Post on 11-Sep-2021
Person,PlaceandContext:TheInteractionbetweentheSocialandPhysicalEnvironmentonAdversePregnancyOutcomesinBritish
Columbiaby
AndersCarlEricksonB.Sc.,UniversityofVictoria,2004
M.Sc.,UniversityofNorthernBritishColumbia,2009
ADissertationSubmittedinPartialFulfillmentoftheRequirementsfortheDegreeof
DOCTOROFPHILOSOPHY
inInterdisciplinaryStudies
intheDivisionofMedicalSciences&DepartmentofGeography
AndersCarlErickson,2016UniversityofVictoria
Allrightsreserved.Thisthesismaynotbereproducedinwholeorinpart,by
photocopyorothermeans,withoutthepermissionoftheauthor.
ii
SupervisoryCommittee
Person,placeandContext:TheInteractionbetweentheSocialandPhysicalEnvironmentonAdversePregnancyOutcomesinBritishColumbia
by
AndersCarlEricksonB.Sc.,UniversityofVictoria,2004
M.Sc.,UniversityofNorthernBritishColumbia,2009
SupervisoryCommitteeDr.LauraT.Arbour,MDFRCPCFCCMG,DivisionofMedicalSciences,UniversityofVictoria&DepartmentofMedicalGenetics,UniversityofBritishColumbiaSupervisorDr.AleckOstry,PhD.,DepartmentofGeography,UniversityofVictoriaCo‐SupervisorLaurieH.M.Chan,PhD.,CenterforAdvancedResearchinEnvironmentalGenomics,UniversityofOttawaOutsideMember
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Abstract Thisstudywasapopulation‐basedretrospectivecohortofallsingletonbirthsin
BritishColumbiafortheyears2001to2006.Thepurposeofthisdissertationistoexamine
howsocialandphysicalenvironmentfactorsinfluencetheriskofadversepregnancy
outcomesandwhethertheyinteractwitheachotherorwithmaternalcharacteristicsto
modifydiseaserisk.Themainenvironmentalfactorsexaminedincludeambientparticulate
airpollution(PM2.5),neighbourhoodsocioeconomicstatus(SES),neighbourhoodimmigrant
density,neighbourhoodlevelofpost‐secondaryeducationlevelandtheurban‐ruralcontext.
Censusdisseminationareas(DAs)wereusedastheneighbourhoodspatialunit.Thedata
(N=242,472)wasextractedfromtheBCPerinatalDataRegistry(BCPDR)fromPerinatal
ServicesBC(PSBC).Themainperinataloutcomesinvestigatedincludebirthweightand
indicatorsoffetalgrowthrestrictionsuchassmall‐for‐gestationalage(SGA),termlowbirth
weight(tLBW),andintrauterinegrowthrestriction(IUGR),pretermbirth(PTB)and
gestationalage,gestationaldiabetesmellitus(GDM)andgestationalhypertension(GH).
Collectively,thisdissertationcontributestotheperinatalepidemiologicalliterature
linkingparticulateairpollutionandneighbourhoodSEScontexttoadversepregnancy
outcomes.AssumptionsaboutthelineareffectofPM2.5andsmokingonbirthweightare
challengedshowingthattheeffectsaremostpronouncedbetweenlowandaverage
exposuresandthatthemagnitudeoftheireffectismodifiedbyneighbourhoodand
individual‐levelcharacteristics.Theseresultssuggestthatfocusingexclusivelyonindividual
riskfactorsmayhavelimitedsuccessinimprovingoutcomeswithoutaddressingthe
contextualinfluencesattheneighbourhood‐level.Thisdissertationthereforealso
contributestothepublichealth,sociologicalandcommunity‐urbandevelopmentliterature
demonstratingthatcontextandplacematters.
iv
ExecutiveSummary Thisstudywasapopulation‐basedretrospectivecohortofallsingletonbirthsin
BritishColumbiafortheyears2001to2006.Thepurposeofthisdissertationistoexamine
howsocialandphysicalenvironmentfactorsinfluencetheriskofadversepregnancy
outcomesandwhethertheyinteractwitheachotherorwithmaternalcharacteristicsto
modifydiseaserisk.Themainenvironmentalfactorsexaminedincludeambientparticulate
airpollution(PM2.5),neighbourhoodsocioeconomicstatus(SES),neighbourhoodimmigrant
density,neighbourhoodlevelofpost‐secondaryeducationlevelandtheurban‐ruralcontext.
Censusdisseminationareas(DAs)wereusedastheneighbourhoodspatialunit.Thedata
(N=242,472)wasextractedfromtheBCPerinatalDataRegistry(BCPDR)fromPerinatal
ServicesBC(PSBC).Themainperinataloutcomesinvestigatedincludebirthweightand
indicatorsoffetalgrowthrestrictionsuchassmall‐for‐gestationalage(SGA),termlowbirth
weight(tLBW),andintrauterinegrowthrestriction(IUGR),pretermbirth(PTB)and
gestationalage,gestationaldiabetesmellitus(GDM)andgestationalhypertension(GH).
Thedissertationiscomprisedof7chapters.InChapter1,Ireviewtheshared
pathoetiologicaleffectsofparticulateairpollutionandthesocialenvironmentin
contributingtoadversepregnancyoutcomes,includingtheroleofoxidativestress,
inflammationandendocrinemodificationonfetal‐placentaldevelopment.Chapter2
providesabackgrounddiscussiononthemethodsanddatausedthroughoutthe
dissertation.Thisincludesthehierarchicalnatureofthesocialenvironmentandhow
multilevelandspatialstatisticalmethodscanbeusedtoexploreenvironmentalhealth
relationships.Thisleadsintothefourresearchchapters(Chapters3to6)whichshowthe
existenceoftheserelationshipsinanobservationalepidemiologicalsetting.Finally,Chapter
7providestheoverallconclusionsandrecommendations.Additionalmaps,resultsand
backgroundinformationareprovidedasappendices.Researchethicsboardapprovalwas
grantedbytheUniversityofVictoria(ethicsprotocol#:11‐043)andbytheUniversityof
Alberta(studyid:Pro00028662)withfundingprovidedinpartbytheCanadianInstituteof
HealthResearch(CIHR)OperationalGrant(protocol#:200903‐202069).
Inthefirstresearchpaper(Chapter3),Iassessthequantityofcigarettessmoked
duringpregnancyandthemagnitudeofadversepregnancyoutcomesfollowedbytesting
theassociationbetweenthequantityofcigarettessmokedwithotherSESandbehavioural
riskfactorsthatalsoinfluencepregnancyoutcomes.Theresultsshowasignificantdose‐
responseincreaseinriskforSGA,tLBWandIUGR,andindicatethatself‐reportsofheavy
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smoking(≥10cigarettes/day)earlyinpregnancywereassociatedwithnothavinghigh
schooleducation:adjustedOR(95%CI)=3.80(3.41‐4.25);beingasingleparent:2.27
(2.14‐2.42);indicationdrugoralcoholuse:7.65(6.99‐8.39)and2.20(1.88‐2.59)
respectively,andattendingfewerthan4prenatalcarevisits:1.39(1.23‐1.58),andtobe
multiparous:1.59(1.51‐1.68)comparedtolight,moderateandnon‐smokerscombined.
Theseresultssuggestthatheavysmokinginpregnancycouldbeusedasamarkerfor
lifestyleriskfactorsthatincombinationwithsmokinginfluencebirthoutcomes.Iusethe
numberofcigarettesandthisheavysmokingsub‐populationinthefollowingtwopapersas
apotentialhighriskgrouppossiblymoresusceptibletoPM2.5exposure.
ThepurposeofChapter4wastodeterminetherelationshipbetweenPM2.5exposure
andcontinuousbirthweight,andtotestthepotentialmodificationbymaternalriskfactors
andindicatorsofsocioeconomicstatus.Theresultsshowanon‐linearnegativeassociation
ofPM2.5andbirthweightandthatthisrelationshipismodifiedbytheneighbourhood
contextandmaternalcharacteristics.Usingrandomcoefficientmodels,thereisevidence
thatneighbourhood‐levelSESvariablesandPM2.5havebothindependentandinteracting
associationswithbirthweightwhichtogetheraccountfor49%ofthebetween‐
neighbourhooddifferencesinbirthweight.Thissuggeststhatcertainsub‐populationsmay
bemoreorlessvulnerabletoevenrelativelylowdosesPM2.5exposure.Iprovidefurther
analysisoftheassociationbetweenPM2.5andtheotherDA‐levelvariablesonmeasureof
birthweight,includingtLBW,SGA,IUGRaswellasPTBinAppendix3.Theresultsshowfind
consistentdose‐responseassociationsbetweenPM2.5exposureandthemeasuresof
impairedfetalgrowth,butnoassociationwithPTB.
InChapter5Ifocusontheinteractionbetweenmaternalsmokingandwhether
neighbourhoodfactorscaneitherpotentiateorbufferitsnegativeeffectonbirthweight.
SimilartoPM2.5,asignificantnegativeandnon‐linearassociationwasfoundbetween
maternalsmokingandbirthweightwhichwashighlyvariablebetweenneighbourhoods
andshowedevidenceofeffectmodificationwithneighbourhood‐levelfactors.HighDA‐level
SEShadastrongpositiveassociationwithbirthweightbuttheeffectwasmoderatedwith
increasedcigarettes/day.Conversely,heavysmokersshowedthelargestincreasesinbirth
weightwithrisingneighbourhoodeducationlevels.IncreasedlevelsofPM2.5andimmigrant
densitywerenegativelyassociatedwithbirthweight,butshowedpositiveinteractionswith
increasedlevelsofsmoking.Oldermaternalageandsuspecteddrugoralcoholusebothhad
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negativeinteractionswithincreasedlevelsofmaternalsmoking.Theresultssuggestthat
thesocialandenvironmentalcontextmattersinhowsmokingcanaffectbirthweight.
InChapter6IassesstheassociationofPM2.5andSES‐relatedneighbourhoodfactors
ontheriskofgestationalhypertension(GH)andgestationaldiabetesmellitus(GDM).The
resultsshowaconsistentdose‐responseassociationintheriskofGHandGDMwith
increasinglevelsofPM2.5.HigherDA‐levelSESandeducationwereassociatedwithlower
risksforbothGHandGDM,whilehigherimmigrantdensityandhigherDA‐meanBMI
showedanincreasedrisk.GDMshowedconsiderableeffectheterogeneityinurbanareas
wheretheinteractionbetweenPM2.5andSESgreatlymodifiedtheriskofGDM.
Furthermore,theseassociationsarepotentiallymorepronouncedamongmotherswith
largerpre‐pregnancyBMI.TheinclusionoftheDA‐levelSESandPM2.5variablesreduceda
substantialproportionofthebetween‐DAvariabilityintheriskofGHandGDM;however,
thewassignificantremainingunexplainedrandominterceptvariancewhichwasshownto
be,atleastpartially,spatiallyclusteredatalocalscale.
Collectively,thisdissertationcontributestotheperinatalepidemiologicalliterature
linkingparticulateairpollutionandneighbourhoodSEScontexttoadversebirthoutcomes.
AssumptionsaboutthelineareffectofPM2.5andsmokingonbirthweightarechallenged
showingthattheeffectsaremostpronouncedbetweenlowandaverageexposuresandthat
themagnitudeoftheireffectismodifiedbyneighbourhoodandindividual‐level
characteristics.Theseresultssuggestthatfocusingexclusivelyonindividualriskfactors
mayhavelimitedsuccessinimprovingoutcomeswithoutaddressingthecontextual
influencesattheneighbourhood‐level.Thisdissertationthereforealsocontributestothe
publichealth,sociologicalandcommunity‐urbandevelopmentliteraturedemonstrating
thatcontextandplacematters.
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TableofContentsSupervisoryCommittee........................................................................................................................iiAbstract.....................................................................................................................................................iiiExecutiveSummary...............................................................................................................................ivTableofContents...................................................................................................................................viiListofTables.............................................................................................................................................xListofFigures..........................................................................................................................................xiListofAbbreviations............................................................................................................................xiiAcknowledgments................................................................................................................................xivDedication................................................................................................................................................xvChapter1:TheSharedPathoetiologicalEffectsofParticulateAirPollutionandtheSocialEnvironmentonFetal‐PlacentalDevelopment...............................................................1Abstract..................................................................................................................................................................11.0Introduction..................................................................................................................................................12.0Person,PlaceandContext:ThePlacental,PhysicalandSocialEnvironments..................32.1ThePlacenta.............................................................................................................................................32.2ThePhysicalEnvironment:ParticulateAirPollution.............................................................42.3TheSocialEnvironment:Socio‐economicStatus,Diet,Smoking&AllostaticLoad...7
3.0BiologicalMechanismsLeadingtoAdversePregnancyOutcomes........................................93.1OxidativeStress......................................................................................................................................93.2InflammationandImmunologicAlterations............................................................................103.3.MechanismsofOxidativeStressandInflammationInvolvedinAdversePerinatalOutcomes........................................................................................................................................................12
4.0ThePhysicalandSocialEnvironmentandtheirRelationtoAdversePerinatalOutcomes.............................................................................................................................................................154.1.PM‐inducedoxidativestressandinflammatorymechanisms.........................................154.2MaternalDietandMicronutrientIntake....................................................................................174.3MaternalSmokingandEnvironmentalTobaccoSmoke(ETS)Exposure....................204.4AllostaticStressandGlucocorticoidExposure........................................................................21
5.0Discussion....................................................................................................................................................226.0Conclusion....................................................................................................................................................247.0Endnotes.......................................................................................................................................................248.0References....................................................................................................................................................30
Chapter2:MethodologicalBackground.......................................................................................511.0Introduction................................................................................................................................................512.0Socio‐economicStatusBackground..................................................................................................522.1MeasuringSocio‐economicStatus................................................................................................522.2Contextual(population‐level)MeasuresofSES......................................................................54
3.0MultilevelModels&Analysis...............................................................................................................563.1RandomInterceptModel..................................................................................................................583.2RandomSlopeModel..........................................................................................................................603.3InclusionofLevel‐2VariablesandCross‐LevelInteractions............................................613.4MultilevelLogisticRegression........................................................................................................63
4.0SpatialDependence:Mechanisms,MethodsandModels.........................................................644.1SpatialDependence&SpatialHeterogeneity...........................................................................654.2SpatialWeightMatrices....................................................................................................................654.3SpatialRegressionModels...............................................................................................................684.4RateSmoothing.....................................................................................................................................69
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5.0PerinatalDataRegistriesandAdversePregnancyOutcomes................................................705.1TheBCPerinatalDatabaseRegistry.............................................................................................705.2AdversePregnancyOutcomes........................................................................................................71
6.0ExposureAssessment..............................................................................................................................746.1ExposureAssessmentTerminology............................................................................................746.2ExposureAssessmentQuantification..........................................................................................74
7.0References....................................................................................................................................................76Chapter3:Heavysmokingduringpregnancyasamarkerforotherriskfactorsofadversebirthoutcomes:apopulation‐basedstudyinBritishColumbia,Canada........86Abstract................................................................................................................................................................861.0Background..................................................................................................................................................872.0DataandMethods.....................................................................................................................................883.0Results...........................................................................................................................................................904.0Discussion....................................................................................................................................................955.0Conclusion.................................................................................................................................................1006.0References.................................................................................................................................................100
Chapter4:Thereductionofbirthweightbyfineparticulatematteranditsmodificationbymaternalandneighbourhood‐levelfactors:amultilevelanalysisinBritishColumbia,Canada................................................................................................................104Abstract.............................................................................................................................................................1041.0Background...............................................................................................................................................1052.0DataandMethods..................................................................................................................................1063.0Results........................................................................................................................................................1104.0Discussion.................................................................................................................................................1185.0Conclusions...............................................................................................................................................1226.0EndnoteforChapter4..........................................................................................................................1227.0References.................................................................................................................................................124
Chapter5:Airpollution,neighbourhoodandmaternal‐levelfactorsmodifytheeffectofsmokingonbirthweight:amultilevelanalysisinBritishColumbia,Canada.........130Abstract.............................................................................................................................................................1301.0Background...............................................................................................................................................1312.0DataandMethods..................................................................................................................................1323.0Results........................................................................................................................................................1354.0Discussion.................................................................................................................................................1425.0Conclusions...............................................................................................................................................1466.0References.................................................................................................................................................146
Chapter6:AssociationofGestationalDiabetesandHypertensionwithincreasedfineparticulatematterandneighbourhood‐levelsocioeconomicfactors:amultilevelanalysisinBritishColumbia,Canada..........................................................................................1511.0Background...............................................................................................................................................1522.0DataandMethods..................................................................................................................................1533.0Results........................................................................................................................................................1564.0Discussion.................................................................................................................................................1685.0Conclusions...............................................................................................................................................1716.0References.................................................................................................................................................171
Chapter7:Conclusions.....................................................................................................................1771.0Introduction.............................................................................................................................................1772.0SummaryofResearchandContributions....................................................................................1772.1.HeavysmokingasamarkerforunmeasuredSES‐relatedlifestyleriskfactors....177
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2.2Effectmodificationofmaternalsmokingonbirthweightbyneighbourhood‐levelfactors...........................................................................................................................................................1782.3Epidemiologicalfindings...............................................................................................................180
3.0Limitations................................................................................................................................................1813.1UseofDAsasneighbourhoods....................................................................................................1813.2ThePM2.5Land‐useRegressionModel.....................................................................................1823.3MissingData........................................................................................................................................1833.4FirstNationsBirths..........................................................................................................................184
4.0OverallImplicationsandFutureConsiderations......................................................................1845.0References.................................................................................................................................................186
Appendix1RiskSurfaceMaps......................................................................................................190Appendix2AdditionalFiguresforChapter4..........................................................................203Appendix3ResultsforSGA‐3,SGA‐10,IUGR,TermLBW,andPTB.................................206
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ListofTablesTable1:Biologicalfactorsinvolvedinpregnancy,theirroleandup/down‐regulation..........29Table2:MaternalCharacteristicsbySmokingStatusinBC,2001‐2006.......................................92Table3:OddsRatiosofCovariateRiskFactorsPredictingLevelofMaternalSmokingin
B.C.2001–2006(n=163,867)......................................................................................................95Table4:Descriptivestatistics#forindividual(Level‐1)andDA(Level‐2)covariates.........111Table5:AdjustedindividualandDA‐levelfixedeffectsoncontinuousbirthweight............112Table6:AdjustedindividualandDA‐levelfixedeffectsoncontinuousandtermbirth
weightandtheirmodificationbyPM2.5(Model‐4)..............................................................114Table7:Randomeffectsandmodeldiagnosticsfromhierarchicallinearmodelsfor
continuousbirthweightinBC,Canada....................................................................................117Table8:AdjustedindividualandDA‐levelfixedeffectsoncontinuousandtermbirth
weightandtheirmodificationbyPM2.5(Model‐5)..............................................................124Table9:Descriptivestatistics#forindividual(Level‐1)andDA(Level‐2)covariateson
termbirthweight..............................................................................................................................136Table10:Adjustedfixedeffectsforlevel‐1andlevel‐2covariatesoncontinuousterm
birthweight.........................................................................................................................................137Table11:AdjustedindividualandDA‐levelfixedeffectsoncontinuousbirthweightand
theirmodificationbymaternalsmoking(Model3)...........................................................138Table12:RandomEffectsandModelDiagnostics................................................................................140Table13:Summaryofpopulationandneighbourhoodcharacteristics,[n(%)].....................158Table14:ORsforGHandGDMinrelationtoPM2.5andDA‐levelSESvariables......................159Table15:ORsforgestationaldiabetesinrelationtoPM2.5,SES,andRuralResidence.........161Table16:ORsforgestationaldiabetesinrelationtoPM2.5,SES,andmaternalBMIª............162Table17:Randomeffectsandmodeldiagnosticsfromhierarchicallogisticmodelsfor
GHinBC,Canada...............................................................................................................................164Table18:Randomeffectsandmodeldiagnosticsfromhierarchicallogisticmodelsfor
GDMinBC,Canada...........................................................................................................................164
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ListofFiguresFigure1:Aconceptualframeworkofthesharedmechanismsofsocio‐economic
determinantsandparticulateairpollutionexposurecontributingtoadversepregnancyoutcomes...........................................................................................................................9
Figure2:Proposedpathwayscontributingtoadversepregnancyoutcomes..............................12Figure3:Proposedpathwaysofparticulateairpollutioncontributingtooxidativestress
andinflammationleadingtoadversepregnancyoutcomes............................................16Figure4:Proposedpathwaysofhowthesocialenvironmentinteractstoproduceexcess
systemicandplacentaloxidativestressandinflammationleadingtoadversepregnancyoutcomes.........................................................................................................................20
Figure5:Schemeofplacentalcirculationandfeatures(Grey’sAnatomylithographs)...........26Figure6:Invasiondefectsinpreeclampsia...............................................................................................26Figure7:Sixtheoreticalmultilevelproposition.......................................................................................58Figure8:nbynbinaryspatialweightmatrixW.......................................................................................66Figure9:Moran’sIscatterplotsshowingthedegreeofclusteringofmodelresidualsusing
differentKNNspatialweightmatrices......................................................................................67Figure10:Moran’sIclustermapshowstheclusteringofmodelresidualsbetweenthe
arealunits(DAs)usinga6‐KNNspatialweightmatrix.....................................................68Figure11:DistributionofMaternalDailyCigaretteConsumptioninBC,2001‐06...................90Figure12:AdjustedOddRatiosofAdverseBirthOutcomesandLevelsofMaternal
Smoking.................................................................................................................................................94Figure13:AdjustedPredictedEffectsofPM2.5onBirthWeight.....................................................112Figure14:AdjustedPredictedEffectsofmaternalriskfactorsonbirthweightacross
levelsofPM2.5....................................................................................................................................115Figure15:AdjustedPredictedEffectsofDA‐levelfactorsonBirthWeightacrosslevels
ofPM2.5.................................................................................................................................................116Figure16:ResultsfromModel‐5includingaSES*Ruralinteraction............................................123Figure17:AdjustedPredictedEffectsofMaternalSmokingonBirthWeight..........................137Figure18:AdjustedPredictedEffectsofMaternalSmokingonBirthWeightacross
DA‐levelFactors..............................................................................................................................138Figure19:AdjustedPredictedEffectsofMaternalSmokingonBirthWeightacross
Maternal‐levelFactors..................................................................................................................139Figure20:Neighbourhood‐specificslopesofmaternalsmokingonbirthweight..................141Figure21:DirectedAcyclicGraphsdepictingthehypothesisedrelationshipsforGHand
GDM......................................................................................................................................................157Figure22:AdjustedORsand95%CIsforGDMandGHinrelationtoPM2.5quintiles
andDA‐levelSESvariables..........................................................................................................160Figure23:PredictedProbabilityofGestationalDiabetesMellituswith95%CIsin
relationtoPM2.5,SESandRuralResidence..........................................................................161Figure24:PredictedProbabilityofGestationalDiabetesMellituswith95%CIsinrelationto
PM2.5,SESandBMI..........................................................................................................................163Figure25:ClustersandOutliersofLocalizedSpatialAutocorrelationinDA‐level(random
intercept)ResidualsforGestationalhypertensioninB.C.,2001–2006.................166Figure26:ClustersandOutliersofLocalizedSpatialAutocorrelationinDA‐level(random
intercept)ResidualsforGestationalDiabetesMellitusinB.C.,2001–2006.........167
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ListofAbbreviations
Acronym Definition
11β‐HSD2 11β‐hydroxysteroiddehydrogenasetype2AhR ArylHydrocarbonReceptorACTH AdrenocorticotropicHormoneAPO AdversePregnancy/PerinatalOutcomeBC BritishColumbiaBCPDR BritishColumbiaPerinatalDatabaseRegistryBMI BodyMassIndexCI ConfidenceIntervalCd CadmiumCOX‐2 Cyclo‐oxygenase‐2CO,CO2 CarbonMonoxide,CarbonDioxideCRA CumulativeRiskAssessmentCRH CorticotropinReleasingHormoneCRP C‐reactiveproteinCSD CensusSubdivisionCVD CardiovascularDiseaseCYP CytochromeP450DA DisseminationAreaDPP DefectiveDeepPlacentationETS EnvironmentalTobaccoSmokeEVT ExtravilliousTrophoblastFGR FetalGrowthRestrictionGDM GestationalDiabetesMellitusGH GestationalHypertensionGPx GlutathionePeroxidaseGST Glutathione‐S‐TransferaseHHC HyperhomocysteimiaHPAaxis Hypothalamus‐Pituitary‐AdrenalaxisICC Intra‐classcorrelationIUGR Intra‐UterineGrowthRestrictionI/Rinjury Ischemic‐reperfusioninjuryLBW LowBirthWeightLDL LowDensityLipoproteinsLHA LocalHealthAreaLUR LandUseRegressionMOR MedianOddsRatioMI MultipleImputation
xiii
NO,NO2 NitrogenOxide/DioxideOR OddsRatioPAH PolycyclicAromaticHydrocarbonsPAP ParticulateAirPollutionPCV ProportionalChangeinVariancePIH/PE PregnancyInducedHypertension/PreeclampsiaPM ParticulateMatterPM2.5 ParticulateMatterlessthan2.5micronsindiameterpPROM (premature)PrelabourRuptureofMembranesPSBC PerinatalServicesBritishColumbiaPTB PretermBirthRI RandomInterceptROS ReactiveOxygenSpeciesRS RandomSlopesEng solubleendoglinsFlt solublefms‐liketyrosinekinaseSES Socio‐economicStatusSESi Socio‐economicStatusIndexSMR StandardizedMorbidityRateSNP SingleNucleotidePolymorphismSOD SuperoxideDismutasetLBW TermLowBirthWeightUFP UltrafineParticlesuNK(cells) uterinenaturalkiller
xiv
Acknowledgments
Firstandforemost,Iwouldliketoacknowledgemysupervisorandmentor
overthepastseveralyearsDr.LauraArbour.Iwouldn’tbeheretodaywithouther
support,guidance,patience,andencouragement.Herhumilityandwhole‐hearted
approachtotheimportantworkthatshedoesinacademe,clinicalandcommunity
settingsisinspirational.Second,I’dliketothankDr.LaurieChanforhissupport
overthepastdecadedatingbacktowhenIstartedmyMastersin2006.His
mentorshipoverthattimeatUNBCtaughtmemanylessonsonhowtobeagraduate
studentandacademicinvolvedincommunity‐levelresearch.I’dliketothankDr.
AleckOstryforhison‐pointadvice,insight,andtherightdoseofinvolvementwhen
needed.AbigthankyoutoformercommitteememberDr.EleanorSettonformany
things,frombringingmeintoCAREXtoputtingmynameforwardforvarious
opportunities,Eleanorhasbeenanenduringsupporterandcheerleader.I’dliketo
acknowledgeDr.ScottVennersasafriend,supporter,andco‐applicantonaCIHR
grantthatfundedthemajorityofmyPhD.I’dalsoliketoacknowledgeandthankDr.
AdrienBarnettforhismentorshipoverthepasttwoyearsonseveralstatistical
issues.Hisfastandclearemailresponseswereinstrumentalinmovingmyresearch
forward.ThankyoutocolleaguesSarah,Beatrixe,SorshaandSirishaforalltheir
helpandfriendlyfacesoverthesemanyyears,aswellastoDr.PerryHystadforthe
useofhisairpollutiondata,adviceandfriendship.I’dliketoacknowledgethestaff
atPerinatalServicesBCfortheirsupportregardingdataaccessandmanuscript
review.Finally,wordscannotdescribetheunconditionalsupport,friendshipand
lovemylifepartner,bestfriendandwifeKeeleyNixonprovidedthroughoutthis
journey.Whetherkillingmewithkindnessorjustgivingmespacetowallowinmy
owndespair,sheisalwaystherenourishingmyheart,soulandstomach.Hercopy‐
editinginthefinalpushtogetthisdissertationinshapeandofftomycommittee
wasinvaluable,Iloveyousomuch.
xv
Dedication
Iwouldliketodedicatethisdissertationtothreepeoplewhoinspiredand
encouragedmetopursuethestudyofmedicalandhealthgeography.Theyinclude,
Dr.DeniseCloutier,Dr.PatrickMcLeodandthelateDr.HarryFoster.Iwashiredby
Deniseasaco‐opstudentinthesummerof2002toworkforPatrick,amedical
geneticistwithakeeninterestindiseasemapping,intheMedicalGeneticsClinicat
VictoriaGeneralHospital.Patrick’spluckyenthusiasmandabilitytocommunicate
complexdiseasemechanismsandDenise’scompassionateandfeministteachingsof
thesocialdeterminantsofhealthgotmehookedonmedicalsciencesand
epidemiology.Iwouldcontinuetoworkandvolunteerpart‐timeforPatrickforthe
nexttwoyears,enrollinginthegeographyhonoursprogramwithhimandDeniseas
myco‐supervisors.Itwasduringthistransitiontohealthgeographyandenrollment
intothehonourprogramthatIwasintroducedtoDr.Foster.Hispassionforthe
underlyingenvironmentalcausationsofvariousdiseases,mostnotablyselenium
andothermicronutrientdeficiencies,sparkedmyinteresttheenvironmentallinks
tohealthanddisease.Coincidently,itwaswhileworkingforPatrickthatImetmy
currentsupervisorDr.LauraArbourwhomanyyearslaterintroducedmetoDr.
LaurieChanwhichbroughtmebackintoacademeformyMastersatUNBCand
initiatedthiswholejourney.Everythinggoesfull‐circle,andsothisiswhyIdedicate
thisworkofstudytothosethreeindividuals.
Chapter1:TheSharedPathoetiologicalEffectsofParticulateAirPollutionandtheSocialEnvironmentonFetal‐Placental
DevelopmentEricksonA.C.,ArbourL.Thesharedpathoetiologicaleffectsofparticulateairpollutionandthesocialenvironmentonfetal‐placentaldevelopment.JournalofEnvironmentalandPublicHealth.2014.Published.
AbstractExposuretoparticulateairpollutionandsocioeconomicriskfactorsareshowntobe
independentlyassociatedwithadversepregnancyoutcomes;however,theirconfounding
relationshipisanepidemiologicalchallengethatrequiresunderstandingoftheirshared
etiologicpathwaysaffectingfetal‐placentaldevelopment.Thepurposeofthispaperisto
exploretheetiologicalmechanismsassociatedwithexposuretoparticulateairpollutionin
contributingtoadversepregnancyoutcomesandhowthesemechanismsintersectwith
thoserelatedtosocioeconomicstatus.Herewereviewtheroleofoxidativestress,
inflammationandendocrinemodificationinthepathoeitologyofdeficientdeep
placentationanddetailhowthephysicalandsocialenvironmentscanactaloneand
collectivelytomediatetheestablishedpathologylinkedtoaspectrumofadversepregnancy
outcomes.Wereviewtheexperimentalandepidemiologicalliteratureshowingthat
diet/nutrition,smokingandpsychosocialstresssharesimilarpathwayswiththatof
particulateairpollutionexposuretopotentiallyexasperatethenegativeeffectsofeither
insultalone.Therefore,socially‐patternedriskfactorsoftentreatedasnuisanceparameters
shouldbeexploredaspotentialeffectmodifiersthatmayoperateatmultiplelevelsofsocial
geography.Thedegreetowhichdeleteriousexposurescanbeamelioratedorexacerbated
viacommunity‐levelsocialandenvironmentalcharacteristicsneedsfurtherexploration.
1.0IntroductionOverthelastdecade,chronicexposuretoambientairpollutionhasbecome
increasinglyrecognizedasanimportantriskfactorunderlyingadversepregnancyoutcomes
(APOs)[1–9].Inparallel,theassociationsbetweensocio‐economicstatus(SES)andAPOs
areamongthemostrobustfindingsinperinatalresearch[10–12],whichpersistevenin
settingswithuniversalaccesstohealthcare[13–16].Whileinterestintheintersection
betweenhealthandthesocialenvironmentislongstanding[17–19],renewedattentionhas
beenpropelledbytwoindependentprogressionsinquantitativeresearch.Thefirstisthe
popularizationofmultilevelstatisticalmodelsandtheabilitytoseparatetheindividual‐
leveleffectsfromthoseoftheirencompassingsocialandphysicalenvironments[20–26].
2
Thesecondistheemergingresearchonthebiologicaleffectsofpsychosocialstresson
healthanditsmodificationbyenvironmentalfactors.Thereisnowmountingevidencethat
stresscaninteractwithchemicalexposurestoexacerbatethetoxiceffectandthe
physiologicalresponsetoagreaterextentthaneitherinsult(stressorchemical)acting
alone[27–31].Furthermore,theaccumulationoflow‐levelexposurestomultiplechemicals
viamultiplesourcesandpathwaysshowevidenceofdoseadditionandsynergism[32–34].
Forexample,synergismwasobservedbetweenaqueouscigarettetarandotherrespirable
particles(e.g.asbestosfibers,particulatematter,dieselexhaust)[35].Recognitionofthese
interactionshavebeenincorporatedintoseveralconceptualmodelsandstudydesignsof
cumulativeriskofchemicalandnon‐chemicalexposures[36–39]withmodelsrecently
developedtoidentifythesepotentiallydouble‐exposedpopulations[40,41].Two
complimentaryreviewsofthesemodelshavebeenrecentlypublished[42,43].
AlthoughthecausesofAPOsaremultifactorial,theplacentaplaysthemain
intermediaryrolebetweenthemother’sphysicalandsocialenvironmentandthefetus,[44–
50].Importantly,aperturbedintrauterineenvironmentinhibitingthefetalgrowth
trajectorymayalsohavelong‐termadulthealthimplicationsassuggestedbythe
developmentaloriginsofdiseasehypothesis[51–53].Thereforeeffortstounderstandthe
underlyingmechanismsofthephysicalandsocialenvironmentthatcontributetothe
disproportionateriskofAPOsacrossthesocio‐economicspectrumisrequiredinorderto
targetpreventativeandrestorativeinterventions.Thisreviewwillexaminehowtheshared
pathoetiologicaleffectsofexposuretoparticulateairpollutionandSESactonthefetal‐
placentalunitleadingtoadversepregnancyoutcomes.Thiswillbeaccomplishedby
buildingonconceptualpathwaymodelsofairpollutionandSESetiologicmechanismson
APOs[54,55].Wereviewtheroleoftheplacentainthiscontext,describingitsphysiology
andobstetricalpathologiesfollowedbyadescriptionofparticulateairpollution,andits
toxicokineticsinrelationtoplacentationandhowitcanleadtoAPOs.Wehighlightspecific
indicatorsofSESandtheirbiologicalpathwaysthatintersectwithairpollutionexposure
andhowthismaycontributetoincreasedsusceptibilityforAPOs.Potentialimplicationsand
interventionsaresummarizedintheconclusion.Ouraimisforthisreviewtobearesource
forresearchersinterestedinenvironmental‐perinatalepidemiology.Understandinghow
correlatedsocialandenvironmentalexposuresattimesoverlaptoproducepotential
synergisticandmodifiableeffectswillhelpguidefutureresearchandintervention
strategieswiththeaimtoimprovetheoverallhealthofthepopulation[36–40].
3
2.0Person,PlaceandContext:ThePlacental,PhysicalandSocialEnvironments
2.1ThePlacenta
Themammalianplacentaismultifunctionalandvitaltofetaldevelopment.Formed
fromtwogeneticallydistinctorganisms,itismultifunctionalandvitaltofetaldevelopment
yetsituatedoutsidethefetalbodywithalimitedlifespan.Notablecharacteristicsuniqueto
humansandtheGreatApesincludedeepinterstitialimplantationandahighlyinvasive
hemochorialphenotypethusallowingthedirectinteractionofmaternalbloodandfetal
chorionictissues[56].Interestingly,thisparticularaspectofplacentalevolutionhaslessto
dowithnutrienttransferefficiencythanpreviouslythoughtandmorelikelyimplicatesthe
highlyregulatedmaternal‐fetalimmunologicalrelationship[57–59].
Thefirsttrimesterisacriticalperiodinpregnancyinvolvingimplantationandinitial
placentation,twoeventshighlysusceptibletodisturbance(seeendnote1).The“Great
ObstetricalSyndromes”[60]suchasearly/recurrentmiscarriage,pregnancyinduced
hypertensionandpreeclampsia(PIH/PE),fetalgrowthrestriction(FGR),placental
abruption,pre‐labourruptureofthefetalmembranes(PROM)andspontaneouspreterm
labourmaysharecommonetiologicalmechanismsarisingfromdefectivedeepplacentation
(DDP)[61,62].Together,theseconditionsmaycomplicatebetween17to29%ofall
pregnancies[63],andareforthepurposeofthisreviewreferredtocollectivelyasAPOs.
Furthermore,theseconditionsmayleadtoepigeneticprogrammingofadultdisease
susceptibilityincludingobesity,diabetes,cardiovascularandreproductivediseases,allwith
theirownsubstantialsocietalcosts[52,64–66].DDPreferstotheshallowinvasionofthe
placentalbedintothematernaldeciduaandmyometriumincludingincompleteremodeling
oftheuterinespiralarteries[62,67].Thelatterisavitaleventduringwhichundernormal
conditionstheendothelialliningofthespiralarterywallsareremodeledtoaccommodate
theinundationofmaternalbloodflowstartinginthesecondtrimester[68].Spiralarteries
thatfailtoundergothisvascularremodelingarenotonlynarrowerindiameter,butalso
remainexcessivelyresponsivetovasoconstrictivecompoundssuchasstresshormones(see
endnote2).Theetiologicaltrigger(s)leadingtoDDParethoughttoinvolveeitherearly
placentaloxidativestresswhichtriggersaninflammatoryresponse,orvise‐versa,an
atypicalinflammatorymaternalimmuneresponsetothefetal‐placentalunitleadingto
placentaloxidativestressandfurtherinflammation[69,70].Thedifferencebetweena
normalandanaffectedpregnancyisamatterofdegreesonacontinuumwithindividual
4
biologicalandbehaviouralvariabilitynestedwithinthesocialandphysicalenvironment
[12,24–26,68,69,71–73].
2.2ThePhysicalEnvironment:ParticulateAirPollution
Airpollutionisageneraltermusedtodescribethepresenceofagents(particulates,
biologicals,chemicals)inoutdoororindoorairthatnegativelyimpacthumanhealth.
SeveralcommonairpollutantshavebeenassociatedwithAPOs,includingcarbonmonoxide
(CO),nitrogendioxide(NO2),sulfurdioxide(SO2),ozone,particulatematter(PM)and
polycyclicaromatichydrocarbons(PAHs)[1];however,attentionhasfocusedonthelatter
twocompoundsshowingstrongmolecularevidenceofcytotoxicity,mutagenicity,DNA
damage,oxidativestressandinflammation[55,74–79].WhiletheobservedrisksofAPOsin
relationtoairpollutiontendtobemodest,thepopulationattributableriskcanbequite
largeduetothepervasivenessofexposuretothegeneralpopulation[9].Significantrisks
havebeenobservedeveninsettingswithrelativelylowambientairpollutionexposure
[80,81].Therefore,asmallincreaseinriskcanhavealargepublichealthimpact.PTBand
FGRaremajorriskfactorsofperinatalmortalityandseriousinfantmorbiditiescontributing
toincreasedhealthcareandsocietalcosts[82–87].
Particulatematter(PM)isacomplexmixtureofvaryingchemicalandphysical
properties.Itisdefinedaccordingtoparticlesizeintotheinhalablecoarsefraction(PM10,
2.5‐10μm),thefinerespirablefraction(PM2.5,≤2.5μm)andtheultrafinefraction(UFP,≤
0.1μm).Theirubiquityandrecognizedhumanhealthriskshavedeemedthemastoxic
[88,89].CharacterizingPMbyparticlesizeisimportantforseveralreasons.First,particle
sizedictatesthelocationofdepositionintherespiratorysystem[88,90].Second,particle
sizecangivesomeindicationofitsgeneralsourceandbehaviour.Forexample,PM10is
mainlyderivedfrommechanicalprocessessuchaswindblownsoil,pollen,mineralsand
dustfromroads,farmsandindustrialoperations.PM10tendstogravitationallysettlesina
matterofhourstodays.Conversely,PM2.5isaprimaryby‐productofcombustionand
atmosphericreactionswithprecursorgasessuchasSO2,nitrogenoxides,ammoniaand
volatileorganiccompounds(VOCs).PM2.5canremainsuspendedinairfordaystoweeks,
andareconsequentlymorepronetolong‐rangetransport.Precipitationaccountsfor80‐
90%ofPM2.5removalfromtheatmosphere[88].Third,thechemicalcompositionis
markedlydifferentbetweenPM10andPM2.5mixtures.DerivedmainlyfromtheEarth’scrust,
PM10typicallycontainsoxidesofiron,calcium,silicon,andaluminum;whereasPM2.5
mixturesderivedfromanthropogeniccombustionsourcesaremainlycomposedof
5
sulphates,nitrates,ammonium,tracemetals,elementalcarbonandorganichydrocarbons
(e.g.PAHs)[88].ChemicaldifferencesandrelativeproportionsalsodifferwithinthePM10
andPM2.5mixtureswithregional(urban‐to‐rural)andinter‐urban(urban‐to‐urban)
differencesaswellasintra‐urbanspatialvariation[88,91–93].Thereforetrimesterand
demographicdifferencesinresidentialmobilityandintra‐urbanpopulationdifferencesare
importantstudydesignissuestoconsider[94,95].Finally,PM10,PM2.5andUFPsdifferby
theirtoxicologicalmechanisms,suchastheiroxidativepotential,whichmayreflecttheir
differencesinsize,surfaceareaand/ortheirchemicalconstituentcompositions,although
theytendtobecorrelated[76,92,96,97].Transitionmetalssuchascopper,nickel,lead,
chromium,iron,vanadiumandcobaltamongothermetalsarevariablypresentinambient
airabsorbedtoPM2.5[92,93].Theirdirectoxidativeactionorredoxpotentialtocreate
reactiveoxidativespecies(ROS)isonepossiblemechanismastohowPMinducesoxidative
DNAandproteindamage[78,97].
ThereisaccumulatingevidencethatsuggestsUFPsmaybethefractionofPM
responsibleformanyoftheadversehealtheffectsreportedinairpollutionstudies
[78,79,97,98].UFPsareasmallproportionbymassbutmakeupalargeproportionin
particlenumberandhavegoneeitherunmeasuredormisclassifiedasPM2.5[88,98].Their
smallsizefacilitatesbettertissuepenetrationdeepintolungalveoliandintoepithelialcells
restrictingtheirclearanceviamacrophagephagocytosis[98].Animalstudieshaveshown
thatUFPscantranslocateacrossthelungepitheliumintobloodcirculationandaccumulate
inotherorgans,includingtheliver,spleen,kidneys,heart,brainandreproductiveorgans
[98].ThehighsurfaceareaofUFPsfavourstheabsorptionofPAHsandpossiblytransition
metalswhichhasshowntolocalizeinthemitochondriainducingmajorstructuraldamage.
ThiscouldbeapossibleexplanationtoUFP’sexhibitedhigheroxidativepotentialcompared
tolargerPMfractionsofthesamematerial[79].Recentattentionhasbeengiventopro‐
inflammatoryandendocrine‐disruptingpropertiesofdieselemissions,amajorsourceof
UFPsinambientair[31,99–101].
Polycyclicaromatichydrocarbons(PAHs)areorganicsubstancesthatconstitutea
classofover100individualchemicalcompoundsmadeupofcarbonandhydrogenatoms
formedintorings[102].WhiletoxicologicaldataexistforindividualPAHs(benzo[a]pyrene
beingthemostcommonlyusedPAHindicator),theyalmostalwaysoccurascomplex
mixtures(e.g.soot,tobaccosmoke,creosote,dieselexhaust)[103].Thusitisdifficult,and
arguablyfutile,toassessthetoxicityofindividualPAHcomponentsonlytobecompounded
6
bythelikelihoodofinteractions[75,104,105].Combustionoforganicmatterandfossilfuels
arethemainsourceofatmosphericPAHswiththeirdistributionandmagnitude
concentratedalongtransportationcorridors(roadandrail)andland‐useareaswithheavy
industrialactivities.However,mainstreamandenvironmentaltobaccosmoke(ETS)remain
aleadingsourceofPAHexposure[106].PAHsaregenerallynon‐volatile(i.e.stable)and
havelowwatersolubility.Asaconsequence,PAHsoftenbindtoPM2.5andUFPinthe
atmosphere.Residencytimesintheatmospheredependonweatherconditions,PAH
molecularweightandtheemissionsource(e.g.stackvs.tailpipe)withatmospheric
depositionasthemainsourceofPAHstosoil,vegetationandsurfacewater.Onceinaquatic
systems,PAHsareoftenfoundabsorbedtosuspendedparticlesorboundtosediments
settledonthebottomwheretheypersistorareslowlybiodegradedbymicroorganisms.
WhilePAHscanbioaccumulateinsomeaquaticandterrestrialorganisms,theytendtonot
biomagnifyinfoodsystemsduetotheirmetabolisminhigherorderspecies[102,106].
However,itistheinefficientclearanceandactionofthehighlyreactivePAHmetabolites
thataresuspectedtocausecytotoxicity,mutagenicity,DNAdamage,oxidativestressand
tumourgenesis[75,106].
MuchoftheworkelucidatingthemechanismsinwhichPMandPAHselicitadverse
cellulareffectshavebeenconductedusingcardiovasculardisease(CVD)andlungcanceras
models[76–78,97,107–109].AlthoughseeminglydifferentdiseasesfromAPOs,thereare
severalsimilaritiesbetweenthem.First,bothAPOsandCVDrelatedoutcomesare
associatedwithPMexposurelevelswhichvarybySES[40,110,111],butarealsoassociated
withothersociallypatternedriskfactorssuchassmoking,poororinadequatediet,
psychosocialstress,obesityanddiabetes[12,112–114].CVDandAPOsalsosharemany
otherriskfactorssuchasthepresenceofsystemicinflammationandpre‐existing
hypertension.Interestingly,PIH/PEisariskfactorformaternalCVDlaterinlifeandalsoin
theoffspringifaffectedbyIUGR[115–117].CVDanddisordersofDDPhavesimilarly
affectedcellulartissuesintheirrespectivetargetsystems(i.e.endothelialcellsofthe
cardiovascularsystemandinthehighlyvascularisedplacenta)whichareparticularly
susceptibletooxidativeandinflammatoryinjury[97,118].Highplasmahomocysteine
concentrationsarepositivelyassociatedwithvasculopathyandinfarctionintheplacental‐
uterineandcoronarysystemsincreasingtheriskofspontaneousPTBandCVDevents
respectively[119,120].Fittingly,highdensitylipoproteincholesterolmaybeprotective
againstspontaneousPTBandCVDevents[120,121].Finally,PMandPAH‐induced
7
mutagenicity,cytotoxicity,DNAdamageandoxidativestresslinkedtolungcancerhavealso
beenobservedinthefetal‐placentalunit[122,123],andexposureearlyinpregnancymay
contributetotheriskofcongenitalanomaliesandearly(sub‐clinical)pregnancyloss[124–
127].
2.3TheSocialEnvironment:Socio‐economicStatus,Diet,Smoking&AllostaticLoad
Thesocialenvironmentplaysasignificantroleinmaternalandperinatalhealthwith
indicatorsoflowsocio‐economicstatus(SES)consistentlyamongthestrongestpredictors
ofadversepregnancyoutcomes[10–12].ThecausalpathwaysinwhichSEScontributesto
APOsandillhealthingeneralcanbeconceptualizedintermsof‘downstream’ormediating
exposures,stressesandbehavioursactingontheindividualthrough‘upstream’society‐
leveldeterminantssuchaspoverty,pooreducation,incomeinequalityandsocial
discrimination/marginalizationoverthelifespan[12].IndicatorsoflowSESassociatedwith
PTBandFGRincludematernalanthropometry(pre‐pregnancyBMI,height,gestational
weightgain),nutritionandmicronutrientstatus,cigaretteuse,genitaltractinfectionsand
inflammation,cocaineandotherdruguse,physicallydemandingwork,quantityandquality
ofprenatalcare,andpsychosocialfactorsincludinganxiety,depressionandstress(e.g.lack
ofsocial,familial,andmaritalsupport,povertyorfinancialhardship,physical/verbalabuse,
neighbourhoodcrime)[12,24,26,54].Forthepurposeofthisreview,thefocusherewillbe
onthreethatengagewiththeoxidativestressandinflammationpathwaystopotentially
interactwithexposuretoparticulateairpollution.Theyinclude:1)adiet‐micronutrient
pathway[55,128–131],2)cigarettesmokeexposure[35,132–135],and3)allostatic
activationoftheHPA‐axisandcorrespondingglucocorticoidproduction[47,72,136–138].
Nutritionanddietcaninfluenceperinatalhealthinopposingdirections.Poor/under‐
nutritionsuchashighfat/caloriedensefoodandlowmicronutrientintakeismore
prevalentamongwomenfromlowSESbackgroundswhichmaypartlyexplainhigherrates
ofsomeAPOs[12,139–142].Conversely,adequatedietandmicronutrientstatusprovides
resilienceagainstoxidativestressandinflammationcausedbyvariousexposuresincluding
airpollution,allostaticstress,infectionorsmoking[55,118,128,129,131,143].Maternal
exposuretomainstreamorenvironmentalcigarettesmokeduringpregnancyisassociated
withnumerousAPOsincludingcongenitalanomalies[127,144–146].Theirexposure
prevalenceisassociatedwithindicatorsoflowSESaswellasothersocially‐patternedrisk
factors[147–149],andremainsoneofthemostmodifiableriskfactorswithpotentialfor
beneficialintervention.OtherriskfactorsassociatedwithlowSESsuchasobesity,
8
(gestational)diabetesandhypertension[13,113,150]alsoengagetheoxidativestressand
inflammatorypathwaysandcouldthereforealsopotentiallyinteractwithPMexposureto
increasesusceptibilitytoadverseeffectsasevidencedinstudiesofcardiovascularhealth
[114,151,152].Recentstudieshaveobservedincreasedrisksofpreeclampsiaand
gestationaldiabetesassociatedwithmeasuresofairpollution[153–156]withonestudy
showingpositiveeffectmodificationbypre‐existingandgestationaldiabetes[154].
