parental infections during pregnancy as risk factors for …...anti-infective agents during...

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Parentalinfectionsduringpregnancyasriskfactorsformentaldisordersinchildhoodandadolescence–anationwideDanishstudy

Prisopgaveipsykiatriafstud.med.CecilieNicolaisenLydholm

Medforfattere:OleKöhler-Forsberg,MereteNordentoft,RobertH.Yolken,PrebenB.Mortensen,LiselottePetersenogMichaelE.Benros.

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INTRODUCTION

Infectionsduringpregnancyarecommonandapproximately40%ofallpregnantwomenin

Denmarkareexposedtoinfectionstreatedwithantibioticsduringpregnancy.1Overthelast

decades,maternalinfectionsandinflammatoryresponsesduringpregnancyhaveincreasingly

beensuggestedtoaffectthefetaldevelopingbrainelevatingtheriskofmentaldisordersinthe

offspring.Themajorityofstudieshavefocusedonpsychosisandschizophrenia.2–16Maternal

infectionsduringpregnancywithrubella,2Toxoplasmagondii,3herpessimplexvirustype2,4,5

influenza6,7andbacterialinfectionsduringthefirsttrimester8havebeenassociatedwithan

increasedriskofschizophreniaintheoffspring.However,thefindingshavenotbeenconsistent3,9–

11,17,18andfewepidemiologicalstudieshaveinvestigatedothermentaldisorderssuchasautism19–

24andaffectivedisorders.3,25–29Mostpriorstudieshavehadseverallimitations,e.g.fewcases,2,3,9

infectionsbasedonmaternalself-report12,20,21orecologicalstudydesign.6,7Inthelargerstudies,

exposurehasmainlybeenbasedoninfectionsrequiringhospitalcontacts11,13,19thusdisregarding

themorecommonlyoccurringinfectionstreatedbygeneralpractitioners.Finally,themajorityof

studieshavenottakenpotentiallyimportantconfoundersintoaccount,e.g.parentalpsychiatric

diagnoses8,21orsocioeconomicfactors.3,13,19

Severalpathwayshavebeensuggestedfortheabovementionedassociations.Althoughthe

infectionitselfcouldimpactthedevelopingfetalcentralnervoussystem(CNS)directly,2,3itisalso

likelythatmaternalimmuneactivationinresponsetoinfectionsplaysasignificantpart16,30,31as

similarlyincreasedrisksofmentaldisordershavebeenfoundacrossawiderangeofinfectionsand

inrelationtofever12,20,21,32andelevatedacutephasereactants.23,33Maternalimmuneactivationis

thoughttoinfluencethefetalmicroglia,whichplayapivotalroleinneuralcircuitformationand

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otherneurodevelopmentalprocesses.30However,onepreviousstudyfoundthatparental

hospitalizationsforinfectionsbefore,duringandafterpregnancysimilarlyincreasedtheriskof

schizophrenia.13Thishasledtothequestionofwhethertheproposedrelationshipbetween

infectionsandmentaldisordersisratherasharedgeneticsusceptibilitytoinfectionsandmental

disorders,whichcouldalsoextendtoothermentaldisorders.

Weaimedtoinvestigatetheassociationbetweenalltreatedparentalinfectionsduringpregnancy

andtheoffspring’sriskofbeingdiagnosedwithanymentaldisorder.Weincludedcomparison

betweenmaternalandpaternalinfectionsbefore,duringandafterthepregnancyperiodto

examineifapossibleassociationwasconfinedtomaternalinfectionsduringpregnancyorifitwas

merelyagenerallyincreasedsusceptibilitytoinfectionsamongtheparentsassuggestedbya

previousstudy.13Additionally,weinvestigatedtheriskofspecificmentaldisorders,dose-response

relationshipsandassociationswithtimingofinfectionexposurebasedonpregnancytrimester.

MATERIALANDMETHODS

Studypopulation

Thepresentstudyisanationwide,register-basedcohortstudycoveringtheentireDanish

population.WeincludedallchildrenborninDenmarkbetweenJuly1,1996,andDecember31,

2011,utilizingtheDanishCivilRegistrationSystem.34Weexcludedchildrenwithmissingparental

informationestablishingacohortof987,667individuals.Allindividualswerefollowedfromfirst

birthdaytofirstoutcome(seebelow),emigration,deathorendofstudyperiodonJuly31,2013,

whichevercamefirst.

