effects of prenatal marijuana exposure on ... · of prenatal marijuana exposure on...

Paediatr Perinat Epidemiol. 2018;1–21. wileyonlinelibrary.com/journal/ppe | 1

Received:24May2018 | Revised:1August2018 | Accepted:17August2018DOI: 10.1111/ppe.12505

R E V I E W A R T I C L E

Effects of prenatal marijuana exposure on neuropsychological outcomes in children aged 1- 11 years: A systematic review

Saida R. Sharapova1 | Elyse Phillips1 | Karen Sirocco2 | Jennifer W. Kaminski3 | Rebecca T. Leeb3 | Italia Rolle1

1OfficeonSmokingandHealth,NationalCenterforChronicDiseasePreventionandHealthPromotion,CentersforDiseaseControlandPrevention,Atlanta,Georgia2DivisionofEpidemiology,ServicesandPrevention,PreventionResearchBranch,NationalInstituteonDrugAbuse,NationalInstitutesofHealth,Bethesda,Maryland3DivisionofHumanDevelopmentandDisability,NationalCenteronBirthDefectsandDevelopmentalDisabilities,CentersforDiseaseControlandPrevention,Atlanta,Georgia

CorrespondenceSaidaR.Sharapova,OfficeonSmokingandHealth,NationalCenterforChronicDiseasePreventionandHealthPromotion,CentersforDiseaseControlandPrevention,Atlanta,GA.Email:[email protected]

AbstractBackground: Normalisation of medicinal and recreational marijuana use has in-creasedtheimportanceoffullyunderstandingeffectsofmarijuanauseonindividual-andpopulation-levelhealth,includingprenatalexposureeffectsonchilddevelopment.Weundertookasystematicreviewoftheliteraturetoexaminethelong-termeffectsof prenatal marijuana exposure on neuropsychological function in children aged1-11years.Methods: Primary research publications were searched from Medline, Embase,PsychInfo, CINAHL EbscoHost, Cochrane Library,GlobalHealth and ERIC (1980-2018). Eligible articles documented neuropsychological outcomes in children1-11yearswhohadbeenprenatallyexposed tomarijuana.Studiesofexposure tomultiple prenatal drugs were included if results for marijuana exposure were re-portedseparatelyfromothersubstances.Dataabstractionwasindependentlyper-formedbytworeviewersusingastandardisedprotocol.Results:Theeligiblearticles (n=21)ondata fromseven independent longitudinalstudieshadhighqualitybasedontheNewcastle-OttawaScale.Someanalysesfoundassociations(P<0.05)betweenprenatalmarijuanaexposureanddecreasedperfor-manceonmemory,impulsecontrol,problem-solving,quantitativereasoning,verbaldevelopmentandvisualanalysistests;aswellasincreasedperformanceonattentionandglobalmotionperceptiontests.Limitationsincludedconcurrentuseofothersub-stancesamongstudyparticipants,potentialunder-reportingandpublicationbiases,non-generalisablesamplesandlimitedpublishedresultspreventingdirectcompari-sonofanalyses.Conclusions:Thespecificeffectsofprenatalmarijuanaexposureremainunclearandwarrantfurtherresearch.Thelargernumberofneuropsychologicaldomainsthatex-hibitdecreasedversusincreasedpsychologicalandbehaviouralfunctionssuggeststhatexposuretomarijuanamaybeharmfulforbraindevelopmentandfunction.

K E Y W O R D S

attention,cannabis,intellect,intrauterine,memory,perception

Published2018.ThisarticleisaU.S.GovernmentworkandisinthepublicdomainintheUSA

www.wileyonlinelibrary.com/journal/ppe

http://orcid.org/0000-0002-1097-2204

mailto:[email protected]

2 | SHARAPOVA et Al.

1 | INTRODUC TION

MarijuanaisthemostcommonlyusedillicitdrugintheUnitedStates,withanestimated22.2millionpast-monthusersaged12yearsorolder in 2015.1 Since1996, lawsallowingmedicinalmarijuanausehavebeenpassedin29states,theDistrictofColumbia(DC),GuamandPuertoRico,andlawsallowingrecreationaluseandsalesofmar-ijuanaforadultsaged21andoverhavebeenpassedin8statesandDCsince2012.2,3Asmorestatesconsiderlegalisingmarijuanauseamongadults,itisimportanttofullyunderstandtheeffectsofmari-juanauseonindividual-andpopulation-levelhealth.3