EvidenceshowsthatchroniclifestressorsassociatedwithlowSESatmultiplelevelsof
organization(individual,household,community)resultinacumulativebiologicaltollonthe
bodyaffectingmultiplesystemsandincreasingsusceptibilitytonumerousailments
[21,157–160]includingAPOs[15,26,161,162].
Theconceptofallostasisandallostaticload/overloadhasbeenproposedtodescribe
theindividualstressresponsetoaneventasanecessaryandadaptiveprocessthereby
removingtheimplicitnegativeconnotationattachedtotheterm‘stress’[163].Stresscanbe
positiveortolerablewhenitimprovesfunctionandperformanceandmayhavelong‐term
adaptivebenefits.However,thismaydependonavailablecopingresourcessuchasone’s
psychologicalresistance,resilienceandabilitytorecover.Negativeortoxicstressoccurs
whenrealorperceivedenvironmental/socialdemands,ortheanticipationofsuch,become
tooextremeorunpredictabletherebyexceedingone’s(perceived)abilitytocope(e.g.no
senseofcontrol,adversechildhoodexperiencesandotherformsoftrauma)[164,165].
Therefore,allostasisisthemultisystembiologicalresponsethatpromotesadaptationusing
systemmediatorssuchascortisol,(nor)epinephrine,vasopressin,renin,andglucagon
[165,166].Whereasallostaticloadandoverloadisthecumulativetoll(wearandtear)on
biologicalsystemsafterprolongedorpoorlyregulated(hyper/hypoactivated)allostatic
responses.Forexample,thecardiovascularsystemisextremelysensitivetostressinterms
ofincreasedbloodpressure;however,metabolicdisorderssuchasdiabetesandobesityas
wellasimmunefunctionimpairmentarealsolinkedtochronicstress.Furthermore,lifestyle
copingmechanismsasaresponsetochronicstresshavetheabilitytoeitherbufferor
exasperatetheeffect(e.g.exercise,diet,sleep,socialinteractionsorlackthereof)[163].
Thereforeinlightoftheabove,itisourbeliefthatthefetal‐placentalunitisthesitewhere
thephysicalandsocialenvironmentsconvergeandinteracttoinfluencereproductivehealth
whichwedescribefurtherbelow.
Figure1illustratestheinter‐connectednessbetweenparticulateairpollution
(PM/PAH)andSESonhowtheymayactdiscretelyorinacombinedmannertoyieldAPOs.
9
UsingFigure1asaguide,thefollowingtextwillreviewthetwomajormechanisms
(oxidativestressandinflammation)throughwhichthephysicalandsocialenvironments
arebelievedtonegativelyaffectthefetal‐placentalunitandhowtheymaycombine/interact
toleadtothemultifactorialnatureofAPOs.
Figure1:Aconceptualframeworkofthesharedmechanismsofsocio‐economicdeterminantsandparticulateairpollutionexposurecontributingtoadversepregnancyoutcomesThephysicalenvironment(orange)consistingofparticulateairpollutionandthesocialenvironment(green)consistingofcommunityandindividual‐levelsocialfactors/stressorsconvergetoaffectthefetal‐placentalenvironment(blue)viaoxidativestressandinflammatorymechanismspotentiallyleadingtoadversepregnancyoutcomes.
3.0BiologicalMechanismsLeadingtoAdversePregnancyOutcomes
3.1OxidativeStress
Aptlyknownas“TheOxygenParadox”,oxygenisbothessentialandtoxictothe
multicellularaerobicorganismswhoseveryevolutionwasdependentonleveragingthis
anaerobicwasteby‐productintoahigherenergyproducingadvantage[167].Observedin
allmammals,asteepoxygentensiongradientfrom20%inouratmosphereto3‐4%oxygen
concentrationinmostinternaltissuesistheprimarydefenseagainstoxidativedamage.
Secondaryandtertiarylayersofprotectionincludeantioxidantdefensesaswellasdamage
removal,repairandapoptoticresponsesystems[168,169].Thesegeneticallyadaptive
responsesareupregulatedinthepresenceofreactiveoxygenspecies(ROS)generatedas
naturalby‐productsofcellularaerobicmetabolismandexposuretovarioustoxins.
Oxidativestressoccurswhenthereisanimbalancebetweenpro‐andantioxidantcapacity.
Forexample,superoxideisthemostcommonintracellularROSinmammals.Itis
producedbythemitochondriaasametabolicby‐productbutalsofromthemetabolismof
10
variousgrowthfactors,drugsandtoxinsbyoxidizingenzymessuchasNADPH‐oxidaseand
cytochromeP450(CYP450).Superoxideisreducedbysuperoxidedismutase(SOD)into
hydrogenperoxide(H2O2)whichisthenfurtherreducedintowaterbyglutathione
peroxidase(GPx)andcatalase.UndernormalphysiologicalconditionsH2O2actsas
intracellularsecondarymessengers;however,it’saccumulationalongwithsuperoxidecan
reactwithfreeironionsornitricoxidetoformhighlytoxichydroxyl(OH∙)orperoxynitrite
(ONOO‐)ionsrespectively[70,168].FreeironisacommonmetalfoundabsorbedtoPM,and
theantioxidanthemeoxygenase‐1(HO‐1)facilitatesitsconjugationandremovalthrough
theincreasedavailabilityofferritintherebypreventingtheformationofreactivehydroxyl
molecules[92,170–172].DeficienciesinHO‐1havebeenassociatedwithseveralAPOssuch
asrecurrentmiscarriage,FGRandpreeclampsia[171,172].
Commonantioxidantsincludeenzymatic(e.g.SOD,GPx,catalase,HO‐1)andnon‐
enzymaticcompounds(e.g.vitaminCandE,glutathione,β‐carotene,ubiquinone)[118].
Geneticpolymorphismsand/ormicronutrientdeficienciesinantioxidantenzymes
precursorscanimpairantioxidantcapacity,whilechronicexposuretotoxicants,
psychosocialstress,bacteria,virusesandotherinducersofinflammationcanfosterpro‐
oxidantburden[70,77,118,172].Oxidativestressisunavoidable;however,underoptimal
conditionsthepresenceofROSleadstohomeostaticadaptationandaresafelyremoved.
Failuretoeffectivelymanageoxidativestresscanresultinalteredcellularfunctionas
excessROSdegradelipids,proteinsandDNApotentiallyinitiatingpathologicalprocesses.
Referto[168]foranextensivereviewontheroleofcellularROSinpregnancyoutcomes.
3.2InflammationandImmunologicAlterations
Itiswellrecognizedthatthematernalimmunesystemplaysacentralrolethroughout
theentirepregnancy,frompre‐implantationtoparturition,andisinfluencedbythe
inflammatoryresponseofthemothertoherenvironmentaswellastoherpartner(see
endnote3).Alternativetopreviouslyhypothesized[173],thematernalimmunesystemis
notpassiveorsuppressedduringimplantationanddevelopmentofthesemi‐allogeneic
placentaandfetus.Rather,itexertsexecutiveinfluenceontheestablishmentand
progressionofthepregnancyasanimmune‐mediatedqualitycontrolmechanismto
maximizematernalandoffspringhealth[44,173].Thisisachievedbyfavouringpro‐oranti‐
inflammatoryenvironmentsatdifferenttimesduringpregnancyfordifferentpurposes.For
instance,implantation,initialplacentationandparturitionarecharacterizedbyapro‐
inflammatoryenvironmentwhereasananti‐inflammatorystateprevailsformostofmid‐
11
gestation[174].Thefavouredlocalizedimmunologicalresponsehoweverishighlymodified
bytheinfectious,inflammatory,stress,nutritionalandmetabolicstatusoftheindividual
andthuscanbeinfluencedbyenvironmentalagentssuchasPM[175–177]and/oravailable
coping,socialandnutritionalresources[44,128,164,178].Therefore,inflammationis
believedtobeonepathwayinvolvedinbothPMandSES‐mediatedAPOs.
Chronicandacuteinflammationisacomplexresponseprocessmediatedbyarealor
perceivedattackfromforeignsubstances.Theinnateimmuneresponseistherapid
automaticresponsetoexternallyoriginating(exogenous)substancessuchaspathogens,but
alsofrominternal(endogenous)dangersignalsincludingproductsoftrauma,ischemia,
necrosisoroxidativestress[179].Theresponseincludesthereleaseofpro‐inflammatory
signalingcytokineproteinssuchasinterleukinsIL‐1β,IL‐6andtumournecrosisfactor
(TNF‐α)whichservetorecruitneutrophilstoaffectedtissues.However,therecruited
neutrophilsreleaseROSandhydrolyticpro‐inflammatoryenzymes(induciblenitricoxide
synthase(iNOS),cyclooxygenase(COX‐2)andprostaglandins(PG‐E2))whichdisturb
normalcellsinadditiontoaffectedtissueswhichinturnleadstoincreasedROSand
oxidativestress[180,181].Theplacentaisamulti‐functionalorgananditsroleatthe
maternal‐fetalinterfaceasthemainproducerofendocrinesteroidandproteinhormonesas
wellastheimmunologicbarrierbetweenmotherandfetuspositivelyinteractforthe
successofthepregnancy[44,173].Thisisachievedthroughanon‐linearseriesofpositive
andnegativefeedbackpathwayswiththestimulationorsuppressionofmoleculeswithpro‐
andanti‐immunosuppressantproperties(interleukins,galectins,placentalgrowthfactor,
andhumanchorionicgonadotropin(hCG))[182–184].Theproductionofthesecytokines,
chemokinesandotherimmune‐regulatoryagentsmediatethecoordination,migrationand
functionofseveralmaternalimmunecells(e.g.uterinenaturalkillercells(uNK))that
participateinearlypregnancyeventssuchasendometrialreceptivityofembryo
implantation,tissueremodeling,immunetoleranceandvascularadaptationtoinvading
placentaltrophoblastcells[44,182–184].Interferenceoraberrantproduction/secretionof
thesesubstancesbyvariousstressorsincludinginfection,toxinsandthoseactingthrough
theHPA‐axismayresultintheimpairedmaternalimmuneresponseleadingtothehallmark
DDPsyndromecomplicationsdescribedabove(earlypregnancyloss,PIH/PE,PROM,FGR,
prematurelabour,Figure2)[44,61,69,134,175,185–187].
12
3.3.MechanismsofOxidativeStressandInflammationInvolvedinAdversePerinatalOutcomes
3.3.1Impairedfertilityand(recurrent)miscarriage
Duetoimmortaltimebias,miscarriageisnoteasilymeasuredinpopulationorcohort
studieswithoutcarefuldesignmethodologies[188,189];however,associationsbetween
infertilityandairpollutionhavebeenmade[190,191].Oxidativestresshasshowntohavea
directeffectonfertilityandembryodevelopment.Forexample,obesemiceshowed
increasedROSsynthesisandoxidationinoocyteswithareducedabilityofzygotesto
developtotheblastocyststageprovidingevidencethatimpairedcellularantioxidant
capacitycanlimitsuccessfulovulationandfertilization[118].Dividingmitoticcellsare
particularlysensitivetooxidativedamageandareshowntoenteratransientgrowth‐
arrestedstateasaprotectivemechanismuntilthestresshaspassed.Thus,severeor
chronicoxidativestressmayhampercelldivisionorcausecellularnecrosisreducingor
terminatingembryoviability[72,169].Alternatively,anexaggeratedinflammatorystatevia
aviral,toxicand/orallostaticloadcouldleadtomaternalimmunemaladaptationto
Figure2:ProposedpathwayscontributingtoadversepregnancyoutcomesTheco‐presenceofmaternalandpaternalbiologicalfactorscanresultinprotectionorincreasedsusceptibilitytotheinteractionwiththephysicalandsocialenvironments.Cumulativenegativeexposuresearlyinpregnancyresultinginexcessoxidativestressandinflammationmaycauseacascadeofeventsleadingtodefectivedeepplacentation.Dependingonthedegreeofseverity,thereducedtransplacentalperfusioncanresultinvariouspathologiesassociatedwitharangeofobstetriccomplicationsandoutcomes[60,61,69,70].
13
conceptionleadingtorestrictedtrophoblaststemcellaccumulationintheearlyperi‐
implantationembryoresponsiblefortheproductionofhormonesthatenablessuccessful
implantation(Figure2)[44,72].
Oxidativestressisimplicatedinfirsttrimestermiscarriagefromprematureplacental
perfusionofmaternaloxygenatedbloodandaccompanyingROSintotheearlyembryonic
environment[192].Earlyembryodevelopmentoccursinalowoxygenstate,anditisnot
untilthetenthtotwelfthweekofgestationthatmaternalbloodbeginstograduallyinfiltrate
theintervilliousspaceoftheyetfullydevelopedplacenta.Thelimitedoxygenenvironment
isthoughttoactasaprotectivemechanismagainstthedeleteriousandteratogeniceffects
ofROSonearlystemcellsatatimeofextensivecelldivision[64,138].Thisearlyhypoxic
environmentalsoplaysavitalphysiologicalroleinplacentalcelltypedifferentiation
switchingfromproliferativevillouscytotrophoblastsintoinvasiveextravillioustrophoblast
(EVT)importantinspiralarteryremodeling[193].Attheendofthefirsttrimester,oxygen
tensionrisessharplywhichcoincideswiththeinfusionofoxygenatedmaternalbloodinto
theplacentaandtriggersanapoptoticcascadethatservestoestablishthedefinitivediscoid
placenta.However,in70%ofearlymiscarriagecasesEVTinvasionisinsufficientallowing
fortheprematureonsetofmaternalintraplacentalcirculationanditsconsequentialburstof
ROSontheconceptus[70,192].Severecasesmayresultinpregnancyfailurewhilemore
modestcasesmayinitiatefetal‐maternaladaptiontoimpairedspiralarteryremodeling
leadingtothepathologyforfurthercomplicationslaterinpregnancysuchasPIH/PE
(Figure2)[69,70,193].
3.3.2Pregnancyinducedhypertension,preeclampsia,andprelabourruptureofmembranes
Whileoxidativestressandinflammationareconditionsofnormalpregnancy,theyare
consistentlyelevatedincasesofPIH/PEandbotharecentralinitspathology.PIH/PEstems
fromadefectinearlytrophoblastinvasioninsufficienttofullyconvertthespiralarteries
intolow‐resistancechannels[68,194].Theretentionofsmoothmusclecellsremainsactive
tocirculatingvasoconstrictingagentssuchasstresshormones(e.g.glucocorticoids)and
otherstimulants.Thediminished,butmoreimportantly,theintermittentperfusionof
maternalbloodintotheintravilliousspaceproducestransienthypoxiaresultinginachronic
ischaemia‐reperfusion(I/R)typeinjury.ThisfurtherprovokesROSsynthesisandexcess
sheddingofplacentalmicrovesicleswhichhavepro‐inflammatory,anti‐angiogenicand
procoagulantactivityinitiatingendothelialdysfunction[68–70].Elevatedcirculatinglevels
ofplacentaldebrisandROSbiomarkersintheplacentaltissuesofpreeclampticwomenare
14
welldocumented[68,179,194].Similarly,PROMcanbeconsideredpartoftheDDP
syndromebutmayrepresentaphenotyperesultingfromalesssevereDDP
pathophysiologycomparedtopreeclampsia[61,62].Excessoxidativestressarisingfrom
multiplecauses(infection,inflammation,smoking,cocaineuse)havebeenimplicatedin
PROMinadditiontoitsroleinDDP[70].BothPIH/PEandPROMareleadingcausesof
pretermbirthwhilePIH/PEisamajorriskfactorforFGR(Figure2)[69].Deficienciesin
HO‐1havebeenassociatedwithvariousAPOssuchasrecurrentmiscarriage,FGRand
preeclampsiaaswellasmorphologicalchangesintheplacentaandelevationsinmaternal
bloodpressure.ThebioactivemetabolitesofHO‐1,COandbilirubin,mayprotectagainst
preeclampsiathroughtheirvasodilatorypropertiesandthesuppressionoftheanti‐
angiogenicfactorsFltrespectively[171,172].
3.3.3Fetalgrowthrestriction
FGRhasmanycauses,howeveroftenarisesfromplacentalinsufficiencydueto
compromisedsupplyofoxygenandnutrientstothefetuswhichmayhavebothshortand
long‐termhealthconsequencesontheoffspring[51,82,195].FGRisstronglyassociatedwith
earlyonsetormoreseverecasesofpreeclampsia,andthereisaclearetiologicallink
betweenIUGRandDDPasitinvolvesabnormalplacentationandreduceduteroplacental
bloodflow(Figure2)[62,70].Alternatively,perturbedcalciumhomeostasiscaninduce
chroniclow‐levelstresswithintheendoplasmicreticulumleadingtosuppressedprotein
synthesisandareducedgrowthtrajectoryoftheplacenta[70].Cadmium,anenvironmental
toxinandhighlypresentincigarettesmoke,isamajorantagonistofcellularcalcium
activities(transport,uptake,binding),aswellasthetransferofothernutrientsandzinc
homeostasiswithintheplacenta[134,185,196].Furthermore,cadmiumisaknown
endocrinedisruptorshowntoimpairhormonesynthesisintheplacentaincluding
progesteroneandleptin[49,175,186].Bothsmokingandairpollutionexposurewere
associatedwithlowerbirthweightsalongwithlowbloodprogesteronelevelsandhigh
placentalcadmiumconcentrationscomparedtoanon‐exposedcontrolgroup[135].
3.3.4Spontaneouspretermlabourandbirth
Inflammationisproposedasonepotentialmechanismleadingtospontaneous
pretermlabour,bothwithintactmembranesorPROM.Theclassificationofpatientswho
deliverpretermcanbecategorizedintotwonon‐mutuallyexclusiveclusters;thosewho
presentwithinflammatorylesions(e.g.acutechorioamnionitisandfunisitis)andthosewith
15
vascularlesionswhotendtohavelongergestationalperiods[61].Theconsequenceof
uteroplacentalischemiaasaresultofsuchlesionswilldependontheseverity,thetiming
anddurationoftheinsult.Whileacompleteblockageofuterinearterieswillleadtofetal
death,lesssevereischemiawillresultindifferentclinicalphenotypesasaresultofadaptive
mechanismsforfetalsurvival.Thismayincludefetalgrowthrestrictionifchronic
underperfusionofoxygenandnutrientspersists,theonsetofmaternalhypertensionto
sustainorincreaseuterinebloodflow,and/ortheinitiationofpretermlabourasa
maternal/fetaladaptationtocontinuedgrowthrestrictioninutero(Figure2)[61,197].
Cardiovascularlesionsindicatingthrombosisandatherosisareshowntobeindirectly
causedbyexposuretoPM2.5andUFPsviainflammatoryand/oroxidativeinjury[97].
4.0ThePhysicalandSocialEnvironmentandtheirRelationtoAdversePerinatalOutcomes
4.1.PM‐inducedoxidativestressandinflammatorymechanismsExposuretoPM2.5anditsconstituents,includingPAHsandmetals,induceoxidative
stressandinflammationinmanybiologicalsystemsthroughvariousmeans(Figure3)
[48,77–79,97,176,177,198].OnemethodisthedirectgenerationofROSfromfreeradicals
andoxidantsonparticlesurfacesincludingsolubletransitionmetalssuchasiron,copper,
chromiumandvanadium.Asmentionedabove,freeironcanreactwithavailablesuperoxide
orhydrogenperoxidetoformhighlyreactivehydroxylradicals[70,77].PAHsandother
organicmoleculesabsorbedtoPM2.5andUFPsmayaccountforalargeproportionoftheir
oxidativepotentialduetotheirabilitytoenterthecellanddisruptthemitochondria[79].
AlteredfunctionofmitochondriamayproduceexcessquantitiesofNADPH‐oxidasewhichin
turngenerateslargeamountsofcellularsuperoxide,aprocessalreadyinoverdrive
throughoutpregnancybutparticularlyinthefirsttrimester[70,77].Interpolatedambient
PM10exposurewasshowntobenegativelyassociatedwiththenumberofplacental
mitochondrialDNA,amolecularmarkerofmitochondrialdisruptionandinflammation.This
associationwasreversedwithincreasingdistancefrommajorroads,aproxyfortraffic‐
relatedairpollution[48].
16
Alternatively,PM/PAHmediatedoxidativestresscanbeinducedbytheactivationof
theinflammationsystem.Immunotoxiccompoundscanpromotethereleaseofpro‐
inflammatorycytokines,TNF‐αandCOX‐2,whichinturnactinapositivefeedbackloopto
generatemoreROSandoxidativestress[77].Forexample,modelledPM10andPM2.5
exposurehasbeenpositivelyassociatedwithelevatedC‐reactiveprotein(CRP)levels,a
biomarkerofsystemicinflammation,inbothmaternalfirsttrimesterbloodandfetalcord
bloodinadose‐dependentmanner[176,200].CRPisproducedintheliverandpartofthe
acute‐phaseresponsereleasedduringinflammatoryreactionsfromcytokinesproducedin
thelungs.RaisedCRPisariskfactorforcardiovasculardiseaseasamarkerofunstable
atheromatousplaguesleadingtothrombosisandischemicevents[97].Exposuretodiesel
exhaustinhealthyhumanvolunteersproduceddefinedhealtheffectsinadditionto
pulmonaryinflammation,includingsystemicinflammation,pro‐thromboticchangesand
othercardiovasculareffectsconsequentofpro‐inflammatoryevents[99,201].Thishyper
pro‐inflammatorystate,alongwithoxidativestress,ishypothesizedtocontributetoseveral
APOs[69,70,174,181,202].
Figure3:ProposedpathwaysofparticulateairpollutioncontributingtooxidativestressandinflammationleadingtoadversepregnancyoutcomesExposuretoPManditsassociatedconstituentsoftransitionmetals,PAHsandotherorganicmoleculesaffectthecardiovascularandmetabolicsystemswhicharehighlyactivethroughoutpregnancy.Forexample,detoxificationofPAHsandotherorganictoxinsactivateAhRsignallingresultinginadditionaloxidativestressifantioxidantdefensesarelimitedorimpaired[55,79,98,108,109,199].
17
Indirectly,thecellulardetoxificationofPAHscaninduceoxidativestressand
cytotoxicitybyformingpotentROSmetaboliteby‐products.Specifically,PAHsandother
organicxenobiotics(notablyPCBsanddioxins)aredetoxifiedbythecytochromeP‐450
(CYP)superfamilyofPhaseIandPhaseIImetabolizingenzymes.Theexpressionofthese
enzymesarehighlymodulatedbygeneticpolymorphisms,steroid/sexhormonessuchas
glucocorticoids,insulin,estrogensandprogesterone,andmicronutrient/dietary
deficiencies[74,75,128,203,204].Furthermore,hypoxia,infectionandinflammationare
shown,ingeneral,todown‐regulateCYPenzymeswhichmayaffecttheclearanceand
bioavailabilityofgrowthfactors,hormones,drugsandtoxins[203,205].CYPhasnumerous
isoformswhichareexpressedinmanytissuesespeciallytheliver.CYP1A1istheonly
isoformalsosignificantlyexpressedintheplacentathroughoutpregnancyresponsiblefor
metabolizingsteroid/sexhormones,growthfactorsandfattyacidsinadditiontotoxins
[75].Theseexogenousandendogenoussubstancesactasligandstoactivatethearyl
hydrocarbonreceptor(AhR),atranscriptionfactorthatmediatesthebiotransformationof
suchligands(PAHs,estradiol,etc.)intomorepolarandbioavailablemetabolitesbyup‐
regulatingCYPenzymes(seeendnote4).However,certainmetabolitesofPAHs(e.g.o‐
quinones,areneoxideanddiolepoxide)bindtoDNA,RNAandproteinmacromoleculesto
formtoxicadductsthatdisruptDNAreplicationandareconsideredmutagenic[72,75].Such
DNAadductshavebeenfoundinnewborncord‐bloodpositivelycorrelatedwithmaternal
exposuretoPAHs[50].PAHshavealsoshowntosignificantlydecreasetheaccumulationof
trophoblaststemcellsintheearlyplacentatherebylimitingtheirdifferentiationintoother
celltypesvitalforhormonesynthesisandongoingplacentaldevelopment,aprocessthat
couldcontributetoDDP[72].DirectprenatalexposuretoairbornePAHshasbeen
associatedwithFGRwithanincreasedexposure‐relatedriskinthefirsttrimester
[206,207].Secondary(PhaseII)metabolizingenzymesarerequiredtofurtherdetoxify
reactivePAH‐metabolites,towhichtheirinefficientclearanceresultsinprolongedexposure
leadingtosustainedcytotoxicityandmutagenicity.PhaseIIenzymesincludeglutathiones‐
transferases(GSTs),UDP‐glucuronosyltransferases(UGTs),NAD(P)H‐dependentquinone
oxydoreductase‐1(NQO1),aldehydedehydrogenase‐3(ALDH3)[75,205].
4.2MaternalDietandMicronutrientIntake
Adequatedietandmicronutrientstatusprovidesresilienceagainstoxidativestress
andinflammationcausedbyvariousexposuresincludingairpollution,allostaticstress,
infectionorsmoking(Figure4)[55,118,128,129,131,143].Manymicronutrientssuchas
18
essentialtracemetalsarevitalco‐factorsinseveralantioxidantenzymesystems.For
example,copperandzincarenecessaryintheproductionofSOD.Similarly,seleniumandits
incorporationintotheaminoacidselenocysteineisrequiredforthefunctionalityofall
selenoenzymes,includingGPxandGST.Thus,seleniumisessentialinseveralaspectsof
humanhealth,particularlyconditionsinvolvingoxidativestressandinflammationsuchas
CVD,immunefunction,cancerandreproduction,butalsothyroidregulationandbrain
diseases[208,209].
ROSmayhavedirecteffectsonoocytequalityandappearstobemodulatedbydietary
antioxidantsupplements[118].Womenwhoareobesetendtohavehigherratesof
infertilitythatcorrelatewithincreasedlevelsofoxidativestressbiomarkersintheirblood
asexcessglucoseavailabilityleadstohighermitochondrialROSsynthesis[70,118].
SeleniumdeficiencyandcorrespondingreducedGPxactivityhasbeendocumentedincases
ofrecurrentmiscarriageandspontaneousabortions[210–212],andhasalsobeen
associatedwithpreeclampsiaandpretermbirth[213,214].However,giventhesupposed
roleofoxidativestressinpreeclampsia,treatmentwithcertainantioxidants(notably
vitaminCandE)hasnotproducedreliablepreventativeresultsinexperimentaltrials[69].
Onehypothesisisthatinappropriateantioxidantregimentand/oradministrationtoolatein
gestationareresponsibleandnewtherapeuticcandidatesincludemelatoninandselenium
[118].Interestingly,nationalprogramsinFinlandandNewZealandfortifyingfoodwith
seleniumhasbeenassociatedwithsignificantreductionintherateofpreeclampsia[215].
Oxidativestressnegativelyaffectstheplacentaltransportofaminoacidsandglucose
[45].Furthermore,fattyacidsandlowdensitylipid(LDL)cholesterolsnecessaryforthe
placentalsynthesisofoestrogensandprogesteroneareparticularlyvulnerabletooxidative
injury[216].Regulationofplacentalnutrienttransportiscontrolledbyseveraldifferent
mechanism,includingimprintedgenes,placentalsignalingpathways,variouscytokinesand
hormonessuchasinsulin,leptin,glucocorticoidsandoestrogens(forreviewsee[45]).The
majorplacentaltransfermechanismsinclude:simplediffusionoflipophilicsubstances(e.g.
oxygen,CO2,fattyacids,steroids,fatsolublevitamins,anestheticgases),restricteddiffusion
ofhydrophilicsubstances,facilitateddiffusionviaamembraneboundcarrier(e.g.glucose
andothercarbohydrates),andactivetransportwhichrequiresenergy(e.g.aminoacids,
iron,calcium,andotherdivalentcations)[45,217].Placentalphysiology,includingspiral
arteryremodelingandplacentalvilloussurfaceareaaremajordeterminantsdictating
19
placentaltransportcapacity,andthedegreeofplacentaldevelopmentaldisruption
correlateswiththeseverityofobstetricalcomplicationsassociatedwithDDP[51,62].
Nutritionanddietcaninfluenceperinatalhealthinopposingdirections(i.e.itcanbe
anantagonistoragonist).Poor/under‐nutritionsuchashighfat/caloriedensefoodandlow
micronutrientintakeismoreprevalentamongwomenfromlowSESbackgroundswhich
maypartlyexplainhigherratesofsomeAPOs[12,139–142].Ontheotherhand,good
nutritionandsupplementalvitaminintakeiscapableofreducingthetoxicityofeveryday
environmentalstressorsaswellaspreventingcertainAPOsandcongenitalanomaliesas
shownwiththesuccessfulreductionofneuraltubedefectswithfolicacid[128,143,218].
Nutritionaland/orgenetically‐induceddeficienciesinfolateandvitaminsB6andB12can
disruptthehomocysteine‐to‐methioninepathwayresultinginhyperhomocyteinemia
(HHC),aknownriskfactorofcardiovascularmorbidities(thrombosis,lesionsandinfarcts)
andmarkersofoxidativestress[54,119,219,220].HHCmaysimilarlyaffectthehighly
vascularizedplacenta,andhasbeenassociatedwithdecidualvasculopathyandpreterm
birth[54,120].Omega‐3fattyacidsabundantfromeatingsalmonwasshowntoimprove
markersofoxidativestress[221],whichmayimpartneurodevelopmentalresilienceagainst
stressors[222,223].Dietaryphytophenolsfromfruits,vegetables,herbsandspiceshave
showntohaveantioxidantandanti‐inflammatorypropertiescapableofreducinginfection‐
inducedinflammatoryandcontractilepathwaysinhumangestationaltissues[129].
SignificantdifferencesinpregnancyoutcomesbetweenDominicansandAfricanAmericans
bothexposedtosimilarlevelsofPAHsinNewYorkcityneighbourhoodswerethoughttobe
duetohealthfuldietary/culturalpracticesintheDominicanimmigrantpopulation[206].
20
4.3MaternalSmokingandEnvironmentalTobaccoSmoke(ETS)ExposureMaternalsmokingduringpregnancyandexposuretoETSremaintobetwo
modifiableriskfactorswiththegreatestpotentialforbeneficialinterventions(Figure4).
TheirassociationwithnumerousAPOsincludingcongenitalanomaliesiswelldocumented
[127,144–146],ashavetheirassociatedprevalencewithindicatorsoflowSESandother
socially‐patternedriskfactors[147–149].ThemechanismsinvolvedleadingtoAPOshave
beenwellreviewed[132,134];however,it’snotablethatthetwomaintoxinspresentin
tobaccosmokearealsoconstituentsofPM(PAHsmoresothancadmium).Cadmium(Cd)
exposurereadilyinterfereswiththeactivetransportofessentialmineralstothefetus,
particularlyzincandcalcium[46,135,196,226–228].Cadmiumandlead(Pb)exposurehas
alsobeenshowntoreduceglycogenconcentrationstherebypotentiallylimitingavailable
glucosetothefetus[229].Cadmiumhasshowntodisruptplacentalleptinsynthesis,a
hormonewithseveralvitalfunctionsincludingplacentalangiogenesis,immunomodulation,
aminoacidandfattyacidtransportaswellasfetalpancreaticdevelopmentimportantinthe
regulationofinsulin‐likegrowthfactorsandfetalbodyfataccumulation[49,51].Finally,
synergisticeffectsinthegenerationofoxidativehydroxylradicalshavebeenobserved
betweentobaccosmokeandbothambientPM2.5anddieselexhaustparticlesspecifically
Figure4:ProposedpathwaysofhowthesocialenvironmentinteractstoproduceexcesssystemicandplacentaloxidativestressandinflammationleadingtoadversepregnancyoutcomesThepregnantwomanisnestedwithinandinfluencedbyneighbourhood/community‐levelfactorswhichcanexasperateorbuffertheindividual‐levelbiologicalandbehaviouralfactors[24,26,54,128,224,225].
21
[35].Interestingly,thecounterintuitiveassociationbetweensmokingandlowerriskof
preeclampsiawasrecentlyshowntovaryaccordingtothetimingandintensityofsmoking
[230].It’spossiblethattheincreasedexposuretocarbonmonoxide(CO)fromsmokingin
lategestationactsasavasodilatoratthesametimeinhibitsthereleaseofsFlt‐1,ahallmark
anti‐angiogenicfactorimplicatedintheendothelialdysfunctionofpreeclampsia[115,230].
4.4AllostaticStressandGlucocorticoidExposureReviewedelsewhere[163],thebrainistheprimarytargetandmediatingorgan
throughwhichSES‐relatedstresspathwaysaretranslatedtootherbodysystemsviathe
hypothalamic‐pituitary‐adrenal(HPA)axis.TheHPA‐axisisactivelyinvolvedinseveral
biologicalsystems,includingthecardiovascular,metabolic,immunologicalandendocrinal
effectsinboththemotherandfetustopromoteallostaticadaptation[165,231].Here,the
neuroendocrinehormonesoftheHPAaxis,corticotrophinreleasinghormone(CRH),
adrenocorticotropichormone(ACTH),andglucocorticoids(GC)respectively,coordinatethe
biologicalresponseviafeedbackloops.ThehumanplacentaisalsocapableofreleasingCRH
andotherneuropeptideswhichinteractwiththeHPAaxistoregulatethematernalstress
responseaswellasothernormalpregnancyfunctions[47].Properlevelsofin‐utero
glucocorticoidsareessentialforsuccessfulembryoimplantation,fetalorganmaturation
andtheinitiationoflabourwithglucocorticoidlevelsgraduallyincreasingoverthecourse
ofgestation.Normally,levelsofmaternalcortisolrisesharplyinthethirdtrimestercausing
thereleaseofplacentalCRHinapositiveadrenal‐placentalfeedbackloop.PlacentalCRH
stimulatesfetalcortisolsecretionwhichinturnsuppressesplacentalprogesteroneand
activatesthereleaseofprostaglandinsandoxytocintopromoteuterinecontractions
[47,232].However,earlyandincreasedlevelsoffetalglucocorticoidscanimpairgrowthand
predisposetoadult‐onsetdiseases[136,233,234].Theplacentalenzyme11β‐
hydroxysteroiddehydrogenasetype2(11β‐HSD2)protectsthefetusfromexcess
endogenousglucocorticoidsbyconvertingactivecortisolintoinactivecortisone.11β‐HSD2
ishormonallyregulatedmakingitsusceptibletoendocrinedisruptionfromchemicaland
non‐chemicalstressorssuchasmaternalanxiety,inflammation,infection,cadmium
exposureandlowcaloricintake[136,138,224,235,236].Placentalhypoxiaassociatedwith
PIH/PEhasbeenshowntosuppress11β‐HSD2activitywhichmaybeanadaptiveresponse
tocounteractcompromisedfetalgrowthbyallowingmorecortisoltoreachthefetusfor
organdevelopment.Lowconcentrations/activityof11β‐HSD2andhighlevelsofcortisol
22
havebeenassociatedwithPTBandFGR[136,237,238],twooutcomesalsoassociatedwith
maternalpsychosocial/mentalhealth[233,234,239].
Factorsaffecting11β‐HSD2activitythatareassociatedwithlowSESincludeallostatic
overloadleadingtotheexcessproductionofglucocorticoidsthatcanoverwhelmthefetal
protectivemechanism(Figure4)[136,231,240].Indirectly,allostaticloadiscapableof
disruptingthemetabolicsystem,leadingtoimpairedglucosetolerance,insulinresistance,
diabetesand/orobesity,allofwhichareriskfactorsforvariousAPOs[138,165,231].
Generalmaternalundernutritionand/oralowdietaryproteinintakehasbeenshownto
impairplacentalglucosetransportandinhibit11β‐HSD2activityinpregnantratsleadingto
FGR,indicatingapossiblemechanismthroughpoordiet[224,241].Additionally,cadmium
hasalsoshowntoinhibit11β‐HSD2activityinbothhumanandrodentplacentas[225],and
prenatalcadmiumexposurehasbeenshowntoincreasefetalcorticosteroneconcentrations
inratswhichresultedinreducedbirthweights[236].Thissuggestsapossiblemechanism
fromactiveorpassivetobaccosmokeexposureorambientPMexposure[135,242,243].
Collectively,it’spossibleforthecumulativeexposuresofPM,smoking,ETS,poordietary
intakeandotherSES‐relatedfactorstointeractthroughthesame11β‐HSD2mechanismto
increasetheriskofimpairedfetalgrowth(Figure4).
5.0DiscussionTheubiquitousexposuretoparticulateairpollutionanditsconstituents(e.g.PAHs
andmetals)isbutoneclassofenvironmentalcontaminantsthatcanactthroughoxidative
stress,inflammationand/orendocrinedisruptiontopromotedevelopmentaltoxicityand
adverseperinatalhealth[177,244,245].SummarizedinFigure2,aperturbedearlyin‐utero
environmentcanleadtodefectivedeepplacentationresultinginacascadeoffetal‐placental
adaptivemechanismscontributingtoarangeofpregnancycomplicationsandadverse
outcomes[60].Heretheunderlyingbiological,socialandphysicalriskfactorslikely
intersecttoproduceexcessiveoratypicaloxidativestress,inflammatoryresponseand
biologicalantagonismineitherinitiatingdefectivedeepplacentationpathologyand/or
contributingtotheseverityofitsphenotype.Socio‐economicdisparitiesareknownto
confoundtheenvironmentalexposureeffects;however,theymayalsoactaspotentialeffect
modifiersgiventheiroverlappingetiologicalmechanismswithPM2.5exposure.Whilethe
traditionalbiomedicalparadigmthatviewspopulationsasacollectionofindependent
individualshasyieldedusefulinformationregardingriskfactors,elucidatingthe
intersectingpathwaysinvolvedinAPOswillrequireplacingindividualbiologicand
23
behaviouraldeterminantswithinthesocialandspatialcontext[22,246].Itisnowwell
recognizedthatSESoperatesatmultiplelevelsoforganization,andneighbourhoodor
community‐levelfactorscanworktoeitherameliorateorexacerbatecertainriskfactors
[15,24–26].Thehealthymigrantparadoxexemplifiestheseeffectsinwhichhomecountry,
educationandneighbourhoodqualitiescombinetomodifytheexpectedperinataloutcomes
oftenobservedwithlowincomehouseholds[161,247].
TheSESriskfactorsthatoverlaporinteractwiththePM‐mediatedmechanisms
includesmoking,nutrition,andpsychosocialstressactingthroughtheHPA‐axisand
allostaticload.Giventhisknowledge,interventionsaimedatamelioratingthesefactorsmay
bethebestwaytocounteractthenegativeinfluencesoflowSESandairpollutionexposure
onfetaldevelopment.Maternalsmokingcontinuestobeoneofthemostmodifiablerisk
factorstolowertheriskofAPOs[134,147].Furthermore,maternalsmokingalsotendsto
interactnegativelywithnutrientintakeandstatus[133,248].Smokersingeneralhave
poorernutritionalprofilesthannon‐smokerswithbothbehaviouralandbiologicalfactors
independentlyaccountingforthedifferencesinmicronutrientssuchasfolateandessential
vitaminsandminerals[133,248–250].Whilesmokerstendtohavelowerdietarynutrient
intakes,theyalsohaveanacceleratedrequirementformicronutrientsduetoincreased
inflammatorycellturnovercausedbytheoxidativestressofsmoking,aneffectmore
pronouncedamongheavyandlong‐timesmokers[248].Theseinteractingeffectsof
smokingandnutritionarefurthercompoundedbytheirassociationwithotherindicatorsof
lowSESsuchasloweducationandincomecontributingtoallostaticload[139,251].
Nutrientintakemaybeameliorativeafteraninsulthasoccurredasshowninratmodelsof
fetalalcoholsyndromewhereanomega‐3fattyacidenricheddietreversedthecellular
effectsofprenatalethanolexposureonthefetalbrain[222].Thereforewithrespectto
policyinterventions,nutritionintheformofimprovedfoodsecurityandmicronutrient
intakemayservetocounteractthenegativeinfluencesofbothlowSESandairpollution
exposure[252–257].
Thecomplexmixtureofparticulateairpollution,especiallyPM2.5andUFPswhich
includesabsorbedPAHsandvariousmetals,alsoemergesasanimportanttargetforrisk
reductionandmanagement.Thedeservedscrutinystemsfromtheubiquityinthe
environment,themyriadofemissionsourcesandtheirestablishedassociationwithAPOs
[88,98,258].TheubiquityofPM2.5andUFPsintheenvironmentmeansthatahigh
proportionofpeopleareexposedresultinginahighetiologicalfraction.Therefore,evena
24
modestreductioninexposurewillhavealargepopulationeffectwithreductionofthe
societalcostsofAPOs[259].Notably,theirsourcesareprimarilylocal,suchasvehicle
emissionsandindustrialland‐use.Thismakesthemmodifiableriskfactorsthatcanbe
addressedatthemunicipalandprovincial/statelevelwithbetterurbanplanningtoreduce
vehicletraffic,increasingaccesstogreen‐spaceandenforcingairqualityregulations[260–
263].
Notunliketheaccumulationofevidenceonsmokingandhealthoutcomesorthatof
airpollutiononcardiovascularandpulmonaryhealth[264],theepidemiologicaland
toxicologicalresearchoverthepasttwodecadeshasestablishedaconsistentdose‐response
associationwithhighbiologicalspecificity,temporalityandplausibility[3,55,177].Takenin
concert,thesecharacteristicsandfurthercorroboratingresearchshouldlendstrengthfor
evidence‐basedpolicyforinterventionstrategiestargetinghighriskareasinorderto
reducetheenvironmentalburdenofdiseaseattributedtoparticulateairpollution
[98,265,266].
6.0ConclusionAdversepregnancyoutcomessuchasfetalgrowthrestrictionandpretermbirtharea
publichealthpriorityofglobalimportance.Wehavebroughttogetherthemultidisciplinary
literatureonthecurrentstateofevidencelinkingthephysicalandsocialenvironmentto
specificadversepregnancyoutcomes.Theevidencesuggeststhatvariousexposures,
whethersociallyorenvironmentallydetermined,maybeinterpretedbythefetoplacental
unitinsimilarwaysresultinginacommonpathologicalset‐upforadverseoutcomes,
namelydeficientdeepplacentation.Giventhisbackground,wellplannedfuture
epidemiologystudiesusingmultilevelmodelsexploringvariousbiologicaleffectsofthe
socialandphysicalenvironmentwillhavethepotentialtoprovidetheevidencetoestablish
crucialwindowsoffetalvulnerabilitywithanaimtoidentifyandmitigatemodifiablerisk
factors.
7.0Endnotes1‐ Implantationoftheblastocyst(0.1mminsize)beginsondaysixfollowingconception
inwhichitcompletelyembedsitselfwithinthematernaluterineendometrium,usually
ontheupperposterior(fundal)wall.Theperi‐implantationperiod(approx.day1‐20
post‐fertilization)isarguablymostcriticalperiodofreproductionastwo‐thirdsof
conceptionsfailatthistime,oftenunbeknownsttotheindividual[72].Individual
variabilityingeneticpredispositioninteractswithbothenvironmental(exogenous)
25
andmaternal(endogenous)stressexposuresthatcanleadtodefectiveplacentation
withsubsequentobstetricalcomplicationsand/orthedevelopmentofbirthdefectsvia
teratogenesis[71,72,245].Indeed,fiftypercentofconfirmedmiscarriages(pregnancy
losspriorto20weeksgestation)areduetoabnormalembryonickaryotype
(chromosomes),anaturalbiosensormechanismtorecognizeandeliminatedefective
embryos[267].Furthermore,ectopicpregnancies(implantationanywhereotherthan
uterinecavity)andplacentaprevia(implantationonthelowerinferiorsegmentofthe
uterusnearthecervix)areriskfactorsofmaternalmortalityormorbidityandareoften
eitherterminatedordeliveredpretermviacaesareanbirthrespectively[268].
Successfulimplantationandsubsequentplacentationinvolvesthecoordinated
differentiationofthetrophoblast(outercelllayeroftheblastocyst)intothreedistinct
cellpopulations,syncytiotrophoblasts(STBs),cytotrophoblasts(CTBs),and
extravilliouscytotrophoblasts(ECTBs)[68,217].TheSTBisthemainendocrine
hormonesynthesiscomponentoftheplacentaandrapidlyexpandsintothematernal
endometrium.TheCTBsarethemitoticallyactiveprogenitor(stem)cellswhich
migratein‐behindtheexpandingmassoftheSTBwhicheventuallygivesrisetothe
basalplateofthedefinitivediscoidplacentaaroundmid‐gestation.Finally,theECTB
aresubsequentlydifferentiatedfromtheadvancingCTBcellsbeyondthebasalplateto
infiltratetheunderlyingmaternaldecidualcellsanduterinespiralarteries.Attheend
ofthethirdweekofgestationthedefinitiveelementsofthediscoidplacentaarein
place:thechorionicplatefromwhichthevilliariseandfetalbloodwillflow,abasal
plateinwhichanchoringvilliareattached,andlacunar(intervillous)spacesintowhich
maternalbloodwillcirculate(Figure5)[217].Thehistologicalstructureofthehuman
placentaiscommonlydescribedashemochorialinwhichthefetal/embryonictissues
areindirectcontactwithmaternalblood.
Thefreeflowofoxygenatedmaternalbloodintotheplacentaalongwithantioxidant
enzymes(SOD‐superoxidedismutase,catalaseandGPx‐glutathioneperoxidise)
servesaphysiologicalrolefacilitatingmaternal‐fetalnutrienttransferandgas
exchange;howevertheconsequentialburstofROSmaynegativelyimpacton‐going
placentaldifferentiationandgrowth,suchasshallowtrophoblastinvasionofmaternal
spiralarteries,ifantioxidantdefencesaredepleted(Figure6)[68,192].
26
Figure5:Schemeofplacentalcirculationandfeatures(Grey’sAnatomylithographs)
(A)NormalPlacenta:Theextravillouscytotrophoblast(ECTB)cells(green)migrateintothedeciduaofthematernalendometriumwheretheyenterandremodelthematernalspiralarteriesfromanendothelialcelltypetoendovascularECTB(eECTB)cellslosingtheirresponsivenesstoendogenousvasoactivecompoundsandmaximizingbloodflowintoplacentalintravilliousspaces.(B)PreeclampticPlacenta:TheECTBinvasionintothedeciduaisshallowandlimited,withmanyECTBcellsinthebasalplateremainingattachedtoanchoringvilli(AV).Endovascularinvasionandremodellingofthespiralarteriesisabsentorreduced,thusconstrictingbloodflowandreactivetomaternalstimulussuchasstressandothervasoconstrictingagents.FV:floatingvilli.[269].ImagecourtesyofTheCuratorsoftheUniversityofMissouri(2011).
2‐ Deficientdeepplacentationisthoughttoresultinreducedandintermittentplacental
perfusiontherebyrestrictingbloodflowandlimitingoxygenandnutrientsupplytothe
fetus.Thematernaladaptiveresponseistoincreasebloodpressuretocompensatefor
therestrictedflow.Theensuingplacentalhypoxiainthelattertwotrimestersleadsto
theupregulatedexpressionandsecretionofsolubleantiangiogenicfactors(sFlt1and
sEng)whichantagonizeproangiogenicfactors(VEGF,PlGF,andTGF‐β1)causing
systemicendothelialdysfunctioncharacteristicofPIH/PE[115].
Figure6:Invasiondefectsinpreeclampsia
27
3‐ Theplacentaisamulti‐functionalorganandisresponsibleforthreemajorrolesatthe
maternal‐fetalinterface.First,theplacentaisanimmunologicbarrierbetweenmother
andfetus,andisthoughtthattheplacentaltrophoblastandmaternalimmunesystem
positivelyinteractforthesuccessofthepregnancy[44,173,217].The
syncytiotrophoblastactsthroughtheproductionofvariouscytokinesandchemokines
responsibleforthecoordination,migration,differentiation,andfunctionofthe
maternalimmunecells[182,183].Thisisachievedthroughanon‐linearseriesof
positiveandnegativefeedbackpathwayswiththestimulationandsuppressionof
moleculeswithbothpro‐andanti‐immunosuppressantproperties(interleukins,
integrinsandglcyodelin–seeTable1).Interferencewiththeproductionorsecretionof
thesesubstancesmayresultintheimpairedmaternalimmuneresponsetothesemi‐
alliographfetal‐placentalunitleadingtoseveralAPOsincludingearlypregnancyloss,
PIH/PE,andPPROM[61,134,175,185,186].
Thesecondmajorfunctionoftheplacentaisitssynthesisofsteroidandprotein
hormonesvitalintheprogressionofthepregnancy(Table1).Mostofthecirculating
substancesinTable1appeartobesynthesizedbythesyncytiotrophoblast.
Interferencewiththeproductionorsecretionofthesesubstancesbyxenobiotics(e.g.
cadmium,lead,arsenic)mayresultinseveralAPOs,suchasearlypregnancyloss,
PIH/PE,impairedimmunoprotectionandPPROM[134,175,185,186,236].Forexample,
thePM‐mediatedoxidationoflow‐densitylipoproteins(LDL)mayinterruptacascade
ofeventsnecessaryforthefetalproductionandexportofoestriol,quantitativelythe
mostsignificantoestrogeninmaternalcirculationinlatepregnancy[97,217].Chronic
oracutematernalpsychosocialstressalsohasthepotentialtodisturbimmuneand
endocrinesignallingpathwaysviathehypothalamic‐pituitaryadrenal(HPA)axis
[47,72,136,138].