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Exposure–assessmentofinfections

Weidentifiedalltreatedmaternalandpaternalinfectionsvia1)prescribedanti-infectiveagents

and2)diagnosedinfectionsrequiringhospitalcontacts.Dataonanti-infectiveagentswere

obtainedthroughtheNationalPrescriptionRegistry,35whichcontainsinformationonallredeemed

prescriptionssinceJanuary1,1995.Infectionsrequiringhospitalcontactswereidentifiedviathe

NationalPatientRegister,36whichhasregisteredalldiagnosesgiveninDanishsomatichospitals

since1977,includinginformationonalloutpatientcontactssinceJanuary1,1995.Infectionswere

dividedintobacterialinfectionsandotherinfections,i.e.viral,parasiticandmycotic.

Exposureperiods

Theabovementionedinfectionswereidentifiedbefore,duringandafterthepregnancyperiod.We

definedthepregnancyperiodasthe40weeksbeforedateofbirth.Thisperiodwassubdivided

intotrimesters;week0-12(1sttrimester),week13-28(2ndtrimester),week29-40(3rdtrimester).

Thepre-pregnancyandpost-pregnancyperiodsweredefinedasthe40weekspriortothe

pregnancyperiodandthe40weeksfollowingdateofbirth,respectively.

Outcome-assessmentofmentaldisorders

TheDanishPsychiatricCentralResearchRegister37includesallhospitalizationsinpsychiatric

hospitalssince1969andoutpatienttreatmentandemergencyroomcontactssinceJanuary1,

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1995.Weidentifiedmentaldisorderswithinthecohortfromfirstbirthdaytotheendofstudyon

July31,2013.Weonlyincludedthemaindiagnosisofthefirstpsychiatrichospitalcontact.Our

mainoutcomewasanymentaldisorderdefinedasadiagnosisofF20-99accordingtothe

InternationalClassificationofDiseases,10thedition(ICD-10).Oursecondaryoutcomeswere

specificdiagnosesdependingoncategoryaccordingtoICD-10(F20-29,F30-39,F40-49,F50-59,

F60-69,F70-79,F80-89&F90-99).

Covariates

SexandbirthyearwerederivedfromtheDanishCivilRegistrationSystem.34Birthyearwas

categorizedintothreegroups(1996-2000,2001-2005,2006-2011).Parentalageatchildbirthwas

categorizedintofivecategories:<25years,25-29y,30-34y,35-39yand≥40y.Informationon

parentaleducationwasobtainedfromtheDanishEducationRegisters38andwasdefinedasthe

highestlevelofeducationatchildbirthdividedintosixcategories(primaryschool,secondary

school,vocationaleducation,shorthighereducation,mediumhighereducationandlonghigher

education).Parentalpsychiatrichistorywasdefinedasanydiagnosis(ICD-10:F00-F99andICD-8:

290-315)priortochildbirthsince1969.37Theriskofspreadofaninfectionfromoneparenttothe

otherwashandledbyadjustingtheanalysesforconcurrentinfection(eithertreatedwithanti-

infectiveagentsorhospitalization)intheotherparent.Parentalinfectionsoutsidethetimeperiod

wasdefinedasoneormorematernalorpaternalinfectioninothertimeperiodsi.e.pre-

pregnancy,post-pregnancyand1stand3rdtrimester,whenanalyzing2ndtrimesteretc.

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Statisticalanalyses

Theprimaryanalysiscomparedindividualswhohadbeenexposedtomaternalinfectionstreated

withanti-infectiveagentsorresultinginhospitalcontactbefore,duringorafterthepregnancy

periodwithnon-exposedindividualsduringthespecificperiodregardingtheriskofanymental

disorder.Weperformedthesameanalysesforpaternalinfections.

Secondly,weinvestigatedpotentialvulnerableperiodsformaternalorpaternalinfectionsduring

pregnancydependingontrimester.

Thirdly,weinvestigatedtheriskofspecificmentaldisordersintheoffspringandlastly,we

investigatedpotentialdose-responserelationshipsbetweenthenumberofinfectionstreatedwith

anti-infectiveagentsandriskofmentaldisorders.