The growing availability and use of marijuana is important toconsider among women of reproductive age. Among US womenaged 18-44years, self-reported past 30-day use ofmarijuana hasincreased from2002 to2014 from2.4%to3.9%amongpregnantandfrom6.3%to9.3%amongnon-pregnantwomen.4Giventhein-creasingtrendsofmarijuanauseamongwomenofreproductiveageincludingpregnantwomenandthechanginglandscapeoflegalandmedicalmarijuanaintheUnitedStates,amorerobustunderstandingoftheconsequencesofprenatalmarijuanaexposureonchildreniscriticaltoinformindividualdecision-makingandpublichealthpolicy,planningandpractice.5,6

Theuseofmarijuanaduringpregnancycouldhaveimplicationsforfoetalbraindevelopment.7-12Marijuanaislipidsolubleandabletocrosstheplacentaandblood-brainbarriertoaccumulateinfoe-tal tissues including brain tissues.13,14 It is processed in the bodythrough the endocannabinoid system, which may be involved inbraindevelopmentthroughneurogenesis,differentiation,migrationandneural circuitwiring.15,16Data suggest that this systemexistsfrom the earliest stages of pregnancy, presenting multiple pointsofvulnerabilitytoexposureofmarijuanathroughoutgestation,al-though the exact processes of this system’s development are stillnotcompletelyunderstoodinhumans.15,17Additionally,thereisev-idenceofseveraladverseeffectsonthebrainandcognition,includ-ingstructuraldamage, learningandmemorydeficits,and impairedmotorfunctioninadolescentsandadultswhoareactivemarijuanausers.18-25Therefore,marijuanaexposurehaspotentialadverseef-fectsonbraindevelopmentinprenatallyexposedchildren.26

Thestrongestevidenceofadverseeffectsofprenatalmarijuanaexposurecomesfromanimalstudies.7-9Thesestudiesdemonstratedthatevenlowdosesofmarijuanaduringpregnancycanresultinad-versecognitiveanddevelopmentaleffectsinoffspring.7-9Inhumanstudies, there are variations in the effect’s direction, degree andduration.11,12Moreover, it isoftendifficult todiscernwhether theeffectsareduesolelytomarijuanaortoacombinationofmarijuanawithanothersubstancethemothermayhaveusedconcurrently.27-29 Synthesesofstudiesthathaveexaminedprenatalmarijuanaeffectson children’s brain development, while controlling for other sub-stancesuse,arelimited.6

Existing systematic reviews have partially examined conse-quencesofprenatalmarijuanaexposureinchildren;however,theyhavecertain limitations.Amonginfants,a2016reviewfoundin-creased irritability, tremors and startles, anddecreased stability

scores inexposedneonatescomparedtounexposedneonates.30 Two systematic reviews from 2007 and 2012 examining cogni-tive functions in childrenwith prenatal exposures tomarijuana,alcohol, cocaine, tobacco, lead andmercury found evidence forlong-termdamagetoattentionresultingfromprenatalmarijuanaexposure,attemptingtocontrolforuseofothersubstances;how-ever, these studies involved adolescents.31,32 By adolescence,subjectsmayhavebeenaffectedbyotherpotentialdevelopmen-tal insults, including their own substance use, and it is difficultto distinguish consequences resulting fromprenatal exposure.33 A2011summaryarticlefocusedmainlyontheendocannabinoidsystemandanimalstudiessupportingevidenceofmarijuana’spo-tentialtointerferewiththeroleofthissystemindevelopmentanddidnotemploysystematicreviewmethodology.15Additionally,arecent consensus study by theNational Academies of Sciences,EngineeringandMedicinenotedthedearthofgoodorfairqualitysystematicreviewsexaminingassociationsbetweenmaternalmar-ijuana use andoffspring’s cognitionor academic achievement.34 Given the abovementioned gaps in the scientific literature, thisstudypresentsthefindingsofasystematicreviewoftheimpactofprenatalmarijuanaexposureonneuropsychologicalfunctioninginchildrenaged1-11years.

2 | METHODS

Literature searches for this review were conducted by a librar-ianspecialising insystematic reviews.An initial literaturesearchtook place in August 2014 in the following databases:Medline,Embase, PsychInfo, Cumulative Index to Nursing and AlliedHealthLiterature(CINAHL)EbscoHost,CochraneLibrary,GlobalHealth and Education Resources Information Center (ERIC).Supplementary searches using the same terms were conductedin April 2015, September 2016, July 2017 and August 2018.Additionally, a cited reference searchwas conducted to identifyarticles missed in the searches.35 Appendix S1 of the supple-mentalmaterialsprovidesanexampleof termsused inMedline.Search terms included terms for marijuana (eg, cannabis, hash,ganja),pregnancy(eg,pregnancy,pregnantwomen, inutero)andoutcomes (eg, cognitive disorders, intelligence, learning, execu-tivefunctions,attention).Alltermswereenteredassubjecthead-ings,textwordsandMedicalSubjectHeadings(MESH)termsperrequirementsofeachdatabase.Detailedoverviewof thesearchand selection strategy is available in the supplementalmaterials(AppendixS1).