Thethirdmajorfunctionoftheplacentainvolvesvarioustransfermechanisms
similartothosefoundinotherepithelialsystems.Themajortransfermechanisms
include:simplediffusionoflipophilicsubstances(e.g.oxygen,CO2,fattyacids,steroids,
fatsolublevitamins,anestheticgases),restricteddiffusionofhydrophilicsubstances,
facilitateddiffusionviaamembraneboundcarrier(e.g.glucoseandother
carbohydrates),activetransportwhichrequiresenergy(e.g.aminoacids,iron,calcium,
andotherdivalentcations),receptor‐mediatedendocytosisandexitmechanisms
[45,217].Regulationofplacentalnutrienttransportiscontrolledbyseveraldifferent
28
endogenousmechanism,includingimprintedgenes,placentalsignalingpathways,
variouscytokinesandhormonessuchasinsulin,leptin,glucocorticoidsandoestrogens
(forreviewsee[45]).Manyoftheabovelistedfactorscanbeindirectlyaffectedby
exogenousmediators(e.g.PMandPAHexposure,stress).However,exogenous
mechanismswithdirectmodesofactiononnutrienttransportincludecadmium(Cd),
lead(Pb)andoxidativestress.Forexample,Cdexposurefromtobaccosmoke,air
pollutionand/ordietreadilyinterfereswiththeactivetransportofessentialminerals
tothefetus,particularlyzincandcalcium[46,135,196,226,227].CdandPbexposure
hasbeenshowntoreduceglycogenconcentrationstherebypotentiallylimiting
availableglucosetothefetus[229],andoxidativestressnegativelyaffectstheplacental
transportofaminoacidsaswellasglucose[45].
29
Table1:Biologicalfactorsinvolvedinpregnancy,theirroleandup/down‐regulation
Name FunctionandRole up/down‐regulation Ref.Progesterone,oestriol(E3),oestrone(E1),17β‐estradiol(E2)
- Steroidhormones,regulatemenstrualcycle,preparesendometriumforimplantation.
- BiosynthesizedbyplacentausingLDLcholesterolinmaternalblood
- Up‐regulatesmanyotheritemsbelow
↓byCd,otherheavymetals↓byPMviaoxidizedLDLcholesterol↑E2metabolismtoreactivemetabolitesviaPAH‐inducedCYP450
[75,216,229,270]
HumanChorionicGonadotrophin(hCG)
- GlycoproteinHormone- Releasedbyblastocyst,initialpregnancyrecognitionandcorpusluteumsurvival
- Detectablebyweek3,peaksweek11- Stimulatesinitialprogesteronerelease- Immunetolerance,trophoblastdifferentiationandangiogenesis
↓byCdexposure,indirectlyviareductionofleptin↓inchorioamnionitis↑uNKcellproliferation↑byGM‐CSF↑byIL‐1β,TNF‐αviaIL‐6↑LIF,VEGF,MMP‐9
[49,182,186,216,271]
Granulocytemacrophage‐colonystimulatingfactor(GM‐CSF)
- Cytokine- PromotesDNAproliferation,differentiationandplacentalsecretoryactivity
- Requiredforoptimalplacentaldevelopment,fetalgrowthandsurvival
- Synthesisinuterineepithelialcellsisregulatedbyestrogen
- Lowbloodconcentrationlevelsinwomenwithrecurringmiscarriages
[271,272]
PlacentalandVascularEndothelialGrowthFactor(PlGF,VEGF)
- Pro‐angiogenicgrowthfactorsforvasculardevelopmentofembryo,placentaandspiralarteryremodelling
- Promotesvasodilation- LowPlGF:sFltratioinpreeclampsia
↑byhCG,hypoxiainearlypregnancy↓bysFltandsEngviaexcessoxidativestress/inflammation
[63,194]
Interleukin(IL),TumourNecrosisFactor(TNF),&LeukemiaInhibitoryFactor(LIF)
- Largefamilyofpro/anti‐inflammatorycytokines(non‐enzymiccellmessenger)
- Involvedinallaspectsofpregnancy- Pro‐inflammatory:IL‐1α/β,IL‐6,TNF‐α- Anti‐inflammatory:IL‐10,IL‐4- LIFessentialforimplantation,releasedbyuNK,regulateinvadingpTBCs
↓IL‐6byhCG,progesterone↑IL‐6byexercise↑LIFbyhCG&IL‐1β↑↓byheavymetals
[174,175,182,183,272]
Prostaglandins(PG‐E2)
- Increasevascularpermeabilityinthedeciduaandatimplantationsite.
- Stimulatescontractions,labouronset- RegulatedbyCOX‐2
↑byIL‐6,IL‐1β,TNF‐α↑byinfections↓bydietaryphytophenols
[129,273]
Glycodelin‐A,Galectins
- EarlysecretionbyuNKcellsmodulatesendometrialimmuneadaptation
↑byhCG,progesterone↓bystress
157,158,162]
Integrins - Cellsurfacereceptorandadhesionmolecules,importantinEVTinvasionofdeciduaandECMremodelling
↑byIL‐6andVEGFAlteredbyCd
[63,185,193]
GlucocorticoidSteroids(GS)e.g.cortisol&corticosterone
- UpregulatedwithHPA‐axisactivation- Involvedinimplantation,fetal‐placentalgrowth,organdevelopment,utero‐placentaladherence,onsetofparturition
- Excessisdetrimental,fetalexposureregulatedbyplacental11β‐HSD2
Hormonallyregulated↑PG‐E2,hCG↑withbloodPb,lifestress↑byIL‐1β,IL‐6↓uNKcells↓11β‐HSD2byCd,hypoxia
[29,136,182,236]
Acronymsused:11β‐HSD2:11β‐hydroxysteroiddehydrogenasetype2;Cd:Cadmium;COX‐2:cyclo‐oxygenase‐2;CYP450:cytochromeP450;ECM:extracellularmatrix;EVT:extravilloustrophoblasts;HPA:hypothalamus‐pituitary‐adrenal;LDL:low‐densitylipoprotein;MMP:matrixmetalloproteinase;Pb:Lead;sEng:solubleendoglin;sFlt:solublefms‐liketyrosinekinase;pTBC:placentaltrophoblastcells;uNK:uterinenaturalkiller.
30
4‐ CrosstalkfromAhRtoothersignallingpathwaysinthefetal‐placentalunitincludes
PAH‐inducedAhRinteractingwiththehypoxia‐induciblefactor(HIF)which,depending
onthetimingofexposure,mayalteroxygentensioninearlypregnancyandresultin
miscarriageorsubsequentlyreducedtrophoblastinvasionleadingtoPIH/PEand/or
IUGR[75].Moreover,dependingonthesourcemixture,PAHsarecapableofinhibiting
theirownmetabolismintoharmfulmetaboliteswhichmayexplainthediscrepanciesin
laboratorytestingofsinglePAHchemicalsversuswholemixtures[75].Similarly,the
differentialAhRinductionbetweenCYP1A1andCYP1B1dictatesmetabolitetoxicity.
Forexample,estradiolmetabolismbyCYP1B1converts17β‐estradiol(E2)to
carcinogenic4‐hydroxyestradiol(4‐OHE2)whichformsDNA‐adductsandgenerates
ROS.Incontrast,CYP1A1convertsE2intonon‐carcinogenic2‐hydroxyestradiol(2‐OH
E2)whichisshowntobemarkedlystimulatedinplacentasofsmokersviatheup‐
regulationofCYP1A1.
IncreasedCYP1A1levelsaresignificantlyincreasedinex‐smokerscomparedto
thosewhoneversmoked.PAHsarelipophilicandtendtobestoredinthekidneys,liver,
andtoalesserdegreethespleen,adrenalglandsandovaries.ThusPAHsmaybere‐
releasedintothebloodcirculationduringpregnancy,similartothemobilizationoflead
frommaternalbonestorespreandpostpartum,[75,274].ToxicPAH‐DNAadductsfrom
smokingaredetectableinovariangranulosa‐luteincells,oocytesandspermatozoa.
PaternaltransmissionofalteredDNAtopreimplantationembryoswereshownin
assistedcontraceptionexperimentsandmaycompromiseembryonicdevelopment
suchasfailedimplantationorearlypregnancyloss[275].Thereforeperhapsthe
increasedratesofinfertilityandotherrisksassociatedwitholdermaternalagehasless
todowithbiologicaldeclineandmoretodowithincreasedtoxicbodyburdensinboth
menandwomen.Exposurestypicalofurbanairpollutionandmoderatepre‐conception
maternalsmokinghaveshowntoadverselyaffectplacentalmorphologyinmicemodels
[276,277].
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Chapter2:MethodologicalBackground“themajorcausesofdiseaseandsufferinginthepopulationarefirmlyrootedinthebehavioural,social,andpsychologicalworldsinwhichpeoplelive…[and]areembeddedinmultipleenvironmental,geographical,institutional,andeconomiccontexts.”‐Kaplan,G.A.ResearchLectureattheNobelForum,April8,1999,p.2[1].
1.0IntroductionWhiletherootsofasocialapproachtohealthcouldarguablybetracedbacktothe
sanitarycampaignsofthe19thcenturyinBritain,thefocuswasprimarilyonimproving
environmentalhygienetopreventtransmissionofpathogeneticdiseasestypicalofnon‐
industrializedstates.ItwastheWhitehallstudywithaLancetpaperin1978that
definitivelyestablishedtheepidemiologicalassociationbetweenchronicdiseasestatusand
socialclassinamodernindustrializedsetting[3].Byfollowingaprospectivecohortof
17,530civilservantsinLondonforsevenyears,itshowedthatriskfactorsforcoronary
heartdisease(CHD)includingsmoking,leisureexercise,plasmacholesterol,bloodpressure,
heightandweightonlypartiallyexplainedoccupationalclassdifferencesinCHDmortality
[3].
Aroundthesametime,JohnCasselproposedina1976lectureseriespaperthat
psychosocialstresswithinthecontextofthelargersocialenvironmentiscapableofaltering
diseaseresistanceofthehosttotheubiquitousmicrobiologicandphysiochemicalagentsin
theenvironment[4].Casseladvancedtheconceptsofseveralscientists,notablyReneDubos
forhis1965bookManAdaptingandL.E.Hinkleforhis1973paperTheConceptofStressin
theBiologicalandSocialSciences,fromwhichhequotes“Itisevidentthatanydisease
process,andinfactanyprocesswithinthelivingorganism,mightbeinfluencedbythe
reactionoftheindividualtohissocialenvironmentortootherpeople”[4][p.3].Hegoeson
toarguethatthepsychosocialprocessorstressorisunlikelytohaveadirectpathologywith
etiologicspecificityoradose‐responserelationshipforanygivendisease;butratherthat
theseprocessescaninpartcontributetoalldiseaseindirectlyviaalteredneuroendocrine
imbalance[4].Fortyyearslater,researchisjustnowstartingtoelucidatethepossible
mechanisms[5,6].
WithrespecttotheWhitehallstudy,theclearmortalitygradientsbysubtle
differencesinsocialpositionwithinwhite‐collaroccupationswasgroundbreakingandin
partledtowhatisnowtermedasthesocialdeterminantsofhealth.Repeatedtwentyyears
laterwithanewcohort(theWhitehallIIstudy),theresultsweresubstantiatedwhich
showednodiminutioninsocialclassdifferencesinmorbidity[7].
52
Thefollowingsectionwilldiscusstwoprincipleissuesinobservationalepidemiology
1)theassessmentsocio‐economicstatus(SES),whatitisandhowtomeasureit;and2)
considerationofhealthoutcomedata,specificallyperinatalhealthdataandthedata
containedintheBCPerinatalDatabaseRegistry(BCPDR).Thesubsequentsectionthen
shiftstoexposureassessment,specificallyscenario‐basedlanduseregressionmodels,and
theirusewithinthecontextofpopulation‐basedepidemiologicresearchsuchasthis
dissertation.
2.0Socio‐economicStatusBackgroundSocio‐economicstatus(SES),orsocio‐economicposition,isanumbrellaterm
generallyusedtomeasuresocialinequity.Thereareseveralvariablesoftenusedas
indicatorsofSES,themostcommonbeingincome,occupationand/oreducational
attainmentmeasuredatboththeindividualandpopulationlevel[8–11].Theindirect
mechanismsbywhichSESvariablesoperatetoaffectindividualandpopulationhealthare
notfullyunderstooddespitethelonghistoryofresearchsupportingtheassociation[12–
16].ItisimportanttorecognizethatthecausalpathwaysofSESoperateatmultiplelevelsof
hierarchy(individual,household,neighbourhood,city,etc.).Socalled‘upstream’
determinants(incomeinequality,impoverishedcommunities)leadto‘downstream’
determinantsormediatingexposures(unhealthybehaviours,allostaticload)thatexistin
relationtooneanothertoinfluencediseaseriskasopposedtobeingindependentlyacting
phenomena[17].Forexample,aperson’sfoodchoiceisinfluencedbytheavailabilityand
accessibilityofhealthyfood(orlackthereof)intheneighbourhoodorcommunity,the
consumptionofwhichinturnreinforcesitsavailabilityinstores,creatingapositive
feedbackloop[18,19].Further,aperson’sbehaviourisinfluencedbytheprevalenceofthat
behaviouramongtheirpeers[20]whichthennormalizesthatbehaviourwithinthesocial
environmentwithpotentialforintergenerationaltransmission[21].Thesetwoexamples
representtwodifferenttypesofdetermination,reciprocalcausationandstructural
causationrespectively[22],andmaysubvertattemptstodisentangletheindividual
(compositional)factorsfromthesocial(contextual)factorsunlesscarefulefforttomodel
thesehierarchicalphenomenaisundertaken[23–26].
2.1MeasuringSocio‐economicStatus
Whenplanningtheconceptualmodelitisimperativetoconsidernotonlythelevelof
measurement(compositional,contextual),butalsothemannerinwhichSESismeasured
53
(absoluteorrelative),itspresumedroleinthemodel(confounderorriskfactor),and
how/ifitwillbeadjustedfor[10].ThethreemainindicatorsofSES(income,education,and
occupation)areinterrelatedbutarenotnecessarilyinterchangeable,andusingone
measureoveranothermayaffecttheresultsandmisleadinterpretations[27–30].Guidance
onselectingameasureofSEScanbevettedusingninecriteriaprovidedbyLiberatosetal.
(1988).Theyinclude:conceptualrelevance(relativestatusorabsoluteclassranking),its
roleinrelationtootherriskfactorsandtheoutcome,itsapplicabilitytothestudy
population,itstimerelevanceandstability,itsreliabilityandvalidity,whetherornotthere
aremultipleversussingleindicators,discreteversuscontinuousmeasures,itssimplicity,
anditscomparabilitywithotherstudies[10].
InequitiesinAPOsacrossracial/ethnicminoritystatusoftenparallelSESdisparities.
Thishasbeenobservedinmanymultiracialcountries,withevidencetosuggestboth
confoundingandeffectmodification.Black‐WhitedifferencesinPTBriskpersistafter
adjustmentforSESdifferences[17].Similarly,inCanadaAboriginalstatuscorrelateswith
manyuniqueupstreamdeterminantsoflowSESgiventhecolonialhistorywhichresultsina
disproportionateincidenceofAPOsafteradjustmentofSESdifferences[31–37].However,
lowSESremainsassociatedwithAPOsevenwithinracial/ethnicpopulationsandwarrants
furtherinvestigationintopossibleeffectmodificationbyneighbourhood‐levelfactors[17,
30].Forexample,the‘healthymigrantparadox’inMontreal,Quebecwasfoundtodepend
onthecountryoforigin,theirlevelofeducationandvariousneighbourhoodfactors[38].
Alternatively,truebiologicalandgeneticdifferencesmaypartlyaccountforthe
observeddiscrepancies;andthepotentialformisclassificationofnewbornsaseither
normal,SGAorlarge‐for‐gestationalage(LGA)mayhaveimplicationsoninterpretingrisk
rates[39].Forexample,FirstNationsbirthsinBritishColumbia(BC)tendtohave
significantlyhighermedianandmeanbirthweightsatallgestationscomparedtoallbirths
inBCdespitehavinglowerSESvaluesingeneral[40].Conversely,infantsofChineseand
SouthAsiandescentborninBCandelsewherehavesignificantlylowerbirthweightsthan
infantsofEuropeandescent[39,41].Usingthestandardprovincialbirthweightchartfor
newbornclassification,lessthantenpercentofFirstNationsinfantswouldbeconsidered
SGA‐10resultinginfalse‐negativesandthepotentialneglectofhealthrisksfacedbysmall
babiesmisclassifiedasnormalgrowth.Theadoptionofethno‐specificorcustomizedfetal
growthchartsmaybewarrantedinordertopreventthepotentialmisclassificationof
newbornsasSGAorLGA[42];however,thebenefitsofcustomizedbirthchartscontinueto
54
bedebated[43–45].Theuseofasmallercut‐point,suchasthe3rdor5thpercentileforbirth
weightwouldreducetheriskoffalse‐positivebycapturingtrulygrowthcompromised
newborns.
Inperinatalepidemiology,theuseofmaternaleducationasanindicatorofSEShas
beenshowntobestrongerthan,andindependentof,neighbourhoodincomeinrelationto
APOs[46].Bothindividual‐levelandarea‐basedmeasuresofmaternaleducationarestrong
predictorsofAPOs,regardlessofwhethereducationwasevaluatedasarelativeorabsolute
inequalitymeasure[47].Maternaleducationisanupstreamdeterminantthatpredicts
manydownstreamexposuresassociatedwithAPOs,includingheavysmoking,druguse,low
levelofprenatalcare,stressfulwork,infectionsandpsychosocialfactors[17].Low
educationandneighbourhoodSEShavebeenassociatedwithnutritionallypoorfoods
choicesandsuboptimalfruitandvegetableintake[19].
2.2Contextual(population‐level)MeasuresofSES
Facilitatedbydevelopmentsinstatisticalsoftwareprogrammingandadvancesin
computingspeed,thepopularizationofmultilevelmodelsoverthepasttwodecadeshas
spawnedaresurgenceofinterestintheanalysisofpopulation‐levelmeasuresofSESon
health[11,48,49].Ofparticularinterestistheabilitytoestimatecoefficientsofthe(cross‐
level)interactionsbetweenlevel‐onepredictorsoftheindividualandlevel‐twopredictors
measuredatthegrouplevel[23,50,51].Thecommonterminologyusedsynonymouslywith
‘contextual’includesneighbourhood,group,level‐2,andarea‐based.Level‐2variablescan
representgeographichierarchies,suchasneighbourhoods,cities,watersheds,butcanalso
representtimepointssuchasinlongitudinalstudies,classrooms,schools,oranygrouping
orclusteringvariable.Hierarchicalmultilevelmodelsarereviewedinmoredetailinthe
followingsection.
Thereareseveralwaystocreateorobtaingrouplevelmeasures,nationalcensus
beingthemostcommondatasource.Similartoindividuallevelmeasures,themost
frequentlyusedareincomeandeducation,oftenrepresentedbythegroupmean.The
percentageofunemployedisacommonoccupationalmeasureused.Compositionalindices
basedonthestatisticalweightingofseveralindicatorvariableshavebeenregularlyusedas
theycanincorporatethemultipledimensionsofSESinaneighbourhood[10].Theconcept
ofmaterialdeprivationreferstotheabilitytoaccessmaterialgoodsandconveniences,
whilesocialdeprivationreflectsthedegreeoffamily‐communitycohesionandsocial
interactions.Withtheaidofgeographicalinformationsystems,area‐baseddeprivation
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indiceshavebecomeacommontooltoassesspatternsanddegreeofSESinequalitiesin
relationtohealth[52,53].Inthisdissertation,IuseanSESindexproducedbyChanetal.
specificallyforthestudyofhealthoutcomesrelatedtoenvironmentalpollution[54].This
indexreflectsmoredimensionsofSESthanthedeprivationindexproducedbyPampalonet
al.[22]byusing22SEScensusvariablesincludingculturalidentitiesandhousing
characteristics,andwasshowntoperformbetterincapturinggradientsinprevalenceof
pregnancyoutcomes.ItalsohadmorecompletespatialcoveragecomparedtothePampalon
index,greatlyreducingthenumberofimputedvaluesforruralcensusDAs.
Indicatorsusedtoconstructadeprivationindexshouldbeassociatedwithhealth,be
relatedtoSES,andbeascertainablebysomestandardizedgeographiccensusarea.Itis
possibletocreategroup‐levelvariablesusingindividual‐levelindicatorsofSESsuchas
education.Thiscouldbeaverageyearsofeducationforadefinedneighbourhoodorthe
percentofthepopulationwithoutahighschooldiploma.Issuesregardingpotential“same
sourcebias”aregenerallytheresultofpoordataqualityand/orhighnumbermissing
values.Arecentstudycomparingindividual‐levelderivedmaternalneighbourhood
educationandacensus‐basedmeasureofeducationfoundthatpotentialbiaswasminimal
yieldingsimilarassociationswithPTB[47].
Onearea‐basedmeasurethatconfoundsandinteractswithmeasuresofSESisrural
location.Thereisnoabsolutedefinitionofruralotherthanbeing‘noturban’,butthis
dichotomizationcanmaskunderlyingtrendsinperinatalhealth[55–59].Definitionsof
ruralareoftenbasedonpopulationsizeanddynamicsandtheinterrelationshipofresidents
betweenotherlocations,particularlylargercitiesandmetropolitanareas.Commuterflows
and“metropolitaninfluencedzones”havebeendevelopedtoclassifyruralinrelationtothe
nearesturbancenteronacontinuousscaleusinghierarchical‐relatedcensusgeographic
areas(i.e.therural‐urbancontinuum)[60,61].InthisdissertationIuseStatisticsCanada’s
MetropolitanInfluenceZone(MIZ)methoddescribedabovetodefineruralresidenceintoa
dichotomous(CensusMetropolitanAreas(CMA)andCensusAgglomeration(CA)areas
versusCensusSubdivisions(CSDs)thatlieoutsidetheseareas)aswellasafivevalue
categoricalvariablerangingfromCMA/CAtothefourzonesofinfluence(strong,moderate,
weak,andnone)accordingtothedegreeofinfluencethatCMA/CAshaveonthem[60].
Finally,whencreatinggroup‐levelSESindicatorsbasedonageographicboundary,
howthatboundaryisdefinedmayinfluencetheresultsobtained.Asstatedabove,
administrativecensusboundariesarethemostcommonforseveralreasons.Thedatais
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routinelycollectedwithahighdegreeofqualityandisfairlystableovertime.However,
researchershaveimplementedtechniquestocreatenewboundarieswithahighdegreeof
within‐areahomogeneitytherebyreducingthepotentialforwithin‐areaconfounding
[62,65,66].InCanada,whileDAsdonotnecessarilyrepresentexistingneighbourhood
communities[62],theycanserveasadequateproxiesforageneralcatchmentareaof
personalhome‐lifeactivities[63,64].
Underlyingtheboundaryselectionissueistheconceptofspatialscaledependencies
orthe‘modifiablearealunitproblem’(MAUP)[67].MAUPhastwodistinctcomponents:the
scaleeffectandthezoningeffect.Thescaleeffectrecognizesthatasoneaggregatesdataup
thespatialhierarchytherelationshipbetweenvariablescanchangeoftenstrengtheningthe
regressionrelationshipbutreducingstatisticalpowerduetotherebeingfewerunitsinthe
analysis.Thezoningeffectreferstotheactualdelineationofboundariesandhowtheir
manipulationcandrasticallyalterneighbourhoodcharacteristicsduetotheinclusionor
exclusionofcertaindatapoints(i.e.peopleordiseaseevents).Considerationofthespatial
unitusedintheanalysisshouldbebasedontheresearchquestionandtheprocessthatis
attemptingtobemodelled.InthisdissertationweusecensusDAsastheneighbourhood‐
levelunitofanalysis.DAsarethesmallestgeographicalunitforwhichcensusdataare
availableandrepresentneighbourhoodblocksrangingbetween200–800people.TheDA
waschosenpartlyduetoconvenienceinthatitwasthespatialunitthatmatchedtheSES
indexaswellastheotherSEScensusdatasuchaseducationandimmigrantdensity.Butthe
DAwasalsochosenforpracticalreasonsduetothescaleofthisprojectencompassingthe
entireprovinceofBC.Whilescalingupinurbanareascouldhavebeenexplored,thiswould
beimpracticalforthelargergeographicsizesofruralDAs.Managingthreedifferent
geographicspatialunitsorhavingdifferentspatialunitsforurbanandruralareaswouldbe
anadditionalcomplicationwithpossiblyminimalbenefitininterpretation.Furthermore,
usingDAsallowsforthecomparisonofresultstootherstudies.
3.0MultilevelModels&Analysis*muchofthissectionhasbeenadaptedfromSnijdersandBoskar,MultilevelAnalysis:AnIntroductiontoBasicandAdvancedMultilevelModeling[25].
Multilevelmodelsgobymanynamesandhaveseveralflavours.Whilenotanew
methodology,itisonlyinthelasttwodecadesthattheiremergencehasmovedbeyondthe
socialsciences(sociology,education,economics,criminology,etc.)andintopopulation
healthandepidemiology.Multilevelanalysisisamethodologyfordatawithnestedsources
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ofvariability,whereinthebetweengroup(orcluster)variabilityisasimportantaresearch
questionasthewithingroupvariability.Bydecomposingtheoverallvariabilityinto‘within’
and‘between’unitsofanalysis,theresearcherisabletoadjustforandquantifyintra‐group
dependencewhilesimultaneouslyquantifyingtheinter‐groupvariability[25].Forexample
ineducationalresearch,therecanbevariabilitymeasuredatthestudentlevelwith
individualattributes(e.g.IQontestscores).Thesestudentsarenestedwithinschoolsthat
havetheirowncharacteristicsanditispossibletomeasurethebetween‐schoolvariability
acrossdifferentschools(i.e.eachschoolwillimpartsomeuniqueeffectonindividualtest
scoresandtheadditionofschool‐levelvariables(e.g.publicvs.private)areusedtohelp
explainthemeasureddifferences).Additionally,schoolsareoftennestedwithinschool
districtswithdistinctcharacteristics.Dependingontheresearchquestion,allthreeofthese
‘levels’(student‐school‐district)mayhaveinterestingandnecessaryvariabilitytoaccount
for.
Multilevelanalysisasitistodaywasformedbytheconvergenceoftwodistinctfields
ofinquiry;namelycontextualanalysisasadevelopmentinthesocialsciencesrecognizing
theinfluenceofsocialcontextonindividualbehaviour/outcomes,andthedevelopmentof
mixedeffectstatisticalmethodsthatallownestedregression‐typemodelcoefficientstobe
eitherfixedorrandom.Theconfluenceofthesetwostreamscoincidedwiththeemergence
ofthecomputationalprocessingeraintheearly1980swhichallowedgreateraccessibility
inrunningmorecomplicatedmodels[25].
Thehierarchicallinearmodelisthebackboneofmultilevelanalysisandisessentially
anextensionofmultiplelinearregressiontoincludenestedrandomeffects[25].The
employmentofanestedresearchdesignsometimesarisesfromnecessityandothertimes
ascuriosity.Respectfully,thiscanbereferredtoasdependenceasanuisanceordependence
asaninterestingphenomenon.Theformerarisesfrommulti‐stagedsamplingdesignswhich
inherentlyleadtodependentobservations(i.e.selectionofagroupingunit(school)
increasesthelikelihoodintheselectionoftheindividualunit(student)).Thisdependence
insamplingviolatesanessentialassumptionofinferentialstatisticscausingdeflated
standarderrorsandpotentiallyleadingtoTypeIerrors.Inthelattersituation,dependence
betweenandwithinnestingstructuresisthefocalinterestwhereonewishestomake
inferenceatbothlevels.Regardlessofthemotivation,single‐levelstatisticalmodelsareno
longervalidalthoughtherearestatisticalmeanstodealwithnuisanceclusteringof
observations(e.g.sandwichestimatorsofstandarderrors)[25].
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Theterminologyusedtodescribethemultilevelmodelisvaried.Forourpurposes
here,wewillrefertothemacro‐unitsaslevel‐2orgroup‐levelunitsandsignifiedin
equationsasasubscriptj.Themicro‐unitswillrefertolevel‐1orindividual‐levelunitsand
signifiedinequationsasasubscripti.Inthestudyofmultilevelsystems,sixpropositions
canbedistinguishedandarediagramedbelowinFigure7tofacilitatecomprehension.
Figure7:Sixtheoreticalmultilevelproposition
3.1RandomInterceptModel
Therandominterceptmodelisoneinwhichtheinterceptisallowedtovaryrandomly
betweenthelevel‐2groups.Thisallowsforeachlevel‐2group(e.g.neighbourhoods,
schools)tohaveitsowninterceptalongwithitsvariancefromtheoverall(global)intercept.
Whenregular(ordinaryleastsquaresorOLS)regressionisusedondatathathasa
meaningfulhierarchicalstructure,itis(erroneously)assumedthatallthegroupstructureis
representedbytheexplanatoryvariableswhichisreflectedbythesinglefixedintercept.
Therefore,foranytwoindividualsitisinconsequentialwhethertheyarefromthesameor
differentschoolorneighbourhood.
Thesimplestwaytothinkaboutrandominterceptmodels,orhierarchicallinear
modelsingeneral,istoconsideritaspecialcaseofregressionmodelsbutwithmorethan
oneerrorterm.Thegroup‐dependentinterceptcanbesplitintoanaverageinterceptand
thegroup‐dependentdeviationfromtheoverallmean(i.e.level‐2randomerror).This
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signifiestherealizationthatsomegroupswillhavehigherresponsesYonaverageand
otherswillhavelowerresponses.Theregressionequationbelow(Eq.1)showsthatthe
interceptdependsonthegroup(signifiedbythesubscriptj).Fornowthe coefficientofX
isconstantorfixed,butthenextsectiondescribeshowittoocanbeallowedtovary
betweengroupstoproducetherandomslopemodel.
(Eq.1)
(Eq.2)
(Eq.3)
ReferringtoEq.1,theinterceptfromlevel‐1, ,isestimatedasamodelparameterwithits
owngroup‐levelregressioncoefficient(γ10)anderrorterm(U0j)thatdeviatesfromthe
overallaverageintercept(γ00).Substitutionproducestherandominterceptmodel
presentedasEq.3,sometimesreferredtoasan‘intercept‐as‐coefficientmodel’.
Theemptyornullmodelisamodelthatdoesnotcontainanyexplanatoryvariables.
Here,thedependentvariable( )isonlyafunctionoftheoverallmean(γ00),thegroup‐
levelrandomeffect(U0j),andtheindividual‐levelrandomeffect(Rij).
(Eq.4)
ItisassumedthattherandomvariablesU0jandRijhaveameanof0,aremutually
independent,drawnfromnormallydistributedpopulations,andhavevariancevar( )=σ2
andvar(U0j)=τ02.Thenullmodelprovidesthebasisforcalculatingtheintraclasscorrelation
coefficient(ICC),aparameterthatindicateshowthevariabilityinthedataispartitioned
betweenthetwolevels.TheICCiszerowhenthereisnobetween‐cluster(macro‐unit)
variance,andincreaseswhenthebetween‐clustervarianceincreasesrelativetothewithin‐
clustervariance.RepresentedbytheGreeksymbolrho(ρ),theICCiscalculatedbydividing
thebetweenpopulationvarianceofthemacro‐unitsbythesumofthemacro‐andmicro‐
unitvariance,τ2/(τ2+σ2).TheICCcanbeinterpretedintwoways:1)itisameasureofthe
correlationbetweentworandomlydrawnmicro‐unitsbelongingtothesamemacro‐unit
drawnatrandom;2)itistheproportionofvarianceaccountedforbythegroup‐level.
Fromthenullmodelwebegintointroduceexplanatoryvariablesinordertoexplain
thevariabilityofYatbothlevel‐1andlevel‐2.ReturningtoEq.3,thismodelhasfour
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parameters:thetworegressioncoefficientsγ00andγ10whichmakeupthefixedeffectsand
thetwovariancecomponentsσ2andτ02(therandomeffects).ThevaluesU0jarethemain
group‐leveleffects(orgroupresiduals)thatareleftunexplainedbyX.Theoverallintercept
γ00isthefixedinterceptfortheaveragegroup(averagedoverallgroupsbutwithlarger
groupshavingmoreinfluenceonitsestimationthansmallgroups).Thefixedregression
coefficientγ10isinterpretedintheusualway(i.e.aone‐unitincreaseinXisassociatedwith
anaverageincreaseinYofγ10units).
Theadditionoflevel‐2explanatoryvariables,denotedbyZ1…Zq,takestheforminone
oftwoways.Level‐2variablescanbedirectlydefinedbyaunitcharacteristic(e.g.thelevel‐
2groupofschoolscanbeeitherprivateorpublic).Alternatively,alevel‐2variablecanbe
definedbytheaggregatedunitsatlevel‐1(e.g.themeanSESofstudentsinaschool).This
lattercharacterizationbasedongroupmeansisaparticularlyimportanttypeof
explanatoryvariableasitallowsforthedifferentiationbetweenwithin‐groupandbetween‐
groupregressionstobeexpressed.Thewithin‐groupregressioncoefficientexpressesthe
expecteddifferenceinYbetweencaseswithinthesamegroupforaone‐unitdifferencein
theexplanatoryvariableX;whereasthebetween‐groupregressioncoefficientisthe
expecteddifferenceinthegroupmeansonYbetweengroupsforaone‐unitdifferencein
theirmeanvaluesofX.Thisisnoteworthybecausetheprocessesatworkwithingroupscan
differfromtheprocessesatworkbetweengroups,andcouldthereforehavevastlydifferent
conceptualinterpretations.Forexample,theeffectofahighproportionofneighbourhood‐
levelmaternalsmokingonbirthweighthasadifferentconceptualinterpretationthanthat
ofindividual‐levelmaternalsmokingonbirthweight.
3.2RandomSlopeModel
Inadditiontogroupsdifferingwithrespecttotheaveragevalueofthedependent
variable(i.e.randombetween‐groupinterceptvariance),itispossiblefortheeffectofan
explanatoryvariabletoalsodifferbetweengroups(i.e.randombetween‐groupslope
variance).Thisisreferredtoasheterogeneityofregressionsacrossgroupsorasgroup‐by‐
covariateinteractionintheanalysisofcovariance(ANCOVA)terminology.Returningto
Eq.1,amodelwithgroup‐specificregressionsofYonalevel‐1variableX,boththeintercept
andtheregressioncoefficients,orslopes, canbesplitintoanaveragecoefficientand
thegroup‐dependentdeviationtoproduceEq.2(asseenaboveintherandomintercept
model)aswellasEq.5.SubstitutionleadstothemodelinEq.6
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(Eq.1)
(Eq.2)
(Eq.5)
(Eq.6)
Againhere, istheoverallaverageinterceptand istheoverallaverage
regressioncoefficientandarereferredtoasthefixedeffects.Thelevel‐2residuals, and
,alongwiththelevel‐1residual arereferredtoasrandomeffectsandareassumedto
haveameanof0giventhevaluesoftheexplanatoryvariableX.Theterm isregarded
asarandominteractionbetweengroupandX;thatis,theeffectofalevel‐1attributecan
differbetweengroups.Therandominterceptandrandomslopeareconsideredlatent
variables,astheyarenotdirectlyobservedbutareinfluentialinproducingtheobserved
variables.TheterminologyisthatXhasarandomslope,orarandomcoefficient,ora
randomeffect.Therandominterceptandslopeareoftencorrelated;however,model
assumptionspresumethemtobeindependentandidenticallydistributedbetweengroups
andthattheyareindependentofthelevel‐1residual .Also,itisassumedthatall are
independentandidenticallydistributed.Thevarianceandcovariancesofthelevel‐2
residualsaredenotedas:
var( )=τ00=τ02
var( )τ11=τ12
cov , )=τ01
Therandomslopemodelimpliesheteroscedasticity(unequalvariance)inthatthe
correlationofindividualswithinthesamegroupaswellasthevarianceofYisdependenton
thevalueofX.Forexample,studentsfromlowSEShouseholdsmaybenefitmuchmorefrom
awell‐resourcedschoolcomparedtostudentsfromhighSEShouseholds.Thereforethe
schooladdsacomponentofvariance,butprimarilyforthelowSESstudentsindicatinghow
thevariancedependsonthevalueofXforstudent‐levelSES.
3.3InclusionofLevel‐2VariablesandCross‐LevelInteractions
Theaimofregressionanalysisistoexplainvariabilityinthedependentvariable.For
multilevelregression,thereisnotonlyvariabilitybetweenindividuals(level‐1residual, )
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butalsovariabilitybetweengroupstowhichtheindividualsbelong(level‐2random
intercept, )andvariabilitybetweengroupsinhowtheyinfluence/interactwith
individual‐levelattributes(level‐2randomslope, ).Eachrepresentdifferentpartsofthe
unexplainedvariability,andthuseachcanbethepointoffocuswhenconsidering
explanatoryvariables.Theadditionofindividual,orlevel‐1,variablesaimtoreducethe
level‐1residualvariance(σ2).Theirinclusionmayalsoreducetheresidualvarianceatlevel‐
2giventhatgroupscandifferwithrespecttotheircompositionoflevel‐1variables.The
additionofgroup,orlevel‐2,variablesaimtoreducethelevel‐2randominterceptresidual
variance(τ02).Thisleadstoanexpandedmodelinwhichthegroup‐dependentregression
coefficients and fromEq.2andEq.5nowincludealevel‐2variableZtoproduceEq.7
andEq.8.Substitutionbackintothebasicmodel(Eq.1)leadstothemodelinEq.9.
(Eq.7)
(Eq.8)
(Eq.9)
Theadditionofthelevel‐2variableZleadstoamaineffectofZ( aswellasa
cross‐levelinteractioneffectofXandZ( .Thecross‐levelinteractioneffectisthe
productbetweenalevel‐1andlevel‐2variablethataimstoreducethelevel‐2randomslope
residualvariance(τ12).Inordertohelptheinterpretationofcross‐levelinteractions,itis
stronglyadvisedtogrand‐meancenterthecomponentvariablesXandZsothatthevalueof
0hasaninterpretablemeaning(e.g.theaveragestudentandschoolSESrespectively)or
thatitcorrespondstoacommonreferencevalue(e.g.malestudents,publicschools).
Theapplicationofcross‐levelinteractionscanbeapproachedeitherinductivelyor
theoretically.Theformerimpliesapost‐hocapproachoftestinglevel‐2variablesbasedon
thepresenceofasignificantrandomslope.Thelatterimpliestheiraprioriinclusionbased
onsubstantiveortheoreticalarguments,regardlessofwhetherarandomslopewasfound.
Thedecisionforwhichvariablestogiverandomslopes,cross‐levelandwithin‐level
interactionswilldependonthesubject‐matteraswellastheoreticalandempirical
considerations.Havingasufficientsamplesizeisimportant,butespeciallyatthegroup‐
level.Includingmanyrandomslopesincreasesthedegreesoffreedomaswellasthe
difficultyinmodelinterpretation.Parsimonyshouldalwaysbeadrivingfactorinmodel
specification.
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3.4MultilevelLogisticRegression
Thepurposeoflogisticregressionistopredicttheprobability(pi)thatsomeevent
occursforanindividual(i)conditionalonanumberofvariables.Duetothenatural
constraintsoftheprobabilitydistributionfallingbetween0and1,piistransformedusinga
logitfunctionwhichgivesitadistributionofvaluesbettersuitedforregressionanalysis,
namely‐∞and+∞.Similartomultilevellinearregression,multilevellogisticregression
considersindividualstobestatisticallydependentontheirareaofresidenceorsome
hierarchicalarealunitforwhichtheindividualsarenestedwithin.Itisthismodeled
dependenceandtheabilitytopartitionitsvarianceatthedifferentlevelsthatisthemodus
operandiofmultilevelregressionrelevantforbothstatisticalandsubstantiveepidemiologic
reasons(i.e.improvedestimationandimprovedcontextualunderstandingofarea‐level
measuresonindividualoutcomes).However,whileforthelinearcasethisdependencecan
bequantifiedusingmeasuressuchastheintraclasscorrelation(ICC)discussedabove;the
componentsofvarianceinlogisticmodelsaremorecomplicatedduetothenonlinear
relationbetweenthecovariatesanddichotomousresponsevariable.Asaresult,theICChas
statisticalandinterpretationaldrawbacks[68,69].
Twoalternativemeasuresofinterpretationhavethereforebeenproposed.These
includethemedianoddsratio(MOR)andtheintervaloddsratio(IOR)[68–70].TheMOR
dependsdirectlyonthearea‐levelvarianceandisdefinedasthemedianoddsratiobetween
anytwoareaspickedatrandomwithdifferingrisk(i.e.whatisthemedianincreaseinrisk
foranindividualmovingtoanareawithahigherrisk).TheaimoftheMORistotranslate
thearea‐levelvariancetothemorewidelyunderstoododdsratioscalewhichpermitsthe
directcomparisonofitsmagnitudetothatofthelevel‐1andlevel‐2factors.AnMORequal
toone,orforwhichits95%confidenceintervals(95%CIs)overlapone,wouldindicateno
between‐areadifferencesintheindividual‐levelprobabilityoftheoutcome.AnMORand
95%CIsgreaterthanonewouldindicatebetween‐areaheterogeneityandthattheareaof
residenceisimportantforunderstandingthevariationsintheindividualprobabilityofthe
outcome.Thiswouldtheninvitetheintroductionofarea‐levelvariablestotestwhether
theycanexplainanyofthebetween‐areavariability[68,69].
Theintervaloddsratio(IOR)isafixed‐effectsmeasureforthelevel‐2variablesthat
takesthearea‐levelvarianceintoaccountwheninterpretingtheirassociationwiththe
outcome.TheIORisanintervalforoddsratiosbetweentwopersonswithsimilarcovariate
patterns,coveringthemiddle80%oftheoddsratios;howeversmallerorlargerintervals
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couldbeselected(e.g.70%or90%).TheIORmakesitpossibletodeterminewhethera
level‐2variableisusefultoidentifyhighriskareas,orwhethertheremainingbetween‐area
variabilityistoolargeforthatvariabletomakeadifference.Forexample,iftheIORfora
level‐2variabledoesnotcontainone,thenthissuggeststhatitseffectislargerelativetothe
area‐levelvariance.Conversely,iftheIORforalevel‐2variabledoescontainone,thenthat
variabledoesnotaccountforasubstantialamountofthearea‐levelvariability.Thewidthof
theIOR,whetherit’snarroworwide,givesanindicationoftheamountofunexplained
between‐areavariationinthepropensityofanindividualtohavetheoutcome.Thus,while
related,theMORandIORprovidedifferentinformationusefulintheanalysisofcontextual‐
leveleffects[68,69].
Inthemultilevelframework,observationswithinaparticulargeographicalareaare
assumedtobestatisticallyindependentofthosefromanotherarea(regardlessof
adjacency)therebyignoringanyspatialassociationsbetweenthegeographicalmacro‐unit
areas[71,72].Therefore,themultilevelframeworkhasbeencombinedwithspatial
regressiontechniquesinordertoaccountforthepotentialofspatialdependency(i.e.spatial
autocorrelation)ofthearea‐levelresiduals[73].Thefollowingsectionprovidesabrief
reviewofthemechanismsandmethodsofspatialdependenceinhealthdata.
4.0SpatialDependence:Mechanisms,MethodsandModelsSpatial(inter)dependenceisubiquitous.AsstatedinTobler’sso‐called1stLawof
Geography:everythingisrelatedtoeverythingelse,butnearthingsaremorerelatedthan
distantthings.Whilesimplistic,thisinterpretationofspatialinterdependenceasitrelatesto
theinteractionbetweenthephysicalandsocialenvironmentsandreproductivehealthis
appropriatetoformthebasisofbuildingempiricalmodels.Inpracticehowever,
accommodatingspatialdependenceintostatisticalmodelsisacomplexendeavour,whichis
whyitisoftenignoredorarguedasirrelevant.Itwasrecognizedover120yearsagobySir
FrancisGaltonthatdrawinginferencesfromsamplesthatarenotstatisticallyindependent
canyieldmisleadingconclusions,astatisticalphenomenonnowknownas
(spatial/temporal)autocorrelation[74].Severalmethodsandmodelshavebeendeveloped
capableofaccountingforspatialeffects(i.e.spatialdependenceand/orspatial
heterogeneity)[75,76],inwhichthefollowingparagraphswillbrieflydescribeasameans
tointroducethemethodologiesandterminologyusedthroughoutthisdissertation.
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4.1SpatialDependence&SpatialHeterogeneity
Ingeneral,spatialdependenceexistswhenthevalueofavariableatonelocationis
dependentonitsvaluesatotherlocations.Itcanariseduetospatialinteractioneffects(e.g.
externalitiesorspill‐overeffects[73,77]),orfrommeasurementerror(e.g.scalemismatch
betweenhowavariablewasmeasuredandthatatwhichitoccurs[78,79]).Spatial
autocorrelationisanindicatorofspatialdependenceinwhichavariableiscorrelatedwith
itselfinspace.Spatialheterogeneity(ornon‐stationarity)ontheotherhandrefersto
structuralchangesinadatasetrelatedtolocation,suchasdifferencesinthemean,variance,
and/orcovariancestructureofavariableacrossspace(e.g.therelativedifferenceofSES
differbetweenurbanandruralregimes[80]).Ignoringtheseaspectsofthedatacanleadto
inefficientorbiasedestimatesresultinginmisleadinginference.Forexample,thepresence
ofpositivespatialautocorrelation,wherehighorlowvaluescorrelatewithhighorlow
neighbouringvalues,resultsinalossofinformationinthecontextofgreateruncertainty,
lessprecision,andlargerstandarderrors.Thepresenceofspatialheterogeneitycanresult
fromheteroscedasticity(non‐constanterrorvariance)acrossspaceandindicatescale‐
relatedmeasurementerrors[78,79].Inpractice,itcanbedifficulttodistinguishbetween
spatialdependenceandspatialheterogeneity,andtestsforonemaysignaltheotherand
viceversa[81,82].
4.2SpatialWeightMatrices
Inspatialanalyses,theconceptofspaceisoperationalizedthroughtheuseofspatial
weightsmatrices.Definedastheformalexpressionofspatialdependencebetween
observations[75],theycontaininformationregardingtheneighborhoodorconnectivity
structureinthedatainordertoassesstheextentofsimilaritybetweenlocationsandvalues
(e.g.spatialautocorrelation).Theresearchermustmakeanassumptionregardingthe
structureofinterdependencebetweenanytwoobservations.Thisiscommonlybasedon
adjacency/contiguity(i.e.sharingacommonboundaryoraspecifiednumberofnearest
neighbours)orproximity(i.e.numberofneighbourswithinagivendistance);however,
morecomplexformalizationsarepossiblesuchasusingafunctionaldistancebasedon
traveltimeasopposedtoEuclidian(straight‐line)distance,addingadistance‐decay
mechanismorevensomenon‐geographicnotionofdistance[83].Inshort,theselectionof
thespatialweightmatrixshouldbebasedonsomesubstantiveknowledgeaboutthespatial
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processbeingmodeledandsensitivityanalysesusingdifferentweightmatricescanbe
appliedtotesttheconnectivityassumptions.
Ingeneraltherearetwobasiccategoriesofweightmatrices:contiguity‐based(i.e.
sharedborders)anddistance‐based.Examplesofcontiguity‐basedweightmatricesinclude
RookandQueencriterionwhichsymbolizetheselectionofneighbourstothemovementof
thecorrespondingchesspieces(e.g.north‐south/east‐westforRook,andallpossible
directionalverticesforQueen).Distance‐basedweightmatricescanincludeafixeddistance
criterionbutcouldincludemorenuancednotionsofdistancesuchastime‐travelled
distances,perceptivedistances,orpolicy‐defineddistance[83].Finally,knearest
neighbours(KNN)isatypeofdistance‐basedweightmatrixwhere“k”referstoaspecified
numberofneighboursforeachobservationalunit.Itusesthedistancebetweenthecentral
points(orcentroids)ofthearealunitpolygonstodeterminethenearestneighbouringunits.
Itisusefulinsituationswherethearealunitsareofvaryingsizetoensurethatevery
locationhasanequalnumberofneighboursaswellasinsituationswheresomearealunits
are“islands”(i.e.havenocontiguousneighbours).KNNweightmatricesareasymmetric,
thatis,areaAisB’snearestneighbourbutnotnecessarilyvisa‐versa;whereasQueenand
Rookcriteriaaresymmetric.Thiscanhaveimplicationsonthetypesofspatialanalysesthat
canbeperformed[82].
Thespatialweightmatrixismadeupofonerowandcolumnforeachobservational
unitusingbinary(0,1)codestodefineneighboursas1andnon‐neighboursandthefocal
locationas0(Figure8).Neighboursofneighbourscanbedefinedbyhigherordersof
contiguity.Row‐standardizationtransformstheweightmatrixsothatthevaluesineach
rowsumstoone.Row‐standardizedweightmatricesareusefulwhenwantingtocompare
differentmodelcoefficients.
Thereisnorealempiricalmethodthatcanbeappliedtoselectthe“correct”spatial
weightmatrix;however,twoconsiderationsshouldbetakenintoaccount.Thefirstis
theoreticalandrelatestothehypothesizedunderlyingspatialprocessthatisbeing
Figure8:n byn binaryspatialweightmatrix
Elementswij representingtheassociationbetweenregionsiandjwherewij=1ifiandjareneighbours,wij=0otherwise.
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assessed.Theotherismoretechnical,andhastodowiththetessellationofareal(polygon)
unitused,beitirregularshapedadministrativeareas(e.g.censusareas),auniformgrid(e.g.
5x5kmgrid),orsomeotherlattice(e.g.Thiessenpolygons).
Somesuggestselectingthespatialweightmatrixbasedonthestrengthofthespatial
autocorrelationtest(e.g.Moran’sI).Figure9shows6Morans’Iscatterplotsshowingthe
degreeofclusteringofamodel’sresidualsusingdifferentk‐nearestneighbour(KNN)
spatialweightmatrices.UsingtheabovecriteriaoflargestMoran’sItest,usingaKNN=6
producesthehighestMoran’sI.
Figure9:Moran’sIscatterplotsshowingthedegreeofclusteringofmodelresidualsusingdifferentKNNspatialweightmatrices.
Thereareseveraltestsofspatialautocorrelation.Ingeneral,theymeasurethe
tendencyforhighorlowvaluestoclusterorcorrelatemorecloselyinspacewithotherhigh
orlowvaluesthanwouldbeexpectedifthedatawererandomlydistributed.Globaltestsfor
spatialautocorrelationmeasurethistendencyacrosstheentirestudyarea,whilelocal
indicatorsofspatialassociation(LISA)identifylocal“hotspot”clustersofhighorlowvalues
betweenarealunits[84],ordeterminethedistancebeyondwhichnodiscernablespatial
autocorrelationismeasured[85].Forexample,theMoran’sIstatisticmeasuresthedegree
oflinearassociationbetweenanattribute(y)atagivenlocationanditsweightedaverageat
Toprow,lefttoright:KNN‐4:I=0.0450;KNN‐6:I=0.0480;KNN‐8:I=0.0472;Bottomrow,lefttoright:KNN‐10:I=0.0443;KNN‐15:I=0.0399;KNN‐20:I=0.0384.