AllanalyseswereperformedwithStataversion13.1.WeconductedCoxregressionanalyseswith

ageastheunderlyingtimescaleandpresentresultsashazardratios(HR)with95%-confidence

intervals(95%CI).Allanalyseswerestratifiedforsexandadjustedforbirthyear,parentalageat

childbirth,parentaleducationallevelatchildbirth,anyparentalmentaldiagnosisbeforechildbirth,

concurrentinfectionintheotherparentandparentalinfectionsoutsidethetimeperiod.We

adjustedformultiplecomparisonsusingBonferronicorrection.

RESULTS:

Thecohortconsistedof987,667childrenbornJuly1,1996toDecember31,2011with7,948,772

person-yearsoffollow-upfromJuly1,1997toJuly31,2013.Atotalof449,904(45.6%)ofthe

childrenwereexposedtomaternalinfectionstreatedwithanti-infectiveagentsduringpregnancy,

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while10,498(1.1%)wereexposedtomaternalinfectionsrequiringhospitalcontactsduring

pregnancy(seeTable1forallexposuresbefore,duringandafterpregnancy).

Parentalinfectionsbefore,duringandafterpregnancyandtheriskofmentaldisordersinthechild

Inthefullyadjustedmodel,wefoundthatchildrenexposedtomaternalinfectionstreatedwith

anti-infectiveagentsduringpregnancyhadanincreasedriskofanymentaldisorderwithaHRof

1.14(95%CI:1.11-1.16)comparedtochildrennotexposedtomaternalinfectionstreatedwith

anti-infectiveagentsduringpregnancy(Table2).Exposuretomaternalinfectionsrequiring

hospitalcontactsduringpregnancyincreasedtheriskofmentaldisorderswithaHRof1.38

(95%CI:1.28-1.50).Wefoundnodifferenceintheincreasedriskofmentaldisordersafter

maternalinfectionsofbacterialorotherorigin(datanotshown).

Incomparison,paternalinfectionstreatedwithanti-infectiveagentsduringpregnancyconferreda

HRof1.01(95%CI:0.99-1.04),whereasinfectionsresultinginhospitalizationincreasedtherisk

withaHRof1.24(95%CI:1.10-1.39).Mostparentalinfectionsinthepre-orpost-pregnancyperiod

showedsimilarlyincreasedriskestimatesforanymentaldisorderastheparentalinfectionsduring

pregnancy(Table2).

WhenperformingWald’stestcomparingtheriskofmentaldisordersaftermaternalandpaternal

infections,wefoundthattherisksaftermaternalinfectionstreatedwithanti-infectiveagents

weresignificantlyhigherthanforpaternalinfections(allp<0.001),butfoundnodifferencefor

parentalinfectionsresultinginhospitalization(allp>0.12).

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Infectionsbasedontrimesterandtheriskofmentaldisorders

Wefoundasimilarlyincreasedriskofmentaldisordersafterexposuretomaternalinfections

acrossallthreetrimestersofpregnancy(Table3).Paternalinfectionsonlyshowedasignificantly

increasedriskafterhospitalizationduringthethirdtrimester.Wefoundnodifferenceacross

trimestersintheincreasedriskdependingonbacterialorotheroriginofmaternalinfection(Table

4).

Riskofspecificmentaldisorders

Themostelevatedriskofspecificmentaldisordersinthechildwasobservedforschizophrenia

spectrumdisorders(F20-29),wherematernalhospitalizationswithinfectionsduringpregnancy

showedanincreasedriskintheoffspringwithaHRof3.22(95%CI:1.70-6.10;N=10cases)(Table

5).Therewerenoincreasedrisksofmooddisorders(F30-39),behavioralsyndromes(F50-59),

personalitydisorders(F60-69)orofmentalretardation(F70-79)(datanotshown).Wefoundan

increasedriskofanxietydisorders(F40-49)andofbehavioralandemotionaldisorders(F90-99)

afterprimarilymaternalinfectionsbefore,duringandafterpregnancy.

Onlymaternalinfectionswereassociatedwithanincreasedriskofdevelopmentaldisorders(F80-

89)withaHRof1.13(95%CI:1.08-1.18)aftermaternalinfectionstreatedwithanti-infective

agentsduringpregnancy,whilematernalinfectionsresultinginhospitalcontactsduringpregnancy

andpost-pregnancyshowedaHR1.43(95%CI:1.23-1.67)and1.48(95%CI:1.29-1.71),

respectively.Theestimatesspecificallyforautism(ICD-10:F84.0,84.1,84.5,84.8,84.9)were

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similarwithHRof1.11(95%CI:1.07-1.16),1.41(95%CI:1.20-1.66)and1.50(95%CI:1.29-1.74),

respectively.

