Customizedfetalweightlimitsfor isotherwiseincompliancewiththelicense.See:http://creativecommons.org/licenses/by-
antenataldetectionoffetalgrowthrestriction.UltrasoundObstetGynecol2000;15:36-40. nc/2.0/andhttp://creativecommons.org/licenses/by-nc/2.0/legalcode.
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RESEARCH
Tables
Table1|Univariateanalysisofriskfactorsassociatedwithstillbirthscomparedwithlivebirths
Riskfactors No(%)ofallbirths No(%)ofstillbirths Rate/1000births Relativerisk(95%CI)
Total 92218(100) 389(100) 4.2 —
Generalmaternalcharacteristics
Age(years): n=92208 n=389
<20 6456(7.0) 33(8.5) 5.1 1.3(0.9to1.9)
20-24 20834(22.6) 99(25.5) 4.8 1.2(0.9to1.6)
25-30 27110(29.4) 107(27.5) 3.9 Reference
30-34 23110(25.1) 79(20.3) 3.4 0.9(0.6to1.2)
≥35 14698(15.9) 71(18.3) 4.8 1.2(0.9to1.6)
Parity: n=91160 n=377
0 38653(42.4) 192(50.9) 5.0 1.9(1.4to2.4)
1 29791(32.7) 79(21.0) 2.7 Reference
2 13421(14.7) 56(14.9) 4.2 1.6(1.1to2.2)
≥3 9295(10.2) 50(13.3) 5.4 2.0(1.4to2.9)
Bodymassindex: n=90350 n=389
<18.5 3109(3.4) 12(3.1) 3.9 1.0(0.5to1.8)
18.5-24.9 43898(48.6) 173(44.5) 3.9 Reference
25-29.9 25156(27.8) 101(26.0) 4.0 1.0(0.8to1.3)
30-34.9 11427(12.6) 61(15.7) 5.3 1.4(1.0to1.8)
≥35 6760(7.5) 42(10.8) 6.2 1.6(1.1to2.2)
Maternalethnicorigin: n=87911 n=334
European:
UK 60130(67.9) 192(57.5) 3.2 Reference
Non-UK 4254(4.8) 17(5.1) 4.0 1.3(0.8to2.1)
African* 2986(3.2) 22(5.7) 7.4 2.3(1.5to3.6)
African-Caribbean* 1796(2.0) 12(3.1) 6.7 2.1(1.2to3.7)
Bangladeshi* 1674(1.8) 7(1.8) 4.2 1.3(0.6to2.8)
Indian:
UK 2282(2.6) 9(2.7) 3.9 1.2(0.6to2.4)
Non-UK 2189(2.5) 14(4.2) 6.4 2.0(1.2to3.4)
Pakistani:
UK 3412(3.9) 14(4.2) 4.1 1.3(0.7to2.2)
Non-UK 4378(4.9) 30(9.0) 6.9 2.1(1.5to3.1)
Other:
UK 1535(1.7) 6(1.8) 3.9 1.2(0.5to2.8)
Non-UK 3275(3.7) 11(3.3) 3.4 1.1(0.6to1.9)
Placeofbirth: n=88559 n=334
UK 69878(78.9) 236(70.7) 3.4 Reference
Other 18681(21.1) 98(29.3) 5.2 1.6(1.3to2.1)
Socialfactors
Mothernotemployed: n=86969 n=330
No 50905(58.5) 176(53.3) 3.5 Reference
Yes 36064(41.5) 154(46.7) 4.3 1.2(1.0to1.5)
Partnernotemployed: n=81624 n=310
No 63212(77.4) 230(74.2) 3.6 Reference
Yes 11950(14.6) 58(18.7) 4.9 1.3(1.0to1.8)
Nopartner 6462(7.9) 22(7.1) 3.4 0.9(0.6to1.4)
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RESEARCH
Table1(continued)
Riskfactors No(%)ofallbirths No(%)ofstillbirths Rate/1000births Relativerisk(95%CI)
Baby’sfatherbloodrelation: n=81627 n=298
No 76084(93.2) 273(91.6) 3.6 Reference
Yes 5543(6.8) 25(8.4) 4.5 1.3(0.8to1.9)
Indexofmultipledeprivation(fifths): n=92218 n=389
1-3(leastdeprived) 34863(37.8) 115(29.6) 3.3 Reference
4 19230(20.9) 69(17.7) 3.6 1.1(0.8to1.5)
5(mostdeprived) 38125(41.3) 205(52.7) 5.4 1.6(1.3to2.0)
Maternalhistory
Mentalhealthproblems: n=89985 n=340
No 79553(88.4) 285(83.8) 3.6 Reference
Yes 10432(11.6) 55(16.2) 5.3 1.5(1.1to2.0)
Pre-existinghypertension: n=90965 n=342
No 88528(97.3) 329(96.2) 3.7 Reference