68
neighbouringlocations(Wy).Itcanbegraphicallydisplayedusingscatterplots(Figure9)
and/orashotspotclustermaps(Figure10)[84].
Figure10:Moran’sIclustermapshowstheclusteringofmodelresidualsbetweenthearealunits(DAs)usinga6‐KNNspatialweightmatrix.
4.3SpatialRegressionModels
Thespatiallagmodelisalinearregressionmodelthatexplicitlyincorporatesspatial
dependenceintoitsframeworkbyaddinga“spatiallylagged”dependentvariableasan
independentvariableontheright‐handsideoftheregressionequation.Sometimesalso
calledaspatialautoregressivemodel,thismodelisappropriatewhenitisbelievedthatthe
valuesofthedependentvariableinthefocalneighbourhoodisdirectlyinfluencedbythe
valueofthedependentvariableinneighbouringunitsaboveandbeyondthepresenceof
othercovariates.Alternatively,ifitisbelievedthatalatentspatiallyclusteredprocessor
variableisinfluencingthedependentvariableinthefocalandneighbouringunits,thenthe
spatialerrormodelmaybemoreappropriate[86].
Asignificantspatiallagtermmayindicatestrongspatialdependence,butmayalso
indicatethepresenceofMAUPregardingthemismatchofspatialscalesbetweenthespatial
processunderstudyanditsmeasurementbysomeproxyvariable.Asignificantspatial
69
errortermindicatesspatialautocorrelationintheerrors,likelyduetothepresenceof
importantunmeasuredexplanatoryvariablesnotincludedinthemodel[81].
Thus,forexample,letthedependentvariablebetheprevalenceofmaternal
smokingwhilepregnantinaneighbourhood.Itcouldbethatthisispartlyafunctionof
maternalsmokinginadjacentneighbourhoods,ratherthanjustbeingrelatedtocommon
unmeasuredvariablesinthoseneighbours.Hencethespatiallagmodelmightofferinsight
intospatialexternalitiesofthespatialtransmissionof(un)healthybehaviours,andimplies
thatthespatialdependenceisaninterestingphenomenontoinvestigate.Thespatialerror
modelontheotherhandimpliesthatthepatternofspatialdependenceisattributableto
unmeasuredcovariates(i.e.thestochasticcomponents)only.Hence,spatialerrormodels
arerarelytheory‐driven,andemployedmainlytoaccommodatenuisancespatial
dependence[83,86].
4.4RateSmoothing
Ratesmoothingisonewaytoaddressthevarianceinstabilityofrawratesin
populationsofdifferentsizes.Smoothedratesarestabilizedbyborrowingstrengthfrom
neighbouringspatialunitsinwhichtheamountofsmoothingisinverselyproportionalto
theunderlyingsizeofthepopulationatrisk.Thatis,areaswithsmallpopulationcountswill
producerawriskrateswithlargestandarderrorsandwillthereforeundergogreater
smoothingadjustments.Thereareseveraldifferentflavoursofratesmoothers[87].
Excessriskmaps(akastandardmortalityratesorSMRs)areusedtovisualizethe
degreetowhicharealunitratesexceedorarebelowtheexpectedaveragerisk.Excessrisk
mapsarebasedontheratiobetweentheobservedtoexpectedcountsofanevent(SMR=
Observed/Expected).Expectedcountsaretheproductofthelocalriskrateandtheaverage
overallriskforthestudyregion.Unlikesmoothers,excessriskmapsonlyre‐scaletheraw
ratesothatthemagnitude,nottheorder,oftheoriginaldatachanges.Thesemapshowever
donotprovideinformationonstatisticalsignificanceoftherates[82,87].
TheSpatialRatesmootherissimilartoaspatialmovingaverageinwhichrawrates
arecomputedforeacharealunitaswellasitsneighboursasdefinedbythechosenweight
matrix.It’sapplicationisusefultoidentifyspatialregimesinthedata,aformofspatial
heterogeneitywhichimpliesstructuraldifferencesacrossspace[82,87].
TheEmpiricalBayes(EB)smootherisbasedontherawrateforeacharealunitthatis
averagedusingapriorestimatebasedontheentirestudyregion(i.e.theoverall(global)
populationmeanandvariance).Inlargestudyareaswhereregionalcharacteristicsmay
70
influencetherates,alocalpriorcanbesubstitutedovertheglobaloneasdefinedbyagiven
spatialweightsmatrix(socalledthespatialEBsmoother).Whenselectingbetween
smoothers,considerationshouldbegiventotheareawherestrengthisborrowedfromand
itsrepresentativenessoftheunderlyingriskinthelocalarea[82,87].
Theadvantageofsmoothingcanbeadouble‐edgedsword.Thebenefitsincludethe
removalofspuriousoutliersandtheabilitytorepresentoverallpatternsbeyond
particularlyhighandlowvalues.Theflipsideisthatresultscanbequitesensitivetoagiven
smoother,andover‐smoothingmayconcealinterestingextremecases.Itiswisetoperform
aseriesofsensitivityanalysesusingdifferentsmootherstogaugethedegreeofchangein
theresults.EBstandardizationprocedureisusedintheglobalMoran’sIscatterplotand
LISAmaps.Itdirectlystandardizestherawratestoobtainaconstantvariancewithazero
meanandstandarddeviationofone.
5.0PerinatalDataRegistriesandAdversePregnancyOutcomes
5.1TheBCPerinatalDatabaseRegistry
TheuseofexistingbirthregistriestoidentifyenvironmentandSES‐relatedhealth
relationshipsisausefultoolinpublichealthmonitoringandsurveillanceresearchwhich
hasbeeninpracticefordecadesinScandinaviancountries[27,88–91].InCanada,the
CanadianPerinatalSurveillanceSystem(CPSS)isapartnershipbetweenseveralfederal
agenciestogetherwiththeprovincesandterritorieswhichareresponsibleforcollecting
specificindicatorvariablesandsharingthemwiththeCPSSfornationalassessmentand
interpretation[92,93].Whilenationalsurveillanceisimportant,theresolutionofthedata
collectedbytheCPSSistoolowforresearchintoputativeenvironmentalexposuresand
accessingprovincialregistrydataisoftenbettersuitedforthistask.
TheBritishColumbiaPerinatalDatabaseRegistry(BCPDR)managedbyPerinatal
ServicesBC(PSBC)isacomprehensive,province‐wideperinataldatabasecollectedforthe
purposeofevaluatingperinataloutcomes,careprocessesandresources,ultimately
improvingmaternal,fetal,andnewborncare.TheRegistryaccountsfor99%ofbirthsinBC
collectedfromfacilitiesthroughouttheprovinceonavoluntarybasis.Datacollected
includes:antenatal,intrapartumandpostpartummaternalandinfantcareandoutcomes,as
wellasneonatalfollow‐upandoutcomesincludinglinkingtoBCVitalStatstoprovideinfant
deathdata.Dataqualityisaddressedbyvalidationedits,errorsandwarningsaspartofthe
dataentrysoftwareprogram,periodendchecksandreports[94].Thirdpartydataaccessis
providedbyaPartnershipAccord/MemorandumofAgreementbetweenallBCHealth
71
AuthoritiesandPSBCthroughtheFreedomofInformationandPrivacyProtectionAct.Data
releaseapplicationsarereviewedbytheResearchReviewCommitteewithrepresentation
fromhealthcareproviders,healthauthorities,andacademicorganizations[95].One
shortcomingoftheBCPDR,aswellasmanybirthregistriesinCanada,isthehandlingof
congenitalanomalysurveillance.Thecompleteandreliableascertainmentofcongenital
anomaliescanbethemostchallengingaspectofmaintainingahighqualitysurveillance
system.Thereforedespitehavingthedata,congenitalanomaliesarenotassessedinthis
dissertation.
5.2AdversePregnancyOutcomes
5.2.1MeasuresofBirthWeight
WhenconsideringmeasuresofbirthweightinstudiesofAPOs,itisimportantto
differentiatebetweenthreerelatedtermssometimesusedinterchangeablybutwhichare
notnecessarilysynonymous.Lowbirthweight(LBW)referstoinfantsbornweighingless
than2,500gramsregardlessofgestationalage,althoughdistinctionsbetweenpreterm,
termandpost‐termLBWcanbemade[96].LBWistheresultoftwooverlappingbut
distinctetiologies,PTBand/orIUGR,thedeterminantsandhealthconsequencesofwhich
arequitedifferent[17].Therefore,theuseofLBWinepidemiologicalstudiescanbe
problematicduetheambiguityofitsunderlyingetiology.Small‐for‐gestationalage(SGA)
referstoinfantswhoseweightfallsbelowathresholdcut‐pointofagivenpercentile(e.g.
the10thor3rd)usingsex‐specificbirthweightforgestationalagedistributioncurves[97],
althoughfurthercustomizationbasedonmaternalcharacteristicshavebeenargued[43–
45].Intrauterinegrowthrestriction(IUGR,orfetalgrowthrestrictionFGR)isdefinedasthe
processthatleadstoSGAorLBWbysomeaetiologythatlimitsthegrowthofthefetusfrom
itsfullpotential[98,99].Itisdiagnosedduringtheantenatalperiodfrommeasurementsof
fetalgrowthusingultrasoundtechniquesandplottingagainststandardizedfetalgrowth
curvesforthegivengestationalage[100].Ifmeasurementsandweightfallbelowthetenth
percentile,fetalgrowthrestrictionissuspectedandtherapeuticmanagementcanbe
initiated.ThedeterminationofwhethertheFGRisasymmetricalorsymmetricalgivesclues
tothecausalmechanism.SymmetricFGRdescribesafetusthatisproportionallysmalland
mayjustbeitsconstitutionalmake‐up;conversely,asymmetricalFGRindicatesthatafetus
isundernourishedandisdirectingitsenergyawayfromtheliver,muscleandfatto
72
prioritizegrowthofvitalorganssuchasthebrainandheart.AsymmetricFGRisindicative
ofplacentalinsufficiencyandisassociatedwithworseperinataloutcomes[99].
5.2.2PretermBirth
Pretermbirth(PTB,deliveriespriorto37completedweeksofgestation)is
consideredasoneofthemostimportantperinatalchallengesfacingindustrializedcountries
duetohighinfantmortality,seriouslong‐termmorbiditiesandelevatedhealthcarecosts
[101].Clinically,PTBiscategorizedaseither1)spontaneouspretermlabourwitheither
intactmembranesorpretermprematureruptureofmembranes(PPROM);or2)medically
indicated(iatrogenic)formaternalorfetalconditionssuchaspreeclampsia,haemorrhage,
non‐reassuringheartrateandIUGRinwhichlabouriseitherinducedorthefetusis
deliveredbypre‐labourCaesareansection[102].
Incidenceratesinmanyindustrializedcountriesarerising,largelyduetoincreasesin
medicallyindicateddeterminantssuchaslabourinductionandprelabourcaesarean
deliverybutalsoattributedtoariseintwin/multiplebirthsandbetterestimatesof
gestationalageviaultrasound[102,103].Whendividedintoearly(<31weeks),moderate
(32‐33weeks)andmild(34‐36)PTB,thelargestrelativeandabsoluteincreasesareinthe
lattercategorywhichalsoaccountforthelargestproportionofPTBsinCanadaandthe
UnitedStates.Therefore,whiletherelativerisk(RR)ofinfantdeathamongmildPTBis
smallercomparedtoearlierPTBcategories,etiologicfractionofmildPTBininfantdeath
hasalargerpopulation‐levelimpactduetoitsmuchhigherincidence[104].
Theratesofspontaneouspretermparturition,eitherwithintactorruptured
membranes(PPROM),havebeenstableoverthepastdecadebutaccountsforoverhalfof
PTBcases[102].Theproposedmechanismsthatinitiatethissyndromeincludefactorsthat
stimulatetheinflammationpathwaysuchasinfection,stress,vasculopathicischemiaand
otherimmunologicalandendocrinedisorders[105–107].Meanwhile,theobservedincrease
iniatrogenicPTBsreflectstheincreaseinmildPTBandprelabourcaesareandelivery.An
analysisinCanadashowedthatthelargestindicationandoverallincreaseinprelabour
caesareandeliverywasduetopregnancyinducedhypertension/preeclampsia(PIH/PE)
andpoorfetalgrowth[108].Thereforeregardlessofwhetherit’sspontaneousoriatrogenic
PTB,bothareassociatedwithanddisplaypathoetiologicmechanismsrelatedtoair
pollutionexposure[109–111].
73
5.2.3PregnancyInducedHypertension&Preeclampsia
Preeclampsia(PE)isamultisystempregnancydisorderuniquetohumansthataffects
between2to7percentofpregnanciesandischaracterizedbysystemicendothelial
dysfunctionandincreasedvascularresistance,plateletaggregationandcoagulation
[112,113].Clinicalfeaturesincludenew‐onset(i.e.pregnancyinduced)hypertension(PIH)
andproteinuriaafter20weeksgestation;however,itspathogenesisisthoughttostart
shortlyafterimplantationwithimpairedofnormalplacentationleadingtoinsufficient
placentalperfusionthateventually,dependingonseverity,cascadesintothematernalPE
syndrome[114].Immunemaladaptation,inflammatoryresponseandoxidativestressare
consideredkeymechanisms,whichisevidencedbymanyofthematernalriskfactors.This
isincludesbeingnulliparousorhavinglimitedexposurewithapartnerpriortoconception
(primipaternity),bothofwhichgivescluestoanimmunologicalpathogenesisandmay
explainthehigherriskinyoungwomenunder20yearsold[112,113].Ontheotherhand,
PIH/PEsharemanyriskfactorsandpathophysiologicalabnormalitiestothoseof
cardiovasculardisease(CVD).Thisincludeschronichypertension,diabetesmellitus,obesity
andadvancedmaternalage,allofwhichareassociatedwithexcessoxidativestress[114–
116].Interestingly,smokingisprotectiveagainstthedevelopmentofPIH/PE;howeverthis
protectionmaybelimitedtosmokinginthethirdtrimester[117].Smokingmayexertits
protectiveeffectbyincreasingVEGFAexpressionintheearlystagesofpregnancy[118],
and/orbyreducinglevelsofVEGFantagonistssuchassolubleFlt‐1(sFlt‐1)andsoluble
endoglin(sEng)releasedbyplacentalvilliincompromisedplacentas[117].Thisproposed
mechanismmayalsotieinwithHO‐1statusandtheincreasedpresenceofCOfromsmoking
asascavengerofsFltandsEng[119,120].Todate,deliveryoftheplacentaistheonly
knowntreatment;thereforePIH/PEisamajorriskfactorforPTBandIUGRanduntil
recentlyhasbeenlargelyneglectedasapotentialmediatingoutcomeonthecausalpathway
betweenairpollutionandAPOs[110].
5.2.4GestationalDiabetes
Gestationaldiabetesmellitus(GDM)isaconditionsthataffectbetween3‐6%of
pregnancies,withratesincreasinginCanada[121,122].GDMisassociatedwithincreased
riskofmaternalandfetal/infantmorbiditiesandmortality[121].Womenwhodevelop
GDMhaveanincreasedlifetimeriskofdevelopingtype2diabeteslaterinlife[123,124].
Riskfactorsincludeincreasedbodymassindex(BMI),familyhistory,andoldermaternal
age[124].Recently,thereisaccumulatingevidencesupportingtheirassociationwith
74
exposuretoairpollution[125–127];therefore,GDMshouldnowbeconsideredamediating
outcomeonthecausalpathwaybetweenairpollutionandotherAPOsco‐relatedwithair
pollution.
6.0ExposureAssessment
6.1ExposureAssessmentTerminology
Themeaningoftheterms‘environment’,‘risk’and‘exposure’candifferamong
differentdisciplines;thisisparticularlytrueforinterdisciplinaryfieldssuchas
epidemiology.Theuseofstandardizedandconsistentlanguageiscriticaltoeffective
communication;thereforesomekeytermsrequiretobeexplicitlydefinedatthistime.The
termagentwillbedefinedasanychemical(e.g.particulatematter),biological(e.g.black
mold),physical(e.g.noise,heat)orpsychosocialstressor(e.g.poverty,violence,housing
quality)towhichanindividualorpopulationisexposed[128,129].Exposureisthenthe
contactofanagentattheinterfacebetweenhumansandtheirenvironmentforsomeperiod
oftime[130].Quantitatively,thiscouldbeachemicalconcentrationinacarriermedium
(e.g.air,water,soil,food),decibels,yearsofeducation;however,theexposurecouldalsobe
assessedqualitativelyorsemi‐quantitativelysuchaspresent/absence,Likertorrelative
scale(e.g.high,medium,orlow).
Inorderforexposureanddosevaluestobeofmuchbenefit,theyneedtoberelated
intointerpretabledescriptorsofrisk.Riskisdefinedastheprobabilityofanadverseeffect
occurring.Thereareavarietyofwaystomodelthelinearornon‐linearrelationshipof
exposuretoindividualorpopulationrisk[131].Inriskassessment,ariskmanagermaybe
interestedintermsofahypothesized‘maximallyexposedindividual’toserveastheupper
limitofariskprobabilityorintermsofhypothesizedscenarios(e.g.lifetimeriskofcancer
forahomeowner2kmfromanoilrefinery).Inobservationalepidemiologyhowever,
obtainingpopulationriskisoftenthegoal(e.g.whatistheprobabilityofadditionalcasesof
diseaseperunitincreaseinexposure)conditionalonage,ethnicity,lifestyle,SES,etc.
6.2ExposureAssessmentQuantification
Thequantificationofexposurecanbeapproachedfromthreedistinctand
independentmethodswhichwillinvariablydictatethetypeofexposuremodeltobe
employed.Theyinclude:point‐of‐contact,reconstructionviatheuseofbiomarkers,and
scenarioevaluation.Eachreflectdifferentapproachestodatameasurementandapplication
(i.e.directorindirectmeasureofexposureordose)withitsownstrengthsandweaknesses.
75
Theapproachtakenultimatelydependsonthepurposeoftheexposureassessmentswell
astheavailabilityofresourcesandqualitydata.
Withrespecttoobservationalorenvironmentalepidemiologicstudies,oftenthe
mainpurposeoftheexposureassessmentistoestablishanexposure‐incidenceordose‐
effectrelationship.Thisusuallyinvolvesestimatinghistoricalexposuresforasegmentof
thepopulationbasedongeographyorthepopulationatriskforwhichscenario
developmenthassuccessfullybeenused[132].Scenarioevaluationisanindirectestimate
ofexposure.Thismethodtypicallyusesmeasuredconcentrationdatainabulkmediaor
locationincombinationwithamodellingproceduretoeitherextrapolateorinterpolate
exposureconcentrationstoothermediaorlocationsforwhichmeasurementsdonotexist
[131].Environmentalfate[133,134],land‐useregression(LUR)[135,136],anddispersion
models[137]arecommonexamplesofscenarioevaluationmodels.Focusherewillbeon
theapplicationofLURmodelswithrespecttoenvironmentalepidemiologicalresearch.
Anexposuremodelisaconceptualormathematicalrepresentationoftheexposure
processbycombiningrealmeasurementsandapplyingvariousassumptionstoprovide
estimatesofexposure/doseforadefinedpopulation[128].LURmodelsareatypeof
empiricalmodelthatestimatesthestatisticalrelationship(e.g.regression)between
pollutantmeasurementsandland‐usecharacteristicsasindependentvariablestopredict
concentrationsandapplythemtounknownlocationsusinggeographicinformationsystems
(GIS).LURmodelshavesuccessfullybeenusedtopredictwithin‐cityairpollutant
concentrationsusingpredictorvariablessuchastrafficdensity,roadlength,proximityto
majorroadorothersources(e.g.gasstations,airports)[136,138–140].AnationalLUR
modelwasdevelopedbyHystadetal.(2011)thatcapturedbothbetweenandwithin‐city
pollutionvariabilityacrossCanada.PM2.5,NO2andVOCairpollutantswereappliedtostreet
block‐facepointstodeterminepopulationexposureestimates.[141].
WhiletheapplicationofLURsinenvironmentalairpollutionepidemiologicstudies
hasmanyadvantagesoverothermethods[132,135],theydohavecertainlimitations.
AlthoughnotlimitedtoLURmodels,thepresenceofmeasurementerrorandexposure
misclassificationisofupmostimportance.Distinctionbetweentwocomponentsof
measurementerrorshouldbemade.Berkson‐likeerrorcanbeconsideredaspartofthe
trueexposurenotpredictedfromthemodelandwillinflatethestandarderrorsofthe
healtheffectbutinducesverylittletonobiasinthemagnitudeoftheeffectestimate.
Classical‐likeerrorontheotherhandresultsfromuncertaintyinthemeasurementofthe
76
exposuremodelparametersandcanbothinflatethestandarderrorsaswellasbiasthe
effectestimate[142,143].
Themagnitudeoftheerrorinhealtheffectestimatesdependspartlyonthestudy
designaswellasthepollutantbeingmodeled.Netheryetal(2008)conductedaseriesof
studiesintheVancouverBCregionthatevaluatedtheabilityofLURmodelstopredict
personalexposuretoairpollutantsinacohortofpregnantwomen.Sheconcludedthatthe
useofoutdoorconcentrationestimatesweregoodproxiesforexposure[144],andthat
specificallyforPM2.5,incorporatingmobilitypatternsintothemodelsdidnotmarkedly
improvetheexposureassessmentsbasedonpersonalmonitoring[145].Thiswas
attributabletothefactthatPM2.5hasarelativelyhomogenousdistributionwithin
communitiescomparedtoanairpollutantsuchasNO2whichhasmuchgreaterlocalspatial
variability[145,146].ThiswasalsoobservedfortheLURmodelbyHystadetal.[141].
Understandingtheimpactofenvironmentalstressorsonhumanhealthisacomplex
undertaking.Inlightofthesechallenges,explicitattentiontoarelevanttheoretical
frameworkiscriticaltounderstanding,assessing,andcommunicatingcumulativerisk
burdens.Thechallengethenbecomeshowtodevelopthenecessarymodelsandevaluation
methodstoclarifytheetiologicpathwaysandmechanismsthatleadtoadversehealth
outcomesthatoftendisproportionatelyaffectaspecificsub‐population.
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Chapter3:Heavysmokingduringpregnancyasamarkerforotherriskfactorsofadversebirthoutcomes:apopulation‐basedstudyin
BritishColumbia,CanadaEricksonAC,ArbourLT.Heavysmokingduringpregnancyasamarkerforotherriskfactorsofadversebirthoutcomes:apopulation‐basedstudyinBritishColumbia,Canada.BMCPublicHealth.2012;12(1):102.
AbstractBackground:Smokingduringpregnancyisassociatedwithknownadverseperinataland
obstetricaloutcomesaswellaswithsocio‐economic,demographicandotherbehavioural
riskfactorsthatindependentlyinfluenceoutcomes.Usingalargepopulation‐based
perinatalregistry,weassessthequantityofcigarettessmokedforthemagnitudeofadverse
birthoutcomesandalsotheassociationofothersocio‐economicandbehaviouralrisk
factorsdocumentedwithintheregistrythatinfluencepregnancyoutcomes.Ourgoalwasto
determinewhethernumberofcigarettessmokedcouldidentifythoseingreatestneedfor
comprehensiveinterventionprogramstoimproveoutcomes.
Methods:Ourpopulation‐basedretrospectivestudyofsingletonbirthsfrom2001to2006
(N=237,470)utilizeddataobtainedfromtheBCPerinatalDatabaseRegistry.Smokingdata,
self‐reportedattheearliestprenatalvisit,wascategorizedas:never,former,light(1to4),
moderate(5to9),orheavysmoker(10ormoreperday).Crudeandadjustedoddsratios
(AOR)with95percentconfidenceintervals(95%CI)werecalculatedusinglogistic
regressionmodelsforsmokingfrequencyandadversebirthoutcomes.Apartial
proportionalodds(pp‐odds)modelwasusedtodeterminetheassociationbetween
smokingstatusandotherriskfactors.
Results:Therewere233,891singletonbirthswithavailablesmokingstatusdata.A
significantdose‐dependentincreaseinriskwasobservedfortheadversebirthoutcomes
small‐for‐gestationalage,termlowbirthweightandintra‐uterinegrowthrestriction.
Resultsfromthepp‐oddsmodelindicateheavysmokersweremorelikelytohavenot
graduatedhighschool:AOR(95%CI)=3.80(3.41‐4.25);beasingleparent:2.27(2.14‐
2.42);haveindicationofdrugoralcoholuse:7.65(6.99–8.39)and2.20(1.88–2.59)
respectively,attendfewerthan4prenatalcarevisits:1.39(1.23–1.58),andbe
multiparous:1.59(1.51–1.68)comparedtolight,moderateandnon‐smokerscombined.
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Conclusion:Ourdatasuggeststhatself‐reportsofheavysmokingearlyinpregnancycould
beusedasamarkerforlifestyleriskfactorsthatincombinationwithsmokinginfluence
birthoutcomes.Thisinformationmaybeusedforplanningtargetedinterventionprograms
fornotonlysmokingcessation,butpotentiallyothersupportservicessuchasnutritionand
healthypregnancyeducation.
1.0BackgroundSmokingduringpregnancyisassociatedwithknownadverseperinataland
obstetricaloutcomes[1‐4];however,itremainsunclearthemagnitudeastowhichadverse
outcomesarerelatedtocigarettesmokeitselfversussurroundingfactorsdifficultto
quantifyandcontrol.Forinstance,socio‐economicstatus(SES)andpsychosocialstressare
bothassociatedwithadversebirthoutcomes[5‐7]aswellaswithprevalenceofsmoking
duringpregnancy[8‐10].Theseobservationsaresupportedbythemountingbiological
evidenceforastress‐relatedpsychoneuroendocrineprocesscontributingtotheunderlying
etiologyofadversefetaldevelopment[11].Thelinkagesbetweensociallypatternedadverse
healthbehavioursandoutcomesaredifficulttounderstandletaloneseparateandmeasure.
Therefore,itmaybebeneficialtouse(heavy)smokingduringpregnancyasamarkerfor
latentandunquantifiableriskfactorsthatalsoaffectoutcomes.
Inarecentreportassessingthenumberofcigarettessmokedduringpregnancyand
adversebirthoutcomesintheQikiqtaaluk(Baffin)regionofNunavut,‘heavysmokers’
(greaterthantencigarettesperday)hadsignificantlyworsebirthoutcomesthannon‐and
lightsmokers[12].IntheQikiqtaalukpopulationwhere80percentofpregnantmothers
smoke,itwassurprisingtoobservewhatresemblesathresholdeffectofheavysmokingon
adversebirthoutcomes,particularlybirthweight.Adose‐responserelationshipwasalso
observedbetweenlevelofsmokingduringpregnancyandhigherself‐reportingofalcoholor
druguse(predominatelymarijuana).Despitecertainlimitations,theresultsledtothe
conclusionthatheavysmokingmaybeamarkerforadditionalriskfactorsandbeusedto
identifyhighriskpopulationsfortargetedintervention[12].
Inadditiontotheinter‐relationshipbetweenadversebirthoutcomes,SESand
psychosocialstressmentionedabove,heavysmokingcouldalsobemarkerforpoor
nutritionalstatus[13].Smokersingeneralareshowntohavepoorernutritionalprofiles
thannon‐smokersinwhichbehaviouralandbiologicalfactorsindependentlyaccountfor
thedifferences,particularlymicronutrients,essentialmineralsandvitamins[14,15].While
smokerstendedtohavereduceddietaryintakeofsomemicronutrients,theobservedlower
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blood/serumconcentrationswereprimarilyattributedtotheincreasedturnoverof
micronutrientsviaaninflammatoryresponsecausedbytheoxidativestressofsmoking.
Further,incertaincasestheinflammationascribedeffectwasmorepronouncedinlong‐
termandheavysmokers[14].Theeffectsarefurtherconfoundedamongstpregnantwomen
whereithasbeenshownthatheavysmoking,lowsocialclass,rentingaccommodation,and
loweducationpredictpoordietaryintake[16].
Asimportantasunderstandingtheetiologyofadversebirthoutcomes,isidentifying
thoseatparticularriskwhomightbenefitfrominterventionwiththegoalofimproving
outcomesatthepopulationlevel.Thepurposeofthisstudyistwo‐fold:1)toassessthe
quantityofcigarettessmokedandthemagnitudeofadversebirthoutcomes,and2)
determinetheassociationofquantityofcigarettessmokedwithothersocio‐economicand
behaviouralriskfactorsdocumentedwithintheregistrythatalsoinfluencepregnancy
outcomes.Weusedawell‐establishedperinatalregistrydatabasetoaskthequestion:can
highquantitiesofcigaretteusereportedatthefirstprenatalvisitbeusedasasurrogateto
identifyhighriskmothersfortargetedsupportservicesthroughoutpregnancy?
2.0DataandMethodsThispopulation‐basedretrospectivestudyofallsingletonbirths(livebornand
stillbirths)inBritishColumbiafrom2001to2006(N=237,470)utilizedthePerinatal
ServicesBritishColumbia(PSBC)PerinatalDatabaseRegistry,andincludedinformationon
maternal‐infanthealthstatusandoutcomes,reproductivehistory,socio‐demographicsand
residentialpostalcodes.TheBCPDRaccountsfor99%ofabout45,000birthsandstillbirths
peryearoccurringintheprovincefrom20weeksgestationorweighingatleast500grams
atbirth.ThirdpartydataaccessisprovidedbyaPartnershipAccord/Memorandumof
AgreementbetweenallB.C.HealthAuthoritiesandthePSBCthroughtheFreedomof
InformationandPrivacyProtectionAct[17].Researchethicsboardapprovalwasgrantedby
theUniversityofVictoria (ethicsprotocol#:11‐043).
Theoutcomevariablesincludedlowbirthweightatterm(LBW<2,500gwith≥37
weeksgestation),pretermbirth(PTB‐between20and36completedweeksgestation),
intra‐uterinegrowthrestriction(IUGR–identifiedduringtheantenatalperiodusing
ultrasoundimaginggrowthparameters),postnatalsmall‐for‐gestationalagebelowthethird
andtenthpercentilesforweightandsexusingBCspecificbirthcharts(SGA‐3andSGA‐10
respectively)[18],andstillbirths(≥20weeksgestationor≥500g).Out‐of‐province
(n=926),recordsmissinggeographicdataonmaternalareaofresidence(n=129),and
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recordsnotmeetingthecriteriaofarecordedbirthinBC(<20weeksgestationand<500
gramsbirthweight,n=12)wereexcluded.Outcomeswerereviewedforcompletenessand
checkedfordoublecountingbetweenvariables(e.g.stillbirthandSGA).
Smokingdataisusuallycollectedatthefirstprenatalvisitfrom12‐18weeks
gestationandiscategorizedintheRegistryas“never”,“former”,and“current”.Thenumber
ofcigarettessmokedperdaybycurrentsmokerswasavailableasanadditionalcontinuous
variableandwascategorizedintothreelevelsofdailymaternalcigaretteuse:light(1to4),
moderate(5to9),andheavy(10ormore).Intermsofformersmokers,itisunknownwhen
inrelationtothepregnancycessationtookplacepriortothefirstprenatalvisit.Despite
beingnon‐smokers,formersmokerswerenotcombinedwiththe‘never’smokedgroupdue
tosignificantmaternalcharacteristicdifferencesbetweenthem.Theadditionalindividual‐
levelvariablesinclude:maternalage,reproductivehistory(parity≥1),numberofantenatal
carevisits,co‐morbiditiessuchasdiabetes,gestationaldiabetesandhypertensionduring
pregnancy,pre‐pregnancyweight,indicationofdrugoralcoholuse,numberofschoolyears
completedandsingleparentstatus(indicationofsupportduringandafterthepregnancy).
Bivariateoddsratio(OR)testsand95percentconfidenceintervals(95%CI)were
calculatedtoassesstheinfluenceofeachcovariateonbirthoutcomeswiththeresults
informingwhichcovariatestoincludeinthemodels.CrudeandadjustedORswith95%CIs
werecalculatedusinglogisticregressiontoassesstheinfluenceofsmokingrateson
outcomes.Sensitivityanalyseswereconductedtoassesstheinfluenceofattritiondueto
missingdataforsomecovariates.ThisincludedbivariateORteststodeterminethe
likelihoodofadversebirthoutcomesandmaternalcharacteristicsbetweenrecordswith
andwithoutdata.
Inordertodeterminetheassociationbetweenthecovariateriskfactorsandthe
differentlevelsofmaternalsmoking,aspecializedcaseofanorderedlogisticmodelwas
usedcalledthepartialproportionalodds(pp‐odds)model.Anordered(ordinalrank)logistic
modelisequivalenttoaseriesofbinarylogisticregressionswherethedifferentlevelsor
groupranksofthedependentvariablearecombinedandcontrasted[19].Inthiscase,there
arefourordinallevelsofsmokingstatus(Never,Light,MediumandHeavy)where:Level1
iscontrastedwithLevels2,3,and4combined;Levels1and2combinedversusLevels3and
4combined;andLevels1,2,and3combinedversusLevel4.Thepp‐oddsmodelisless
restrictivecomparedtoaregularorderedlogisticmodel(alsoknownasaparallel‐linesor
proportional‐oddsmodel),whichassumesallβregressioncoefficientstobeparallel.The
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pp‐oddsmodeleasesthisrestrictionallowingsomeβcoefficientstobethesameandsome
todiffer[19].Formersmokerswerenotusedinthepp‐oddsanalysisduetoitsnon‐ordinal
status.Interactionsbetweencovariateswerecheckedwithnosignificantinteractioneffects
observed.AllanalyseswereconductedinStata11IC[20].
3.0ResultsBetween2001and2006,therewere236,403singletonbirths≥500gramsorover
20weeksgestationinBC.Amongthem,26,564(11.2%)wereactivesmokers,197,583
(83.6%)reportedneversmoking,and12,256(5.2%)wereformersmokers.Oftheactive
smokers,7,806(3.3%oftotalN)werelightsmokers(1‐4cigarettes/day),5,839(2.5%)
weremoderatesmokers(5‐9cigarettes/day),10,407(4.4%)wereheavysmokers(≥10
cigarettes/day),and2,512(1.1%)hadmissingdataonthenumberofcigarettessmokedper
daywhichwereexcludedfromtheanalysis.Thedistributionofdailycigaretteconsumption
wasexponentialwithnotablespikesatincrementsoffivecigarettesperday(Figure11).A
comparisonofthematernalcharacteristicsacrosssmokinggroupsisprovidedinTable2.
Maternalcharacteristicsvariedsubstantiallyacrosslevelsofmaternalsmoking
(Table2).Motherswhowereheavysmokersweremorelikelytobemultiparous,asingle
parent,hadnotcompletedhighschool,beidentifiedforalcoholordruguseandattended
fewerprenatalcarevisits.Heavysmokerswerelesslikelytohavehadhypertensionduring
thepregnancyandallsmokerswerelesslikelytohavegestationaldiabetes.Thehighest
proportionofsmokerswasunder25yearsofage,buttendedtobelightsmokers(inter‐
quartilerange,IQR=3‐6‐10).Incontrast,thesmallerproportionofoldermothers(≥35)
whodidsmoketendedtobeheavysmokers(IQR=4‐10‐10).Withinagecohorts,athirdof
allmotherslessthan20yearsofageandnearlyaquarterofwomenaged20to24reported
smokingwith11.5and9percentofthosebeingheavysmokersrespectively.Conversely,ten
Figure11:DistributionofMaternalDailyCigaretteConsumptioninBC,2001‐06
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percentoftheoldestthreeagecohortsreportsmokingbuthadroughlytwicethe
proportionofheavysmokersaslightsmokers(3.6and1.6percentrespectively).Consistent
withtheyoungestgroupreportingthegreatestproportionofcurrentsmokers,thetwo
youngestagecohortsalsohadthehighestproportionofformersmokers,13.1and8.5
percentrespectively.
FurtherbivariateORtestswithmaternalagerevealedthatwomenundertheageof
30,butparticularlyteens(under20)andthose20to24weresignificantlymorelikelytobe
identifiedfordruguse,OR(95%CI)=9.06(8.19‐10.03)and4.36(4.00‐4.74)respectively;
alcoholuse,OR(95%CI)=9.44(8.13‐10.97)and3.87(3.40‐4.42)respectively;andattend
fewerthan4prenatalcarevisits,OR(95%CI)=4.45(3.91‐5.07)and2.35(2.12‐2.60)
respectivelycomparedtowomen30to34yearsofage.Lackofhighschoolgraduationfor
womenaged20to24werealsolowcomparedtothe30‐34agecohort,OR(95%CI)=
9.80(8.60‐11.39).Furthermore,amongwomenunder25yearsofage,thosewhowere
heavysmokerswereovertentimesmorelikelybeidentifiedfordrugusethannon‐smokers
whereaslightandmoderatesmokershadabouthalftherisk,OR(95%CI)=10.59(9.46‐
11.86)and6.67(5.79‐7.67)forheavyandmoderatesmokersrespectively.Whileheavy
smokersunder25yearsoldalsohadthehighestriskforalcoholindication,lowprenatal
careattendance,singleparentandnograde12educations,thedifferencesbetweenlevelsof
smokingwerelessstark.
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Table2:MaternalCharacteristicsbySmokingStatusinBC,2001‐2006
BirthsbySmokingStatus,*%Characteristic
Nevern=197,583
Formern=12,256
1–4n=7,806
5–9n=5,839
10+n=10,407
Missingn=2,512
Total(%missing)
Age,yr<20 2.3 7.8 14.0 12.2 9.2 11.8 8,620(3.5)
20‐24 12.4 24.3 32.4 32.7 30.3 29.0 35,817(2.0)
25‐29 27.9 29.5 26.8 27.2 26.8 25.7 65,877(1.0)
30‐34 34.7 24.5 17.4 17.3 20.3 21.1 76,616(0.7)
35‐39 18.7 11.5 7.7 8.8 10.8 10.1 40,808(0.6)
40+ 4.0 2.4 1.7 1.8 2.5 2.2 8,665(0.7)
Parity≥1No 44.3 59.3 54.7 47.3 40.2 52.5 107,381(1.2)
Yes 55.7 40.7 45.3 52.7 59.8 47.5 129,022(0.9)
SingleParentNo 92.7 87.1 76.5 77.8 75.1 75.6 214,054(0.9)
Yes 3.7 8.7 15.0 15.1 16.7 18.3 12,726(3.6)
Unknown 3.6 4.1 8.6 7.1 8.2 6.1 9,623(1.6)
HasGrade12†No 0.8 3.0 5.2 5.2 5.4 3.1 3,301(0.7)
Yes 10.7 12.9 9.6 9.4 6.5 6.7 24,908(2.4)
missing 88.5 84.1 85.2 85.4 88.1 90.2 208,194(1.1)
GestationalNo 93.3 94.6 96.2 95.8 95.1 94.7 221,256(1.1)
diabetesYes 6.7 5.4 3.8 4.2 4.9 5.3 15,147(0.9)
Pre‐existingNo 99.6 99.7 99.6 99.6 99.4 99.6 235,465(1.1)
diabetesYes 0.4 0.3 0.4 0.4 0.6 0.4 938(1.2)
HypertensionNo 97.8 97.1 98.1 98.0 98.2 97.8 228,674(1.1)
inpregnancyYes 2.2 3.0 1.9 2.0 1.8 2.2 5,272(1.0)
AlcoholFlagNo 99.7 98.1 95.9 96.6 95.1 93.8 234,290(1.0)
Yes 0.4 1.9 4.1 3.4 4.9 6.3 2,113(7.4)
DrugFlagNo 99.2 96.9 90.8 90.3 84.6 86.7 231,267(0.9)
Yes 0.8 3.1 9.2 9.7 15.4 13.1 5,136(6.4)
Pre‐pregnancy<55 21.0 16.4 19.0 19.9 18.8 16.4 48,430(0.9)
weight55‐74 42.9 43.6 38.8 38.6 36.2 35.0 99,973(0.9)
>74 14.7 22.0 18.1 18.4 20.3 16.7 36,720(1.1)
missing 21.5 18.1 24.1 23.1 24.7 31.8 51,280(1.6)
PrenatalVisits≥3 92.1 93.4 92.3 91.2 89.5 85.9 217,461(1.0)
<3 1.2 1.2 2.5 3.0 3.4 3.8 3,364(2.9)
missing 6.7 5.5 5.2 5.8 7.1 10.3 15,578(1.7)*Likelihood‐RatioChi‐squaredtestsforindependenceacrossthe5smokingcategorieswereallsignificantatp<0.05,exceptpre‐existingdiabetes(p=0.06).†Maternaleducationwasmeasuredinyearsofeducationwith‘12years’indicatinghighschooleducation.
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Missingvalueswereaconcernintwokeycovariates,educationlevelandpre‐
pregnancyweight,thereforesensitivityanalyseswerecarriedouttodeterminethe
differenceincharacteristicsofthosewithmissingdata.Sensitivityanalysesonthose
missingeducationdata(88.1%)revealedsmallbutsignificantlyincreasedrisksformost
adversebirthoutcomes(ORrangebetween1.11–1.29)andnostatisticaldifferencefor
stillbirths.Light,moderateandformersmokerswerelesslikelytobemissingeducation
datacomparedtothosewhoneversmoked,whiletherewasnodifferencebetweenheavy
smokersandneversmokerswithmissingeducationdata.However,overalldifferencesin
ageandcigarettesconsumptionwerenegligiblewiththeIQRofthosewithandwithoutdata
being3‐6‐10and3‐7‐10respectivelyforcigarettesuseamongsmokersandanidenticalIQR
forage.Thesensitivityanalysesonthoserecordsmissingpre‐pregnancyweightdata
(21.7%)demonstratedsignificantlyincreasedrisksofPTBandstillbirths,asignificantly
lowerriskofIUGR,andnostatisticaldifferencefortheotheroutcomes.Alllevelsofsmoking
weresignificantlymorelikelytobemissingpre‐pregnancyweightdatacomparedto
motherswhoneversmoked,althoughtheIQRofcigaretteusebetweenthosewithand
withoutdataweresimilar(3‐6‐10and3‐7‐10respectively).Intermsofothermaternal
characteristics,thereweresomedifferencesinthevariableswhichweremoreorlesslikely
tobemissingdata,howevernocleartrendswereobserved.
Figure12showstheadjustedoddsratiosofadversebirthoutcomeswithmaternal
smokingstatus(differencesbetweencrudeandadjustedORswereunremarkable).
Comparedtomotherswhoneversmoked,therewasasignificantdose‐dependentincrease
inriskforalladversebirthoutcomeswithmaternalsmokingwiththeexceptionof
stillbirths.Furthermore,heavysmokershadasignificantlygreaterriskofSGA‐3,SGA‐10
andIUGRcomparedtolightandmoderatesmokers.Theadditionoftheeducationvariable
attenuatedtheeffectoflightsmokersforalloutcomesresultinginnosignificantdifference
comparedtonon‐smokers.Similarly,allobservedeffectsofsmokingandPTBwerereduced
tothenullafterincludingtheeducationvariabletothemodel.However,theeducation
variabledidnotaltertheeffectofoutcomesonheavysmokerswhileitstrengthenedthe
effectofmoderatesmokersforSGA‐3,SGA‐10andLBW.
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Resultsfromthepp‐oddsmodeldescribehowdifferentcovariateriskfactors
predicthigherorlowerlevelsofmaternalsmoking(Table3).Allvariablesexceptolder
maternalagewereriskfactorsforsmokingduringpregnancy,butofthose,onlymultiparity
andpre‐pregnancyweightgreaterthan74kilogramspredictedheavysmokingoverthe
lowerlevelsofsmoking.Thisisdemonstratedbytheincreasingeffectofthesetwovariables
acrossthethreecomparisons.Oldermaternalagealsopredictedhigherlevelsofsmoking
despitebeingassociatedwithneversmoking.Youngmaternalage(<25years),single
parent,drugandalcoholindicatorswereallstronglyassociatedwithmaternalsmoking
acrossallcomparisons,butexhibitedtheirstrongesteffectsforLevel‐1(neversmoked
versusallsmokers).Forexample,womenwhosmokedwere10timesmorelikelytobe
indicatedfordrugusecomparedtowomenwhoneversmoked,whileheavysmokerswere
7.6timesmorelikelytobeindicatedfordrugusecomparedtomoderate,lightandnon‐
Figure12:AdjustedOddRatiosofAdverseBirthOutcomesandLevelsofMaternalSmokingSGA‐3–SmallforGestationalAgebelowthe3rdpercentile(n=172,667),SGA‐10–SmallforGestationalAgebelowthe10thpercentile(n=172,667),LBW–LowBirthWeightatterm(n=161,041),PTB–PretermBirth(n=172,690),IUGR–Intra‐UterineGrowthRestriction(n=172,849),Stillbirth(n=173,397).Testswereadjustedfor:maternalage,parity>1,alcoholflag,drugflag,prenatalcarevisits,priorandgestationaldiabetes,hypertensionduringpregnancy,pre‐pregnancyweight,andloneparent.
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smokerscombined.Havingthreeorfewerprenatalcarevisitsandadiagnosisofpre‐
existingdiabetes(p=0.06)mettheparallel‐linesassumption,andthereforehadaconstant
effectacrossalllevelsofcomparison.Thesegeneraltrendsweresustainedwiththeaddition
oftheeducationvariableintothepp‐oddsmodeldemonstratingastrongconstanteffect
acrossalllevelsofcomparison,OR=3.80(95%CI3.41–4.25)withareducedpopulation
sizeof21,775.Onlythevariablesprenatalcareandpre‐existingdiabeteshadtheireffects
significantlyreducedtothenull(p=0.9and0.4respectively).
Table3:OddsRatiosofCovariateRiskFactorsPredictingLevelofMaternalSmokinginB.C.2001–2006(n=163,867)
Characteristic
OR(95%CI)
OR(95%CI)
OR(95%CI)
Level1Vs.Level2+3+4
Level1+2Vs.Level3+4
Level1+2+3Vs.Level4
YoungMaternalAge(<25) 3.66(3.52–3.80) 3.27(3.13–3.42) 2.86(2.70–3.02)
OlderMaternalAge(≥35) 0.67(0.64‐0.71) 0.71(0.67‐0.76) 0.77(0.71‐0.83)
SingleParent 2.42(2.31‐2.53) 2.25(2.14‐2.37) 2.27(2.14‐2.42)
Parity≥1 1.26(1.22‐1.31) 1.49(1.43‐1.55) 1.59(1.51‐1.68)
AlcoholIndication 3.06(2.63‐3.57) 2.41(2.08‐2.81) 2.20(1.88‐2.59)
DrugIndication 10.19(9.32‐11.15) 8.17(7.50–8.90) 7.65(6.99–8.39)
PrenatalCareVisits(≤3) 1.39(1.23–1.58) 1.39(1.23–1.58) 1.39(1.23–1.58)
Pre‐existingDiabetes 1.27(0.99‐1.64) 1.27(0.99‐1.64) 1.27(0.99‐1.64)
Pre‐pregnancyweight(≥75kg) 1.48(1.43‐1.54) 1.49(1.43‐1.56) 1.56(1.48‐1.65)
Level1=neversmoked,Level2=lightsmoker,Level3=moderatesmoker,Level4=heavysmoker.
4.0Discussion Theresultsofthislargepopulation‐basedstudysupportthatsmokingduring
pregnancyisamodifiabledose‐dependentriskfactorofadversefetalgrowththatalsohasa
strongrelationshipwithotherriskbehaviourandlowSESindicators.Comparedtoalllower
levelsofsmoking,heavysmokers(≥10cigarettes/day)hadsubstantiallyworsebirth
outcomesandwerealsoatincreasedrisktobeidentifiedforalcoholuseanddruguse,bea
singleparent,attendedfewerprenatalcarevisitsandhavepre‐pregnancyweightgreater
than74kilograms.AlthoughtheadditionofamajorSESvariable,levelofeducation,was
limitedtoonly10%ofourstudypopulation,themaineffectsandgeneraltrendswere
corroborated.Heavysmokerswere3.8timesmorelikelytohavenotgraduatedhighschool
comparedtomoderate,lightandnon‐smokerscombinedsupportingthepossibilitythat
reportsofsmokinggreaterthantencigarettesperdaymightbeanearlymarkerforthe
needforcomprehensivesupportstoreduceadverseoutcomes.
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TheadjustedORsfortheimpairedfetalgrowthoutcomes(SGA,IUGRandterm‐
LBW)werenearlytwicethemagnitudebetweenheavyandlightsmokers.Theadditionof
theeducationvariableintothelogisticmodelsattenuatedtheeffectoflightsmokerstothe
degreeofnosignificantdifferencebetweenlight,formerandneversmokerswhiletheeffect
ofmoderateandheavysmokingremainedrelativelystablewithroughlydoubletherisk.
TheeffectofsmokingonPTBwascompletelyremovedafteradjustingformaternal
education.ThissuggeststhatwhilebehaviouralandSESindicatorvariables,particularly
maternaleducation,explainsomeoralloftheriskattributedtolightsmoking,heavy
smokingremainsarobustmarkerofincreasedriskfortheimpairedfetalgrowthoutcomes.
Whetherthisobservedeffectisstrictlybiologicalorispartiallyamarkerforsomelatent
unmeasuredriskfactor,heavysmokingreadilyidentifiesapproximatelyfivepercentofthe
BCpopulationwhocouldbenefitfromadditionalsupportservices.Theseresultswere
consistentwithfindingsfromapopulation‐basedstudyfromNovaScotia[21]aswellasa
prospectivecohortstudythatusedanthropometricultrasoundmeasurementstocompare
fetalgrowthinsmokingandnon‐smokingexpectantmothers[22].