Dose-responseassociations

Figure1indicatesthattheriskforanymentaldisorderincreasedinadose-responserelationship

dependingonthenumberofmaternalprescriptionsbefore,duringandafterpregnancy(all

p<0.001).Wefoundnodose-responseassociationswithpaternalprescriptionsorthenumberof

maternalorpaternalhospitalcontacts.

DISCUSSION

Ournationwidestudyisthelargesttodateinvestigatingtheassociationbetweenparental

infectionsduringpregnancyandriskofmentaldisordersintheoffspring,coveringalltreated

infectionsintheprimaryandsecondaryhealthcaresector.Weshowedthatmaternalinfections

duringpregnancyincreasedtheriskofmentaldisordersinthechildwith14%forinfections

treatedwithanti-infectiveagentsandwith38%forinfectionsrequiringhospitalization.Maternal

infectionsduringpregnancytreatedwithanti-infectiveagentsdisplayedahigherriskthanpaternal

infections,whereastherewasnosignificantdifferenceforinfectionsrequiringhospitalcontact.

Furthermore,theriskestimatesaftermaternalinfectionsoutsideofthepregnancyperiodwere

similarlyelevatedcomparedtotheriskaftermaternalinfectionsduringpregnancy.Maternal

infectionstreatedwithanti-infectiveagentsincreasedtheriskwithadose-responserelationship

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bothduringpregnancyandoutsidethepregnancyperiod,whereasnodose-responserelationships

wereobservedforpaternalinfections.

Previousstudieshaveshownconflictingresults,3,9–11,17,18withsomestudiesindicatingthat

maternalinfectionsduringpregnancycouldincreasetheriskofparticularlyschizophrenia2–8,13and

autism;19,20,22–24however,thisisthefirststudytoinvestigatetheriskofanymentaldisorderinthe

offspring.Bacterialinfectionsduringthefirsttrimesterhavebeenassociatedwithschizophrenia,8

butastudybyNielsenetal.13foundthattheriskofschizophreniainthechildwassimilarly

increasedaftermaternalandpaternalinfectionsrequiringhospitalcontactsbefore,duringorafter

pregnancy.Inaddition,Blomströmetal.11foundanincreasedriskofpsychosisassociatedwith

maternalinfectionsrequiringhospitalizationfiveyearspriortopregnancyandwithmaternal

infectionsduringpregnancyformotherswithmentaldisorders.Regardingtheriskofautism,

increasedriskshavebeenobservedafterviralinfectionsduringfirsttrimesterandbacterial

infectionsduringsecondtrimester.19Furthermore,Zerboetal.22foundthatmaternalinfection

diagnosedduringhospitalizationinthepregnancyperiodwasassociatedwithautismspectrum

disordersbyanoddsratioof1.48(95%CI:1.07-2.04).Ourlargerstudyfoundnovulnerableperiod

dependingonthetimingoftheparentalinfectionbasedonpregnancytrimestersnordidwefinda

differenceintheriskdependingonbacterialorotheroriginoftheinfection.Althoughwealso

foundsimilarriskestimatesbefore,duringandafterpregnancy,wefoundmaternalinfectionsto

increasetheriskofmentaldisordersmorethanpaternalinfectionstreatedintheprimarysector.

Specificallyforschizophreniaspectrumdisordersweonlyfoundmaternalinfectionsrequiring

hospitalizationduringpregnancytoincreasetherisk(Table5).

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Ourfindingsaswellasothers11,13suggestthattheassociationsbetweenparentalinfectionsand

higherrisksofmentaldisordersintheoffspringarenotonlyduetoapossibleeffectofthe

infections,inflammationorpregnancycomplicationsduetoinfections,butcouldalsopartlybe

explainedbysharedgeneticsusceptibilitytoinfectionsandmentaldisordersduetothesimilarrisk

estimatesafterinfectionsoutsidethepregnancyperiod.Nevertheless,itcouldalsobean

epiphenomenonduetoreducedimmunityoftheparentswithpoorlivingconditions,

psychologicalstress,39,40lifestylefactorsormedical-seekingbehavior.However,allanalyseswere

adjustedforparentallevelofeducationandparentalpsychiatricdiagnosescapturingmany

importantsocioeconomicfactors.Moreover,ourinvestigationdidnotlookintospecificinfections

thatduringspecificvulnerableperiodspotentiallycouldinfluencethefetalneurodevelopment.