PreferredReporting ItemsforSystematicReviewsandMeta-Analyses(PRISMA)guidelineswereusedtotrackliteraturereviewresultsandtostandardisethereviewprocess.36ThePRISMAflowdiagram is displayed in Figure1. Inclusion and exclusion criteria(the supplemental materials, Appendix S1) were designed to in-clude published or unpublished studies documenting neuropsy-chological outcomes in children aged 1-11years who had beenprenatallyexposedtomarijuana.Studiesofprenatalexposureto

| 3SHARAPOVA et Al.

multipledrugswereincludedifresultsformarijuanaexposureanditsassociationswiththeoutcomeswerereportedseparatelyfromresults for other substance exposures.Grey literature, includingconferenceabstracts,dissertations,whitepapersandreportsre-trieved by the literature searches,was considered for eligibility.Reviewersidentified1doctoraldissertationand4conferenceab-stracts thatmetcriteria for full-text review.Authorsof thecon-ferenceabstractswerecontacted in regard topotentialpendingpublicationoftheirstudies.Full-textreviewandfurtherresearchleadtoexclusionofthesearticles.

The literature search and selection consisted of two steps: (a)titleandabstractscreening,and(b)full textandreferencereview.Aprimaryandasecondaryreviewerindependentlyreviewedallar-ticlesretrievedfromtheliteraturesearch.Thearticlesweredividedbetweenninereviewerswhowereeithersubjectmatterexpertsinchilddevelopmentand/orsubstanceabuse(authors:SRS,KS,JK,RL,IR)orpublichealthscientists(acknowledged:KA,RP,AJ,LP)trainedtoperformthereviewbythesubjectmatterexperts.Aprimaryandasecondaryreviewerscreenedeachreferencetodeterminewhetherthereferencemetinclusionorexclusioncriteria.

All articles thatwere foundeligibleduring the full-text reviewreporteddata from longitudinal studies.Additionally, itwas foundthatsomearticlesutiliseddatafromasinglestudyreportingresultsfromdifferentanalysesorfromdifferenttimepointsofthestudy.Thereviewersutilisedthelistofauthorsandthemethodologyde-scriptionofeacheligiblearticle,includingreferencestopublications

reportingstudymethodology,inordertodeterminewhetherarticlesbelongedtoaparticularstudy.

Thedataabstraction instrumentdevelopedby theCommunityPreventiveServicesTaskForcewasusedtoabstractdatafromtheeligiblearticles.37Asthedataabstractioninstrumenthadbeenorig-inallydesignedtoassesspublichealthinterventions,itwasadaptedforassessingreportsfromlongitudinalstudies.Thearticlesselectedforthereviewweredividedamongthreereviewers(SRS,RPandAJ)fordataabstraction.Tworeviewersindependentlycodedqualitativeandquantitativedatafromeachselectedarticle.

Study quality was graded using the Newcastle-Ottawa scaledesignedtoassesslongitudinalstudies.38Ittookintoaccountfac-torsof representativeness, comparabilityandoutcome.Thescaleincludedassessmentof thesuitabilityofstudydesignandqualityofstudyexecutiontodetermineeachstudy’sutilitytoanswertheresearchquestions.Atanystepofthereview,whendiscrepanciesoccurred,primaryandsecondaryreviewersdiscussedthediscrep-ancytoachieveconsensus.Additionalreviewerswereconsultedifneeded.

Resultsweresynthesisedqualitatively.Utilisingaconservativeapproach,onlyresultsthatwerestatisticallysignificant(P < 0.05) in analyses adjusted for potential confounders were consideredto be different from the null. Negative association was definedas association between prenatal marijuana exposure and dimin-ishedneuropsychologicalfunction(eg,lowerscoreforverbalde-velopmentandhigherscorefor inattention).Positiveassociation

F IGURE 1 Flowchartofliteraturereview Note: AdaptedfromMoheretal36(http://www.bmj.com/content/339/bmj.b2535)

* Databases: Medline, Embase, PsychInfo, CINAHL EbscoHost, Cochrane Library, Global Health, and ERIC. Limits: publication date 1980-present, English.