Themechanismstowhichcigarettesmokeexposureeffectsfetalgrowthisnot
completelyunderstood;however,IUGRcorrelateswithdefectsinplacentaltransportand
metabolismfunctionswhichseemstorestrictnutrientsupply[23].Zdravkovicetal.report
thatconstituentsincigarettesmokedirectlyaffectplacentalcytotrophoblastproliferation
anddifferentiationwhichreducesbloodflowandcreatesahypoxicenvironment[24].Using
amousemodel,Detmaretal.foundthatpolycyclicaromatichydrocarbons(PAHs),amain
componentincigarettesmoke,causedIUGRinthefetusesofexposeddamsandyielded
alterationsinplacentalvascularisationwithsignificantlyreducedarterialsurfaceareaand
volume[25].PAHsarealsoamainconstituentofvehicularexhaust,particularlydiesel,and
thereismountingevidenceofanassociationbetweensaidpollutantandgrowthrestricted
birthoutcomes[26,27].
Theresultsfromthepp‐oddsmodelshowthatmostofthecovariateriskfactors
primarilypredictmaternalsmokingingeneralversusnon‐smokers.Variablessuchassingle
parent,drugandalcoholindicationandyoungmaternalageweresignificantacrossall
levelscomparison,buthadthestrongesteffectsincomparingnon‐smokerstoallother
levelsofsmoking.Conversely,parityexhibiteditsstrongesteffectsinthethirdcomparison
(heavysmokersversusnever,light,andmoderatesmokerscombined).Thissuggeststhat
whilebeingmultiparousisamarkerformaternalsmokingingeneral,itpredictsheavy
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smokingversusmoderateorlightsmokinghabits.Asimilarobservationwasfoundina
studyofUKwomenregardinggravidaandsmokingbehaviourinsubsequentpregnancies,
commentingonthedoubleexposureofthepreviouschildrentocigarettesmokebothpre‐
andpostnatally[28].Whileoldermaternalagewasassociatedwithhavingreported‘never
smoked’,oldermotherswhodidsmokeweremorelikelytobeheavysmokers.Thistrendof
oldermothersbeingheavysmokerswasalsoobservedintheNunavutchartreviewstudy
[12].
Theresultsforthepp‐oddsmodelincludingmaternaleducationgenerallyholdtrue
tothefirstmodel.Theeffectsforage,parity,singleparent,drugflag,andalcoholflagare
slightlyattenuatedbutremainsignificantwiththesametrend.Education(nograde12)had
astrongconstanteffectonmaternalsmokingacrossalllevelsofcomparison,suggestingan
importantroleinhealthliteracy.Maternallevelofeducationhasbeenshowntobea
powerfuldeterminantofperinatalhealth,independentof,andstrongerthanthatof
neighbourhoodincome[29].Havinglowmaternaleducationalattainment,beingyoungand
asingleparentareindicatorsoflowsocio‐economicstatusthatmayexertadditionalstress
onthepregnancy.Thebiochemicalresponsetostressviaelevatedbasalcortisollevelshas
beenassociatedwithlowbirthweight[30].Threemajorsystemsarethoughttobeinvolved
inthebiologicalpathwaylinkingmaternalmentalhealthandstresswithadversebirth
outcomeswhichincludetheneuroendocrine,theimmune/inflammatory,andthe
cardiovascularsystemswithplacentalcorticotrophinreleasinghormoneplayingacentral
coordinatingrole[31].Indicatorsofwomen’smentalhealthduringpregnancysuchas
psychosocialstress,levelofsocialandfinancialsupportanddepressionmaybeone
possiblepathwaytowhichlowSESisassociatedwithadversebirthoutcomes.
ThemajorityofresultsfromthisBritishColumbiabasedstudywereconsistentwith
recentfindingsfromNorway[32],Germany[33],andanationalCanadiansurveythat
analyzedtheassociatedriskfactorsofsmokingduringpregnancy[8].TheCanadianstudy
foundthatnon‐immigrant,singleparent,lowhouseholdincome,no/littleprenatalclasses,
lesseducation,passive(i.e.partner)smoking,oldermaternalageandahighernumberof
stressfuleventsweresignificantlyassociatedwithmaternalsmokingingeneralbutdidnot
assessquantityofcigarettessmoked[8].AnAustralianstudyofsimilardesigntoour
researchalsousedregistrydataandfoundyoungmaternalage,lackofantenatalcareand
lowSESwereassociatedwithmaternalsmoking[34].Bothpapershighlightedthe
importanceofantenatalcareasacriticalaccesspointtoeducateexpectantmothers
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regardingahealthypregnancy.Importantly,thestudyfromAustraliafoundthatfirst‐time
mothersandthosewhoaccessedprenatalcareearlyintheirpregnancieshadanincreased
likelihoodofsmokingcessation[34].
TheprovinceofBChasarelativelyhealthybirthingpopulationcomparedtotherest
ofCanadaandhasamongstthelowestratesofmaternalsmokingandexposureto2ndhand
smokeinCanada[35].Further,BChashighgrade12completionratesamongpregnant
womenwhichlikelyinfluencetherelativelylowratesofriskbehaviourssuchasmaternal
smoking.BChadlowerratesofpretermbirthandisaroundtheCanadianaverageforrates
ofSGA.Despitethesepositiveoutcomes,theabilitytorecognizethoseatparticularrisk
earlyinpregnancyandprovidepreventativeprogramscouldhelpachievebetteroutcomes
forallexpectantmothers.Specifically,ourfindingssuggestthatheavymaternalsmoking
willidentifyapproximatelyfivepercentofwomeninBCatparticularincreasedriskof
adverseoutcomesthatmaybenefitfromadditionalservicestopromoteahealthy
pregnancy.Withrespecttoepidemiologicalanalysisofpopulation‐basedperinataldatasets,
thereispotentialtouseheavymaternalsmokingasaproxyforunreliableorunmeasured
individual‐levelbehaviouraland/orsocio‐economicdata.Maternalself‐reportedsmoking
tendstoberoutinelycollectedformostbirthregistriesmakingitanaccessiblevariable
comparedtomanyotherriskfactorvariablesorwhenlinkagetoexternaldatainnot
available.
Therewereseverallimitationstothisanalysis.First,therewerenodataonpassive
smokingrates(i.e.exposuretoenvironmentaltobaccosmokeorhavingapartnerwho
smokes),psychosocialstress,ethnicity,whetherthepregnancywasplanned,birthintervals
formultiparouswomen,potentialoccupationalexposures,orhouseholdincome.Further,
someofthecovariatesexaminedhadhighmissingdata.Asdescribedearlier,pre‐pregnancy
weightwasmissingapproximately25percentofitsvalues,andmaternaleducationdata
wereonlyavailablefor28,210records(12%).Thegreatestconcernwhenanimportant
variableispoorlypopulated,isthattheabsence/presenceofvaluesisbiased(i.e.arenot
missingatrandom).Forinstance,careprovidersmayonlybeaskingthoseindividualsabout
theireducationstatuswhereliteracyisaconcern,andasaresultthedistributionwouldbe
biasedandshiftedtotheleft.Thereforemissingdatanotonlyreducesthestatisticalpower
duetolist‐wisedeletion(i.e.recordswithmissingdataarenotusedinthatparticulartest),
butalsoreducestheoverallreliabilityofthatvariableandpotentiallytheappropriateness
ofthemodel.
99
Toaddressthispotentialbias,sensitivityanalyseswerecarriedoutforlevelof
educationandpre‐pregnancyweight.Thesetestsdemonstratedthatrecordswithmissing
educationdatatendedtohavesmallincreasedrisksforalladversebirthoutcomesand
somematernalriskcharacteristics;whilethosemissingpre‐pregnancyweightdatahad
mixedbirthoutcomesresultsbutincreasedriskformostmaternalcharacteristics.
However,theoverallagestructureandcigaretteconsumptionbetweenthosewithand
withoutmissingdatawerenearlyidenticalwithsimilarmediansandinter‐quartileranges.
Takenasawhole,theseresultssuggestthatthemissingeducationandpre‐weightdatamay
resultinunderestimatingtheriskofsomeadversebirthoutcomesbutthedegreeofmissing
dataisrelativelyconsistentacrossthelevelsofsmokingandthereforeitwouldbepredicted
nottoaffecttheobservedgeneraltrendsofouranalyses.Further,areviewofthemean
numberofyearsofeducationfortheCanadianfemalepopulation(age25‐36)fallwithinthe
meanandstandarddeviationofourmaternalyearsofeducationvariable,14.2versus13.9
±2.6[36].However,giventhestrongassociationbetweenmaternaleducation,smokingand
riskofadverseoutcomes,theseresultsreinforcetheimportanceforthestandardizedand
completecollectionofSESvariablesforallpatientsbyallprenatalhealthcareproviders.
Anotherpotentiallimitationistheself‐reportingbiasofcigaretteconsumption.Self‐
reportedsmokingstatusamongpregnantwomenissusceptibletobias,andmayleadto
attenuationofthetrueeffectofsmokingonbirthoutcomes[37].Ratesofmisclassification
intheUnitedStatesusingdatacollectedfromtheNationalHealthandNutrition
ExaminationSurveys(NHANES)estimatednon‐disclosuretobearound20percent[38].
Therateofmisclassificationwasconsistentwithotherstudies[39],aswasthedemographic
predictorsofnon‐disclosure.Manystudiesusedserum,salivary,orurinarycotinineasa
biomarkertoassessthedegreeofnon‐disclosureinsmokingstatus,andhavefoundarange
ofbetween13‐25percentdependingonthecut‐offvaluesusedtoclassifyoneasanactive
smoker.Non‐disclosurewashigheramongthosewhoreportedtheywereformersmokers,
andyoungermaternalage(20‐24).Thestigmaaroundmaternalsmokingmayleadsome
respondentstounderreporttheiractualconsumptionhabits.Possiblerecallbiascanalso
beassumedgiventhepeaksinthehistogram(Figure11)correspondingatmultiplesof5.
Thiscouldbeduetoresponsesgivenintermsofsomefractioninpacksofcigarettesper
day,suchthathalfapackisequaltotencigarettes.Nonetheless,ourresultssuggestthat
reportednumberofcigarettessmokedcorrelateswithadversebirthoutcomesand
100
associatedsocio‐economicriskfactorssuggestingtheinformationasprovidedwillhelp
identifythoseathighestrisk.
Futureanalysesmayincluderunningahierarchicalmultilevelmodelwiththe
inclusionofneighbourhood‐leveldeprivationscorestodetermineifclusteringof
observationsbyneighbourhoodsregardingbirthoutcomes,smokingratesorprenatalcare
attendance.Thistypeofanalysiswouldbeusefulasabaselinetofurtherstudytheeffectof
localairpollutionexposuremeasuredattheneighbourhood‐levelonbirthoutcomesand
thepotentialinteractionswithSESandotherriskvariables.
5.0ConclusionWehavedemonstratedthatself‐reportsofheavysmoking(≥10cigarettes/day)
earlyinpregnancycouldbeusedasamarkerforlatentorotheroftenunmeasuredlifestyle
riskfactorsthatinfluencebirthoutcomes.Heavysmokershadworseoutcomesandwere
substantiallymorelikelytodemonstrateotherriskfactorscomparedtootherlevelsof
smoking.Whilestrategiesforsmokingcessationareimportantandsupportedbyourstudy,
theunderlyingissuesthatleadtoadversebirthoutcomesmightnotbeaddressedwitha
narrowfocus.Thisinformationmaybeusedforplanningtargetedinterventionprograms
notonlyforsmokingcessationbutpotentiallyothermaternalsupportservicessuchas
nutritionandhealthypregnancyeducationwiththeoverallgoalofoptimizingbirth
outcomes.
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29. LuoZC,WilkinsR,KramerMS:Effectofneighbourhoodincomeandmaternaleducationonbirthoutcomes:apopulation‐basedstudy.CanadianMedicalAssociationJournal2006,174(10):1415‐1420.
30. WustS,EntringerS,FederenkoIS,SchlotzW,HellhammerDH:Birthweightisassociatedwithsalivarycortisolresponsestopsychosocialstressinadultlife.Psychoneuroendocrinology2005,30(6):591‐598.
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Chapter4:Thereductionofbirthweightbyfineparticulatematteranditsmodificationbymaternalandneighbourhood‐levelfactors:amultilevelanalysisinBritishColumbia,Canada
EricksonA.C.,OstryA,ChanL.H.M.,ArbourL.Thereductionofbirthweightbyfineparticulatematteranditsmodificationbymaternalandneighbourhood‐levelfactors:amultilevelanalysisinBritishColumbia,Canada.EnvironmentalHealth;2016Apr14;15(1).
AbstractBackground:Thepurposeofthisresearchwastodeterminetherelationshipbetween
modeledparticulatematter(PM2.5)exposureandbirthweight,includingthepotential
modificationbymaternalriskfactorsandindicatorsofsocioeconomicstatus.
Methods:Birthrecordsfrom2001to2006(N=231,929)werelinkedtomodeledPM2.5data
fromanationalland‐useregressionmodelalongwithneighbourhood‐levelSESandsocio‐
demographicdatausing6‐digitresidentialpostalcodes.Multilevelrandomcoefficient
modelswereusedtoestimatetheeffectsofPM2.5,SESandotherindividualand
neighbourhood‐levelcovariatesoncontinuousbirthweightandtestinteractions.
Gestationalagewasmodeledwitharandomslopetoassesspotentialneighbourhood‐level
differencesofitseffectonbirthweightandwhetheranybetween‐neighbourhood
variabilitycanbeexplainedbycross‐levelinteractions.
Results:Modelsadjustedforindividualandneighbourhood‐levelcovariatesshoweda
significantnon‐linearnegativeassociationbetweenPM2.5andbirthweightexplaining8.5%
ofthebetweenneighbourhooddifferencesinmeanbirthweight.Asignificantinteraction
betweenSESandPM2.5wasobserved,revealingamorepronouncednegativeeffectofPM2.5
onbirthweightinlowerSESneighbourhoods.Furtherpositiveandnegativemodificationof
thePM2.5effectwasobservedwithmaternalsmoking,maternalage,gestationaldiabetes,
andsuspectedmaternaldrugoralcoholuse.Therandominterceptvarianceindicating
between‐neighbourhoodbirthweightdifferenceswasreduced75%inthefinalmodel,
whiletherandomslopevarianceforbetween‐neighbourhoodgestationalageeffects
remainedvirtuallyunchanged.
Conclusion:Weprovideevidencethatneighbourhood‐levelSESvariablesandPM2.5have
bothindependentandinteractingassociationswithbirthweight,andtogetheraccountfor
49%ofthebetween‐neighbourhooddifferencesinbirthweight.Evidenceofeffect
modificationofPM2.5onbirthweightacrossvariousmaternalandneighbourhood‐level
105
factorssuggeststhatcertainsub‐populationsmaybemoreorlessvulnerabletoeven
relativelylowdosesPM2.5exposure.
1.0BackgroundStudiesofexposuretoparticulateairpollutionhaveconsistentlyshownan
associationwithlowbirthweight,apredictoroffetalgrowthrestrictionandimportant
determinantofinfantandchildwellbeing[1–3].Thefinefractionofparticulatematter
(PM2.5‐lessthan2.5microns)isacomplexmixtureofelementalandorganiccarbon
compounds,metalsandgasesthatstempredominantlyfromvehicleexhaust,residential
heatingandindustrialemissions.PM2.5,whichincludesultrafineparticleslessthan0.1
microns,canpenetratedeepintothepulmonaryalveolartissuewhereinflammatory
mediatorsandpossiblytheparticlesthemselvestranslocateintothebloodstreamcausing
systemiccardiovascularandimmunologicalalterationssuchasplateletactivation,
coagulationandendothelialdysfunction[4–6].Thesephysiologicalchangesextendtothe
placenta,ahighlyvascularizedorganandextensionofthematernalcardiovascularsystem
withsimilarlyaffectedendothelialcellulartissuesparticularlysusceptibletooxidativeand
inflammatoryinjury[7–9].Excessoruncontrolledoxidativestressandinflammationearly
inpregnancymaydisruptplacentalcellgrowthanddifferentiationpotentiallyleadingto
deficientdeepplacentationandmorphologicaladaptationsassociatedwithseveraladverse
pregnancyoutcomesincludingfetalgrowthrestriction[10].
ThesemechanismsbywhichPM2.5mayacttoadverselyimpactthereproductive
systemarenotfullyunderstood;however,evidencesupportsthepotentialforashared
modeofdevelopmentaltoxicitywithseveralotherknownriskfactors[5,11].Thisincludes
factorsthatalsopromoteorareassociatedwithoxidativestressandinflammationsuchas
smoking[12],druguse[13],advancedmaternalage[14]andgestationaldiabetes[15],and
lowsocioeconomicstatus(SES)ingeneral[16].ThecausalpathwaysinwhichSES
contributestoadversepregnancyoutcomescanbeconceptualizedintermsof‘downstream’
ormediatingexposures,stressesandbehavioursactingontheindividualthrough
‘upstream’society‐leveldeterminantssuchaspoverty,pooreducation,incomeinequality
andsocialdiscrimination/marginalizationoverthelifespan[17,18].Thisimpactofthe
socialenvironmentonhealthbehavioursandoutcomescreateshierarchicalstructures
withinwhichindividualsarenestedinneighbourhoodsandcommunitieswiththeirownset
ofattributesthatcanpromoteorantagonizehealthandhealthybehaviours[19,20].
106
Aparticularchallengeinenvironmentalepidemiologyishandlingdataatdiffering
geographicscales.Birthregistriesandvitalstatisticsprovidedataonindividualbirthsand
certainriskfactors,butmaynothavedataonsociallypatternedriskfactors.Alternatively,
reliableSESdatasuchaseducation,incomeandhousingqualityareoftenonlyavailable
fromnationalcensusdatabasesusingarbitraryadministrativespatialunits.Finally,
obtainingindividual‐levelenvironmentalexposuredataisoftennotpossible.Therefore,the
epidemiologistisoftenleftwithamixofindividual‐levelobservationsclusteredwithin
neighbourhoodareaseachwithdistinctattributes.Theuseofmultilevelstatisticalmodels
separatetheindividual‐leveleffectsfromthecontextoftheirsocialandphysical
environmentsandcanthereforequantifythedegreeofclusteringofindividualswithin
neighbourhoodareasandtestwhetherneighbourhoodfactorsthemselveshavedirect
effectsonthehealthoutcomeoractindirectlyviathemodificationofindividual‐level
variables[21,22].
Throughthemechanismsofoxidativestressandinflammationthereisevidencethat
SESmaynotonlyconfoundbutmodifythePM2.5‐birthoutcomerelationship[23–25].
Variousexposuresandexperiencesmayactinanon‐additivemannertoinfluencefetal
development[5].Wepresentamultilevelcross‐sectionalanalysisoftheassociation
betweenbirthweightandPM2.5inBritishColumbia,CanadawherelevelsofPM2.5are
relativelylowbutcanvarysubstantiallybetweendifferentcommunities[26].Weexplore
thepotentialforbetween‐neighbourhoodvariabilityfortheslopeofgestationalageonbirth
weightandwhetherinteractionswithPM2.5,neighbourhood‐levelSESindicators,and/or
individual‐levelriskfactorsareabletoexplainanyneighbourhood‐levelvariability.Wehad
threeresearchquestions:1)doesexposuretoPM2.5andresidenceinlowSES
neighbourhoodsinBChavesignificantindependentnegativeassociationswithbirthweight;
2)doestheeffectofgestationalageonbirthweightdifferbyneighbourhoods;and3)does
PM2.5interactwithneighbourhood‐levelSESand/orindividual‐levelriskfactorstomodify
theirindependenteffectsonbirthweighttohelpexplainanyneighbourhood‐level
differences.
2.0DataandMethodsThiswasapopulation‐basedretrospectivecohortofsingletonbirthsinBritish
Columbiafrom2001to2006(N=237,470).DatafromtheBCPerinatalDataRegistrywere
providedbyPerinatalServicesBritishColumbia(PSBC)whichincludedinformationon
maternal‐infanthealthstatusandoutcomes,reproductivehistory,maternalriskfactors,
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attributesandresidentialpostalcodes.TheRegistryaccountsfor99%ofbirthsand
stillbirthsinBCofatleast20weeksgestationoratleast500gramsbirthweight.Research
dataaccessisprovidedbyaPartnershipAccord/MemorandumofAgreementbetweenall
BCHealthAuthoritiesandPSBCthroughtheFreedomofInformationandPrivacyProtection
Act[27].ResearchethicsboardapprovalwasgrantedbytheUniversityofVictoria(ethics
protocol#:11‐043).
Theoutcomevariablewascontinuousbirthweightofsingletonbirths.Inorderto
avoidpotentialselectionbias,weincludedallbirths(stillbirthandlive)forallgestational
ages(20‐42weeks).Excludedrecordsincludedout‐of‐provinceandinvalidpostalcodes
(n=1,096),non‐viablebirthspriorto20weeksgestationor500grams(n=14),andthelist‐
wisedeletionofbirthsmissingimportantdataincluding:cigarettessmokedperday
(cigarettes/day,n=2,501),PM2.5(n=1,510),gestationalage(n=373)birthweight(n=41).All
continuousvariables,exceptcigarettes/day,werestandardizedandcenteredtoease
interpretationandaidmodelconvergence.
Thespatiallocationofeachbirthrecordwasgeocodedbasedonthelatitude‐
longitudecoordinateofthemother’sresidentialpostalcodeatthetimeofdeliveryusing
GeoRef[28].Birthrecordswererelatedtotheircorrespondingcensusdisseminationarea
(DA)byperformingapoint‐in‐polygonspatialjoinprocedureinArcGIS10.2[29].DAsare
thesmallestgeographicalunitforwhichcensusdataareavailableandrepresent
neighbourhoodblocksrangingbetween200–800people.WhileDAsdonotnecessarily
representexistingneighbourhoodcommunities[30],theycanactasproxiesforageneral
catchmentareaofpersonalhome‐lifeactivities[31,32].Birthrecordswereidentifiedas
beingeitherruralorurbanusingtheStatisticsCanadaMetropolitanInfluenceZone(MIZ)
codeswhicharebasedoncommutingflowsofsmalltownsintolargercitiesand
metropolitanareas[33].
ExposuretoPM2.5wasestimatedusinganationalland‐useregression(LUR)model
developedtoestimatePM2.5atthecensusstreetblock‐facelevel[34].Themodeluseda
numberofpredictorsincludingsatellitemeasures,proximitytomajorroadsandindustryto
accountfor46%ofthevariabilityinmeasuredannualPM2.5concentrations.Unlikenitrogen
dioxide(NO2),PM2.5tendstohaveamorehomogeneousintra‐urbandistributionbetween
personal,indoorandambient[35].TheLURmodelestimatesusedforthisstudyshowed
verylittlevariabilityofPM2.5exposuresbetweenindividualswithinagivenDA.We
108
thereforeaggregatedthepoint‐levelestimatesofPM2.5totheirDA‐levelmeanandrelatedit
toindividualbirthrecordsasanarea‐levelvariable.
TheDA‐levelSESanddemographicdatawererepresentedbythreerelatedbut
independentdatasetsallbasedonthe2006StatisticsCanadanationalcensus.Thefirstwas
aCanadianSESindex(SESi)developedbyChanetal[36].Thesecondwasaneducation
variablerepresentingtheproportionofpopulationover15withanypost‐secondary
education,includingcollege,trades,oruniversity.Thethirdwastheproportionof
continentalAsianimmigrantsbyDAasit’sbeenshowninBCandelsewherethathealthy
babiesfromAsianandSouthAsianbackgroundsareconstitutionallysmallercomparedto
theirCaucasiancounterparts[37,38].AsianandSouthAsianethnicitiesarewell‐
representedthroughoutBCbutparticularlyinconcentratedpocketsthroughoutthemajor
urbancenterofMetroVancouverwherelevelsofPM2.5arealsohigh.Thecorrelation
betweenimmigrantdensitywithSESiandPM2.5was‐0.62and0.53respectively(p<0.001),
wethereforecreatedaresidualimmigrantdensityvariableusingasequentialregression
technique[39].Here,immigrantdensitywasregressedagainstSESiandPM2.5withthe
savedresidualsrepresentingtheuncorrelatedandindependentcontributionofimmigrant
densityonbirthweightfreedfromitscollinearitywithSESiandPM2.5.Thissamemethod
wasusedbetweenSESiandeducation(r=0.25)creatingandresidualeducationvariable.
TheeducationandimmigrantdatawereobtainedbyaccesstoABACUSviatheData
LiberationInitiative[40].
InordertoavoiddatalossfromruralDAs,imputationformissingSES,education
andimmigrantdensityvalueswasperformed.Takingadvantageofthenestedhierarchical
structureoftheadministrativecensusandhealthboundaries,themeanvalueforalarger
encompassingcensussubdivision(CSD)orlocalhealtharea(LHA)wasimputedfora
nestedDAwithamissingvalue.Therewere1,441valuesimputedin52DAsforSESi(0.6%
offinalN,0.8%ofDAs),and3,170valuesimputedin108DAsforbotheducationand
immigrantdensity(1.4%offinalN,1.7%ofDAs).Sensitivityanalyseswereperformedusing
onlythenon‐missingdata.
Hierarchical(multilevel)linearregressionmodelswereusedtotestourresearch
questions,therebyaccountingfortheclustering,ornon‐independence,ofindividuals(level‐
1)belongingtoagivenDAneighbourhood(level‐2).Themultilevelmodelallowsthe
interceptandslopetoactasrandomparametershavingbetween‐area(DA)variabilityfrom
anoverall(BC‐wide)meaninterceptandslope.Thatis,eachDAhasitsowninterceptand
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slopeinwhichtheirvariabilityfromtheoverallinterceptandslopecanbeinvestigatedwith
theadditionoflevel‐1andlevel‐2variablesandtheirinteractions[41].Wefolloweda
bottom‐upapproachtomodelbuildingtoquantifytheexplainedproportionalchangein
variance(PCV),themultilevelmodelequivalenttoanR2[22].Westartedwithanempty
(null)randominterceptmodelwithoutanyindependentvariablesinwhichbirthweightis
onlyafunctionofthemother’sresidentialDA.Thepresenceofsignificantrandomintercept
varianceindicatesthereareunexplaineddifferencesbetweenneighbourhoodmeansof
birthweight.Theproportionofthetotalvarianceinbirthweightthatarisesdueto
neighbourhooddifferencescanbequantifiedbycomputingtheintra‐classcorrelation(ICC),
andhenceprovidesthedegreeofclusteringofindividualbirthweightwithin
neighbourhoods[22].
Gestationalagewasaddedtothenullmodelandgivenarandomslope(i.e.themean
within‐DAeffectofgestationalagewasallowedtodifferbetweenDAs).Thepresenceofa
significantrandomslopeindicatesthatitseffectonbirthweightisnotconstant(orequal)
forallDAs.SubsequentmodelsincludedtheindividualandDA‐levelvariablesalongwith
cross‐levelandwithin‐levelinteractionsinordertoassesstheirfixedeffectsonbirthweight
buttoalsodetermineiftheirinclusionaddressedanyunexplainedinterceptorslope
variance.ModelsweretestedusingtheAkaikeInformationCriterion(AIC)toevaluate
modelperformance.AllstatisticalanalyseswereconductedinStata13IC[42].
Finally,whilemultilevelmodelsaddressintra‐areadependencewhilequantifying
inter‐areavariance,theyassumespatialindependenceamongneighbouringareas.However
environmentalandsocialprocessescanextendbeyondarbitraryneighbourhood
boundaries.Additionallyasmentionedabove,censusDAsdonotnecessarilyrepresent
neighbourhooddynamics,services,infrastructure,etc.;andevidenceofspatialclustering
betweenDAsmayindicatethatanalternativeneighbourhoodarealunitshouldbe
considered.Weusedspatialmethodstotestforthisbycheckingthelevel‐1modelresiduals
andlevel‐2predictedrandomparameters(interceptsandslopes)forspatial
autocorrelationusingthelocalMoran’sIstatistic[43].Thepresenceofsignificantresidual
spatialautocorrelationindicatestheexistenceofunobservedspatialprocessescausingDAs
toclusterandisasignofmodelmisspecification.PredictionoftheDA‐levelrandom
interceptandslopeerrorsusedanEmpiricalBayesmethod[44]availableasapost‐
estimationcommandinStata13IC.
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3.0ResultsAfterexclusionstherewere231,929singleton(liveandstillborn)birthslocatedin
6,338neighbourhoodDAs(min.=1,max.=781,avg.=37).Table4summarizesthe
untransformedindividualandneighbourhoodcovariates(non‐centered,non‐standardized).
Table5reportstheadjustedcoefficientsfortheindividualandDA‐levelcovariatefixed
effectsoncontinuousbirthweight(Model1to3).Gestationalagewasmodeledusinga
quadratictermtoaccountfortherapidfetalgrowthinmid‐gestationsanditsslowergrowth
post‐term(>37weeks).Maternalsmoking(cigarettes/day)andPM2.5werealsomodeled
usingaquadraticterms,bothindicatingasubdueddose‐responsewithincreasingexposure.
Model2addedtheDA‐levelvariablesofSESi,education,immigrantdensityandrural
residence.TheirfixedeffectsshowthatlowerSESandhigherAsianimmigrantdensitywere
significantlyassociatedwithlowerbirthweights(Table5).RuralDAsandDAswithhigher
proportionofpost‐secondaryeducationwerenotsignificantlyassociatedwithbirthweight
inthismodel.However,bothbecamesignificantaftertheadditionofPM2.5andseasonof
birth(coldvs.warm)inModel3.Highereducationhadapositiveassociationwithbirth
weight,whileruralareashadasignificantnegativeassociationwithbirthweight.PM2.5was
foundtohaveasignificantnon‐linearnegativeassociationonbirthweightwherebythe
negativeeffecttapersoffathigherconcentrationsofPM2.5(Figure13).Beingborninacold
(fall‐winter)monthalsohadasignificantnegativeassociationwithbirthweight(Table5).
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Table4:Descriptivestatistics#forindividual(Level‐1)andDA(Level‐2)covariates
Variables Mean Std.Dev. Min‐Max PM2.5Mean(SE)ªLevel‐1(individual) Absence/
1stquintilePresence/
5thquintileBirthweight(grams) 3433.3 566.51 135‐6475 7.30(.016) 7.36(.018)†1
Gestationalage(weeks) 38.8 2.02 19‐44 7.30(.016) 7.30(.017)2
Maternalage(years) 29.8 5.60 11‐55 7.10(.022) 7.39(.014)†
Nulliparous 0.45 0.50 0‐1 7.27(.016) 7.34(.016)†
Gestationaldiabetes 0.06 0.25 0‐1 7.29(.016) 7.53(.016)†
Pre‐existingdiabetes 0.004 0.06 0‐1 7.30(.016) 7.34(.034)
Gestationalhypertension 0.02 0.15 0‐1 7.30(.016) 7.44(.019)†
Poorprenatalcare 0.09 0.29 0‐1 7.28(.016) 7.47(.02)†
Drug/Alcoholflag 0.02 0.15 0‐1 7.31(.016) 7.08(.026)†
Cigarettes/day 0.79 2.91 0‐20 7.33(.015) 7.02(.023)†3
Fall/Winterseason 0.48 0.50 0‐1 7.29(.016) 7.31(.016)†
Level‐2(DA)Variables
SESi ‐0.08 0.58 ‐2.22– 1.18 7.82(.027) 6.95(.032)†‡
Highereducation 0.50 0.12 0– 0.95 7.16(.04) 7.53(.022)†‡
Immigrantdensity 0.16 0.19 0– 0.86 6.75(.023) 7.95(.021)†‡
Ruraladdress 0.11 0.32 0– 1 7.39(.014) 6.59(.061)†‡
PM2.5(μg/m3) 7.30 0.86 4.41‐10.23 ‐‐ ‐‐
#valuesshownareunstandardized,non‐centered;PoorPrenatalCare:havinglessthan4prenatalcarevisitsorwasmissing;Drug/AlcoholFlag:suspectedpossibleuseofillicitdrugsoralcoholbyhealthcareprovider;Cigarettes/day:self‐reportednumberofcigarettessmokeddailyat1stprenatalvisit(excludingnon‐smokers:7.7(5.41));Fall/WinterSeason:birthmonth=Sept–Feb;ªrobuststandarderrorsadjustedfor6338DAclusters;†signi icantdifferenceatp<0.05usingWaldtests;‡1stvs.5thquintile;1normalbirthweightvs.lowbirthweight;2termbirthvs.pretermbirth;3non‐smokervs.currentsmoker.
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Table5:AdjustedindividualandDA‐levelfixedeffectsoncontinuousbirthweight
VariablesLevel‐1(individual)
Model‐1β(95%CI)
Model‐2β(95%CI)
Model‐3β(95%CI)
Gestationalage 310.2(307.6–312.7) 308.7(306.1–311.2) 308.5(306.0–311.1)
Gestationalageª ‐11.6(‐12.2–‐11.1) ‐11.9(‐12.4–‐11.3) ‐11.9(‐12.5–‐11.4)
Maternalage ‐6.6(‐8.6–‐4.7) ‐6.0(‐8.0–‐4.0) ‐4.7(‐6.6–‐2.7)
Nulliparous ‐137.2(‐141.0– ‐133.4) ‐135.7(‐139.5– ‐131.9) ‐134.8(‐138.6– ‐131.1)
Gestationaldiabetes 54.5(47.1– 61.8) 60.0(52.7– 67.4) 62.0(54.6– 69.4)
Pre‐existingdiabetes 320.7(292.1– 349.3) 320.6(292.1– 349.1) 321.2(292.6– 349.7)
Gestationalhypertension ‐90.1(‐102.3– ‐77.9) ‐88.9(‐101.0– ‐76.7) ‐87.6(‐99.7– ‐75.4)
Prenatalcarevisits ‐59.0(‐65.3– ‐52.8) ‐55.0(‐61.2– ‐48.7) ‐52.2(‐58.4– ‐45.9)
Drug/Alcoholflag ‐79.1(‐91.2– ‐67.1) ‐79.2(‐91.2– ‐67.2) ‐81.7(‐93.7– ‐69.7)
Cigarettes/day ‐20.8(‐22.5–‐19.0) ‐22.0(‐23.8–‐20.3) ‐22.7(‐24.4–‐20.9)
Cigarettes/dayª 0.63(0.51–0.74) 0.68(0.57–0.79) 0.7(0.59–0.82)
Fall/Winterseason –– –– ‐6.8(‐10.4–‐3.2)
Level‐2(DA)
SESi –– 37.4(35.2–39.7) 29.4(27.0–31.8)
Highereducation –– ‐2.1(‐4.4–0.2) 3.0(0.7–5.3)
Immigrantdensity –– ‐29.2(‐31.4–‐26.9) ‐31.3(‐33.5–‐29.1)
Ruraladdress –– 4.8(‐3.4–12.9) ‐14.6(‐22.6–‐6.7)
PM2.5 –– –– ‐23.9(‐26.5–‐21.3)
PM2.5ª –– –– 2.8(1.3–4.3)
SeeTable4legendforvariabledefinitions;ª Variablesweremodeledasquadratics.
Figure13:AdjustedPredictedEffectsofPM2.5onBirthWeightPredictedeffectsofPM2.5onbirthweightwith95%confidenceintervalsareconditionalonmodelcovariatesincludedinModel4.BlackverticallinesrepresentthefrequencydistributionofPM2.5.
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Model4testedinteractionswithPM2.5includingcross‐level(level‐1bylevel‐2)and
level‐2bylevel‐2interactionstoexplainthebetween‐DArandominterceptvariability.The
modelresultsarepresentedinTable6includingthemaineffectsaswellastheinteraction
effectswithPM2.5.FourmaternalvariablesshowedeffectmodificationwithPM2.5onbirth
weight.Maternalsmokingandsuspecteddrugoralcoholusebothhadpositiveinteractions
withPM2.5onbirthweightrevealingasubduedassociationwithincreasedPM2.5exposure
(Figure14Aand14Brespectively).MaternalagewasalsomodifiedbydifferencesinPM2.5
exposurewithyoungermaternalagesshowingalargerreductioninbirthweightwith
increasedPM2.5exposure(Figure14C).Alternatively,gestationaldiabeteswasassociated
withamuchgreaterreductioninbirthweightwithincreasingPM2.5comparedtonormal
births,essentiallynullifyingthehigherbirthweightsproducedbythecondition(Figure
14D).ThreeDA‐levelvariablesshowedsignificanteffectmodificationwithPM2.5onbirth
weight.First,theinteractionbetweenSESiandPM2.5revealedamorepronouncedeffectof
PM2.5inlowerSESneighbourhoods(Figure15A).HigherAsianimmigrantdensitybuffered
thePM2.5effect(Figure15B),whileruralDAsshowedanadditionalreductioninbirth
weightwithincreasingPM2.5levelscomparedtourbanDAs(Figure15C).
Therandomeffects,theexplainedproportionalchangeinvariance(PVC),andmodel
diagnosticsarepresentedinTable7.TheunadjustedICCfortheNullrandomintercept
modelwas0.019,indicatingthat1.9%ofthetotalresidualdifferencesinbirthweightare
attributabletoDA‐levelcontextualfactors.Withtheinclusionofthelevel‐1covariatesalong
withtherandomslopeforgestationalagetheICCadj,nowconditionalonmean‐centred
gestationalage(i.e.38.8weeks),increasedto2.3%.Thiswasduetothelargereductionin
thelevel‐1residualvariance(560.5to435.2)relativetothereductioninthelevel‐2random
interceptvariance(78.8to67.0).TheadditionofDA‐levelvariablesinModel2andModel3
removedalotoftheDA‐levelvariancereducingtheICCadjto1.1%and0.8%respectively.
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Table6:AdjustedindividualandDA‐levelfixedeffectsoncontinuousandtermbirthweightandtheirmodificationbyPM2.5(Model‐4)Variables MainEffect
β(95%CI)ModificationbyPM2.5
β(95%CI)Corresponding
Figure
PM2.5ª ‐22.4(‐25.2–‐19.7) 4.9(3.2–6.7) 1
Cigarettes/dayª ‐22.0(‐23.8–‐20.2) 2.8(2.2–3.4) 14A
Drug/Alcoholflag ‐80.6(‐93.0–‐68.2) 15.3(4.4–26.2) 14B
Maternalage ‐4.2(‐6.2–‐2.2) 5.5(3.7–7.4) 14C
Gestationaldiabetes 70.2(62.6–77.8) ‐33.8(‐41.9–‐25.8) 14D
SESi 30.2(27.7–32.7) 4.6(2.0–7.2) 15A
Immigrantdensity ‐33.3(‐35.8–‐30.7) 6.3(3.3–9.2) 15B
Ruraladdress ‐29.1(‐39.1–‐19.1) ‐16.4(‐24.5–‐8.3) 15C
TermBirths,excludingstillbirthsandcongenitalanomalies(N=207,405)
PM2.5ª ‐24.1(‐26.9–‐21.2) 5.0(3.2–6.8) ‐‐
Cigarettes/dayª ‐21.9(‐23.8–‐20.0) 2.8(2.2–3.4) ‐‐
Drug/Alcoholflag ‐80.1(‐93.6–‐66.6) 13.2(1.2–25.2) ‐‐
Maternalage ‐3.1(‐5.2–‐1.1) 5.0(3.1–6.9) ‐‐
Gestationaldiabetes 60.2(52.1–68.4) ‐30.7(‐39.2–‐22.1) ‐‐
SESi 30.5(27.9–33.1) 4.3(1.5–7.0) ‐‐
Immigrantdensity ‐36.0(‐38.7–‐33.3) 6.9(3.8–9.9) ‐‐
Ruraladdress ‐31.2(‐41.6–‐20.8) ‐16.9(‐25.3–‐8.5) ‐‐
ªModeledasaquadratic,Cigarettes/day:0.7(0.6–0.8);Modeladjustedforgestationalage,nulliparous,diabetesmellitus,gestationalhypertension,prenatalcarevisits,seasonofbirth,DA‐leveleducation.
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Figure14:AdjustedPredictedEffectsofmaternalriskfactorsonbirthweightacrosslevelsofPM2.5(A)MaternalSmoking(B)SuspectedDrugorAlcoholUse(C)MaternalAge(D)GestationalDiabetes.Predictedeffectsonbirthweightwith95%CIsareconditionalonmodelcovariatesincludedinModel4.BlackverticallinesrepresentthefrequencydistributionofPM2.5.
116
Thelevel‐2randominterceptstandarddeviationindicatesthatthemeanbirthweight
foreveryDAhasadegreeofvariabilityfromtheoverall(BC‐wide)meanbirthweight.For
theNullmodel,theoverallbirthweightinterceptis3,434.2gramswithastandarddeviation
of78.8givingan8.6%differenceinrangebetween95%oftheDAs(3,434.2±(1.96x78.8)
=3,280.0and3588.8grams).Similarly,wecalculatethebetween‐DA95%distributional
rangeofslopesforgestationalagetofallbetween255.8and361.6grams(308.7±(1.96x
26.6)),a29.3%differenceinhowoneweekgestationincreasesbirthweightbetweenDAs.
Figure15:AdjustedPredictedEffectsofDA‐levelfactorsonBirthWeightacrosslevelsofPM2.5(A)SocioeconomicStatusIndex(SESi)(B)AsianImmigrantDensity(C)RuralResidence.Predictedeffectsonbirthweightwith95%CIsareconditionalonmodelcovariatesincludedinModel4.BlackverticallinesrepresentthefrequencydistributionofPM2.5.
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Table7:RandomeffectsandmodeldiagnosticsfromhierarchicallinearmodelsforcontinuousbirthweightinBC,CanadaRandomEffects&ModelDiagnostics
NullModel
Null+r.slope
Model‐1(level‐1)
Model‐2(SES)
Model‐3(PM2.5)
Model‐4(PM2.5interact)
VarianceComponents L1residual(sd) 560.5 442.9 435.2 435.3 435.3 435.1L2intercept(sd) 78.8 67.6 67.0 45.9 39.7 37.9L2slope(sd) ‐‐ 30.1 26.6 27.0 27.2 27.4Intercept 3434.2 3448.4 3524.2 3521.3 3523.4 3522.6AIC 597007 489148 480867 479403 478997 478753L1‐PCV(%) Ref 37.5 39.7 39.7 39.7 39.7L2‐PCV(%) Ref 26.4 27.7 66.0 74.5 76.8ICC/VPC# 0.019 0.023 0.023 0.011 0.008 0.008L1Moran’sI˟ 0.122 0.108 0.105 0.043 0.022 0.018L2riMoran’sI˟ 0.300 0.301 0.310 0.113 0.079 0.071L2rsMoran’sI˟ ‐‐ 0.018 0.018 0.018 0.017 0.017
L1:level‐1=individual‐level;L2:level‐2=DA‐level;sd:standarddeviation;AIC:AkaikeInformationCriterion;PCV:proportionalchangeinvariance;#ICC:Intra‐classcorrelation–iscalledtheVPC(variancepartitioncoefficient)whenconditionalontherandom‐slopevariable,thusvaluesintablerepresentinterceptsforindividualswithmeangestationalage(~39weeks);L2ri:level‐2randomintercept;L2rs:level‐2randomslope;˟allresultsweresignificantp<0.05with999permutationsusingaqueencriterionspatialweightmatrix.
Thelevel‐1andlevel‐2explainedPCV(L1‐PCV&L2‐PCV)summarizestherelative
degreeofexplainedvarianceatthedifferentlevelsbetweenthedifferentmodels.Usingthe
Nullmodelasthereference,theL1‐modelresultedinanL1‐PCV&L2‐PCVof39.7%and
27.7%respectively(Table7).ThesearefairlylargePCVs,indicatingthewithinand
between‐DAvarianceinbirthweightshownintheNullmodelwasmoderatelyattributable
totheseindividual(level‐1)compositionalfactors,largelygestationalage.Theadditionof
theDA‐levelvariablesinModel2explainedanadditional38.3%oftheDA‐levelvariance
(cumulativeL2‐PVC=66%).TheadditionsofPM2.5andseasonofbirthinModel3further
explainedanadditional8.5%ofthelevel‐2interceptvariancebeyondthatofModel2.
Model4accountedforanadditional2.3%L2‐PCV.
Spatialanalyseswereusedasamodeldiagnostictotestforsignificantspatial
autocorrelationofthemodelresiduals.ThelocalMoran’sIstatisticsreportedinTable7
indicatethedegreeoflocalspatialautocorrelation(i.e.spatialclustering)ofthelevel‐1(L1)
residualsaswellasthelevel‐2predictedrandomintercepts(L2ri)andslopes(L2rs)forall
fivemodels.Interpretedinasimilarmannerasaregularcorrelationcoefficient,theMoran’s
Istatisticrevealtheexistenceofsignificantlocalizedclusteringofresidualsatbothlevel‐1
andlevel‐2intheNullandlevel‐1model.Theadditionoflevel‐2variablesreducedthe
Moran’sIsubstantially;howeversmallbutsignificantclusteringremained.
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Sensitivityanalysesusingonlythenon‐imputedDAs(N1=228,765in6,230DAs)
showedveryminordifferencesinmagnitudeofsignificantvariablesinthebirthweight
models.Inasecondsensitivityanalysis,werestrictedthesampletoonlytermbirths
excludingstillbirthsandcongenitalanomalies.Asexpected,therewasalargereductionin
therandom‐slopevarianceforgestationalageduetodroppingpretermbirthsbutnoother
differencesintheobservedrelationships(Table6,bottomhalf).
Finally,acheckforpotentialcolliderbiaswasperformedbyomittinggestationalage
asacovariatefromthemodels[45].Randominterceptmodelsequivalenttothose
presentedinTables5and6wererunandassessedfordifferences.Manyoftheindividual‐
levelcovariatereturnedtoresembletheirunadjustedestimateslistedinTable4.The
interactionbetweenPM2.5andcigarettes/dayremainedunchanged,whereasthePM2.5
interactionwithdrugoralcoholflagwasnolongersignificant(p=0.066).Theinteraction
betweengestationaldiabetesandPM2.5wasreducedbyhalf,butwasstillsignificant.The
effectsoftheDA‐levelvariablesSESiandimmigrantdensityincreasedmoderatelybeyond
their95%CIslistedforModel4.TheeffectforPM2.5decreasedbutwasstillsignificant(‐
18.0(95%CI‐21.3‐‐14.7)).TheDA‐levelinteractionbetweenPM2.5immigrantdensitywas
reducedbyhalfandmarginallynotsignificant(p=0.051),whiletheinteractionbetween
SESiandPM2.5wasalsoreducedtonon‐significance(p=0.33).
AdditionalTablesandFiguresofmodelresultsanddiagnosticsareavailablein
Appendix2.Resultsandinterpretationregardingtheothermeasuresofimpairedbirth
weight(SGA,tLBW,andIUGR)andpretermbirthareavailableinAppendix3.
4.0Discussion Thisstudyemployedmultilevelrandomcoefficientmodelstoassesstheeffectof
PM2.5onbirthweightandtestingitsinteractionwithindividualandneighbourhood‐level
riskfactors.Ourresultsshowthatindividualandneighbourhood‐levelfactorsarecapable
ofmodifyingtheassociationbetweenPM2.5exposureandfetalgrowth.Furthermore,
throughtheuseofrandom‐slopesmodelsweshowthattheeffectofgestationalageonbirth
weightcanvaryconsiderablybetweenneighbourhoodDAswhichwasonlymoderately
addressedinourmodels.Afteradjustingforindividual‐levelcovariatesandDA‐levelsocio‐
economicandsocio‐demographicvariables,wefoundasignificantnon‐lineareffect
betweenPM2.5andbirthweightin231,929birthsinBritishColumbia,Canada.This
associationwasrobusttotheexclusionofstillbirthsandcongenitalanomaliesaswellasthe
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useofonlytermbirthsandmodelsdroppinggestationalageasacovariate,demonstrating
thatselectionbiasdoesnotaffecttheobservedresults.
Ourresultscorroboratethegrowingliteraturesupportinganegativeassociation
betweenPM2.5andbirthweight[3,46,47].Eveninsettingsofrelativelylowairpollution
exposuresimilartoourstudy,significantreductionsinbirthweighthavebeenobserved
[48].Thisstrengthenstheevidenceofthelow‐doseeffectsofPM2.5andisexemplifiedby
Figure13whichshowsthelargestpotentialeffectsonbirthweightareseenatthelowto
midconcentrationsofPM2.5,anotuncommondose‐responsephenomenonalsoobservedin
otherexposure‐diseasecontexts[49].Otherstudiestestingfornon‐lineareffectsoftraffic‐
relatedairpollutantsonfetalgrowthhavebeenmixed[23,50,51].Interestingly,wefounda
similarnon‐lineardose‐responsebetweencigarettes/dayandbirthweight,aneffectalso
shownbyEnglandetalusingbothself‐reportedcigarettes/dayaswellasurine‐cotinine
levelstoassessexposure[52].
OurresultsshowanegativeinteractionbetweenPM2.5andSESsuchthatamore
pronouncedeffectofPM2.5wasseeninlowerSESneighbourhoods(Figure15A).Wealso
observedsignificantinteractionsbetweenPM2.5andAsianimmigrationdensityaswellas
withPM2.5andlivinginarurallocation(Figure15Band15Crespectively).Thissuggests
thatthatnotonlycanneighbourhoodcharacteristicsinfluencefetalgrowthbutcanalso
modifyexposureseitherpositivelyornegatively.Thebiologicalmechanismssupporting
suchinteractionshavebeenrecentlyreviewed[5],andhavebeenindirectlysupportedin
epidemiologicalstudiesthatfoundstrongereffectsofPM2.5acrossrace,ageandSESgroups
[23,25,53].Forexample,theobservedlowerbirthweightsassociatedwithneighbourhoods
withhigherdensitiesofcontinentalAsianimmigrantsislikelyduetoconstitutionalbirth
sizedifferences[37,38],butthepositiveinteractionwithPM2.5mayreflectthebuffering
effectofstrongcommunitycohesivenessandbeneficialculturalpractices[23,32].Asimilar
interactionwasfoundbyBasuetalinwhichbirthstoAsianmothersexhibitedsmallerbirth
weightreductionsforPM2.5constituentscomparedtoCaucasianbirths[23].However,
similarinteractionswerenotfoundbyCurrieetalbetweentraffic‐relatedCOexposureand
riskfactorssuchasrace,education,orlowincome[54].