Strengthsandlimitations

Thisstudyisanationwideregister-basedcohortstudywiththeadvantagesofcompletefollowup

andisnotsubjecttorecallbias.Wehadalargecohortyieldingstatisticalpowertoinvestigate

infectionsinspecificvulnerabletimeperiods,suchasonatrimesterbasis.Furthermore,wewere

abletoadjustforimportantconfounders.However,untreatedinfectionscouldnotbeincluded.

Hence,wecannotexcludetheconsequencesofuntreatedinfections,asmostvirusessuchas

influenzaareonlyrarelytreatedwithanti-infectivemedications.Furthermore,wewerenotable

toseparatethetreatmentfromtheinfectionitself,soitispossiblethattheriskofmental

disordersisassociatedwiththemedicationratherthantheinfection.However,wefoundsimilarly

increasedrisksbefore,duringandafterpregnancyindicatingthattheuseofanti-infectiveagents

duringpregnancyisassafeastheuseoutsideofthepregnancyperiodinregardtothefuture

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mentalhealthofthechild.Lastly,ourcohortwasfairlyyoungsothementaldisordersweremainly

withinthespectrumofchildhoodandadolescencementaldisorders,asthechildrenwere

followeduntilamaximumageof17years.Hence,theestimatesforthedevelopmentofe.g.

schizophreniawasbasedonasmallsubpopulationwithearlyonsetcomparedtothegeneral

populationofindividualswithschizophreniaandshouldthereforebeinterpretedwithcaution.

Conclusionandperspectives

Wefoundsimilarlyincreasedrisksofmentaldisordersintheoffspringafterexposuretomaternal

infectionsbothbefore,duringandafterpregnancy-indicatingthatthepregnancyperiodwasnot

aperiodofparticularrisk.Theriskofmentaldisorderswasgenerallyhigherformaternalinfections

andforinfectionsresultinginhospitalcontact.Wefoundnovulnerableperioddependingonthe

timingoftheparentalinfectionbasedonpregnancytrimesters.Futurestudiesneedtoinvestigate

specificimmunecomponentsduringpregnancytogetherwithsharedgeneticfactorsbetween

infectionsandmentaldisorders.

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TABLESANDFIGURES

Table1:Maternalandpaternalinfectionsbefore,duringorafterpregnancyamong987,667individuals.Numbersbasedononeormoreprescriptionforanti-infectiveagentsorhospitaldischargediagnosesforinfectionspr.individualduringthedesignatedperiod.Numberofindividuals(%)

Beforepregnancy Duringpregnancy Afterpregnancy Maternalinfections Prescriptions 443,673(44.9) 449,904(45.6) 467,643(47.4)Bacterial 382,990(38.8) 414,762(42.0) 415,805(42.1)Other 148,845(15.1) 92,367(9.4) 137,043(13.9)Hospitalizations 7,869(0.8) 10,498(1.1) 11,354(1.2)Bacterial 5,030(0.5) 6,554(0.7) 8,995(0.9)Other 3,133(0.3) 4,283(0.4) 2,634(0.3) Paternalinfections Prescriptions 278,044(28.2) 280,824(28.4) 285,548(28.9)Bacterial 230,758(23.4) 233,709(23.7) 243,014(24.6)Other 76,652(7.8) 77,161(7.8) 71,526(7.2)Hospitalizations 4,696(0.5) 4,755(0.5) 4,849(0.5)Bacterial 2,288(0.2) 2,411(0.2) 2,425(0.3)Other 2,549(0.3) 2,483(0.3) 2,610(0.3)

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Table2:Riskofanymentaldisorderinoffspringbymaternalandpaternalinfectionsbefore,duringorafterpregnancy. Pre-pregnancyperiod Duringpregnancy Post-pregnancyperiod No.

casesFullyadjustedHR(95%CI)1

No.cases

FullyadjustedHR(95%CI)1

No.cases


Maternalinfectiontreatedwithanti-infectiveagents

Noinfection 16,074 1.00(ref) 16,529 1.00(ref) 15,684 1.00(ref)