Yes 2437(2.7) 13(3.8) 5.3 1.4(0.8to2.5)
Pre-existingdiabetes: n=90965 n=342
No 90238(99.2) 332(97.1) 3.7 Reference
Yes 727(0.8) 10(2.9) 13.8 3.7(2.0to6.9)
Cardiacdisease: n=90965 n=342
No 89051(97.9) 331(96.8) 3.7 Reference
Yes 1914(2.1) 11(3.2) 5.7 1.5(0.8to2.8)
Previousstillbirthpara≥1(n=53565): n=52475 n=184
No 51482(98.1) 173(94.0) 3.4 Reference
Yes 993(1.9) 11(6.0) 11.1 3.3(1.8to6.0)
Pregnancyrelatedfactors
Smokinginpregnancy: n=85337 n=333
Non-smoker 52473(61.5) 166(49.8) 3.2 Reference
Smoker 17834(20.9) 104(31.2) 5.8 1.8(1.4to2.3)
Passivesmoker 15030(17.6) 63(18.9) 4.2 1.3(1.0to1.8)
Alcoholconsumption: n=88569 n=329
No 81288(91.8) 305(92.7) 3.8 Reference
Yes 7281(8.2) 24(7.3) 3.3 0.9(0.6to1.3)
Antenatalfolicacid: n=88173 n=326
Yes 74526(84.5) 262(80.4) 3.5 Reference
No 13647(15.5) 64(19.6) 4.7 1.3(1.0to1.8)
Latebooking(≥13weeks): n=89886 n=338
No 74644(83.0) 269(79.6) 3.6 Reference
Yes 15242(17.0) 69(20.4) 4.5 1.3(1.0to1.6)
Complicationsinpregnancy
Gestationaldiabetes: n=91010 n=339
No 88134(96.8) 326(96.2) 3.7 Reference
Yes 2876(3.2) 13(3.8) 4.5 1.2(0.7to2.1)
Pregnancyinducedhypertension: n=91010 n=339
No 86640(95.2) 322(95.0) 3.7 Reference
Yes 4370(4.8) 17(5.0) 3.9 1.0(0.6to1.7)
Pre-eclampsia: n=91010 n=339
No 89938(98.8) 328(96.8) 3.6 Reference
Yes 1072(1.2) 11(3.2) 10.3 2.8(1.5to5.1)
Antepartumhaemorrhage: n=91010 n=339
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RESEARCH
Table1(continued)
Riskfactors No(%)ofallbirths No(%)ofstillbirths Rate/1000births Relativerisk(95%CI)
No 83902(92.2) 277(81.7) 3.3 Reference
Yes 7108(7.8) 62(18.3) 8.7 2.6(2.0to3.5)
Fetal/neonatalcharacteristics
Sex: n=92136 n=383
Boy 47308(51.3) 209(54.6) 4.4 Reference
Girl 44828(48.7) 174(45.4) 3.9 0.9(0.7to1.1)
Gestationalageatdelivery n=92218 n=389
Median(interquartilerange)days 280(272-286) 240(198-271)
Birthweight(g): n=91858 n=389
Mean(SD) 3343.3(569.1) 1931.6(1146.2)
Gestationrelatedoptimalweightcentile: n=88053 n=380
Median(interquartilerange) 41.5(19.5-67.5) 9.7(0.6-37.3)
≤10 69840(75.7) 168(43.2) 16.7 6.8(5.6to8.4)
10-90 11697(12.7) 195(50.1) 2.4 Reference
>90 6516(7.1) 17(4.4) 2.6 1.1(0.7to1.8)
Fetalgrowthrestriction†: n=88053 n=380
No 76356(86.7) 185(48.7) 2.4 Reference
Yes
Detectedantenatally 3601(4.1) 35(9.2) 9.7 4.0(2.8to5.7)
Notdetectedantenatally 8096(9.2) 160(42.1) 19.8 8.0(6.5to9.9)
*Placeofbirthcombinedifeithersubgroup<1000women.
†Birthweight<10thgestationrelatedoptimalweightcentile.
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RESEARCH
Table2|Smokingandfetalgrowthrestriction(birthweight<10thgestationrelatedoptimalweightcentile)
Variables Proportionoftotal(%) Stillbirthrate/1000births
All 100.0 4.2
Smokers: 18.7 5.8
Fetalgrowthrestriction 4.3 13.0
Nofetalgrowthrestriction 13.7 3.7
Non-smokers: 81.3 3.8
Fetalgrowthrestriction 8.3 18.3
Nofetalgrowthrestriction 68.7 2.1
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