ThesignificantnegativeinteractionbetweenruraladdressandPM2.5mayreflectthe
underestimationofPM2.5inruralareasbytheLURmodel[34].ThecompositionofPM2.5,
andthusitsrelativetoxicity,isshowntovaryspatiallydependingonitssource(e.g.wood
smokevs.traffic‐relatedemissions)andmaypartiallyexplaintheobservedrural‐urban
120
differences[4,6].Thesignificantnegativeassociationbetweenseasonofbirthandbirth
weightcouldalsoreflecttheincreasedpresenceofwoodheatingandvehicleexhaustin
combinationwithwinterstagnationevents,butcouldalsoreflectachangeindietor
increasedinfectionrates[4,55].AninteractionbetweenseasonofbirthandPM2.5wasnot
statisticallysignificant.
InteractionsbetweenPM2.5andmaternal‐levelvariablesshowntoreducebirth
weightindependentlyrevealedsomecounter‐intuitiveresults.ThisincludedthePM2.5
interactionwithmaternalsmoking(cigarettes/day)andwithsuspecteddrug/alcoholuse
whereincreasingPM2.5levelstemperedthenegativeeffectoftheseriskfactors(Figure14A
and14B).Thisfindingwascounterintuitivetoouroriginalhypothesisandpublished
literature[54],andgaverisetothesuspicionofsurvivalbiasduetocompetingrisks(i.e.
riskbehavioursleadingtoearlymiscarriage,pretermorstillbirths).Althoughwewerenot
abletocontrolforfetallosspriorto20weeksgestation,survivalbiaswasmitigatedby
usinganearfullpopulationsamplethatincludedstillbirths,congenitalanomaliesand
pretermbirths.Furthermore,thepositiveinteractionbetweenmaternalsmokingandPM2.5
wasunchangedafterthesensitivityanalysesusingonlytermbirthsaswellasforpotential
colliderbias;whereastheinteractionbetweendrugandalcoholuseandPM2.5remained
positivebutwasnolongersignificant(p=0.054)[45].Thepersistenceofthisfindingleads
toahypothesisthatsomeindividual‐levelexposuresmayactasapre‐conditioningstress
thatactivatesanadaptiveresponseofincreasedbiologicalresistancetosimilarorother
stressors[56].
AprotectiveeffectofoldermaternalageagainstPM2.5exposurewasalsoobserved
byBasuetal[23],andmaystemfromincreasednutritionalawarenessamongolderwomen
and/ormoresecureincomeandsupportnetworkstherebyreducingpotentialstressand
anxiety[57,58].Currieetalalsofoundsignificantinteractionsbetweentraffic‐related
carbonmonoxideexposureandmaternalage,butthatbothyounger(<age19)andolder(>
age34)maternalagehadgreaterreductionsinbirthweight[54].Gestationaldiabeteshas
beenshowntobeassociatedwithPM2.5andotherairpollutants[59,60];however,their
interactionwithrespecttobirthweighthasnotbeenassessed.Ourstudyshowedthat
pregnanciesaffectedbygestationaldiabeteshadsignificantlyhigherbirthweightsas
expectedbutrevealedasharpreductioninbirthweightwithincreasingPM2.5.This
significantnegativeinteractionbetweenPM2.5andgestationaldiabetescouldberelatedto
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excessofsystemicorplacentaloxidativestressandinflammationresultinginrestricted
fetalgrowth[15,61].
Whiletheapplicationofmultilevelmodelsinperinatalepidemiologyhavebecome
morecommon[62],mosthavebeenrandominterceptmodelswithveryfewincludinga
random‐slopeparameter.Permittingtheslopeforindividual‐levelgestationalagetobe
randomcanelucidatehowitseffectonbirthweightdiffersbetweenDAs.Forexample,the
additionoflevel‐1covariatesreducedtherandom‐slopevariabilityfrom30.1to26.6.This
suggeststhatthatthesematernalriskfactorsactthroughgestationalagetoinfluencebirth
weightandarenotdistributedhomogeneouslyacrossDAs.Inlightofthesefindings,
significantinter‐DAvarianceremainedforboththerandominterceptandslope.Inother
words,despiteexplainingasubstantialproportionofthebetween‐DAvarianceinbirth
weightwithbothlevel‐1compositionalandlevel‐2contextualfactors,thereremained
unmeasuredDA‐levelmechanismsactingeitherdirectlyonfetalgrowthand/orthrough
gestationalagetoproducebetweenneighbourhooddifferencesinbirthweight.
Spatialanalyseswereusedtoexaminethewiderspatialcontextwithinwhichthe
DAsaresituatedaswellasaservingasameasureofmodelspecificationandhowwellthe
chosenrepresentativeneighbourhood(DA)unitperformed.TheinclusionoftheDA‐level
variablesandinteractionssubstantiallyreducedthespatialautocorrelationinthelevel‐1
andlevel‐2randominterceptresiduals(L1&L2riMoran’sIinTable7).Therewasvery
littlespatialautocorrelationinthelevel‐2random‐slopeparameters(L2rsMoran’sI),but
wasalsoslightlyreducedintheDA‐levelmodels.Althoughverysmall,significantspatial
autocorrelationremainedintheresiduals,particularlyfortherandomintercept,which
couldbiasthemodelstandarderrorsandincreasetheriskofmakingTypeIerrors[35].
Akeycomponentofthisresearchwastheuseofaland‐useregression(LUR)model
ofairpollution[34].WhiletheLURmodelwasindependentlyvalidatedandachieveddecent
overallresultsinitspredictedestimates,theverynatureofourstudydesignensuressome
degreeofexposuremisclassificationtoourstudypopulation.Ouranalysiswasbasedon
maternalplaceofresidenceatdelivery,andthereforeintra‐urbancommutingandpotential
inter‐urbanrelocationwithinthepregnancyperiodwasnotaccountedforwhichcould
affecttheresults.Time‐activitypatternsshowthatpregnantwomenspendmoretimeat
homeinthelaterstagesofpregnancy,butmobilitypatternsmaydifferbyage,parityand
SES[63,64].AnotherlimitationregardingthePM2.5exposureassessmentisthattheLUR
modeliscross‐sectionalbasedon2006airqualitymonitoringdata,whilethestudyperiod
122
ofourperinataldatasetspans6years(2001to2006).Wethereforeassumeallpregnancies
wereexposedtothesamelevelsofPM2.5fortheirentirepregnancy,regardlessoftheiryear
ofbirth,basedontheirresidentialDA.Whilethismethodpreventstheassessmentof
exposurewindowsbytrimester,spatiotemporalstudiesofPM2.5haveshownlittletono
differencebetweentrimester‐specificandentirepregnancyeffectsonbirthweight
[3,46,48].Finally,themeanPM2.5concentrationsmaybeunderestimatedbytheLURmodel
withlessvariabilityandmissingseveralhighPM2.5outlierlocationsinBCcomparedto
compiledmonitoreddata[26].Thiscouldpotentiallyresultinanunderestimationofour
observedassociationofreducedbirthweightwithincreasingPM2.5levels.
Wewereunabletocontrolformaternal‐levelSES,andthereforethe
neighbourhood‐leveleffectestimatesandinteractionscouldreflectindividual‐level
differences.Forexample,theprotectiveeffectofoldermaternalagebufferingthePM2.5
effectonbirthweightcouldbeduetoindividual‐levelSESfactorsnotaccountedforinour
modelssuchasdiet,incomeorstress.However,studieshavefoundthatadjustmentfor
individual‐levelmeasuresofSESdidnotsignificantlychangethearea‐levelassociations
[20,65].MaternaleducationisavariableprovidedintheBCPerinatalDataRegistry,butwas
onlyavailablefor10%ofourpopulation.However,theadjustmentforsocially‐patterned
behaviouralriskfactorssuchasmaternalsmoking,suspecteddrugoralcoholuseandlow
numberofprenatalcarevisitswillcontrolforsomeindividual‐levelSESdifferences[66].
5.0ConclusionsThisstudysupportsthegrowingliteratureofaneffectofPM2.5onbirthweightandits
modificationbybothmaternalandneighbourhood‐levelfactors.Mostnotably,itshowsthat
lowerSESneighbourhoodsmaybemorenegativelyaffectedbyhigherlevelsofPM2.5.We
observedbothpositiveandnegativeinteractionsbetweenmaternalfactorsandPM2.5that
requirefurtherscrutinybutmayreflectaPM2.5‐oxidiativestresspathwayexpressedvia
eitherprotectivepre‐conditioningorharmfuloverload.Targetedmunicipal‐level
interventionstoreducePM2.5andimprovedneighbourhoodSESmayhelpimprovebirth
outcomesatthepopulation‐level.
6.0EndnoteforChapter4 Figure16andTable8belowshowtheresultsfromamodelthatwassubsequently
runaftertheinitialmanuscriptforChapter4wasacceptedforpublication.Thismodel
(Model5)doesnotsubstantiallyalteranyoftheresults,interpretation,orconclusionsfrom
thepreviousmodels;however,itdoesprovideamorenuancedunderstandingofthe
123
observedrelationshipsbetweenPM2.5,ruralresidenceandSESoncontinuousbirthweight.
InFigure16,themiddlepane(MeanSES)correspondstoFigure15cinthemaintext
showingthemorepronounceddeclineinbirthweightforruralbirthswithincreasinglevels
ofPM2.5.ByaddinganinteractiontermbetweenruralandSES,thestarkcontrastoftheSES
effectonurbanandruralbirthsbecomesclear.Theredlinerepresentingruralbirths
remainsfairlystatic,indicatingthatwithinruralareasSEShasalimitedroleonbirth
weight,anobservationthathasbeennotedinotherstudies[67,68].Conversely,theblue
linerepresentingurbanbirthsshowsadramaticincreaseinbirthweightwithincreasing
SESwhileitsslopewhichsignifiesthePM2.5effectbecomesslightlylesssteep
demonstratingtheprotectiveroleofimprovedSESonthenegativeeffectsofPM2.5onbirth
weight.ComparedtoModel3and4,Model5showstohaveaslightlybetterAICscore,as
wellasexplainingslightlymoreoftheDA‐levelvarianceintherandomintercept.
Figure16:ResultsfromModel‐5includingaSES*Ruralinteraction
124
Table8:AdjustedindividualandDA‐levelfixedeffectsoncontinuousandtermbirthweightandtheirmodificationbyPM2.5(Model‐5)
Variables MainEffectβ(95%CI)
ModificationbyPM2.5β(95%CI)
PM2.5ª ‐21.0(‐23.7–‐18.2) 4.0(2.2–5.7)Cigarettes/dayª ‐21.9(‐23.6–‐20.1) 2.7(2.1–3.3)
Drug/Alcoholflag ‐80.5(‐92.9–‐68.2) 15.3(4.4–26.2)
Maternalage ‐4.3(‐6.3–‐2.3) 5.5(3.7–7.3)
Gestationaldiabetes 70.3(62.7–77.9) ‐33.7(‐41.8–‐25.7)
SESi 33.7(31.1–36.2) 1.3(‐1.4–3.9)Immigrantdensity ‐30.4(‐33.1–‐27.8) 3.7(0.8–6.7)
Ruraladdress ‐17.7(‐28.3–‐7.1) ‐15.7(‐23.7–‐7.6)
Rural*SESi ‐31.8(‐42.1–‐21.4) ‐‐
RandomEffects&ModelDiagnostics
VarianceComponents L1residual(sd) 435.2
L2intercept(sd) 36.4
L2slope(sd) 27.4
Intercept 3521.22
AIC 478665
L1‐PCV(%) 39.7
L2‐PCV(%) 78.7
ICC/VPC# 0.007
ªModeledasaquadratic,Cigarettes/day:0.7(0.6–0.8);Modeladjustedforgestationalage,nulliparous,diabetesmellitus,gestationalhypertension,prenatalcarevisits,seasonofbirth,DA‐leveleducation,on‐reservebirth.
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130
Chapter5:Airpollution,neighbourhoodandmaternal‐levelfactorsmodifytheeffectofsmokingonbirthweight:amultilevelanalysis
inBritishColumbia,CanadaEricksonA.C.,OstryA.,ChanL.H.M.,ArbourL.Airpollution,neighbourhoodandmaternal‐levelfactorsmodifytheeffectofsmokingonbirthweight:amultilevelanalysisinBritishColumbia,Canada.BMCPublicHealth.Accepted,inpress.
AbstractBackground:Maternalsmokingduringpregnancynegativelyimpactsfetalgrowth,butthe
effectisnothomogenousacrossthepopulation.Wesoughttodeterminehowthe
relationshipbetweencigaretteuseandfetalgrowthismodifiedbythesocialandphysical
environment.
Methods:BirthrecordswithcovariateswereobtainedfromtheBCPerinatalDatabase
Registry(N=232,291).Maternalsmokingstatuswasself‐reportedasthenumberof
cigarettessmokedperdayusuallyatthefirstprenatalcarevisit.Censusdissemination
areas(DAs)wereusedasneighbourhood‐levelunitsandlinkedtoindividualbirthsusing
residentialpostalcodestoassignexposuretoparticulateairpollution(PM2.5)and
neighbourhood‐levelattributessuchassocioeconomicstatus(SES),proportionofpost‐
secondaryeducation,immigrantdensityandlivinginaruralplace.Randomcoefficient
modelswereusedwithcigarettes/daymodeledwitharandomslopetoestimateits
between‐DAvariabilityandtestcross‐levelinteractionswiththeneighbourhood‐level
variablesoncontinuousbirthweight.
Results:Asignificantnegativeandnon‐linearassociationwasfoundbetweenmaternal
smokingandbirthweight.Therewassignificantbetween‐DAinterceptvariabilityinbirth
weightaswellasbetween‐DAslopevariabilityofmaternalsmokingonbirthweightof
which68%and30%respectivelywasexplainedwiththeinclusionofDA‐levelvariables
andtheircross‐levelinteractions.HighDA‐levelSEShadastrongpositiveassociationwith
birthweightbuttheeffectwasmoderatedwithincreasedcigarettes/day.Conversely,heavy
smokersshowedthelargestincreasesinbirthweightwithrisingneighbourhoodeducation
levels.IncreasedlevelsofPM2.5andimmigrantdensitywerenegativelyassociatedwith
birthweight,butshowedpositiveinteractionswithincreasedlevelsofsmoking.Older
maternalageandsuspecteddrugoralcoholusebothhadnegativeinteractionswith
increasedlevelsofmaternalsmoking.
131
Conclusion:Maternalsmokinghadanegativeandnon‐lineardose‐responseassociation
withbirthweightwhichwashighlyvariablebetweenneighbourhoodsandevidenceof
effectmodificationwithneighbourhood‐levelfactors.Theseresultssuggestthatfocusing
exclusivelyonindividualbehavioursmayhavelimitedsuccessinimprovingoutcomes
withoutaddressingthecontextualinfluencesattheneighbourhood‐level.Furtherstudies
areneededtocorroborateourfindingsandtounderstandhowneighbourhood‐level
attributesinteractwithsmokingtoaffectbirthoutcomes.
1.0BackgroundSmokingduringpregnancyisamodifiableriskfactorassociatedwithadversebirth
outcomesandmayimpartlong‐termhealthconsequences[1–3].Thisrelationshiphowever
isconfoundedbythepresenceofmanyotherriskfactors,includingmaternalage,education,
alcoholordruguse[4–6].Furthermore,it’sbeenshownthattheseindividual‐levelrisk
factorshaveadose‐responseassociationwiththelevelofsmoking,withadistinction
betweenheavysmokers(greaterthan10cigarettesperday)andmoderateorlightsmokers
[4].Forexample,whiletheprevalenceofsmokingduringpregnancydecreaseswith
increasingmaternalage,thelevelofsmokingisheavieramongtheoldermotherswhodo
smoke.Theeffectofsmokingonbirthweighthasbeenshowntobemodifiedbymaternal
ageandotherbehaviouralriskfactors[7,8].Similarly,neighbourhood‐levelfactorsmight
directlyorindirectlymodifytheeffectofsmokingonbirthweightsuchasneighbourhood
deprivationorlevelsofparticulateairpollution[9–11].
Exposuretothefinefractionofparticulatematter(PM2.5,particleswithaerodynamic
diameter≤2.5μm)hasshowntobeaconsistentriskfactorassociatedwithreducedbirth
weight[12].ThecomplexmixtureofPM2.5includeselementalandorganiccarbon
compounds,metalsandgasesthatstempredominantlyfromvehicleexhaust,residential
heatingandindustrialemissions[13].ThemechanismsbywhichPM2.5anditsconstituents
adverselyaffectthereproductivesystemarenotfullyunderstood;however,evidence
supportsthepotentialforasharedmodeofdevelopmentaltoxicitywithtobaccosmoke
exposure[14–16].Withsimilarchemicalcomponents,bothPM2.5andtobaccosmoke
penetratedeepintopulmonaryalveolartissuesandtranslocatetoextrapulmonarytissues
causingsystemiccardiovascularandimmunologicalalterations,includingplatelet
activation,coagulation,endothelialdysfunction,DNAdamageandmutagenesis[13,16,17].
LowSESremainsoneofthemostrobustpredictorsofadversepregnancyoutcomes
suchasfetalgrowthrestrictiondespiteuniversalhealthcareprogramsinCanadaand
132
Europe[9,18,19].Thesociety‐leveldeterminantssuchaspoverty,pooreducation,income
inequalityandsocialdiscriminationandmarginalizationactindirectlyontheplacentaand
fetusthroughthepromotionof‘downstream’ormediatingexposures,stressesand
behaviours[20,21].Instudiesofcardiovasculardisease,neighbourhood‐levelfactorswere
associatedwithincreasedlevelsofsmokingandotherriskfactorssuchasobesity,lackof
exercise,lowerhealthknowledgeandlowerpositivebehaviourchanges[11,22].These
epidemiologicalobservationshavebeenshownwiththeuseofmultilevelstatisticalmodels
capableofseparatingtheindividual‐leveleffectsfromthecontextoftheirsocialand
physicalenvironments[23].Theuseofmultilevelmodelsinperinatalepidemiologyhas
uncoveredneighbourhood‐levelfactorsthatinteractwithmaternal‐levelriskfactorsto
eitherbufferormediateadversebirthoutcomes[21,24].
Wepresentamultilevelcross‐sectionalanalysisofbirthregistrydatainBritish
Columbia,Canada(population4.6million)toinvestigateneighbourhood‐leveldifferencesin
theeffectofcigarettesmokingduringpregnancyonbirthweightandtoquantifythedegree
towhichindividualandneighbourhood‐levelvariablesexplainanyobserveddifferences.
Specifically,wesoughttodeterminewhetherexposuretoPM2.5andlivinginlowSES
neighbourhoodsexplainbetween‐neighbourhooddifferencesintheeffectofmaternal
smokingonbirthweight.Wealsoexaminewhethertheseneighbourhood‐levelfactors
modifythedirecteffectofmaternalsmokingonbirthweight.Birthweightisamongthe
mostimportantfactorsaffectingneonatalmortalityandisasignificantdeterminantofpost‐
neonatalinfantmortalityandchildhoodmorbidity[25].Understandingtheunderlying
individualandinteractiveeffectsofexposuresonbirthweightiscrucialforeffective
communityplanningandstrategicinterventionstoimprovingreproductivehealth
outcomes.
2.0DataandMethodsThiswasapopulation‐basedcross‐sectionalstudyofsingletonbirthsinBritish
Columbiafrom2001to2006(N=237,470).DatafromtheBCPerinatalDatabaseRegistry
wereprovidedbyPerinatalServicesBC(PSBC),andincludedinformationonindividual‐
levelmaternal‐infanthealthstatusandoutcomes,reproductivehistory,socio‐
demographics,riskfactors,andresidentialpostalcodes.TheRegistryaccountsfor99%of
birthsandstillbirthsinBCofatleast20weeksgestationoratleast500gramsbirthweight.
ResearchdataaccessisprovidedbyaPartnershipAccord/MemorandumofAgreement
betweenallBCHealthAuthoritiesandPSBCthroughtheFreedomofInformationandPrivacy
133
ProtectionAct[26].ResearchethicsboardapprovalwasgrantedbytheUniversityof
Victoria(protocol#11‐043).
Theoutcomevariablewascontinuousbirthweightofsingletonbirths.Includedwere
allbirths(stillbirthandlive)forgestationalagesof20to42weeks.Excludedbirthrecords
included:out‐of‐provinceandinvalidpostalcodes(n=1,096),non‐viablebirthspriorto20
weeksgestationandlessthan500grams(n=15),andthelist‐wisedeletionofbirthsmissing
importantdataincluding:cigarettessmokedperday(cigarettes/day,n=2,510),PM2.5
(n=1,512),birthweight(n=46).Table9providesthefulllistofcovariatesusedalongwith
theirsummarystatistics.Allcontinuousindependentvariables,exceptcigarettes/day,were
grand‐meancentredandstandardizedtoeaseinterpretationandaidmodelconvergence.
Thus,avalueofzerorepresentsthetransformedvariable’smeanandreferencevalueand
hasastandarddeviationequaltoone.Thevariablecigarettes/daywaskeptun‐transformed
sincethevaluezero(i.e.non‐smokers)wasthedesiredreferencelevel.Smokinglevelswere
cappedat20cigarettes/daywithhighervaluesassignedavalueof20tostabilizethe
distributiontail(n=245,min.21max.80).Twovariablesindicatingtheuseofalcoholor
druguse(prescription,non‐prescription,illicit)asariskfactorinthepregnancyidentified
byaphysicianwerecombinedintoasingledichotomousvariable.
Birthrecordsweregeocodedbasedonthelatitude‐longitudecoordinateofthe
mother’sresidentialpostalcodeatthetimeofdeliveryusingGeoRefbyDMTI[27].Birth
recordswerethenlinkedtotheircorrespondingcensusdisseminationarea(DA)by
performingapoint‐in‐polygonspatialjoinprocedureinArcGIS10.2[28].DAsrepresentthe
smallestgeographicalunitforwhichcensusdataareavailablewithaspatialcoverage
rangingbetween200–800peopledependingonthelevelofurbandevelopment.WhileDAs
donotnecessarilyrepresentexistingneighbourhoodcommunities[29],theycanactas
proxiesforageneralcatchmentareaofpersonalhome‐lifeactivities[21,30].Birthrecords
wereidentifiedasbeingeitherruralorurbanusingtheStatisticsCanadaMetropolitan
InfluenceZone(MIZ)codeswhicharebasedoncommutingflowsofsmalltownsintolarger
citiesandmetropolitanareas[31].
PM2.5exposurewasestimatedusinganationalland‐useregression(LUR)model
developedtoestimatePM2.5atthecensusstreetblock‐facelevel[32].Themodeluseda
numberofpredictorsincludingsatellitemeasures,proximitytomajorroadsandindustryto
accountfor46%ofthevariabilityinmeasuredannualPM2.5concentrations.Individualbirth
recordswererelatedtotheblock‐facepointestimatesusinganearest‐pointprocedurein
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ArcGIS10.2.Streetblock‐facepointestimateswererelatedtoindividualbirthrecordsusing
anearest‐pointprocedureinArcGIS10.2andthenaggregatedtotheirDA‐levelmeanto
representanarea‐levelairpollutionvariableonindividualbirths.
Threerelatedbutindependentdatasetsallbasedonthe2006StatisticsCanada
nationalcensuswereusedtorepresenttheDA‐levelSESanddemographicdata.Thefirst
wasaCanadianSESindex(SESi)developedbyChanetalwhichprovidesameasureof
overallsocioeconomicneighbourhoodwell‐being[33].Thesecondwastheproportionof
populationover15withanypost‐secondaryeducation,includingcollege,trades,or
universityrepresentinghigherDA‐leveleducationattainmentlevels.Thethirdwasthe
proportionofcontinentalAsianimmigrantsbyDA.It’sbeenshowninBCandelsewhere
thathealthybabiesfromAsianandSouthAsianbackgroundsareconstitutionallysmaller
comparedtoCaucasianbabies[34,35].AsianandSouthAsianethnicitiesarewell‐
representedthroughoutBCbutparticularlyinconcentratedpocketsthroughoutthemajor
urbancenterofMetroVancouverwherelevelsofPM2.5arealsohighandcouldtherefore
confoundanyPM2.5effect.Furthermore,concentratedethniccommunitiesmayimpart
bufferingmechanismsthroughenhancedsocialinteractionsandsupportnetworks[21,24].
AsequentialregressiontechniquewasusedtoremovethecollinearitybetweensetsofDA‐
levelvariables[36].Here,immigrantdensitywasregressedagainstSESiandPM2.5withthe
savedresidualsrepresentingtheuncorrelatedandindependentcontributionofimmigrant
densityonbirthweightfreedfromitscollinearitywithSESiandPM2.5(r=‐0.62and0.53
respectively).ThismethodwasrepeatedforSESiandeducation(r=0.26)creatinga
residualimmigrantdensityandresidualeducationvariable.Theeducationandimmigrant
datawereobtainedbyaccesstoABACUSviatheDataLiberationInitiative[37].
ImputationformissingSES,educationandimmigrantdensityvalueswasperformed
inordertoavoiddatalossofruralDAswithlowpopulationcounts.Takingadvantageofthe
nestedhierarchicalstructureoftheadministrativecensusandhealthboundaries,themean
SESivalueforalargerencompassingcensussubdivision(CSD)orlocalhealtharea(LHA)
wasimputedforanestedDAwithamissingvalue.Therewere1,441valuesimputedin52
DAsforSESi(0.6%offinalN,0.8%ofDAs),and3,170valuesimputedin108DAsforboth
educationandimmigrantdensity(1.4%offinalN,1.7%ofDAs).Sensitivityanalyseswere
performedusingonlythenon‐imputeddata.
Hierarchical(multilevel)linearregressionmodelswereusedtotestourresearch
questions,therebyaccountingfortheclustering,ornon‐independence,ofindividuals(level‐
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1)belongingtoagivenDAneighbourhood(level‐2).Themultilevelmodelallowsthe
interceptandslopetoactasrandomparametershavingbetween‐area(DA)variabilityfrom
anoverall(BC‐wide)meaninterceptandslope.ThereforeeachDAhasitsowninterceptand
slopeinwhichtheirvariabilityfromtheoverallmeaninterceptandslopecanbe
investigatedwiththeadditionofindividual(level‐1)andDA‐level(level‐2)variablesand
theirinteractions[38].Wefollowedabottom‐upapproachtomodelbuildingtoquantifythe
explainedproportionalchangeinvariance(PCV)withtheadditionofsetsofvariables,the
multilevelmodelequivalenttoanR2[23].Westartedwiththeempty(Null)random
interceptmodelwithoutanyindependentvariablesinwhichbirthweightisonlyafunction
ofthemother’sresidentialDA.Thepresenceofsignificantrandominterceptvariance
indicatesthereareunexplaineddifferencesbetweenneighbourhoodmeansofbirthweight.
Theproportionofthetotalvarianceinbirthweightthatarisesduetoneighbourhood
differencescanbequantifiedbycomputingtheintra‐classcorrelation(ICC)which
representsthedegreeofclusteringofindividualbirthweightwithinneighbourhoods[23].
TheNullmodelwasfollowedbyModelthatincludedtheindividual‐levelcovariatesas
wellastheadditionofarandomslopeforthecontinuousvariableofmaternalsmoking
(cigarettes/day,self‐reportedatthefirstprenatalvisit).Byallowingcigarettes/daytobe
random,themeanwithin‐DAeffectofmaternalsmokingisallowedtodifferbetweenDAs.
Thepresenceofasignificantrandomslopeindicatesthatitseffectonbirthweightisnot
constant(orequal)forallDAs;thatis,thereareimportantunexplaineddifferencesbetween
thewithin‐DAgroupeffectsofmaternalsmokingonbirthweight.Subsequentmodels
includedtheDA‐levelvariablesalongwithcross‐levelinteractionstoassesstheirfixed
effectsonbirthweightbuttoalsodetermineiftheirinclusionaddressedanyunexplained
slopevariance.SeveralmodelsweretestedusingtheAkaikeInformationCriterion(AIC)to
evaluatemodelperformance.Wereporttheresultsofthreemodelstocomparethedegree
ofchangebetweenthelevel‐1andlevel‐2homogeneous(non‐interaction)modelsanda
modelwitheffect‐measurevariation.StatisticalanalyseswereconductedinStata13IC[39].
3.0ResultsAfterexclusions,thefinaldatasetincluded232,291singleton(liveandstillborn)
birthslocatedin6,338neighbourhoodDAs(min.=1,max.=782,avg.=37).Table9
summarizestheuntransformedindividualandneighbourhoodcovariates(non‐centered,
non‐standardized).Theprevalenceofmaternalsmokinginthispopulationwas10.3%(n=
23,836)withanaverageof7.5cigarettes/dayamongsmokers.Table10reportsthe
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adjustedcoefficientsfortheindividualandDA‐levelcovariatefixedeffectsoncontinuous
birthweight(Model1and2).Model1wasalevel‐1modelthatincludedonlythematernal‐
levelcovariates.Therelationshipbetweenbirthweightandcigarettes/daywasfoundtobe
non‐linearandwasbestmodeledusingaquadratictermindicatingasubdueddose‐
responsewithincreasingexposure(Figure17).Model2addedtheDA‐levelvariables.Their
fixedeffectsshowthatDAswithhigherSESandhigherproportionofpost‐secondary
educationweresignificantlyassociatedwithhigherbirthweights;whereasDAswith
increasedlevelsofPM2.5,higherAsianimmigrantdensityandruralDAswereall
significantlyassociatedwithlowerbirthweights.Seasonofbirth(fallorwinter)wasalso
significantlyassociationwithreducedbirthweight.TheresultsinTable10representthe
fixedeffectsfromhomogeneousmodels(i.e.thosewithoutanymodeledheterogeneityof
theeffectmeasureformaternalsmoking).
Table9:Descriptivestatistics#forindividual(Level‐1)andDA(Level‐2)covariatesontermbirthweightVariable Mean(sd) Min‐Max
Level‐1(individual)
Maternalage 29.8(5.60) 11–55
Nulliparous 0.45(0.50) 0–1
Drug/Alcoholflag 0.02(0.15) 0–1
Cigarettes/day 0.79(2.91) 0–20
Fall/Winterseason 0.48(0.50) 0–1
Level‐2(DA)Variables
SESi ‐0.08(0.58) ‐2.22–1.18
Education 0.50(0.12) 0–0.95
Immigrantdensity 0.16(0.19) 0–0.86
PM2.5 7.30(0.86) 4.41–10.23Ruraladdress 0.11(0.32) 0–1
#valuesshownareunstandardized,non‐centered;Nulliparous:patienthasneverdeliveredababyofatleast500gramsbirthweightoratleast20weeksgestationinapreviouspregnancy;DrugorAlcoholFlag:physicianindicateduseofdrugs(prescription,non‐prescription,illicit)oralcoholasriskfactorinpregnancy;Cigarettes/day:numberofcigarettessmokeddailyat1stprenatalvisit(self‐reported);Fall/WinterSeason:monthorbirthbetweenSeptembertoFebruary;SESi:socioeconomicstatusindex;Education:proportionofpopulationover15withanypost‐secondaryeducation(trade,college,university);ImmigrantDensity:proportionofthepopulationidentifiedasimmigrantstatusfromcontinentalAsia;PM2.5:ParticulateMatterlessthan2.5microns;Rural:thosehavingaruralresidentialaddress.
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Table10:Adjustedfixedeffectsforlevel‐1andlevel‐2covariatesoncontinuoustermbirthweightVariables Model1
β(95%CI)Model2β(95%CI)
Maternalage ‐16.9(‐19.3–‐14.4) ‐14.9(‐17.4–‐12.4)
Nulliparous ‐107.7(‐112.5–‐103.0) ‐105.5(‐110.3–‐100.7)
Drug/Alcoholflag ‐171.6(‐186.9–‐156.3) ‐172.2(‐187.5–‐157.0)
Cigarettes/daycigarettes/dayª
‐23.5(‐25.8–‐21.2)0.66(0.51–0.80)
‐26.2(‐28.5–‐23.9)0.75(0.61–0.90)
Fall/Winterseason ‐9.6(‐14.1–‐5.0) ‐8.8(‐13.3–‐4.3)
SESi ‐‐ 42.7(39.8–45.6)
Education ‐‐ 6.3(3.5–9.1)
Immigrantdensity ‐‐ ‐35.8(‐38.5–‐33.2)
Ruraladdress ‐‐ ‐18.8(‐28.4–‐9.2)
PM2.5PM2.5ª
‐‐ ‐25.0(‐28.2–‐21.8)3.3(1.5–5.2)
SeeTable9captionforvariabledefinitions;ªModeledasaquadratic.
Model3testedinteractionswithcigarettes/dayincludingcross‐level(level‐1by
level2)andlevel‐1bylevel‐1interactionstoexplainthebetween‐DArandominterceptand
randomslopevariability.ThemodelresultsarepresentedinTable11includingthemain
effectsaswellastheinteractioneffectswithcigarettes/day.Thedegreeofheterogeneity
acrosslevelsofmaternalsmokingmodifiedbytheDA‐levelcontextualfactorsisgraphically
presentedinFigure18.ThefivegraphsshowthepredictedconditionalfixedeffectsofSESi,
education,PM2.5,Asianimmigrantdensityandruralresidenceonbirthweightandtheir
interactionswithspecifiedlevelsofmaternalsmoking(Figure18A,18B,18C,18D,and18E
respectively).Forexample,Table11andFigure18AshowthathigherSEShasasignificant
positiveassociationwithbirthweightbutislesspronouncedwithincreasedlevelsof
maternalsmokingwherebyveryheavysmokers(≥20cigarettes/day)donotincurany
Figure17:AdjustedPredictedEffectsofMaternalSmokingonBirthWeightPredictedeffectsofmaternalsmoking(cigarettes/day)onbirthweightwith95%CIsareconditionalonmodelcovariatesincludedinModel3.Blackverticallinesrepresentthefrequencydistributionofcigarettes/day(non‐smokers,0cigarettes/day,havebeenomittedfordisplaypurposes).
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benefitofhigherSES.Conversely,veryheavysmokersshowedthegreatestgainsinbirth
weightinDAswithhigherproportionsofpost‐secondaryeducatedpeople(Figure18B).
Recallthatthehighereducationvariablewasanuncorrelatedresidualvariableindependent
ofSESi,andthereforetheseobservedassociationsareinadditiontotheeducation‐related
effectcapturedbySESi.
Table11:AdjustedindividualandDA‐levelfixedeffectsoncontinuousbirthweightandtheirmodificationbymaternalsmoking(Model3)
Variables MainEffectβ(95%CI)
ModificationbyCigarettes/dayβ(95%CI)
CorrespondingFigure
Cigarettes/dayª ‐25.7(‐28.1–‐23.3) 0.83(0.68–0.98) 1SESi 43.8(40.9–46.8) ‐2.7(‐3.7–‐1.6) 18AEducation 5.2(2.3–8.1 1.3(0.3–2.3) 18BPM2.5PM2.5ª
‐26.3(‐29.6–‐23.0)3.4(1.5–5.3)
1.8(0.9–2.7) 18C
Immigrantdensity ‐36.5(‐39.2–‐33.7) 2.6(1.5–3.7) 18DRuraladdress ‐15.0(‐25.1–‐5.0) ‐2.9(‐5.6–‐0.2) 18EMaternalage ‐12.1(‐14.8–‐9.5) ‐2.9(‐3.6–‐2.1) 19ADrug/Alcoholflag ‐161.2(‐180.4–‐142.1) ‐3.7(‐6.3–‐1.2) 19BSeeTable9captionforvariabledefinitions;ªModeledasaquadratic;Model3covariatesnotlisted:nulliparousandseasonofbirth.
Figure18:AdjustedPredictedEffectsofMaternalSmokingonBirthWeightacrossDA‐levelFactors.A)SocioeconomicStatusIndexB)ProportionofPopulationwithPost‐secondaryEducationC)PM2.5D)AsianImmigrantDensityE)RuralResidence.Predictedeffectsonbirthweightwith95%CIsareconditionalonmodelcovariatesincludedinModel3.Blackverticallinesrepresentthefrequencydistributionofthevariableonthex‐axis(exceptFigure18Ewhichshowsthefrequencydistributionofcigarettes/day).
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IncreasingPM2.5levelshadasignificantnon‐linearassociationwithreducedbirth
weight;however,itshowedapositiveinteractionwithmaternalsmokingsuchthatthe
effectofincreasedsmokingonbirthweightwasattenuatedinDAswithhigherlevelsof
PM2.5(Figure18C).Similarly,higherAsianimmigrantdensitywassignificantlyassociated
withlowerbirthweightsbuthadapositiveinteractionwithincreasedcigaretteuse
demonstratingaprotectiveeffectofhigherimmigrantdensityDAs(Figure18D).RuralDAs
hadasignificantnegativeinteractionwithmaternalsmokingindicatingafurtherreduction
inbirthweightwithincreasedcigaretteuseamongruralresidents(Figure18E).
Twolevel‐1interactionswithmaternalsmokingweresignificant,maternalageand
suspecteddrugoralcoholuse.Thepredictedconditionalmarginaleffectsofthesetwo
interactionsareshowinFigure19Aand19Brespectivelyindicatingthatthereductionof
birthweightamongheaviersmokersisexasperatedbyoldermaternalageandthose
suspectedofdrugoralcoholuse.Avariableforneighbourhood‐levelsmoking(DA‐average
cigarettes/day)wascreatedandtestedinmodelsalongwithacross‐levelinteractionwith
maternal‐levelcigarettes/daybutneitherparametersweresignificantnorexplainedany
additionalvariability.
Figure19:AdjustedPredictedEffectsofMaternalSmokingonBirthWeightacrossMaternal‐levelFactors.A)MaternalageB)SuspectedDrugorAlcoholUse.Predictedeffectsonbirthweightwith95%CIsareconditionalonmodelcovariatesincludedinModel3.Blackverticallinesrepresentthefrequencydistributionofthevariableonthex‐axis(exceptFigure19Bwhichshowsthefrequencydistributionofcigarettes/day).
Therandomeffects,theexplainedproportionalchangeinvariance(PVC),andmodel
diagnosticsarepresentedinTable12.TheunadjustedICCfortheNullrandomintercept
modelwas0.019,indicatingthat1.9%ofthetotalresidualdifferencesinbirthweightare
attributabletoDA‐levelcontextualfactors.However,theICCincreasedto2.2%forModel1
withtheinclusionofthelevel‐1covariatesandrandomslopeforcigarettes/day.Thiswas
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duetothereductioninthelevel‐1residualvariance(560.5to554.7)relativetotheincrease
inthelevel‐2randominterceptvariance(78.7to83.4).The(nowadjusted)ICCadjis
conditionalfortheindividualcompositionoftheDAs,includingtherandomslopefor
cigarettes/dayheldconstantat0(i.e.non‐smokers).TheadditionofDA‐levelvariablesin
Model2removedalotoftheDA‐levelvariancereducingtheICCadjto0.6%.
Table12:RandomEffectsandModelDiagnostics
NullModel
Model1 Model2 Model3
L1residual(sd) 560.5 554.7 555.0 554.9L2intercept(sd) 78.7 83.4 44.4 44.2
L2slope(sd) ‐‐ 10.7 9.8 9.0
Intercept 3434.3 3505.9 3501.8 3500.9
AIC 602672 598513 596639 596514
L1‐PCV Ref. 2.0% 2.0% 2.0%
L2‐PCV Ref. ‐12.3% 68.2% 68.5%
ICC/VPC# 0.019 0.022 0.006 0.006
Int‐slopecorr. ‐‐ ‐0.53 ‐0.28 ‐0.28
L1residual(sd):Level‐1residualstandarddeviation;L2intercept(sd):Level‐2randominterceptstandarddeviation;L2slope(sd):Level‐2randomslopestandarddeviation;PCV:proportionalchangeinvariance;#VPC(variancepartitioncoefficient)isequivalenttotheICCbutconditionalontherandom‐slopevariable,thusvaluesintablerepresentinterceptsfornon‐smokingindividuals;Int‐slopecorr:intercept‐slopecorrelation.
Thelevel‐2randominterceptvarianceterm(reportedasstandarddeviationsinTable
12)indicatesthatthemeanbirthweightforeveryDAhasadegreeofvariabilityfromthe
overall(BC‐wide)meanbirthweight.FortheNullmodel,theoverallbirthweightintercept
is3,434.3gramswithastandarddeviationof78.7givingan8.6%differenceinrange
between95%oftheDAs(3,434.3±(1.96x78.7)=3,280.0and3588.6grams).The
quadraticformoftherandomslopeforcigarettes/dayinModel1preventsasimilar
calculationtobeperformed,butFigure20givesanindicationofthelargebetween‐DAslope
variabilitywhichshowstheDA‐specificslopesofmaternalsmokingonbirthweight.The
intercept‐slopecorrelationlistedinTable12indicatesthepresenceofDA‐level
heterogeneitysignifyingthatDAswithhigheraveragebirthweightsfromnon‐smoking
mothershavealowerwithin‐DAeffectofsmoking(i.e.higheraverageDAinterceptsofbirth
weighttendtohaveloweraverageslopesforsmoking)[23,38].
Thelevel‐1andlevel‐2explainedPCV(L1‐PCV&L2‐PCV)summarizestherelative
degreeofexplainedvarianceatthedifferentlevelsbetweenthedifferentmodels(Table12).
UsingtheNullmodelasthereference,theModel1resultedinanL1‐PCVof2.0%,andthe
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L2‐PCVintherandominterceptwas‐12.3%.ThenegativeL2‐PVCisaresultofthelarger
level‐2interceptvariancerelativetotheNullmodel.TheadditionoftheDA‐levelvariables
inModel2explained68.2%oftheDA‐levelvariancecomparedtotheNullmodel.Model3
accountedforanadditional0.3%oftheL2‐PCV.
Sensitivityanalysesusingonlythenon‐imputedDAs(N1=229,067in6,230DAs)
showedveryminordifferencesinmagnitudeofsignificantvariables.MostoftheDAsthat
weremissingdatawereinruralareaswithsmallpopulationnumbers,thelikelyreasonwhy
theirdataweresuppressedfromthecensustables.Whilesomeparameterswereslightly
attenuated,manyoftheinteractiontermsincreasedinmagnitude.Therandomintercept
standarddeviationwasalsoslightlysmallerthanthatofthesamemodelusingthefull
datasetwhilerandom‐slopestandarddeviationshowednodifference.Inasecond
sensitivityanalysis,werestrictedthesampletoonlytermbirthsexcludingstillbirthsand
congenitalanomalies.Asexpected,therewasalargereductionintherandomslope
variability(L2slope(sd)=5.7)andasmalldecreaseintherandominterceptvariability(L2
intercept(sd)=43.0)duetousingonlytermbirths.ChangesinthecoefficientsfortheDA‐
levelvariablesaswellastheircross‐levelinteractionswithcigarettes/daywereminorand
withintheir95%confidenceintervalsreportedinTable11.Theexceptionwasthemain
effectofeducationwhichwasnolongersignificant(p=0.151),butitsinteractionwith
cigarettes/dayremainedsignificant(p=0.025).Thematernal‐levelvariableswere
attenuatedbutremainedsignificantwiththeexceptionoftheinteractionbetween
drug/alcoholflagandcigarettes/daywhichwasnolongersignificant(p=0.106).
Figure20:Neighbourhood‐specificslopesofmaternalsmokingonbirthweightEmpiricalBayespredictionsofDA‐specificregressionlinesforModel1.
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4.0DiscussionThisstudyemployedmultilevelrandomcoefficientmodelstoassesswhether
neighbourhood‐levelcontextualfactorscanmodifytheeffectofmaternalsmokingonbirth
weight.Ourresultsshowthattheeffectofmaternalsmokingonbirthweight,self‐reported
asthenumberofcigarettessmokedperday,ismodifiedbybothindividual‐leveland
neighbourhood‐levelvariables.However,theobserveddirectionoftheeffectmodification
wasnotalwaysasexpected.Furthermore,throughtheuseofrandom‐slopemodelswe
showthattheaverageeffectofmaternalsmokingonbirthweightcanvaryconsiderably
betweenneighbourhoodswhichwasonlypartiallyexplainedbythecross‐levelinteractions.
Afteradjustingforindividual‐levelcovariatesandDA‐levelsocio‐economic,socio‐
demographicandairqualityvariables,therewasasignificantnon‐lineareffectbetween
cigarettes/dayandbirthweightinBCforsingletonbirthsfrom2001to2006.This
associationwasrobusttotheexclusionofstillbirthsandcongenitalanomaliesaswellasthe
useofonlytermbirthsdemonstratingthatselectionbiasdoesnotlikelyaffecttheobserved
results.
Theobservednon‐linearassociationbetweencigarettes/dayandbirthweightshown
inFigure17suggeststhatthelargestpotentialeffectsareseenatthelowtomiddlerangeof
smokinglevels.Englandetal[40]foundaverysimilarnon‐linearassociationofmaternal
smokingontermbirthweightusingself‐reportedcigarettes/dayaswellasusingurine
cotinineconcentrations.Therefore,effortstoreducethenumberofcigarettessmoked
duringpregnancymayhavelimitedresultsformoderateandheavysmokerswithout
substantialreductionsorfullcessation[41].Interestingly,wefoundasimilarcurvilinear
relationshipwithincreasinglevelsofmodeledPM2.5andbirthweight(Figure18C),adose‐
responsephenomenonobservedinotherexposure‐diseasecontexts[42].
Beyondthenon‐linearassociationbetweencigarettes/dayandbirthweight,other
factorswereabletomodifythisrelationshipbothpositivelyandnegatively.Ouranalysis
confirmpreviouslyshownmodificationofthesmoking‐birthweightrelationshipby
maternalriskfactors[7,8];however,toourknowledgethisisthefirststudytoshowthat
neighbourhood‐levelfactorsareabletomodifythisrelationship.Wefoundasignificant
negativeinteractionbetweencigarettes/dayandneighbourhood‐levelSESithatresultedin
theattenuationofthebeneficialroleofrisingneighbourhood‐levelSESonbirthweightwith
increasedlevelsofmaternalsmoking.ThepredictedeffectspresentedinFigure18A
suggestsisthatmaternalsmokingmayhavelittlerelevanceinaffectingbirthweightinvery
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lowSESneighbourhoods,butbecomesmoreprominentasneighbourhood‐levelSES
increasesandperhapsotherstressorsnegativelyimpactingbirthweightarereduced.Hence
interventionsfocusingexclusivelyonindividualbehavioursmayhavelimitedsuccess
withoutaddressingthecontextualinfluencesattheneighbourhood‐level[9,43–45].
Conversely,thesmallbutsignificantpositiveinteractionbetweenhigherproportions
ofneighbourhood‐levelpost‐secondaryeducationandcigarettes/dayfoundthatheavy
smokersmaybenefitthemostbylivinginhighereducatedneighbourhoods(Figure18B).
Thistypeofcross‐leveleffecthasbeenobservedinotherepidemiologicalscenarioswhere
higherriskindividualshavebetteroutcomesthanwouldbeexpectedduetosomebeneficial
capacityoftheneighbourhoodcontext[11,22].Themechanismsbywhichneighbourhood‐
levelfactorsaffectindividualhealthisindirectlyexertedthroughindividual‐levelprocesses,
suchasbehaviours,adaptationsandattitudeswhichmaybetransmittedbetweenpeople
[46,47].Mengetalfoundthatloweducationneighbourhoodsexertanimpactonlowbirth
weightandpretermbirththroughunhealthybehaviours,psycho‐socialstress(i.e.senseof
control)andSES‐relatedsupport[21].Thereforeitcouldbethatsmokingcessationratesin
pregnancyarehigherinbettereducatedneighbourhoodswherehealthierbehavioursare
morecommon[48,49].Figure18Bsuggeststhatlivinginhighereducatedneighbourhoods
mayencouragemoderateandheavysmokerstoreducetheirsmokingfrequencytoless
thanfivecigarettes/day.
Neighbourhoodsocialsupportsandtransmissionofbehaviourscouldalsoexplainthe
observedinteractionswithhigherimmigrantdensityandruraladdress,albeitinopposite
directions.Thepositiveinteractionbetweenhigherimmigrantdensityandmaternal
smoking(Figure18D)mayreflectthebufferingeffectofstrongcommunitycohesiveness
andbeneficialculturalpractices[21,43,47].Conversely,theobservednegativeinteraction
betweenruraladdressandcigarettes/day(Figure18E)couldbeduetothetransmissionof
negativebehavioursbeingmorecommon[50],andwherelesssupportforcessationmay
leadtosmokingthroughoutpregnancy[51].Thedichotomizeddefinitionusedtorepresent
ruralresidentialaddressesmayobscuremechanismswhichcanbemodifiedbymaternal
factorssuchaseducation[52].
ThebufferingeffectofPM2.5withincreasedlevelsofmaternalsmoking(Figure18C)is
curiousbutcouldprovideevidenceforaprotectivepre‐conditioningstressthatactivatesan
adaptiveresponseandincreasesbiologicalresistancetocigarette‐inducedharms[53,54].
WefoundasimilarpositiveinteractionbetweensuspectedalcoholanddruguseandPM2.5
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inadifferentanalysis[55].Thesuspicionofsurvivalbiasduetocompetingriskswaspartly
mitigatedbyusinganearfullpopulationsamplethatincludedstillbirths,congenital
anomaliesandpretermbirths,althoughwewerenotabletocontrolforfetallosspriorto20
weeksgestation.Otherexplanationsrequirefurtherscrutinyasevidenceoftheopposite
(negativeandsynergistic)effectbetweensmokingandairpollutantshasbeenshown
[10,16].
Wehaveshowninanearlierpaperthatwomenwhoreportedsmoking10ormore
cigarettes/dayattheirfirstprenatalvisitweresignificantlymorelikelytohaveother
maternalriskfactors,suchaslowereducation,suspecteddrugoralcoholuse,andfewer
prenatalcarevisits[4].Ourcurrentresultscomplimentthispreviousstudybyshowingthat
thecumulativeimpactofmultipleriskfactorscanhavemorethananadditiveeffectonbirth
weightreduction.Thenegativeassociationbetweenoldermaternalageandbirthweight
wasmarkedlygreaterwithincreasedlevelsofmaternalsmoking,particularlyamongthe
heaviestsmokinggroup(Figure19A).Similarly,thosewhoreportedhigherlevelsof
smokingwhowerealsosuspectedofdrugoralcoholuseshowedapronouncedeffect
comparedtothosewhoreportedtonotsmoke(Figure19B).Theseresultscorroboratethe
establishedliteratureshowingsimilarsynergisticinteractionsbetweenbothmaternal
alcoholuseandsmokingonlowerbirthweights[8,56],aswellasbetweenmaternal
smokingandoldermaternalageonbirthweight[7,57].