≥1infection 17,538 1.11(1.09-1.13)* 17,083 1.14(1.11-1.16)* 17,928 1.09(1.07-1.11)*

Maternalinfectionrequiringhospitalcontact


≥1infection 479 1.20(1.09-1.31)* 653 1.38(1.28-1.50)* 636 1.27(1.17-1.38)*

Paternalinfectiontreatedwithanti-infectiveagents


≥1infection 10,189 1.01(0.99-1.04) 10,277 1.01(0.99-1.04) 10,649 1.04(1.02-1.07)*

Paternalinfectionrequiringhospitalcontact


≥1infection 265 1.19(1.06-1.35) 282 1.24(1.10-1.39)* 277 1.18(1.05-1.33)

1Adjustedforsex,birthyear,concurrentinfectionintheotherparent,parentalinfectionsoutsidethetimeperiod,parentallevelofeducationatchildbirth,parentalageatchildbirth,anyparentalpsychiatricdiagnosesatchildbirth(ICD-10:F00-F99).*=Significantafteradjustmentformultiplecomparisons

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1Adjustedforsex,birthyear,concurrentinfectionintheotherparent,parentalinfectionsoutsidethetimeperiod,parentallevelofeducationatchildbirth,parentalageatchildbirth,anyparentalpsychiatricdiagnosesatchildbirth(ICD-10:F00-F99).*=Significantafteradjustmentformultiplecomparisons

Table3:Riskofanymentaldisorderinoffspringbymaternalandpaternalinfectionsduring1st,2ndand3rdtrimesterofpregnancy. Firsttrimester Secondtrimester Thirdtrimester No.


No.cases


No.cases


Maternalinfectiontreatedwithanti-infectiveagents


≥1infection 7,453 1.07(1.04-1.09)* 8,220 1.12(1.09-1.14)* 8,407 1.10(1.08-1.13)*

Maternalinfectionrequiringhospitalcontact


≥1infection 154 1.28(1.09-1.50)* 214 1.42(1.24-1.62)* 320 1.37(1.23-1.53)*

Paternalinfectiontreatedwithanti-infectiveagents


≥1infection 3,991 1.02(0.99-1.06) 4,455 1.01(0.98-1.04) 4,357 0.99(0.95-1.02)

Paternalinfectionrequiringhospitalcontact


≥1infection 87 1.20(0.97-1.49) 99 1.18(0.97-1.44) 108 1.33(1.10-1.61)*

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Table4:Riskofanymentaldisorderinoffspringbymaternalandpaternalinfectionsdividedintobacterialorotherinfectionsduring1st,2ndand3rdtrimesterofpregnancy. Firsttrimester Secondtrimester Third No.


No.cases


No.cases


Maternal PrescriptionAntibacterial 6,498 1.06(1.03-1.09)* 7,498 1.12(1.09-1.15)* 7,652 1.10(1.07-1.13)*PrescriptionOther 1,599 1.09(1.04-1.15)* 1,324 1.07(1.01-1.13) 1,357 1.11(1.05-1.17)*HospitalcontactBacterial 90 1.28(1.04-1.57) 121 1.51(1.26-1.80)* 234 1.42(1.25-1.62)*HospitalcontactOther 69 1.31(1.03-1.66) 96 1.28(1.04-1.56) 90 1.23(1.00-1.51)Paternal

PrescriptionAntibacterial 3,303 1.05(1.01-1.09) 3,620 1.01(0.98-1.05) 3,606 1.01(0.98-1.05)PrescriptionOther 908 0.95(0.89-1.01) 1,105 1.00(0.94-1.07) 1,019 0.93(0.87-0.99)HospitalcontactBacterial 42 1.14(0.84-1.55) 42 0.97(0.72-1.32) 53 1.25(0.95-1.63)HospitalcontactOther 47 1.25(0.94-1.66) 59 1.40(1.09-1.81) 55 1.37(1.05-1.79)Reference(HR=1.00)ischildrenwithnomaternal/paternalinfectiontreatedwithanti-infectiveagents/requiringhospitalcontactsduringthespecifiedtimeperiod.

1Adjustedforsex,birthyear,concurrentinfectionintheotherparent,parentalinfectionsoutsidethetimeperiod,parentallevelofeducationatchildbirth,parentalageatchildbirth,anyparentalpsychiatricdiagnosesatchildbirth(ICD-10:F00-F99).

*=Significantafteradjustmentformultiplecomparisons

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Table5:Riskofspecificcategoriesofmentaldisordersintheoffspringafterexposuretomaternalorpaternalinfectionsbefore,duringorafterpregnancy.a,b

No.cases

SchizophreniadisordersF20-29

No.cases

AnxietydisordersF40-49

No.cases

DevelopmentaldisordersF80-89

No.cases

BehaviouralandemotionaldisordersF90-99

Totalno.cases

245 4,756 9,875 15,489

BeforepregnancyMaternalPrescriptions

131

1.05(0.81-1.36)

2639

1.15*(1.08-1.22)

4692

0.99(0.95-1.03)

8347

1.19*(1.15-1.23)

Hospitalcontacts

- - 87 1.60*(1.29-1.98) 128 1.32(1.11-1.57) 224 1.21(1.06-1.38)

PaternalPrescriptions

66

0.81(0.61-1.08)

1532

1.05(0.99-1.13)

2838

0.98(0.94-1.03)

4760

1.02(0.99-1.06)

Hospitalcontacts

- - 42 1.33(1.00-1.85) 73 1.32(1.05-1.67) 117 1.15(0.96-1.37)

DuringpregnancyMaternalPrescriptions

121

1.05(0.81-1.36)

2448

1.13*(1.06-1.20)

4843

1.13*(1.08-1.18)

8031

1.15*(1.12-1.19)

Hospitalcontacts

10 3.22*(1.70-6.10) 92 1.46*(1.19-1.80) 171 1.43*(1.23-1.67) 328 1.48*(1.33-1.66)


84

1.25(0.95-1.65)

1523

1.05(0.99-1.12)

2840

0.96(0.92-1.01)

4881

1.05(1.01-1.08)

Hospitalcontacts

- - 38 1.27(0.92-1.74) 70 1.21(0.96-1.54) 150 1.43*(1.21-1.68)

AfterpregnancyMaternalPrescriptions

134

1.07(0.82-1.38)

2681

1.15*(1.08-1.22)

4923

1.01(0.97-1.06)

8451

1.14*(1.10-1.17)

Hospitalcontacts

6 1.77(0.78-3.98) 82 1.23(0.98-1.53) 194 1.48*(1.29-1.71) 301 1.31*(1.17-1.47)


76

0.99(0.75-1.31)

1596

1.11(1.04-1.18)

2964

1.00(0.96-1.05)

4983

1.05(1.02-1.09)

Hospitalcontacts

- - 37 1.14(0.83-1.58) 73 1.25(0.99-1.58) 139 1.32(1.11-1.55)

aAdjustedforsex,birthyear,concurrentinfectionintheotherparent,parentallevelofeducationatchildbirth,parentalageatchildbirth,anyparentalpsychiatricdiagnosesatchildbirth(ICD-10:F00-F99).

bReference(HR=1.00)ischildrenwithnomaternal/paternalinfectiontreatedwithanti-infectiveagents/requiringhospitalcontactsduringthespecifiedtimeperiod.

-=Riskestimatenotavailableduetofewcases

*=p<0.001,significance-levelafteradjustmentformultiplecomparisons.

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Figure1A:Riskofanymentaldisorderinthechilddependingonthenumberofparentalinfectionstreatedwithanti-infectiveagentsduringpregnancy

Figure1B:Riskofanymentaldisorderinthechilddependingonthenumberofparentalinfectionstreatedwithanti-infectiveagentsbefore,duringorafterpregnancy.

1.11

1.22 1.25

1.32

1.4

1.02 1.03 1.041.06

1.22

0,9

1

1,1

1,2

1,3

1,4

1,5

1 2 3 4 5+

Hazardra

'o

Numberofinfec'onstreatedwithan'-infec'veagents

Riskofmentaldisordersinthechild

PregnancyMaternal

PregnancyPaternal

p-value<0.001

p-value=0.105

Pre-pregnancy

Pregnancy

Post-pregnancy

Pre-pregnancy

PregnancyPost-pregnancy

0,9

1

1,1

1,2

1,3

1,4

1,5

1 2 3 4 5+

Hazardra

'o

Numberofinfec'onstreatedwithan'-infec'veagents

Riskofmentaldisordersinthechild

Maternal

Paternal

parental infections during pregnancy as risk factors for …...anti-infective agents during...

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