Whiletheapplicationofmultilevelmodelsinperinatalepidemiologyhavebecome
morecommon[58],mosthavebeenrandominterceptmodelswithveryfewincludinga
random‐slopeparameter.Permittingtheslopeforthematernalcigarettes/dayexposureto
berandomprovidesinformationonhowitseffectonbirthweightdiffersbetween
neighbourhoodsandenablesthesearchforneighbourhood‐levelvariablestohelpexplain
thebetween‐neighbourhoodvariance[38].Forexample,therandom‐slopestandard
deviationpresentedinTable12dropsfrom10.7inModel1to9.0inthefullyadjusted
Model3.Thisrepresentsa30%changeinexplainedrandom‐slopevariance(10.72–
9.02/10.72).Furthermore,theadditionofthelevel‐2variablesexplained68.5%ofthe
randominterceptvariancecomparedtotheNull(empty)model.Howeverinlightofthese
findings,significantinter‐DAvarianceremainedforboththerandominterceptandslope.
Thisstudyusedself‐reportsofsmoking(cigarettes/day)recordedatthefirstprenatal
visit;however,therewerenodataonexposuretoenvironmentaltobaccosmokeorwhether
smokingreductionorcessationoccurredduringthepregnancy.Theself‐reportingbiasof
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cigaretteconsumptioncanleadtotheattenuationofthetrueeffectofsmokingonbirth
weight[59],andmaythereforealterobservedinteractions.Studiesofsmoking
misclassificationintheUnitedStateshaveestimatednon‐disclosuretobearound20%
[60,61].Thedemographicpredictorsofnon‐disclosureincludeformersmokersand
youngermaternalagewhichcouldpartiallyexplaintheobservedinteractionbetween
maternalageandcigarettes/day[61].Similarly,recallbiasandperceivedstigmamayresult
inunder‐reportingofactualconsumptionhabits.Thiscouldaccountfortheobserved
curvilineareffectonbirthweightifwomensmoking10cigarettes/dayreportonlysmoking
5perday,althoughEnglandetalobservedasimilarslopeusingurine‐cotinine
concentrations[40].Whilerelativelysmall,thelist‐wisedeletionofobservationswith
missingsmokingdatamayexcludepotentiallyat‐riskpregnanciesandcouldthereforealter
coefficientestimates(n=2,501,1.1%ofsample).
Anotherlimitationincludespotentialmeasurementerrorandmisclassificationbiasin
thePM2.5exposureassessmentwhichcouldaffectitsestimates.First,theLURPM2.5
concentrationsmaybeunderestimatedwithlessvariabilitycomparedtocompiled
monitoringdatawhichcouldpotentiallyunderestimateitsassociationwithbirthweightin
certainareas[62].AlsothePM2.5LURmodeliscross‐sectionalbasedon2006airquality
monitoringdata,andwethereforeassumethatthestudypopulationwasexposedtothe
samelevelsofPM2.5acrosssixyearstudyperiodbasedontheirresidentialDA.Finally,our
analysiswasbasedonmaternalplaceofresidenceatdelivery,andthereforeintra‐urban
commutingandpotentialinter‐urbanrelocationwithinthepregnancyperiodwasnot
accountedfor.Time‐activitypatternsshowthatpregnantwomenspendmoretimeathome
inthelaterstagesofpregnancy,butmobilitypatternsmaydifferbyage,parityandSES
[63,64].
Amainstrengthofthisstudyisthequalityoftheperinatalregistrydata[65].The
near100%ascertainmentofbirthrecordsfortheprovinceofBCandqualitycontrol
measuresusedindatabasemanagementpracticesproduceshighlyreliabledataon
maternalandnewbornhealthoutcomes,co‐morbiditiesandexposures.However,the
inabilitytocontrolforindividual‐levelSES,particularlymaternaleducation,mayinfluence
theneighbourhood‐leveleffectestimatesandinteractions.Maternaleducationisavariable
providedinthePSBCPerinatalRegistry,butwasonlyavailablefor10%ofourpopulation
cohort.Theadjustmentforsocially‐patternedbehaviouralriskfactorssuchasmaternal
smokingandsuspecteddrugoralcoholusewillcontrolforsomeindividual‐levelSES
146
differences[4].Notwithstanding,ourresultssuggestthatreportednumberofcigarettes
smokedcorrelateswithasubstantialreductioninbirthweightandismodifiedbysocio‐
economic,demographicandenvironmentalriskfactorssuggestingtheinformationas
providedwillhelpidentifythoseathighestrisk.
5.0ConclusionsTheeffectofmaternalsmokingonbirthweightisnotconstantacrossgeography,but
ratheriscontextspecificgiventhesocialandphysicalenvironment.Theuseofrandom
coefficientmodelsrevealedneighbourhood‐leveldifferencesinhowmaternalsmoking
negativelyimpactedbirthweightanddemonstratedeffectmodificationbyneighbourhood
andmaternal‐levelfactors.TheinclusionoftheDA‐levelSES,demographicandPM2.5
variablesexplained68.5%oftherandominterceptvariabilityinDA‐meanbirthweight.
However,therandomslopevariabilitywasonlypartiallyexplainedbythecross‐level
interactionssuggestingothercontextualfactorsareinvolvedindeterminingthemagnitude
ofmaternalsmokingonbirthweight.Furtherstudiesareneededtocorroborateour
findingsandtounderstandhowneighbourhood‐levelattributesinteractwithsmokingto
affectbirthoutcomes.
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Chapter6:AssociationofGestationalDiabetesandHypertensionwithincreasedfineparticulatematterandneighbourhood‐levelsocioeconomicfactors:amultilevelanalysisinBritishColumbia,
CanadaAbstract
Background:Gestationaldiabetes(GDM)andgestationalhypertension(GH)are
independentriskfactorsofpretermbirthandlowbirthweight,andhavebeenassociated
withincreasedexposuretoparticulatematter(PM2.5).Thepurposeofthisresearchwasto
determinetherelationshipbetweenmodeledparticulatematter(PM2.5)exposureand
gestationaldiabetesandhypertensionandthepotentialmodificationbyindicatorsof
socioeconomicstatus(SES)andmaternalBMI.
Methods:Birthrecordsfrom2001to2006(N=166,369and165,727forGHandGDM
respectively)werelinkedtomodeledPM2.5datafromanationalland‐useregressionmodel
alongwithneighbourhood‐levelSESandsocio‐demographicdatausing6‐digitresidential
postalcodes.Logisticmultilevelrandominterceptmodelswereusedtoestimatetheeffects
ofPM2.5,SESandotherindividualandneighbourhood‐levelcovariatesonGDMandGH.
Results:TheincidenceofGHandGDMwas2.4%and6.8%respectivelyacrossthe6‐year
studyperiod.PM2.5wassignificantlyassociatedwithanincreasedriskforbothGHandGDM,
(highestvs.lowestquintile,OR95%CI=1.69(1.51–1.91),and1.63(1.50–1.78),
respectively)afteradjustingforindividualandneighbourhood‐levelcovariates.Higher
neighbourhood‐levelSESaswellashighereducationalattainmentwerebothassociated
withalowerriskofGHandGDM,whilehigherimmigrantdensityandhigherDA‐meanBMI
showedanincreasedrisk.GDMshowedconsiderableeffectheterogeneityinurbanareas
wheretheinteractionbetweenPM2.5andSESgreatlymodifiedtheriskofGDM.These
associationsweremorepronouncedamongmotherswithlargerpre‐pregnancyBMI.
Conclusion:ThisstudysupportsthegrowingliteratureoftheassociationofPM2.5onthe
riskofGHandGDMandprovidesnewinsightsintotheroleofneighbourhood‐levelSESand
demographicfactors.TheimplicationsofapotentiallinkbetweenGHandGDMwithPM2.5
exposureareprofoundasthisairpollutantispervasivethroughouttheworld,andtherefore
evenmodestmitigationinexposurewillprovidesubstantialpublichealthbenefits.
152
1.0BackgroundGestationaldiabetesmellitus(GDM)andgestationalhypertension(GH)aretwo
complexpregnancyconditionsthataffectbetween3‐6%and3‐9%ofpregnancies
respectively,withratesforbothconditionsincreasinginCanada[1–4].GH,definedhereas
excludingthemoreseverediagnosisofpreeclampsia,andGDMarebothassociatedwith
increasedriskofmaternalandfetal/infantmorbiditiesandmortality[3–6].Womenwho
developtheseconditionsduringpregnancyhaveanincreasedlifetimeriskofdeveloping
type2diabetes,cardiovasculardiseaseandobesitylaterinlife[5,7].Althoughtheyare
independentconditions,theyshareseveralriskfactorssuchasincreasedbodymassindex
(BMI),familyhistory,andoldermaternalage[6,8].Recently,thereisaccumulatingevidence
supportingtheirassociationwithexposuretoairpollution[9–15].
Particulateairpollutionlessthan2.5microns(PM2.5)isacomplexmixtureof
elementalandorganiccarboncompounds,metalsandgasesthatstempredominantlyfrom
vehicleexhaust,residentialheatingandindustrialemissions.PM2.5,whichincludesultrafine
particleslessthan0.1microns,canpenetratedeepintothepulmonaryalveolartissue
whereinflammatorymediatorsandpossiblytheparticlesthemselvestranslocateintothe
bloodstreamcausingsystemiccardiovascular,metabolic,andimmunologicalalterations.
Theseincludesystemicinflammation,plateletactivation,coagulation,elevatedleptin,
reducedadiponectin,andendothelialdysfunction[16–22].Increasedoxidativestressand
inflammationinbothGDMandGHhavebeenobservedinpreviousstudies[13,14,16,17].
WhiletheepidemiologicalevidencelinkingPM2.5toacuteandchronichypertensionand
cardiovasculardiseasesiswellestablished[21,23–26],theliteraturesupportingthe
associationbetweendiabetesandPM2.5ismorerecent[16,18,27–29].
Theimpactofthesocialenvironmentonindicatorsandbiomarkersofcardiovascular
andmetabolicsystemdiseasesiswelldocumented[30–34],andlowerSEShasbeen
associatedwithhigherprevalenceofbothGDMandGH[10,35].Thesocialenvironmentcan
beconceptualizedasaseriesofoverlappinghierarchicalstructureswithinwhich
individualsarenestedinneighbourhoodsandcommunitieswiththeirownsetofattributes
thatcanpromoteorantagonizehealthandhealthybehaviours[36–41].Thismixof
individual‐levelobservationsclusteredwithinneighbourhoodswiththeirowndistinct
attributescreatesopportunitiestoquantifythedegreeofinfluenceneighbourhoodfactors
haveonindividual‐levelhealthoutcomesaswellaspotentialinteractionsbetweenthem
[42,43].
153
WepresentamultilevelretrospectivecohortanalysisoftheassociationbetweenGDM
andGHwithPM2.5andSESinBritishColumbia,Canada.Weuserandominterceptlogistic
regressionmodelstoexplorethebetween‐neighbourhoodvariabilityintheriskofGDMand
GHandwhetherinteractionswithPM2.5,neighbourhood‐levelSESindicators,and/or
individual‐levelriskfactorsareabletoexplainanyobservedvariability.
2.0DataandMethodsThiswasapopulation‐basedretrospectivecohortofsingletonbirthsinBritish
Columbiafrom2001to2006(N=237,470).DatafromtheBCPerinatalDataRegistrywere
providedbyPerinatalServicesBritishColumbia(PSBC)whichincludedinformationon
maternal‐infanthealthstatusandoutcomes,reproductivehistory,maternalriskfactors,
attributes,andresidentialpostalcodes.TheRegistryaccountsfor99%ofbirthsand
stillbirthsinBCofatleast20weeksgestationoratleast500gramsbirthweight.Research
dataaccessisprovidedbyaPartnershipAccord/MemorandumofAgreementbetweenall
BCHealthAuthoritiesandPSBCthroughtheFreedomofInformationandPrivacyProtection
Act[44].ResearchethicsboardapprovalwasgrantedbytheUniversityofVictoria(ethics
protocol#:11‐043).
Thetwooutcomevariablesweregestationalhypertension(GH)andgestational
diabetesmellitus(GDM).ThediagnosisofGH(inisolationofproteinuria)istheindication
thatthemotherhadanantepartumbloodpressurereadingofgreaterthanorequalto
140/90ontwoconsecutivereadingsduringthecurrentpregnancy.However,itisimportant
tonotethatthisvariableislimitedtothedegreethatitdoesnotimplythehypertensionwas
inducedbythecurrentpregnancy,andthatthemothercouldhavehadchronic
hypertension.ThediagnosisofGDMistheindicationthatthemotherdeveloped
carbohydrateintoleranceduringpregnancy,whichhasbeencontrolledbydietorrequires
insulintoregulatebloodglucoselevels.ApositivediagnosisforGDMrequiresaminimumof
twoabnormalreadings(outoffour)intheglucosetolerancetest[44].Thehypothesized
causalpathwaysforbothoutcomesarepresentedinFigure21.
Inordertoavoidpotentialselectionbias[45,46],weincludedallbirths(stillbirthand
live)forallgestationalages(20‐42weeks).Excludedrecordsincludedout‐of‐provinceand
invalidpostalcodes(n=1,096),non‐viablebirthspriorto20weeksgestationandlessthan
500grams(n=14),andmissingPM2.5(n=1,510).Duetothesubstantialamountofmissing
maternalBMIvalues(n=68,407;29%),twosetsofmodelswererunusingcomplete‐case
assessmentandmultipleimputationasasensitivityanalysis.
154
Thespatiallocationofeachbirthrecordwasgeocodedbasedonthelatitude‐
longitudecoordinateofthemother’sresidentialpostalcodeatthetimeofdeliveryusing
GeoRef[47].Birthrecordswererelatedtotheircorrespondingcensusdisseminationarea
(DA)byperformingapoint‐in‐polygonspatialjoinprocedureinArcGIS10.2[48].DAsare
thesmallestgeographicalunitforwhichcensusdataareavailableandrepresent
neighbourhoodblocksrangingbetween200–800people.WhileDAsdonotnecessarily
representexistingneighbourhoodcommunities[49],theycanactasproxiesforageneral
catchmentareaofpersonalhome‐lifeactivities[50,51].Birthrecordswereidentifiedas
beingeitherruralorurbanusingtheStatisticsCanadaMetropolitanInfluenceZone(MIZ)
codeswhicharebasedoncommutingflowsofsmalltownsintolargercitiesand
metropolitanareas[52].
ExposuretoPM2.5wasestimatedusinganationalland‐useregression(LUR)model
developedtoestimatePM2.5atthecensusstreetblock‐facelevel[53].Themodeluseda
numberofpredictorsincludingsatellitemeasures,proximitytomajorroadsandindustryto
accountfor46%ofthevariabilityinmeasuredannualPM2.5concentrations.Unlikenitrogen
dioxide(NO2),PM2.5tendstohaveamorehomogeneousintra‐urbandistributionbetween
personal,indoorandambient[54].TheLURmodelestimatesusedforthisstudyshowed
verylittlevariabilityofPM2.5exposuresbetweenindividualswithinagivenDA.We
thereforeaggregatedthepoint‐levelestimatesofPM2.5totheirDA‐levelmeanandrelatedit
toindividualbirthrecordsasanarea‐levelvariable.
TheDA‐levelSESanddemographicdatawererepresentedbythreerelatedbut
independentdatasetsallbasedonthe2006StatisticsCanadanationalcensus.Thefirstwas
aCanadianSESindex(SESi)developedbyChanetal[55].Thesecondwasaneducation
variablerepresentingtheproportionofpopulationover15withanypost‐secondary
education,includingcollege,trades,oruniversity.Thethirdwastheproportionof
continentalAsianimmigrantsincludingtheMiddleEastandSouthAsia.It’sbeenshownthat
theseethnicpopulationstendtohavehigherratesofGDMand/orGHcomparedtotheir
Caucasiancounterparts[35,56,57].AsianandSouthAsianethnicitiesarewell‐represented
throughoutBC,butparticularlyinconcentratedpocketsthroughoutthemajorurbancenter
ofMetroVancouverwherelevelsofPM2.5arealsohigh.CollinearitybetweentheDA‐level
variableswaseliminatedusingasequentialregressiontechniquetocreateuncorrelatedand
independentvariablesforeducationandimmigrantdensity[58].Theeducationand
immigrantdatawereobtainedbyaccesstoABACUSviatheDataLiberationInitiative[59].
155
Allcontinuousvariableswerestandardizedandcenteredtoeaseinterpretationandaid
modelconvergence.
InordertoavoiddatalossfromruralDAs,imputationformissingSES,education,and
immigrantdensityvalueswasperformed.Takingadvantageofthenestedhierarchical
structureoftheadministrativecensusandhealthboundaries,themeanvalueforalarger
encompassingcensussubdivision(CSD)orlocalhealtharea(LHA)wasimputedfora
nestedDAwithamissingvalue.Therewere1,441valuesimputedin52DAsforSESi(0.6%
offinalN,0.8%ofDAs),and3,170valuesimputedin108DAsforbotheducationand
immigrantdensity(1.4%offinalN,1.7%ofDAs).Sensitivityanalyseswereperformedusing
onlythenon‐missingdata.
Multilevel(randomintercept)logisticregressionwasusedtotestourresearch
questions.Thisallowedustoaccountforandmeasurethedegreeofclusteringof
individuals(level‐1)belongingtoagivenDAneighbourhood(level‐2),aswellasquantify
thebetween‐areavariabilityindiseaseriskbeforeandafteradjustmentforlevel‐1and
level‐2riskfactors.Thisexampleofageneralizedlinearmixedmodelallowstheinterceptto
actasarandomparameterwitheachDAhavingitsowninterceptthatvariesfromthe
overall(BC‐wide)intercept.Anyexplainedvariabilitycanthenbeinvestigatedand
measuredwiththeadditionoflevel‐1andlevel‐2variablesandtheirinteractions[60].We
followedabottom‐upapproachtomodelbuildingtoquantifytheexplainedproportional
changeinvariance(PCV),themultilevelmodelequivalenttoanR2[43].Westartedwithan
empty(null)randominterceptmodelwithoutanyindependentvariablesinwhichthe
probabilityofGHorGDMisonlyafunctionofthemother’sresidentialDA.Thepresenceof
significantrandominterceptvarianceindicatesthereareunexplaineddifferencesbetween
neighbourhoodsintheriskofGHandGDM.Wecalculatethemedianoddsratio(MOR)to
translatethearea‐levelvariancetotheoddsratioscalewhichpermitsthedirect
comparisonofitsmagnitudetothatofthelevel‐1andlevel‐2factors[61,62].TheMOR
dependsdirectlyonthearea‐levelvarianceandisdefinedasthemedianoddsratiobetween
anytwoareaspickedatrandomwithdifferingrisk(i.e.whatisthemedianincreaseinrisk
foranindividualmovingtoanareawithahigherrisk).
SubsequentmodelsincludedtheindividualandDA‐levelvariablesalongwithcross‐
levelandwithin‐levelinteractionsinordertoassesstheirfixedeffectsontheoutcomes.
Specifically,wewereinterestedintwoeffectinteractionmodels.First,doestheassociation
ofPM2.5onGDMandGHdifferbySESstatus;andsecond,isthereeffectheterogeneityby
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BMIstatus.Modelswerethencomparedtodeterminehowmuchtheinclusionofcertain
setsofvariablesaddressedanyunexplainedinterceptvariance.Modelsweretestedusing
theAkaikeInformationCriterion(AIC)toevaluatemodelperformance.Allstatistical
analyseswereconductedinStata13IC[63].
Weconductedseveralsensitivityanalysestotesttherobustnessoftheresults.First,
todetermineifthemissingBMIdatabiasedmodelestimates,multipleimputationwas
performed[64].Wewerealsointerestedifmaternalleveleducationwouldattenuatethe
DA‐leveleducationandSESassociations.ImputedChainedEquations(ICE)wereusedto
impute68,151missingBMIvaluesand205,889missingmaternaleducationvalues.All
covariates,exposureandoutcomevariableswereincludedintheimputationprocess,and
twentysetsofmissingvalueswereimputedafteraninitialburn‐inof10iterations[65].We
usedlogisticregressionwithrobuststandarderrorstoestimatethemodelswithinthe
multipleimputationframeworktoaccountforclusteringofindividualswithinDAs.
Second,weusedabnormalglucosefactor(AGF)asanindicatorofpre‐GDMandtest
itsassociationwithPM2.5andSESvariables.AGFindicatesthepossiblepresenceof
gestationaldiabetesinpregnancy,withoutconfirmationofdiagnosis(e.g.themothermay
haveoneabnormalglucosetolerancetest,carbohydrateintolerance,butadiagnosisof
diabeteshasnotbeenmade)[44].Lastly,weusedtestsforspatialautocorrelation(local
Moran’sIstatistic)tocheckforresidualspatialautocorrelationintheresidualsthatwould
indicatetheexistenceofunobservedspatialprocessescausingDAstoclusterandasignof
possiblemodelmisspecification[66].Wethenranspatiallagregressionmodelstoquantify
themagnitudeofanyremainingspatialdependenceusingthelevel‐1adjustedrandom
interceptresidualsastheDA‐leveldependentvariable.Duetothepresenceofislands(DAs
withnoneighbours),weusedanearestneighbourof7(KNN=7)spatialweightmatrixasit
wasthemostfrequentneighbouramountandproducedthehighestMoran’sIvalueswhen
testingmodelrandomeffects(comparedtoKNNof4,5,6,8,10,15).PredictionoftheDA‐
levelrandomintercepterrorusedanEmpiricalBayesmethodavailableasapost‐estimation
commandinStata13IC[67].
3.0ResultsDuetodifferencesintheexclusioncriteria,thetotalnumberofbirthsforGHandGDM
differed.Therewere166,369and165,727singleton(liveandstillborn)birthsforGHand
GDMrespectivelylocatedin6,312neighbourhoodDAs(min.=1,max.=698/694,avg.=
26).Table13summarizestheuntransformedindividualandneighbourhoodcovariates
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(non‐centered,non‐standardized).Oldermaternalage,largerBMI,andhigherPM2.5were
notablyhigherinbothGHandGDMcases;whereasruralresidencehadanotablelower
proportionofGHandGDMdiagnoses.Table14reportstheadjustedoddsratios(ORs)with
95%confidenceintervals(95%CI)forGHandGDMinrelationtothePM2.5quintilesaswell
astheDA‐levelvariables.Inadditiontotherandomintercept(RI)modelestimates,the
resultsfromthemultipleimputed(MI)estimationarealsoreported.Theresultsshowa
similardose‐responseassociationbetweentheriskofbothGHandGDMwithincreasing
PM2.5concentrations.HigherimmigrantdensityalsoshowedanincreasedriskforbothGH
andGDM,whilehigherSESandDA‐leveleducationshowedprotectiveassociations.The
multipleimputedmodelforGH(GH‐MI‐m1)showedaslightattenuationintheORsforPM2.5
andimmigrantdensity,butremainsignificant.Conversely,themultipleimputedmodelfor
GDM(GDM‐MI‐m1)showedaslightincreaseintheORsforPM2.5butareattenuated(shift
towardone)fortheotherDA‐levelvariables.Theimputationandinclusionofmaternal‐
leveleducationmayhavehadanattenuatingeffectontheDA‐levelSESandhigher
educationinthemodelforGDMmoresothanforGH,butbothremainsignificantpredictors
intheirrespectivemodels.TheresultsaregraphicallypresentedinFigure22.
Figure21:DirectedAcyclicGraphsdepictingthehypothesisedrelationshipsforGHandGDM
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Table13:Summaryofpopulationandneighbourhoodcharacteristics,[n(%)]
Characteristic GH3,918(2.4)
Total(n=166,369)
GDM11,306(6.8)
Total(n=165,727)
Level‐1(individual) Nulliparous 2,580(65.9) 80,359(48.3) 6,136(40.7) 106,325(45.5)
Maternalage
<=24years 632(16.1) 28,485(17.1) 758(6.7) 28,415(17.2)
25–35years 2,196(56.1) 102,497(61.6) 6,681(59.1) 102,148(61.6)
>=36years 1,090(27.8) 35,387(21.3) 3,867(34.2) 35,164(21.2)
BMI
UnderWt(<18.5) 121(3.1) 10,323(6.2) 459(4.1) 10,318(6.2)
NormalWt(18.5–24.9) 1,714(43.8) 104,112(62.6) 5,385(47.6) 103,904(62.7)
OverWt(25–29.9) 1,056(27.0) 33,570(20.2) 2,879(25.5) 33,378(20.1)
Obese(>=30) 1,027(26.2) 18,364(11.0) 2,583(22.9) 18,127(10.9)
GestationalDiabetes 535(13.7) 11,306(6.8) ‐‐ ‐‐
Pre‐existingDiabetes 74(1.9) 642(0.4) ‐‐ ‐‐
GestationalHypertension ‐‐ ‐‐ 535(4.7) 3,844(2.3)
DrugorAlcoholFlag 90(2.3) 3,679(2.2) 131(1.2) 3,666(2.2)
Smokedduringpregnancy 363(9.3) 17,519(10.5) 874(7.7) 17,437(10.5)
FallorWinterSeason 1,847(47.1) 80,152(48.2) 5,606(49.9) 79,836(48.2)
Level‐2(DA)Variables
SESi* ‐1.57–1.12 ‐1.36–1.16 ‐1.64–1.04 ‐1.36–1.16
HigherEducation* 0.36–0.66 0.36–0.66 0.36–0.58 0.35–0.66
ImmigrantDensity* 0–0.50 0–0.47 0–0.52 0–0.47
RuralAddress 257(6.6) 13,920(8.4) 416(3.7) 13,871(8.4)
OnFirstNationReserve 29(0.7) 1,694(1.0) 74(0.7) 1,687(1.0)
PM2.5quintile Q1 595(15.2) 33,257(20.0) 1,491(13.2) 33,124(20.0)
Q2 659(16.8) 33,277(20.0) 1,765(15.6) 33,145(20.0)
Q3 752(19.2) 33,277(20.0) 2,419(21.4) 33,158(20.0)
Q4 949(24.2) 33,268(20.0) 2,683(23.7) 33,138(20.0)
Q5 963(24.6) 33,290(20.0) 2,948(26.1) 33,162(20.0)
Pre‐existingDiabetes:indicationofpre‐existingdiabetesmellitus(Type1or2)orinsulin‐dependentdiabetesmellitus;DrugorAlcoholFlag:physicianindicateduseofdrugs(prescription,non‐prescription,illicit)oralcoholasariskfactorincurrentpregnancy;Smoked:indicationthatthemothersmokedatsomepointduringthepregnancy;Fallorwinterseasonofbirth:Sept–Feb;HigherEducation:proportionofpopulationwithanypost‐secondaryeducation;ImmigrantDensity:proportionofpopulationidentifiedasimmigrantsfromcontinentalAsia(includingMiddleEastandSouthAsia).*showthe10thand90thpercentiles.
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Table14:ORsforGHandGDMinrelationtoPM2.5andDA‐levelSESvariables GH‐RI‐m1
N=166,369OR(95%CI)
GH‐MI‐m1N=234,776OR(95%CI)
GDM‐RI‐m1N=165,727OR(95%CI)
GDM‐MI‐m1N=233,842OR(95%CI)
PM2.5quintile
Q1 1.00(reference) 1.00(reference) 1.00(reference) 1.00(reference)
Q2 1.18(1.05–1.33) 1.12(1.00–1.25) 1.17(1.08–1.27) 1.23(1.14–1.33)
Q3 1.32(1.17–1.49) 1.18(1.06–1.33) 1.39(1.28–1.50) 1.43(1.33–1.55)
Q4 1.69(1.51–1.91) 1.50(1.34–1.67) 1.54(1.42–1.68) 1.57(1.45–1.70)
Q5 1.69(1.50–1.91) 1.61(1.44–1.81) 1.63(1.50–1.78) 1.74(1.61–1.89)
SESi 0.91(0.88–0.94) 0.94(0.91–0.98) 0.78(0.76–0.80) 0.84(0.82–0.86)
HigherEducation 0.95(0.92–0.99) 0.94(0.91–0.97) 0.91(0.89–0.94) 0.95(0.93–0.98)
ImmigrantDensity 1.12(1.09–1.16) 1.09(1.06–1.12) 1.17(1.15–1.20) 1.15(1.13–1.18)
DA‐meanBMI 1.04(1.00–1.09) ‐‐ 1.09(1.06–1.12) ‐‐
RuralResidence* ‐‐ ‐‐ 0.56(0.49–0.62) 0.57(0.51–0.64)
TheORsforthethreecontinuousDA‐levelvariablescorrespondtoa1standarddeviationchangefromthemean.ModelsforGHadjustedfor:maternalage,nulliparous,pre‐existingdiabetes,BMI,maternalsmoking,drugflag;ModelsforGDMadjustedfor:maternalage,nulliparous,BMI,drugoralcoholflag,FirstNationon‐reservebirth;MI‐modelsadditionallyadjustedforimputedmaternaleducationandimputedBMI,butnotDA‐meanBMI.*Duetothecorrelationbetweenrural,PM2.5andSES,theORsreportedherearethedirecteffectsofruralresidenceonGDMconditionalontheothervariablesinthemodel.RuralwasnotsignificantforGH.
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Figure 22: Adjusted ORs and 95% CIs for GDM and GH in relation to PM2.5 quintiles and DA-level SES variables
Table15reportstheresultsfromtheinteractionmodelbetweenPM2.5,SESandrural
residenceonGDMforboththerandominterceptandmultipleimputedmodels.Theresults
showthatthedose‐responseassociationbetweentheriskofGDMandincreasinglevelsof
PM2.5ispresentonlyforurbanbirthsandthattheprotectiveassociationofSESonGDMis
alsolesspronouncedinruralareas.TheseresultsaregraphicallypresentedinFigure23
whichclearlyshowsthestarkcontrastineffectsbetweenurbanandruralbirths.The
multipleimputedmodelshowsslightchangesinthemagnitudeoftheORs,butdoesn’talter
theirdirectionorinterpretations.
Table16reportstheresultsfromtheinteractionmodelbetweenPM2.5,SESand
maternalBMI(aboveorbelowBMI=25).TheresultsaregraphicallypresentedinFigure24
whichshowthatlivinginhigherSESneighbourhoodsreducestheriskofGDMamonghigher
BMImothersaswellasbeingprotectiveagainstincreasedlevelsofPM2.5.Theinteraction
betweenBMIandPM2.5suggeststhattheeffectofPM2.5onGDMisstrongeramonglarger
BMImothers,butonlyamongthoselivinginlowerSESDAs.
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Table15:ORsforgestationaldiabetesinrelationtoPM2.5,SES,andRuralResidence
GDM‐RI‐m2
SES*Rural*PM2.5OR(95%CI)
GDM‐MI‐m2SES*Rural*PM2.5OR(95%CI)
PM2.5quintile Q1 1.00(reference) 1.00(reference)Q2 1.32(1.19–1.42) 1.40(1.27–1.55)Q3 1.59(1.44– 1.67) 1.72(1.57–1.88)Q4 1.72(1.55– 1.79) 1.85(1.68–2.03)Q5 1.83(1.65– 1.92) 2.05(1.87–2.26)SESi 0.93(0.85–1.02) 0.93(0.86–1.02)RuralResidence 0.71(0.59–0.84) 0.75(0.63–0.89)Rural*PM2.5quintile Rural*Q1 1.00(reference) 1.00(reference)Rural*Q2 0.79(0.60–1.05) 0.75(0.58–0.98)Rural*Q3 0.62(0.42–0.91) 0.65(0.47–0.90)Rural*Q4 0.58(0.33–1.05) 0.53(0.35–0.81)Rural*Q5 0.52(0.28–0.97) 0.63(0.46–0.86)SESi*PM2.5quintile SESi*Q1 1.00(reference) 1.00(reference)SESi*Q2 0.84(0.75–0.94) 0.91(0.82–1.02)SESi*Q3 0.89(0.80–0.99) 0.91(0.83–1.01)SESi*Q4 0.79(0.72–0.88) 0.85(0.77–0.93)SESi*Q5 0.82(0.74–0.91) 0.86(0.78–0.94)Rural*SESi 0.84(0.72–1.00) 0.87(0.76–1.00)Modeladjustedfor:maternalage,nulliparous,BMI,drugoralcoholflag,DA‐leveleducation,DA‐levelAsianimmigrantdensity,FirstNationon‐reservebirth;DA‐meanBMI;Multipleimputedmodeladditionallyadjustedfor
Figure23:PredictedProbabilityofGestationalDiabetesMellituswith95%CIsinrelationtoPM2.5,SESandRuralResidence
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Table16:ORsforgestationaldiabetesinrelationtoPM2.5,SES,andmaternalBMIª
GDM‐RI‐m3SES*BMI*PM2.5OR(95%CI)
GDM‐MI‐m3SES*BMI*PM2.5OR(95%CI)
PM2.5quintile
Q1 1.00(reference) 1.00(reference)
Q2 1.32(1.16–1.51) 1.35(1.23–1.49)
Q3 1.70(1.50– 1.93) 1.69(1.54–1.86)
Q4 1.91(1.68– 2.17) 1.87(1.69–2.07)
Q5 2.00(1.76– 2.28) 2.13(1.90–2.38)
BMI(≥25) 2.83(2.52–3.16) 2.69(2.40–3.01)
SESi 0.87(0.79–0.95) 0.87(0.80–0.95)
BMI*SESi 1.06(1.02–1.11) 1.04(1.00–1.09)
DA‐meanBMI 1.12(1.09–1.16) 1.11(1.09–1.14)
SESi*PM2.5
SESi*Q1 1.00(reference) 1.00(reference)
SESi*Q2 0.86(0.77–0.96) 0.95(0.85–1.05)
SESi*Q3 0.92(0.83–1.02) 0.95(0.86–1.05)
SESi*Q4 0.83(0.75–0.92) 0.88(0.80–0.97)
SESi*Q5 0.86(0.78–0.95) 0.90(0.82–0.99)
BMI*PM2.5 0.95(0.92–0.98)†
BMI*Q1 1.00(reference)
BMI*Q2 0.93(0.80–1.08)
BMI*Q3 0.81(0.70–0.93)
BMI*Q4 0.75(0.65–0.86)
BMI*Q5 0.77(0.66–0.88)
ªBMItransformedtodichotomousvariable(overweightorobese,BMI≥25);Modeladjustedfor:maternalage,nulliparous,drugoralcoholflag,Ruralresidence,DA‐leveleducation,DA‐levelAsianimmigrantdensity,FirstNationon‐reservebirth;Multipleimputedmodeladditionallyadjustedformaternaleducation.N=165,727forGDM‐M3‐ri;N=233,842forGDM‐M3‐mi;†interactionusingimputedcontinuousinteractionvariable.
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TheDA‐levelrandominterceptvariance,MOR,explainedproportionalchangein
variance(PVC),modeldiagnostics(AIC)andspatialeffectsarepresentedinTables17and
18forGHandGDMrespectively.InTable17fortheGHmodels,theMORand95%CIforthe
Nullrandominterceptmodelwas1.39(1.30–1.50),indicatingthatarandomlyselected
individualwouldexperience,inmedian,a40%increaseintheirriskofGHmovingfroma
lowriskDAtoahigherriskDA.Theadditionofthelevel‐1covariatesincreasedtheMORto
1.45likelyduetotheincreaseinthelevel‐2randominterceptvariance(0.119to0.151).
IncludingtheDA‐levelSESandPM2.5variablespartiallyaddressedtheDA‐levelvariance,
resultinginacumulativePCVof11.3%and32.1%respectivelycomparedtotheNullmodel.
TheMORwasreducedto1.31(1.22–1.45)forthefinalmodel,signifyingthatagooddealof
significantbetween‐areaheterogeneityintheriskofGHremained.Similartrendswereseen
inTables18fortheGDMmodels,butwithlargerDA‐levelrandomeffects.TheMORand
95%CIfortheNullrandominterceptmodelwas1.62(1.57–1.67)whichwasreducedto
1.38(1.33–1.43)inthefinalmodels.TheadditionoftheSESandPM2.5variablesresultedin
acumulativePCVof46%and55%respectively,aconsiderablereductionintheDA‐level
variance.Theinclusionoftheinteractioneffectsaddressedasmalladditionalamountof
variance;however,asignificantamountofDA‐levelheterogeneityremainedunexplained.
Figure24:PredictedProbabilityofGestationalDiabetesMellituswith95%CIsinrelationtoPM2.5,SESandBMI
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Table17:RandomeffectsandmodeldiagnosticsfromhierarchicallogisticmodelsforGHinBC,CanadaRandomEffects&ModelDiagnostics
NullModel Level‐1Model
Level‐2(+SES)
Level‐2(+PM2.5)
Intercept 0.023 0.008 0.008 0.006RIvariance 0.119 0.151 0.106 0.081
PCV(%) Ref. ‐26.9 11.3 32.1
MOR(95%CI)
1.39(1.30–1.50)
1.45(1.36–1.56)
1.36(1.28–1.49)
1.31(1.22–1.45)
AIC 37094 35155 35033 34936
Moran’sI˟ ‐‐ 0.090 ‐‐ 0.049
RIvariance:randominterceptvariance;MOR:Medianoddsratio;AIC:AkaikeInformationCriterion;PCV:proportionalchangeinvarianceexpressesthecumulativechangeintheDA‐levelvariancebetweenthecorrespondingmodelandNullmodel;Moran’sI:LocalMoran’sIforspatialautocorrelation,allresultsweresignificantp<0.01with999permutationsusinganearestneighbor(knn=7)spatialweightmatrix.
Table18:RandomeffectsandmodeldiagnosticsfromhierarchicallogisticmodelsforGDMinBC,CanadaRandomEffects&Model
NullModel Level‐1Model
Level‐2(+SES)
Level‐2(+PM2.5)
GDM‐M2‐ri(SES‐Rural‐PM2.5)
GDM‐M3‐ri(SES‐BMI‐PM2.5)
Intercept 0.064 0.039 0.042 0.032 0.028 0.026RIvariance 0.255 0.295 0.137 0.115 0.110 0.112
PCV(%) Ref. ‐15.7 46.3 55.0 56.6 56.1
MOR(95%CI)
1.62(1.57–1.67)
1.68(1.63–1.73)
1.42(1.38–1.47)
1.38(1.34–1.43)
1.37(1.33–1.42)
1.38(1.33–1.43)
AIC 81917 77576 76579 76427 76410 76834Moran’sI˟ ‐‐ 0.281 ‐‐ 0.098 ‐‐ ‐‐
SeeTable17captionofabbreviationdefinitions.
Spatialanalyseswereusedasamodeldiagnostictotestforsignificantspatial
autocorrelationofmodelresidualsusingthelevel‐2predictedrandomintercepts.Thelocal
Moran’sIstatisticsreportedinTables17and18fortheLevel‐1modelsindicatethe
presenceoflocalspatialclusteringbetweenneighbourhoods,particularlyforGDM.The
additionoflevel‐2variablesreducedtheMoran’sIsubstantially;however,smallbut
significantclusteringremainedforbothGHandGDM(Figures25and26).Spatiallag
modelsfurtherconfirmedthestatisticalsignificanceoftheDA‐levelvariableswhile
accountingforspatialdependenceinthedependent(y)variable.Astatisticallysignificant
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spatiallagcoefficient(rho,ρ)indicatesthattheinterceptvalueforagivenfocalDAcovaries
withthatofitsneighbours.Spatially‐laggedversionsofPM2.5andSESiwereaddedtothe
spatiallagmodelsforGHandGDMtotesttheinfluenceofthevaluesoftheneighbouring
unitsonthefocalDA.Whilesignificant,theyonlyslightlyreducedtherhocoefficient(0.22
to0.21)indicatingresidualspatialdependenceofthedependentvariablewithits
contiguousneighbours.
Furthersensitivityanalysesusingonlythenon‐imputedDAsshowedveryminor
differencesinmagnitudeofsignificantvariablesinboththeGHandGDMmodels.Asan
additionalsensitivitytest,abnormalglucosefactor(AGF)wasusedasanoutcomeaspre‐
diabetesindicator.ThemagnitudeanddirectionoftheDA‐levelvariablesweresimilarto
thoseforGDMshowninTable14,withtheexceptionofPM2.5.HigherlevelsofPM2.5were
showntohaveastrongdose‐dependentassociationwithriskofAGF,OR(95%CI)Q2vs.
Q1:=1.52(1.30–1.78)andQ5vs.Q1:2.41(2.06–2.82).Similarheterogeneitywaspresent
betweenSES,PM2.5andruralresidenceforAGFasitwasforGDM;however,unlikeGDM,the
interactionbetweenBMI,SESandPM2.5wasnotsignificant.
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Figure25:ClustersandOutliersofLocalizedSpatialAutocorrelationinDA‐level(randomintercept)ResidualsforGestationalhypertensioninB.C.,2001–2006Thismapshowsthelocalizedspatialautocorrelation(clustering)oftherandominterceptresidualsafteradjustmentfortheindividualandDAneighbourhood‐levelvariables.AreasindarkredindicateDAclusterswherethemodelunder‐predictedtheriskofGH,whileareasindarkblueindicateDAclusterswherethemodelover‐predictedtheriskofGH.Thelightershadesofblueandredindicatespatialoutlierswherelowareasarenexttohighandhighnexttolow,respectively.Significancewasestimatedusing99,999MonteCarlosimulations,andareawithoutcross‐hatchingindicateareaswheretheprobabilityoftypeIerrorwaslessthan0.01.
167
Figure26:ClustersandOutliersofLocalizedSpatialAutocorrelationinDA‐level(randomintercept)ResidualsforGestationalDiabetesMellitusinB.C.,2001–2006Thismapshowsthelocalizedspatialautocorrelation(clustering)oftherandominterceptresidualsafteradjustmentfortheindividualandDAneighbourhood‐levelvariables.AreasindarkredindicateDAclusterswherethemodelunder‐predictedtheriskofGDM,whileareasindarkblueindicateDAclusterswherethemodelover‐predictedtheriskofGDM.Thelightershadesofblueandredindicatespatialoutlierswherelowareasarenexttohighandhighnexttolow,respectively.Significancewasestimatedusing99,999MonteCarlosimulations,andareawithoutcross‐hatchingindicateareaswheretheprobabilityoftypeIerrorwaslessthan0.01.
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4.0DiscussionThisstudyemployedmultilevelrandominterceptlogisticregressionmodelstoassess
theassociationofPM2.5andSES‐relatedneighbourhoodfactorsontheriskofGHandGDM
inBCfortheyears2001to2006.ItisimportanttonotethattheGHvariableusedinthis
studyonlyidentifiespregnancieswherehypertensionwasmeasured,regardlessoftiming
ofonset(i.e.previouschronicorgestational).Regardless,ourresultsshowaconsistent
dose‐responseassociationintheriskofGHandGDMwithincreasinglevelsofPM2.5.Higher
DA‐levelSESandeducationwereassociatedwithlowerrisksforbothGHandGDM,while
higherimmigrantdensityandhigherDA‐meanBMIshowedanincreasedrisk.However,
onlyGDMshowedconsiderableeffectheterogeneity,particularlyinurbanareaswherethe
interactionbetweenPM2.5andSESgreatlymodifiedtheriskofGDM(Figure23).
Furthermore,theseassociationsarepotentiallymorepronouncedamongmotherswith
largerpre‐pregnancyBMI(Figure24).Theuseofrandominterceptmodelsrevealedthat
therewasamoderatedegreeofindividual‐levelclusteringwithinneighbourhoodDAsand
significantbetween‐DAvariabilityintheriskofGHandGDM.WhilethisDA‐levelintercept
variancewaslargelyexplainedwiththeinclusionoftheDA‐levelSESandPM2.5variables,
somevarianceremainedandwasshowntobe,atleastpartially,spatiallyclusteredatalocal
scale.ThislatterobservationsuggeststhepresenceofotherunmeasuredDA‐levelvariables
thatcouldbecausingtheinterceptresidualstocluster.
Ourresultscorroboratethegrowingliteraturesupportingtheassociationbetween
PM2.5exposureandtheriskofGHandGDM[9,10,13–15].Studiesthattesteddifferentair
pollutants(NO2)orusedproximitytoroadsastheexposuremeasurealsofoundsignificant
risksofGDMandhypertensivedisorders,includingpreeclampsia[11,68–70].Wealsofound
anassociationbetweenPM2.5andthepre‐diabeticindicatorofabnormalglucosefactor
(AGF),aresultfoundbyFleischetalaswell[71].WhilethelinkbetweenPM2.5andnon‐
pregnancyhypertensionandcardiovascularinjuryiswellestablished[21,72],thereis
mountingevidenceofanassociationbetweenairpollution(NO2andPM2.5)andtypeII
diabetes[16,27,29,73].Luietal[27]reviewedthehypothesizedmechanismsofPM2.5
mediateddiabetes/insulinresistance,whichhasseveraloverlappingpathwayswiththe
hypothesizedmechanismsofPM2.5mediatedcardiovascularinjuryandgestational
hypertensivedisorders[19,20].Theseincludeendothelialdysfunction,endoplasmic
reticulumstress‐inducedapoptosis,andalteredmitochondrialmorphologyandfunction
largelyinducedbysystemicinflammationandoxidativestress[19,27,74].
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OurresultsshoweffectheterogeneitybetweenPM2.5andSESontheriskofGDMsuch
thatthoseresidinginlowerSESneighbourhoodsshowedamorepronouncedeffectof
increasedlevelsofPM2.5,butonlyinurbanareas(Figure23).Thesignificantinteraction
betweenruraladdressandPM2.5mayreflecttheunderestimationofPM2.5inruralareasby
theLURmodel[53].ThecompositionofPM2.5,andthusitsrelativetoxicity,isshowntovary
spatiallydependingonitssource(e.g.woodsmokevs.traffic‐relatedemissions)andmay
partiallyexplaintheobservedrural‐urbandifferences[19,23].LowerSEShasbeen
associatedwithanincreasedriskofGDMinCanada[3,75],anddisparitiesinbirthoutcomes
byneighborhoodindicatorsofSESareoftenmorepronouncedinurbanversusruralareas
duetogreaterincomeinequality[76,77].Otherexplanationscouldbeduetoaccesstocare
andtheunderdiagnosesoftypeIIdiabetesinruralareas[78],orthattheprevalenceofGDM
islowerinruralcomparedtourbanareasinCanada[7,79].
WealsoobservedsignificanteffectheterogeneitybetweenPM2.5,SESandmaternal
BMI(Figure24).TheseresultsshowthattheeffectofPM2.5ontheriskofGDMisgreateron
motherswhohadapre‐pregnancyBMIof25andabove,butonlyamongthoseinlowerSES
neighbourhoods.Thissuggeststhatnotonlycanneighbourhoodcharacteristicsinfluence
theriskofGDMbutcanalsomodifyexposureeffectsandareconditionalonmaternal
characteristics.It’sbeenshownthatobesitymayenhancetheassociationsbetweenPM2.5
andsystematicinflammation[80],thereforemotherswithlargerpre‐pregnancyBMIsmay
bemoresusceptibletotheeffectsofairpollutionwhencompoundedbyother
neighbourhood‐levelstressors.
Theapplicationofmultilevelmodelsinperinatalepidemiologyhasbecomemore
common,demonstratingtheimportanceofneighbourhoodandcommunity‐levelcontextin
thehealthofindividuals[38,81].Bypermittingtheintercepttovaryrandomlybetweenthe
neighbourhood‐levelunits,itispossibletoquantifythemagnitudetheneighbourhood‐level
factorshaveonaddressingthebetween‐areavariability.Furthermore,specifictologistic
multilevelmodels,computingthemedianoddsratio(MOR)permitstheexpressionofthe
neighbourhood‐levelvarianceontheORscaletherebypermittingthedirectcomparisonof
themagnitudeofthearea‐levelvariancewiththatofthemodelcovariates[62].For
example,inthepresentstudytheMOR(95%CI)fortheLevel‐2modelforGDMadjustedfor
theSESvariablesandPM2.5was1.38(1.34–1.43),signifyingthatinthemediancasethe
residualheterogeneitybetweenDAswillincreasetheriskofGDMby38%whenrandomly
selectingtwopeopleindifferentareas.Therefore,aperson’sresidentialneighbourhoodis
170
ofgreaterrelevancetotheirriskofGDMthansomematernal‐levelfactorsandonparwith
someDA‐levelfactorssuchasDA‐meanBMI,immigrantdensity,andbeinginthe3rd
exposurequartileforPM2.5.Despiteexplainingasubstantialproportionofthebetween‐DA
variance,thereremainedunmeasuredneighbourhood‐levelprocessesproducingbetween
neighbourhooddifferencesinGHandGDMrisk.
WeusedspatialanalysestoexaminewhethertheremainingDA‐levelheterogeneity
wasclusteredspatiallyatthelocalscaleaswellasaservingasameasureofmodel
specificationandhowwellthechosenrepresentativeneighbourhood(DA)unitperformed.
WhiletheinclusionoftheDA‐levelvariablessubstantiallyreducedthespatial
autocorrelationintherandominterceptvariance(Moran’sIinTables17and18),there
remainedsomesignificantspatialautocorrelationforbothGHandGDM(Figures25and
26).Thiscouldsuggestthatsomeunmeasuredspatialprocessisoccurringatthelocallevel,
misspecificationwithrespecttoanunmeasuredcovariateriskfactor,and/ortheuseofDAs
astheneighbourhoodspatialunitbeinglessoptimaltoassesstheneighbourhood‐level
effects.Testingthislastpoint,wefoundthatspatiallylaggedversionsofPM2.5andSESwere
significantinspatiallagregressionmodelsforGHandGDMrespectively.Thissuggeststhe
possiblepresenceofspatialexternalitiesinwhichneighbouringvaluesofthesevariables
influencetheriskofGHorGDMinthefocalneighbourhood[82,83].
Akeycomponentofthisresearchwastheuseofaland‐useregression(LUR)modelof
airpollution[53].WhiletheLURmodelwasindependentlyvalidatedandachieveddecent
overallresultsinitspredictedestimates,theverynatureofourstudydesignensuressome
degreeofexposuremisclassificationtoourstudypopulation,althoughitisexpectedtobe
non‐differential.Theselimitationsincludetheoccurrenceofmaternalintra‐urban
commutingandpotentialinter‐urbanrelocationwithinthepregnancyperiod,thecross‐
sectionalnatureofthePM2.5LURmodelbasedon2006airqualitymonitoringdatawhilethe
studyperiodofourperinataldatasetspans6years(2001to2006)and,finally,thattheLUR
PM2.5concentrationsmaybeunder‐predictedwithhavelessvariabilitycomparedto
compiledmonitoredairqualitydata[84].
Thestrengthsofthisstudyincludealargepopulation‐basedcohortinordertotestfor
potentialeffectheterogeneity,goodcontrolformaternal‐levelconfounderssuchas
smoking,pregnancyhistory,andBMI,andtheabilitytolinktoandassessneighbourhood‐
levelsocioeconomicanddemographiccontextualfactorsthatinfluencethedisease
outcomes.Furthermore,theuseofmultipleimputationmodelsforthemissingBMIaswell
171
asmaternaleducationdatafurthersubstantiatedthemainfindings.Thecalculationofthe
MORfromtherandominterceptvariancetermanduseofspatialanalysesshowthatlocal
neighbourhoodfactorsareimportantinreproductivehealthandfurthereffortsto
understandtheirroleshouldbeprioritized.
5.0ConclusionsThisstudysupportsthegrowingliteratureoftheeffectofPM2.5ontheriskofGHand
GDMandprovidesnewinsightsintotheroleneighbourhood‐levelSESanddemographic
factorsplay.WithrespecttoGDM,higherSESneighbourhoodshadastrongprotectiveeffect
againstPM2.5exposureinurbanareaswhileatthesametimewerealsoshowntotemper
thenegativeeffectoflargermaternalBMIsonGDMrisk.Theuseofspatialanalyses
indicatesthatunmeasuredlocalizedprocessesareresponsiblefortheunexplained
between‐neighbourhoodheterogeneity,andthecommunicationusingriskmapsmay
informpublichealthandmunicipalplannersonpossiblemechanismstotarget
improvements.TheimplicationsofapotentiallinkbetweenGHandGDMwithPM2.5
exposureareprofoundasthisairpollutantispervasivethroughouttheworld,andtherefore
evenmodestmitigationinexposurewillprovidesubstantialpublichealthbenefits.
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Chapter7:Conclusions
1.0IntroductionOnOctober1,2015,theInternationalFederationofGynecologyandObstetrics(FIGO)
announceditsground‐breakingpolicystatementonenvironmentalhealthregardingthe
needtoreduceandpreventthereproductivehealthimpactsfromexposuretotoxic
environmentalchemicals[1].Astheleadingvoiceofreproductivehealthprofessionals
worldwide,thisstancebyFIGOhasprofoundglobalresonance.
Theobjectiveofthisdissertationwastoexaminehowfactorsofthesocialand
physicalenvironmentinfluencetheriskofadversepregnancyoutcomesandwhetherthey
interactwitheachotherorwithmaternalcharacteristicstomodifydiseaserisk.Each
researchchapterinthisthesiswasdesignedforindependentpublicationsandcontains
specificconclusions,contributionsandlimitations.Therefore,thisfinalchapterservesto
synthesizetheoverallfindingsandkeycontributions,highlightoveralllimitationsofthe
research,andproposefutureresearchdirections.
2.0SummaryofResearchandContributionsThisdissertationcontributedtotheliteratureaswellastopublicandpopulation
healththrough:(1)theuseofheavymaternalsmokingduringpregnancyasamarkerfor
unmeasuredSES‐relatedlifestyleriskfactorsthatinfluencebirthoutcomes;(2)creating
newepidemiologicalevidenceregardingthevariabilityintheeffectofmaternalsmokingon
birthweightandhowmaternalandneighbourhood‐levelfactorscanexasperateor
attenuateitseffect;and(3)corroboratingthegrowingepidemiologicalknowledge
concerningPM2.5exposureandadversepregnancyoutcomesanditsinteractionwith
neighbourhoodSESanddemographicvariables.
2.1.HeavysmokingasamarkerforunmeasuredSES‐relatedlifestyleriskfactorsMaternalsmokingremainsoneofthemostimportantmodifiableriskfactors,with
potentialimplicationsonsubsequentchilddevelopmentandhealth.Theresultsofthislarge
population‐basedstudyfindthatsmokingduringpregnancyisamodifiabledose‐dependent
riskfactorofadversefetalgrowththatalsohasastrongrelationshipwithotherrisk
behavioursandindicatorsoflowSES.Theseresultsalsoreinforcetheimportanceofthe
standardizedandcompletecollectionofSESvariablesforallpatientsbyperinatalhealth
careproviders.Theimpactofthispaperonthepublichealthliteratureisnotable,being
178
designatedasa“highaccess”articleontheBMCPublicHealthwebsiteandbeingreferenced
45timesinotherpeer‐reviewedandotheracademicworks.
Comparedtoalllowerlevelsofsmoking,heavysmokers(≥10cigarettes/day)had
substantiallyworsebirthoutcomesandwerealsoatincreasedrisktobeflaggedforalcohol
ordruguse,beasingleparent,attendfewerprenatalcarevisits,andtohaveapre‐
pregnancyweightgreaterthan74kilograms.Heavysmokerswere3.8timesmorelikelyto
havenotgraduatedhighschoolcomparedwithmoderate,lightandnon‐smokerscombined.
Furthermore,theadditionofthebehaviouralandSESindicatorvariables,particularly
maternaleducation,explainedsomeoralloftheriskattributedtolightsmokingbutheavy
smokingremainedastrongmarkerofincreasedriskforimpairedfetalgrowth.
Thissupportsthepossibilitythatreportsofsmokinggreaterthantencigarettesper
daymightbeanearlymarkerfortheneedforcomprehensivesupportstoreduceadverse
outcomes.InBC,thiswouldidentifyapproximatelyfivepercentofwomenatparticular
increasedriskofadverseoutcomesthatmaybenefitfromadditionalservicestopromotea
healthypregnancy.Theabilitytorecognizethoseatparticularriskearlyinpregnancyand
providepreventativeprogramscouldhelpachievebetteroutcomesforallexpectant
mothers.Whilestrategiesforsmokingcessationareimportantandsupportedbyourstudy,
theunderlyingissuesthatleadtoadversebirthoutcomesmightnotbeaddressedwitha
narrowfocus(demonstratedbytheresultsinChapter5).Thisinformationmaybeusedfor
planningtargetedinterventionprogramsnotonlyforsmokingcessationbutpotentially
othermaternalsupportservicessuchasnutritionandhealthypregnancyeducationwith
theoverallgoalofoptimizingbirthoutcomes.Antenatalcareisacriticalaccesspointforthe
educationofexpectantmothersregardingahealthypregnancy,particularlyforfirst‐time
mothers,whomaybemoreamenabletosmokingcessationandotherhealthylifestyle
changes.
2.2Effectmodificationofmaternalsmokingonbirthweightbyneighbourhood‐levelfactors
Newandimportantepidemiologicalfindingswerereportedinthisdissertationonthe
abilityofneighbourhood‐levelfactorstomodifythenegativeeffectsofmaternalsmokingon
birthweight.
Theassumptionthatmaternalsmokingaffectsallpregnanciesequally,whilesafein
itself,maynotcaptureimportantinsightsintopossiblecessationinterventions.Theresults
inChapter5showthattheeffectofmaternalsmokingonbirthweightisnotconstantacross
geography,butdependsonthesocialandphysicalenvironment.Theuseofrandom
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coefficientmodelsrevealedneighbourhood‐leveldifferencesinhowmaternalsmoking
negativelyimpactedbirthweightanddemonstratedeffectmodificationbyneighbourhood
andmaternal‐levelfactors.TheinclusionoftheDA‐levelSES,demographicandPM2.5
variablesexplained68.5%oftherandominterceptvariabilityinDA‐meanbirthweight.
However,therandomslopevariabilityofmaternalsmokingonbirthweightwasonly
partiallyexplainedbythecross‐levelinteractionssuggestingthepresenceofother
contextualneighbourhood‐levelfactors.
Ouranalysesconfirmpreviouslyshownmodificationofthesmoking‐birthweight
relationshipbymaternalriskfactors;however,toourknowledgethisisthefirststudyto
showthatneighbourhood‐levelfactorsareabletomodifythisrelationship.Wefounda
significantnegativeinteractionbetweencigarettes/dayandneighbourhood‐levelSESi.This
suggeststhatmaternalsmokingmayhavelittlerelevanceinaffectingbirthweightinvery
lowSESneighbourhoods,butbecomesmoreprominentasneighbourhood‐levelSES
increaseswhenperhapsotherstressorsnegativelyimpactingbirthweightarereduced.
Higherproportionsofneighbourhood‐levelpost‐secondaryeducationhadpositive
interactionwithcigarettes/daysuggestingthatheavysmokersmaybenefitthemostby
livinginhighereducatedneighbourhoods.Explanationscouldbethatsmokingcessation
ratesinpregnancyarehigherinbettereducatedneighbourhoodswherehealthier
behavioursaremorecommon.Neighbourhoodsocialsupportsandtransmissionof
behaviourscouldalsoexplaintheobservedpositiveinteractionwithhigherimmigrant
densityandmayreflectthebufferingeffectofstrongcommunitycohesivenessand
beneficialculturalpractices.Conversely,theobservednegativeinteractionbetweenrural
addressandcigarettes/daycouldbeduetothetransmissionofnegativebehavioursbeing
morecommon,andwherelesssupportforcessationmayleadtosmokingthroughout
pregnancy.
ThebufferingeffectofPM2.5withincreasedlevelsofmaternalsmokingiscuriousbut
couldprovideevidenceforaprotectivepre‐conditioningstressthatactivatesanadaptive
responseandincreasesbiologicalresistancetocigarette‐inducedharms.Hence
interventionsfocusingexclusivelyonindividualbehavioursmayhavelimitedsuccess
withoutaddressingthecontextualinfluencesattheneighbourhood‐level.
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2.3Epidemiologicalfindings
2.3.1TheinteractionbetweenPM2.5andneighbourhoodSESvariablesonbirthweightandmeasuresofadversefetalgrowth.
Themainenvironmentalfactorsexaminedincludeambientparticulateairpollution
(PM2.5),neighbourhoodsocioeconomicstatus(SES),neighbourhoodimmigrantdensity,
neighbourhoodlevelofpost‐secondaryeducationlevelandtheurban‐ruralcontext.The
resultsshowthatindividualandneighbourhood‐levelfactorsarecapableofmodifyingthe
associationbetweenPM2.5exposureandfetalgrowth.Furthermore,throughtheuseof
random‐slopesmodelsweshowthattheeffectofgestationalageonbirthweightcanvary
considerablybetweenneighbourhoods.
TheseresultsshowasmallnegativeinteractionbetweenPM2.5andSESsuchthata
morepronouncedeffectofPM2.5wasseeninlowerSESneighbourhoods;howeverthis
resultappearsforbirthsinurbanareasonly.Theprotectiveinteractionwithhigher
immigrantdensityonPM2.5exposureshowsthatnotonlycanneighbourhood
characteristicsinfluencefetalgrowthbutthattheycanalsomodifyexposureseither
positivelyornegatively.
InteractionsbetweenPM2.5andmaternal‐levelvariablesshowntoreducebirth
weightindependentlyrevealedsomecounter‐intuitiveresults.Whilefurtherstudiesare
neededtoconfirmthesefindings,thepersistenceoftheresultsaftervarioussensitivity
analysessuggestsahypothesisthatsomeindividual‐levelexposuresmayactasapre‐
conditioningstressthatactivatesanadaptiveresponseofincreasedbiologicalresistanceto
similarorotherstressors.AprotectiveeffectofoldermaternalageagainstPM2.5exposure
wasalsoobservedandmaystemfromincreasednutritionalawarenessamongolderwomen
and/ormoresecureincomeandsupportnetworkstherebyreducingpotentialstressand
anxiety.Pregnanciesaffectedbygestationaldiabeteshadsignificantlyhigherbirthweights
asexpectedbutrevealedasharpreductioninbirthweightwithincreasingPM2.5.
Ourresultscorroboratethegrowingliteraturesupportinganegativeassociation
betweenPM2.5andbirthweightinasettingofrelativelylowairpollutionconcentrations.
Thisstrengthenstheevidenceofthelow‐doseeffectsofPM2.5.Furthermore,thisstudy
supportsthegrowingliteratureofaneffectofPM2.5onfetalgrowthanditsmodificationby
bothmaternalandneighbourhood‐levelfactors.Mostnotably,itshowsthatlowerSES
neighbourhoodsmaybemorenegativelyaffectedbyhigherlevelsofPM2.5,butonlyinurban
areas.
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2.3.2PM2.5exposureincreasestheriskofgestationaldiabetesmellitus(GDM)andgestationalhypertension(GH).
ThisstudysupportsthegrowingliteratureofaneffectofPM2.5ontheriskofGHand
GDMandprovidesnewinsightsintotheroleofneighbourhood‐levelSESanddemographic
factorshaveontheirprevalence.Ourresultsshowaconsistentdose‐responseassociationin
theriskofGHandGDMwithincreasinglevelsofPM2.5.HigherDA‐levelSESandeducation
wereassociatedwithlowerrisksforbothGHandGDM,whilehigherimmigrantdensityand
higherDA‐meanBMIshowedanincreasedrisk.Further,higherSESneighbourhoodshada
strongprotectiveeffectagainstPM2.5exposurefortheriskofGDMinurbanareaswhilealso
showntotemperthenegativeeffectoflargermaternalBMIsonGDMrisk.
Themedianoddsratio(MOR)permitstheexpressionoftheneighbourhood‐level
varianceontheORscaletherebypermittingthedirectcomparisonofthemagnitudeofthe
area‐levelvariancewiththatofthemodelcovariates.TheMOR(95%CI)fortheadjusted
level‐2modelforGDMwas1.38(1.34–1.43),signifyingthatinthemediancase,arandomly
selectedindividualmovingfromalowriskDAtoahigherriskDAwillrealizea38%
increasedriskofGDM.Thus,afteradjustingforindividualandneighbourhood‐levelknown
riskfactors,aperson’sresidentialneighbourhoodstillexhibitsagreaterrelevancetotheir
riskofGDMthanmanyofthemeasuredmodelvariables.
Theuseofspatialanalysesindicatesthatunmeasuredlocalizedprocessesare
responsiblefortheunexplainedbetween‐neighbourhoodheterogeneity,andthe
communicationusingriskmapsmayinformpublichealthandmunicipalplannerson
possiblemechanismstotargetimprovements.Theimplicationsofapotentiallinkbetween
GHandGDMwithPM2.5exposureareprofoundasthisairpollutantisubiquitous,and
thereforeevenmodestmitigationinexposurewillprovidesubstantialpublichealth
benefits.
3.0Limitations
3.1UseofDAsasneighbourhoodsWeusedspatialanalysestoexaminewhethertheremainingDA‐levelheterogeneityin
themodelswasclusteredspatiallyatthelocalscalewhichservedasameasureofmodel
specificationaswellashowwellthechosenrepresentativeneighbourhood(DA)unit
performed.Inmostcases,theinclusionoftheDA‐levelvariablessubstantiallyreducedthe
spatialautocorrelationintherandominterceptvarianceindicatingthattheDAsperformed
welltocapturetheunderlyingspatialheterogeneity.However,thereremainedsome
significantspatialautocorrelationforsomeofthepregnancyoutcomes,particularlyGHand
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GDM.Thiscouldsuggestthatsomeunmeasuredspatialprocessisoccurringatthelocal
level,misspecificationwithrespecttoanunmeasuredcovariateriskfactor,and/ortheuse
ofDAsastheneighbourhoodspatialunitbeinglessoptimaltoassesstheneighbourhood‐
leveleffectsfortheseoutcomes.Theadditionofotherneighbourhood‐levelvariablessuch
asgreenspaceandneighbourhoodwalkabilityscorewouldbeapossibleavenuetoexplore
first.
3.2ThePM2.5Land‐useRegressionModelAkeycomponentofthisresearchwastheuseofaland‐useregression(LUR)modelof
airpollution.WhiletheLURmodelwasindependentlyvalidatedandachieveddecent
overallresultsinitspredictedestimates,theverynatureofourstudydesignensuressome
degreeofexposuremisclassificationinourstudypopulation.Ouranalysiswasbasedon
maternalplaceofresidenceatdelivery,andthereforeintra‐urbancommutingandpotential
inter‐urbanrelocationwithinthepregnancyperiodwasnotaccountedforwhichcould
affecttheresults.Time‐activitypatternsshowthatpregnantwomenspendmoretimeat
homeinthelaterstagesofpregnancy,butmobilitypatternsmaydifferbyage,parityand
SES.
AnotherlimitationregardingthePM2.5exposureassessmentisthattheLURmodelis
cross‐sectionalbasedon2006airqualitymonitoringdata,whilethestudyperiodofour
perinataldatasetspans6years(2001to2006).Wethereforeassumeallpregnancieswere
exposedtothesamelevelsofPM2.5fortheirentirepregnancy,regardlessoftheiryearof
birth,basedontheirresidentialDA.Thismethodalsoassumesthatairpollutionlevelshave
remainedrelativelyconsistentwithnointer‐regionalvariationbetweentheyears.AirZone
reportsfromtheBCMinistryofEnvironmentshowthatwhiletheaveragelevelsofPM2.5
acrossBChavegenerallydeclinedovertheyearsfrom2004to2006,inter‐regional
variationhasalsoremainedfairlyconsistentintherateofdecreasewhichwillreducedthe
amountofpotentialexposuremisclassification[2].TheuseofthisPM2.5LURmodelalso
preventstheassessmentofexposurewindowsbytrimester,spatiotemporalstudiesofPM2.5
haveshownlittletonodifferencebetweentrimester‐specificandentirepregnancyeffects
onbirthweight.Finally,themeanPM2.5concentrationsmaybeunderestimatedbytheLUR
modelwithlessvariabilityandmissingseveralhighPM2.5outlierlocationsinBCcompared
tocompiledmonitoreddata.Thiscouldpotentiallyresultinanunderestimationofour
observedassociationofreducedbirthweightwithincreasingPM2.5levels.
183
Althoughdirectcomparisonstootherstudiesaredifficulttomakeduetoour
estimationofnon‐lineareffects,substantiallygreaterdifferencesareseeninmyresults,
especiallyinChapter3.Thisislargelyduetomycontrolfortheproportionof
neighbourhoodAsianimmigrantdensityandtheuseofasequentialregressionprocedure
toremovethecollinearitybetweenimmigrantdensityandPM2.5andSESi.Recallthata
residualizedororthogonalvariableforimmigrantdensity(aswellasproportionofhigher
education)wascreatedinordertodisentanglethedirecteffectsofPM2.5andSESfrom
immigrantdensityshowntobemoderatelycorrelated(r=0.53and0.63respectively).
Whenmodelswererunthatusedthenon‐transformedvariables,theestimatedassociations
betweenbirthweightandPM2.5arereducedbyapproximatelyhalf(‐9.9grams,95%CI=‐
12.8to‐7.1);however,despitethelargechangeineffectsizeforPM2.5onbirthweight,all
relationshipsandinteractionswithotherparametersremainedunchangedandstatistically
significant.ThissmallereffectsizeismoresimilartootherstudiesofPM2.5onbirthweight
(seethesupplementarytablesfor[3,4]).Moremethodologicalworkneedstobedonein
futurestudiesinordertocorrectforcorrelatedconfoundingvariablesinordertoestimate
truedirecteffects.
InarecentpaperbyGehringetal.(2014)thatlookedattheimpactofnoiseandair
pollutiononpregnancyoutcomesinMetroVancouverBCCanada,asub‐regioncoveredby
mystudythatalsousedBCPDRdata,theyfoundthatnoiseexposurewaslargely
responsibleforthenegativeassociationswithtermbirthweightinjointmodelsarguing
thatnoisecouldbethepredominantexposure[3].Theiradjustedmeandifference
associationbetweenPM2.5andtermbirthweightwas‐3.1grams(95%CI=‐5.1to‐1.1),
whereasforthetransportationnoiseexposureitwas‐19.1grams(95%CI=‐22.9to‐15.3).
Combined,theirestimatedmeandifferencesareverysimilartotheassociationspresented
inChapter3.Iftheirconclusionsareshowntobetruebyfurtherresearch,itcouldbethat
ourestimatedPM2.5associationsareconfoundedbyunmeasurednoiseexposure.Inurban
areas,thiseffectwillbeverydifficulttoseparatefromairpollutiongiventhatboththese
exposuresarelargelydrivenbylocalvehicletraffic.Studieswithaspecialfocuson
comparingpopulationslivingclosetochronicpointsourcesofnoisewillbeneededto
disentangletheseeffects.
3.3MissingDataWewereunabletocontrolformaternal‐levelSES,andthereforetheneighbourhood‐
leveleffectestimatesandinteractionscouldreflectindividual‐leveldifferences.Maternal
184
educationisavariableprovidedintheBCPerinatalDataRegistry,butwasonlyavailablefor
10%ofourpopulation.InChapter6,maternaleducationwasincludedintheanalysisusing
astatisticallyacceptedmultipleimputationtechniquewithresultsshowingthatwhile
maternaleducationwasprotectiveinitselffortheriskofGDMandGH,itdidnotalterthe
overallDA‐levelassociations.AsweshowedinChapter3,theadjustmentforsocially‐
patternedbehaviouralriskfactorssuchasmaternalsmoking,suspecteddrugoralcoholuse
andfewprenatalcarevisitswillcontrolforsomeindividual‐levelSESdifferences.
3.4FirstNationsBirthsHealthoutcomeresearchandsurveillanceofAboriginalbirthsinCanadaisacomplex
andchallengingendeavour.FirstNationsinCanadamakeupabout4%ofthepopulation,
butisthefastestgrowingsub‐populationinCanada.FirstNationspeopleareincreasingly
livingincitiesoroff‐reserves,somebychoiceandsomebynecessity.Reproductivehealth
surveillanceisasimportantinFirstNationsofBC,asinmainstreamBC,toensurethat
evidence‐basedpoliciesandsupportsaretargetedtoareaswheretheycanhavethemost
beneficialimpactforhealthymaternalandchildhealthoutcomes[5,6].
ThisresearchwaslargelyfundedbyaCIHRInstituteofAboriginalHealthPriority
initiativealthoughitwaspeerreviewedbytheChildren’shealthcommittee.Thestartofthis
projectoccurredduringthetransitiontotheFirstNationsHealthAuthority(FNHA).Dr.
ArbourandIheldthreemeetingswithvariousrepresentativesfromtheresearcharmofthe
organizationthatlaterbecametheFNHA.Giventhattherewerenospecificprocessesin
placeatthattimeforpopulationepidemiologystudiessuchasours,wewereprovidedwith
theinformationthatindividualFirstNationcommunityapprovalforeverycommunityinBC
wouldberequiredtoobtainFirstNationsidentifiersforBCbirthrecords.Asthiswas
unfeasible,ourresearchcombinedallbirths(FirstNationsandnon‐FirstNations)without
evaluatingFirstNationsspecificrisksastheyrelatedtothesocialandphysical
environment.IthasbeenshownthataftercontrollingforSESandothermaternalrisk
factors,Aboriginalidentityisnotanindependentriskfactorforsomeadversebirth
outcomesordifferencesinriskbetweenFirstNationandnon‐FirstNationbirthwere
greatlyattenuated[7‐9].Ourmethodswillallowforahigherlevelofcomprehensive
analysis,onceprotocolsforresearchinBCareestablishedbytheFNHA.
4.0OverallImplicationsandFutureConsiderationsReproductivehealthandpregnancyoutcomesareimportanthealthmeasurestostudy
forseveralreasons,themostimportantbeingthatexposuresandstressorsinuteroand
185
earlychildhoodcaninfluenceone’sentirelifetrajectory[10‐13].Thefetaloriginsofdisease,
or“BakerHypothesis”,postulatesthatperturbationoftheearlynutritionalenvironment
haslong‐termstructural,physiologicalandneurologicalimpactsonnewbornsthat
predisposethemtochronicdiseasesinadulthoodincludingtype2diabetes,hypertension,
coronaryheartdiseaseandobesity[11,12].Thishypothesishasbeenexpandedtoinclude
excessfetalglucocorticoidexposurefrommaternalsocialstressorsactingontheHPA‐axis
andpotentiallyleadingtoearlylifeprogrammingofdisease[14,15].Theseearly
developmentalexposuresmayelicitepigenomicmodificationsanddysregulationsuchas
DNAmethylationthathavelifelongandpotentiallytransgenerationalimplicationsfor
health[16–18].
Similarly,itisnowwelldemonstratedthatSES‐relatedriskfactorscanalsohavea
life‐coursetrajectorylatencyperiodonhealth[19–22]whichcanleadtothe
intergenerationaltransmissionofpovertyandpoorhealth[23].Thisisparticularlyrelevant
forIndigenouspopulationsinNorthAmericaandelsewherewhohaveenduredcenturiesof
colonizationandon‐goingsystemicandinstitutionallyentrenchedviolence,racismand
marginalization.Theeffectofthistypeofenduringtraumagoesbeyondthelifespanof
individualstopersistinter‐generationallywithinfamiliesandwholecommunities[24–28].
Therefore,theinequitiesofhealthamongnewbornsasaresultofdifferentsocialand
geographicsub‐populationsrepresentanintolerablebutincessantcycleofinjustice.
InCanada,roughly6%ofbirthsareconsideredLBWwhichcorrespondsto
approximately25,000affectedinfantseachyear[29].Itisestimatedthatbetweentwoand
tenpercentofthesecanbedirectlyattributabletoenvironmentalexposuresexcluding
tobacco,alcoholandillicitdruguseamountingtoroughly$1.5millionindirectandindirect
costseachyear[30].However,thisfiguredoesnotcapturethelatentandlong‐termcosts
associatedwithLBWthatdisproportionatelyaffectlowSEShouseholds[31‐33].
Theassessmentofthelong‐termeffectsofbeingbornsmallisdifficulttodiscerndue
totheconfoundingofotherSES‐relatedriskfactors.A26yearfollow‐upstudyofthe1970
BritishBirthCohortfoundthatchildrenbornfull‐termbutSGAbelowthe5thpercentile
demonstratedsmallbutsignificantdeficitsinacademicachievementsatfollow‐upagesof5,
10and16[34].Thesesmalldifferencesinschoolperformancemayhaveledtobeingless
likelytohaveprofessionalormanagerialjobsandlowerweeklyincomeatage26.There
wasalsoasignificantheightdifferentialbetweenSGAandaveragebirthweightparticipants.
However,andperhapsjustasimportantly,therewerenoreporteddifferencesintotalyears
186
ofeducation,employment,hoursofworkperweek,maritalstatus,orsatisfactionwithlife.
Theseresultsremainedsignificantevenafteradjustingforsocialclass,sex,regionofbirth,
andthepresenceoffetalorneonataldistress[34].
Inotherstudiesofshorterfollow‐uptimes,moderateandearlypretermbirth(<30
weeksgestation)andlowerbirthweightswereshowntonegativelyaffectschool
performanceaftercontrollingforparentaleducation,andremainedwhencomparingsibling
pairs[35].However,similarresultsoflowerphysicalsize,cognitivescoresandacademic
achievementatage8wereonlyfoundforthoseSGAinfantswithimpairedpost‐natal
growth(i.e.SGA+failuretothrive)whileSGAinfantswithadequatepostnatalgrowth
showednodifferencecomparedtonormalgrowthchildren[36].Furthermore,whilelow
andverylowbirthweightwerenegativelyassociatedwithacademicperformance,the
growthrestrictedchildrenshowedgreatersensitivitytoparentingtechniquesaround
learningandshowedcompensatoryacademiceffectsunderconditionsofsensitive
parentingexperiences[37].Thesestudiesshowthatbeingbornsmallorpretermdoesnot
necessarilyimplyalifesentenceofstruggleandhardship,butthatthehomeand
communityenvironmentmatters[38–40].Itisnowwell‐establishedthataccessand
proximitytogreen‐spaceshasapositiveeffectontheriskofadversepregnancyoutcomes,
bufferingtheexposuretotraffic‐relatedairpollutionandnoise,andmaythereforebelinked
tootherchronichealthoutcomesinthegeneralpopulationinadditiontopregnantwomen
andtheiroffspring[41‐46].Thisisanareaofincreasingimportanceandmitigation.
ReturningtotheFIGOpolicystatement,theymakefourrecommendations:1)
advocateforexposurereductionpolicies;2)worktoensureahealthyfoodsystemforall;3)
makeenvironmentalhealthpartofhealthcare;and4)championenvironmentaljustice[1].
Researchers,policymakers,healthprofessionalsandcommunityorganizersneedtowork
togethertoaccomplishtheserecommendations.
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Appendix1RiskSurfaceMaps
Spatialepidemiologyislargelyconcernedwiththeanalysisofspatially
continuousdiseaseriskandriskfactors.Asaresult,continuoussurfaceriskmaps
(orisoplethmaps)aredesired.
Thereareseveralmethodsavailableforthespatialinterpolationofregional
dataintoarisksurface.Fortherisksurfacemapspresentedbelow,Ifollowedthe
kriggingmethodologypresentedbyOlafBerke(BerkeO.2004.Exploratorydisease
mapping:krigingthespatialriskfunctionfromregionalcountdata.International
journalofhealthgeographics.2004,3(18)).Here,twosophisticatedmethodsare
combinestocreatecontinuousspatialriskmapsofadversepregnancyoutcomes.
First,empiricalBayesestimationisusedtosmooththespatialriskestimatesto
stabilizethestandarderrorsandreducetheimpactofoutliersby“borrowing
strengthfromtheensemble”inwhichunstablevariancesfromsmallareasamples
areshrunktotheglobalvariancebypoolinginformationacrossthestudyregion.
Theprocesscouldbeseenasrelatedtointernalstandardizationinepidemiology.
Second,ordinarykrigingwasusedtopredict(interpolate)thesmoothedrates
intoacontinuousrisksurface.Inordertoremovethepotentialforover‐smoothing
thatkriggingwouldperformbymodelingthesmallscalespatialvariability,the
semivariogramwasmodelledwithoutnuggeteffectwhichleadstothedirect
interpolationatthesamplingsites(i.e.theDAswithknownrates)andsmoothed
predictionsattheunknownsitesshrunktowardstheglobalmeanvalueofthe
estimatedtrendsurface.Theresultingmapsareeasilyinterpretabletomapusers,
includingotherresearchersandpolicymakers.
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Map1
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Map2
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Map3
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Map4
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Map5
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Map6
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Map7
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Map8
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Map9
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Map10
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Map11
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Map12
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Appendix2AdditionalFiguresforChapter4
DirectionalAcyclicGraphicofhypothesizedcausalprocess,whereE:PM2.5exposure,D:birthweight,PTB:pretermbirth,gdiab:gestationaldiabetes,htn:gestationalhypertension,Z:level‐2orneighbourhood‐levelvariables
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CaterpillarplotoftheDA‐levelrandominterceptscomparingtheLevel‐1modelwithonlyindividual‐levelvariables(A1&B1)totheLevel‐2modelcontainingDA‐levelvariables(A2&B2)fortwodifferentHealthServiceDeliveryAreas.TheLevel‐2modelsexplainasubstantialproportionofthebetween‐DArandominterceptvarianceinbirthweight
205
ExampleofthevariabilitybetweentherandomslopesforgestationalageonbirthweightfortheneighbourhoodDAswithinagivenregionalhealthauthority(VancouverIsland)
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Appendix3ResultsforSGA‐3,SGA‐10,IUGR,TermLBW,andPTB
BCspecificbirthweightreferencecharts[1]wereusedtoidentifybirthsthatwere
small‐for‐gestationalagebelowthe3rdand10thpercentileforweightandsex(SGA‐3and
SGA‐10respectively).Afterexclusions,therewere230,903singletonlivebornbirthslocated
in6,338neighbourhoodDAs(min.=1,max.=779,avg.=36).Excludedobservations
included:missingbirthweight(n=46),missinggestationalage(n=373),stillbirths(n=
1,047),missingcigarettes/day(n=2,484),missingPM2.5(n=1,502),missingsex(n=5).
SensitivityanalyseswererunincludingstillbirthsaswellasusingaCanadian‐widebirth
weightreferencetoclassifySGA‐3andSGA‐10[2]withonlyveryminordifferencesfor
somecoefficientsandstandarderrors.
Termlowbirthweight(tLBW)isdefinedasbirthwhichreachedagestationalageof
37completedweeksbuthadbirthweightslessthan2,500grams.Therewere214,178
singleton(livebornandstillborn)birthslocatedin6,337neighbourhoodDAs(min.=1,max.
=709,avg.=34).Excludedobservationsincluded:birthswithamissingorlistedgestational
age<37weeks(18,547),missingbirthweight(n=46),missingcigarettes/day(n=2,204),
missingPM2.5(n=1,381),missingsex(n=4).
Intrauterinegrowthrestriction(IUGR)isapre‐definedBCPDRfieldderivedfrom
birthchartsasbeingphysicianidentifiedIUGRduringtheantenatalperiodusingultrasound
imaginggrowthparameters.Afterexclusions,therewere231,305singletonslivebornbirths
locatedin6,338neighbourhoodDAs(min.=1,max.=780,avg.=37).Excluded
observationsincluded:stillbirths(1,052),missingcigarettes/day(n=2,493),missingPM2.5
(n=1,502),missingsex(n=5).Asensitivityanalysisincludingstillbirthswasnotabletobe
performed;however,resultsarenotexpectedtodiffermuchgiventheoutcomeofsimilar
previousanalyses.
Bothregular(maximumlikelihood)logisticregressionwithrobuststandarderrorsas
wellasrandominterceptlogisticregressionwereusedtocalculateandcomparedresults.
WhilebothtypesofstatisticaltechniquesaccountforthewithinDAclusteringofthe
individualobservations,thedesiretoquantifythevariabilityforthebetween‐DAintercept
wasthereasonforusingtherandominterceptmethods.Comparisonofthecoefficientsand
standarderrorsbetweensimilarmodelspecificationssawonlyveryslightdifferencesin
someofthestandarderrorswhilemostofthecoefficientswerenearlyidenticalforall
207
outcomesandmodelstested.Allthefiguresbelowthereforeusetheresultsfromtheregular
logisticregressions.
Figure1showstheoddsratioswith95%confidenceintervals(OR,95%CI)forthe
individualandDA‐levelvariables.Allfourbirthweightoutcomesshowsimilartrendsfor
mostofthevariables.Thetwoexceptionsfortheindividual(level‐1)variablesincludetype
IIdiabetesmellitus(T2‐diabetes)andgestationaldiabetes(Gest.Diabetes),demonstrating
protectiveassociationsforSGA‐3andSGA‐10.Thereasonforthisisunclear.Withrespectto
theDA(level‐2)variables,onlyruralresidencestandsoutforIUGRasdemonstratinga
protectiveassociation.ThiscouldbeadataregistryrelatedissuegiventhatIUGRistheonly
outcomeofthefourwhichisanindependentBCPDRdatafieldandforwhichdata
completenessforruralhealthcentrescanbesub‐optimal(personalcommunicationwith
BCPDRstaff).
Figure1:Adjustedoddsratiosand95%confidenceintervals(95%CI)individualandneighbourhood‐levelvariablesonmeasuresofadversefetalgrowth
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TheobservedORsinFigure1forallfouroutcomesconfirmourfindingsinChapter4
regardingthenegtiveassociationofPM2.5onbirthweightandfetalgrowth.Figure1shows
aconsistentdose‐effectforallfourmeasureofadversefetalgrowth.Theseresultsalso
furtherconfirmthefindingsofSES,higherproportionsofneighbourhood‐levelpost‐
secondaryeducationandthetrendsobservedforneighbourhoodswithhigherdensitiesof
Asianimmigrantpopulations.TheincreasedORsfortheAsianimmigrandensityvariableis
likelynotduetoaninherentpathologicalmechanismoraproxieforanunmeasured
exposure,butlikelyduetotheconstitutionaldifferencesinbirthsize[3,4].
SGA‐3&SGA‐10
Table1showstheresultsforSGA‐3andSGA‐10fromaninteractionmodelbetween
PM2.5,SESandurban‐ruralresidence.Thepredictedprobabilitiesderivedfromthese
modelsarepresentedinFigure2usingtwodifferentvariableperspectives.Whatthese
modelsshowisthatrisingPM2.5alwaysincreasestheriskofSGA,andthatthisriskis
modestlytemperedbyrisingSES,butonlyinurbanareas.Themedianoddsratio(MOR)
translatethearea‐levelvariancetotheORscalewhichpermitsthedirectcomparisonofits
magnitudetothatofthelevel‐1andlevel‐2factors[5,6].TheMORforSGA‐3andSGA‐10
signifythat,inthemediancase,arandomlyselectedindividualmovingfromalowriskDA
toahigherriskDAwillrealizea38%and13%increasedriskofSGA‐3andSGA‐10
respectively.Thus,afteradjustingforindividualandneighbourhood‐levelknownrisk
factors,aperson’sresidentialneighbourhoodstillexhibitsagreaterrelevancetotheirrisk
ofSGAthanmanyofthemeasuredmodelvariables.
Non‐linearspecificationsofPM2.5conditionalonSESandurban‐ruralresidence
weretestedusingaquatradicexpressionofthecontinuousPM2.5variableaswellasits
quintiletransformation.TheformerdidnotshowtobesignificantforSGA‐3,andjust
borderlinenon‐significantforSGA‐10(p=0.07).ThequiniletransformationofPM2.5
showedsomeindicationofnon‐linearityconditionalonSESandurban‐ruralresidence
(Table2andFigure3).Forurbanareasonly,therewasclearmodificationofthePM2.5
associationbySESontheriskofSGA‐3andSGA‐10.Forruralareas,therewasaconsistent
increaseinriskofSGA‐3andSGA‐10withrisingPM2.5levels,butshowednostatistically
significantdistinctionacrossthelevelsofSES.Theseresultsareconsisentwiththefindings
presentedintheendnoteforChapter4,demonstratingthatthemechanismsthatoperate
209
throughneighbourhoodlowSEStoaffectfetalgrowtharemorestronglyexperiencedwithin
urbanareaswheretherelativedisparitiesaremorepronounced[7].
Table1:ORs(95%CI)forSGA‐3andSGA‐10inrelationtoPM2.5,SES,andRuralResidence
SGA‐3‐m1SES*Rural*PM2.5OR(95%CI)
SGA‐10‐m1SES*Rural*PM2.5OR(95%CI)
tLBW‐m1SES*Rural*PM2.5OR(95%CI)
PM2.5 1.10(1.06–1.15) 1.11(1.09–1.14) 1.11(1.06–1.17)
SESi 0.83(0.80–0.86) 0.85(0.83–0.87) 0.84(0.80–0.88)
RuralResidence 1.06(0.92–1.23) 1.10(1.02–1.19) 1.02(0.85–1.22)
AsianImmigrantDensity 1.07(1.04–1.10) 1.12(1.10–1.14) 1.07(1.03–1.12)
Post‐SecondaryEducation 0.92(0.89–0.95) 0.95(0.94–0.97) 0.89(0.85–0.92)
SESi*PM2.5 0.99(0.96–1.02) 1.00(0.98–1.02) 0.98(0.94–1.02)
Rural*SESi 1.29(1.09–1.52) 1.11(1.02–1.21) 1.44(1.16–1.79)
Rural*PM2.5 1.12(1.00–1.26) 1.05(0.99–1.12) 1.22(1.06–1.41)
MultilevelModelOutputs
Intercept 0.011 0.047 0.007
RandominterceptVariance 0.036 0.017 0.022
MedianOR(95%CI) 1.20(1.11–1.38) 1.13(1.09–1.20) 1.15(1.04–1.76)
Logisticrandominterceptmodelsadjustedfor:maternalage,nulliparous,drugoralcoholflag,maternalsmoking;seasonofbirth,FirstNationon‐reservebirth.
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Figure2:TwodifferentperspectivesofthesamemodelPlotAandBshowthepredictedprobabilitieswith95%CIsfromSGA‐3model‐1(SGA‐3‐m1).PlotCandDshowthepredictedprobabilitieswith95%CIsfromSGA‐10model‐1(SGA‐10‐m1).
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Table2:ORs(95%CI)forSGA‐3,SGA‐10,andtLBWinrelationtoPM2.5,SES,andRuralResidence
SGA‐3‐m2
SES*Rural*PM2.5OR(95%CI)
SGA‐10‐m2SES*Rural*PM2.5OR(95%CI)
tLBW‐m2SES*Rural*PM2.5OR(95%CI)
PM2.5quintile Q1 1.00(reference) 1.00(reference) 1.00(reference)
Q2 1.17(1.01–1.35) 1.16(1.07–1.25) 1.07(0.90–1.28)
Q3 1.27(1.11– 1.46) 1.26(1.18– 1.36) 1.22(1.03–1.45)
Q4 1.34(1.17– 1.54) 1.36(1.26– 1.46) 1.27(1.08–1.52)
Q5 1.41(1.22– 1.64) 1.42(1.32– 1.53) 1.50(1.26–1.77)
SESi 0.93(0.83–1.04) 0.92(0.87–0.98) 1.00(0.87–1.15)
RuralResidence 0.94(0.78–1.13) 1.03(0.94–1.14) 0.73(0.57–0.93)
Rural*PM2.5quintile
Rural*Q1 1.00(reference) 1.00(reference) 1.00(reference)
Rural*Q2 1.13(0.82–1.06) 1.02(0.89–1.17) 1.35(0.97–1.89)
Rural*Q3 1.26(0.92–1.04) 1.28(1.07–1.51) 1.57(1.07–2.31)
Rural*Q4 1.03(0.77–0.94) 1.06(0.84–1.32) 1.92(1.22–3.02)
Rural*Q5 1.34(0.98–1.03) 1.12(0.94–1.34) 1.52(0.91–2.56)
SESi*PM2.5quintile
SESi*Q1 1.00(reference) 1.00(reference) 1.00(reference)
SESi*Q2 0.92(0.80–1.06) 0.98(0.91–1.05) 0.92(0.77–1.10)
SESi*Q3 0.91(0.80–1.04) 0.90(0.84–0.97) 0.81(0.69–0.96)
SESi*Q4 0.82(0.72–0.94) 0.89(0.83–0.96) 0.73(0.62–0.86)
SESi*Q5 0.91(0.80–1.03) 0.93(0.87–1.00) 0.88(0.76–1.03)
Rural*SESi 1.21(1.04–1.41) 1.05(0.96–1.14) 1.33(1.08–1.63)
Modeladjustedfor:maternalage,nulliparous,drugoralcohol flag,maternalsmoking,seasonofbirth,DA‐leveleducation,DA‐levelAsianimmigrantdensity,FirstNationon‐
b h
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Figure3:Predictedprobabilitieswith95%CIsfromSGA‐3model‐2(SGA‐3‐m2)andSGA‐10model‐2(SGA‐10‐m2)
TermLowBirthWeight(tLBW) Table1showstheresultsfortLBWfromaninteractionmodelbetweenPM2.5,SES
andurban‐ruralresidence.Thepredictedprobabilitiesderivedfromthesemodelsare
presentedinFigure4usingtwodifferentvariableperspectives.SimilartoSGA,these
modelsshowisthatrisingPM2.5alwaysincreasestheriskoftLBW,andthatthisriskis
modestlytemperedbyrisingSES,butonlyinurbanareas(Figure4A).Interesting,rural
areasshowareversaloftheSESassociationsuchthathigherSESneighbourhoods
demonstratealargerriskoftLBWcomparedtolowSESneighbourhoods.Thistrendwas
partiallyevidentforSGA‐3,butthewideconfidenceintervalsobscuredtherelationship.The
explanationforthisobservationisunclear;however,itcouldberelatedtothesizeofthe
DAsinruralareaswhichencompassageographicareamuchlargerthanatypical
neighbourhood.AsimilarfindingwasobservedbyAugeretal(2009)whichshowedthat
remoteruralareaswereassociatedwithadversebirthoutcomesamonguniversity
educatedmothersonly[8].
TheMORfortLBW(Table1)signifythat,inthemediancase,arandomlyselected
individualmovingfromalowriskDAtoahigherriskDAwillrealizea15%increasedriskof
tLBW,MOR95%CI:1.15(1.04–1.76).Thus,afteradjustingforindividualand
neighbourhood‐levelknownriskfactors,aperson’sresidentialneighbourhoodstillcarriesa
gooddegreeofrelevancetotheirriskoftLBW.
Non‐linearspecificationsofPM2.5werealsotestedconditionalonSESandurban‐rural
residence.ThequatradicexpressionofthecontinuousPM2.5wasnotsignificant,butthe
quiniletransformationdidshowindicationofnon‐linearity(Table2andFigure4B).For
213
urbanareas,therewasclearmodificationofthePM2.5associationbySESontheriskof
tLBW.Forruralareas,therewasaconsistentincreaseinriskoftLBWwithrisingPM2.5
levels,butshowednostatisticallysignificantdistinctionacrossthelevelsofSES.The4th
quintileforPM2.5displaysananomalyinitseffectestimation,likelyduetosmallnumbers
withinthestrtifications.Theseresultsareconsisentwiththefindingspresentedinthe
endnoteforChapter4,demonstratingthatthemechanismsthatoperatethrough
neighbourhoodlowSEStoaffectfetalgrowtharemorestronglyexperiencedwithinurban
areaswheretherelativedisparitiesaremorepronounced[7].
Figure4:TwodifferentperspectivesofthesamemodelPlotAandBshowthepredictedprobabilitieswith95%CIsfromtLBWmodel‐1inTable1(tLBW‐m1).
Intra‐uterineGrowthRestriction(IUGR)Unliketheothermeasuresofadversefetalgrowth(tLBWSGA‐3,SGA‐10),IUGR
showsaprotectiveassociationwithruralresidenceinFigure1.ThiscouldbewhyIUGRdid
notdemonstrateanytrend(statisticallysignificantorotherwise)ofeffectheterogeneity
betweenurbanandruralbirthswithrespecttoSESandPM2.5.Theexplanationofthis
findingisunclear;however,itcouldbeduetoregionaldifferencesinthecompletionofBC
perinatalformsandmaternalcharts.IUGRdiddemonstratetohaveanon‐linearassociation
withPM2.5,andasignificantinteractionbetweenSESandPM2.5.Thisinteractionwasnot
presentwhenPM2.5wasmodeledasalineareffect(Table4andFigure5).
TheMORforIUGR(Table4)signifiesthat,inthemediancase,arandomlyselected
individualmovingfromalowriskDAtoahigherriskDAwillrealizea34%increasedriskof
IUGR,MOR95%CI:1.34(1.26–1.46).ThisisafairlylargeMOR,evenafteradjustingforthe
individualandneighbourhood‐levelriskfactors,andsuggeststhatasubstantialportionof
thebetween‐DAvarianceisleftunexplained.
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Table4:ORsforgestationaldiabetesinrelationtoPM2.5,SES,andRuralResidence
IUGR
SES*PM2.5OR(95%CI)
PM2.5 1.17(1.12– 1.22)
PM2.5*PM2.5 0.93(0.91– 0.96)
SESi 0.90(0.86– 0.93)
RuralResidence 0.75(0.66– 0.86)
ImmigrantDensity 1.07(1.04– 1.10)
HigherEducation 0.96(0.93– 1.00)
SESi*PM2.5 0.95(0.91– 0.99)
Rural*SESi ‐‐
Rural*PM2.5 ‐‐
MultilevelModelOutputs
Intercept 0.013
RandominterceptVariance 0.096
MedianOR(95%CI) 1.34(1.26– 1.46)
Logisticrandomintercept modelsadjustedfor:maternalage,nulliparous,drugoralcoholflag,maternalsmoking;seasonofbirth,FirstNationon‐reservebirth.
Figure5:Predictedprobabilitieswith95%CIsfromSGA‐3model‐2(SGA‐3‐m2)andSGA‐10model‐2(SGA‐10‐m2)
215
PretermBirth(PTB) Pretermbirthisdefinedasabirthwhichreachedaminimumgestationalageof37
completedweeks.Afterexclusions,therewere231,970singleton(liveandstillborn)births
locatedinlocatedin6,338neighbourhoodDAs(min.=1,max.=781,avg.=36).Excluded
observationsincluded:birthswithmissinggestationalage<37weeks(378),missing
cigarettes/day(n=2,501),andmissingPM2.5(n=1,511).PTBwascategorizedbyits
severitybasedongestationalage(mild:34to36weeks,moderate:32to33weeks,early:28
to31weeks,andveryearly:<28weeks).
Figure6showstheresultsfromapartialproportionalodds(pp‐odds)regression
model(similartoanologitregressionbutallowsthecoefficientsfortheparameterstovary
betweenthelevelsofthecategoricaldependentvariable)[9].Thepp‐oddsmodelallowsthe
researchertoseewhichvariableshaveaconstantriskacrossalllevelsofPTBseverityand
whichoneshavevaryingimportance.Thebottomthreesetsofvariableslistedunderthe
differentPTBseveritieshavevaryingrisks.Whilesomevariableschangeverylittle(e.g.
nulliparous),othershavegreatervariation(e.g.gestationalhypertension).
TheriskofPM2.5wasshowntohaveasmallbutsignificantprotectiveassociationfor
PTBrisk.ThisassociationisconstantforallPTBseveritysub‐types.TheassociationforSES
ontheotherhandshowsacleartrendofincreasingprotectiveassocitionswiththemore
severePTBsub‐types.PTBisacomplexbirthoutcomewithmanyunderlyingriskfactors.
FurtherresearchintotheobservedrelationshipbetweenPTBandPM2.5needstobe
exploredforpotentialbias[10,11].
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Figure6:AdjustedORsand95%CIrange(shadedregions)formaternalandneighbourhood‐levelfactorsassocitedwiththeseverityofPTBrisk.
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