Records identified through database* searching

(n = 2307)

Screen

ing

Includ

edEligibility

Iden

tification

Additional records identified through the Cited reference search

(n = 62)

Records after duplicates removed (n = 1943)

Records excluded (animal studies, outcomes in adults, non-research publications, reviews, studies of the prevalence of marijuana use,

outcomes other than cognitive and executive function, conference abstracts and duplicates

missed by the automated de-duplication)(n = 1648)

Full-text articles excluded (reviews, animal studies, a case report, a paper in Danish

language, a paper with no full text available, conference abstracts, duplicates missed

previously, polydrug exposure with no dis-aggregated marijuana data, outcomes outside

the 1-11 years age range, marijuana studies not investigating association with cognitive

development) (n = 274)

Full-text articles assessed for eligibility

(n = 295)

Studies included in qualitative synthesis

(n = 21)

http://www.bmj.com/content/339/bmj.b2535

http://www.bmj.com/content/339/bmj.b2535


TAB

LE 1 Methodologysummaryoftheeligiblearticles

Aut

hor,

year

St

udy

Sam

ple

size

s (at

fo

llow

- up/

recr

uite

d)

Age

at f

ollo

w- u

pA

naly

ses c

ompa

rison

gro

ups b

y m

ariju

ana

expo

sure

Pren

atal

exp

osur

e to

sub

stan

ces o

ther

than

mar

ijuan

a an

d ot

her c

ovar

iate

s tha

t ana

lyse

s con

trol

led

for

Stud

y bi

ases

and

lim

itatio

ns (r

epor

ted

by th

e au

thor

s and

add

ition

ally

iden

tifie

d by

the

revi

ewer

s)

Hayes,1991

Jamaicastudy

54/59

4 an

d 5

yNon-users

Lightusers(<10marijuana

cigarsor“spliffs”perweek)

Moderate(11-20)

Heavy(21-70)

QualityofHousingIndex

(a)Resultsmaynotbegeneralisableassample

consistedoflowerincomeruralwomen.(b)

Impossibletodistinguishbetweenexposure

effectsofmarijuanaandchild’senvironment.(c)

Authorsdonotprovideresultsoftheanalysesfor

5-y-olds

Fried,1988

OPPS

153/217

1 an

d 2

yJointsperweek(range0-153,

mean15in12-mosample,and

18in24-mosample)

Heavyuse(>5joints/wk)

Cigarettes,alcohol

Familyincome,maternalageandeducation,maternal

caffeine,protein,andcaloricintakeduringpregnancy,

difficultiesduringpregnancy,maternalandpaternalhealth

history,exposuretoX-raysorrubella,gestation,birthweight,

parity,methodoffeedingandtheHOMEscale

(a)Prenatalmarijuanausewasconfoundedby

nicotineandalcoholuse.(b)Studyresultsmaynot

begeneralisable

Fried,1990

OPPS

133/190

3 an

d 4

yInfrequent/nouse

Moderate(>1-<6joints/wk)

Heavy(≥6joints/wk)

Cigarettes,alcohol

Familyincome,mother’sweightandpregnancyweightgain,

age,education,nutritionandthetwodrugsnotofprimary

interest.Perinatalcontrolsweresex,parity,gestation,

birthweightandHOMEscale

(a)Volunteersubjectsarealow-risksamplewhich

mayrepresentaconservativeestimateofdrug

effects.(b)Varianceexplainedbymaternaldrug

usewasrelativelysmallcomparedwiththeHOME

test

Fried,1992

OPPS

139/190

5and6y

Infrequent/nouse(≤1joint/wk)



Cigarettes,alcohol

Familyincome,mother’spregnancyweightandpregnancy

weightgain,mother’sageatdelivery,averagelevelofparental

education,parentalrelationship,predominantlanguage

spokenbythechild,child’sgender,HOMEscaleandthetwo

drugsnotofprimaryinterest

(a)Instrumentsthatprovideageneraldescriptionof

cognitiveabilitiesmaynotbecapableofidentify-

ingnuancesinneuro-behaviourthatmay

discriminatebetweenmarijuanaandnon-marijuana

exposedchildren.(b)Verylow-risksamplewhich

mayrepresentaconservativeestimateofdrug

effects.(c)Potencyofmarijuanapreparationshas

increasedseveralfoldssincetheentranceof

pregnantwomeninthestudy

Fried,1992

OPPS

127/190

6y

Infrequent/nouse



Cigarettes,alcohol

Familyincome,mother’spre-pregnancyweight,mother’s

caffeineintakeandnutritionduringpregnancy,pregnancy

difficulties,mother’sageatdelivery,averagelevelofparental

education,parity,child’ssex,predominantlanguagespoken

bychild,parentalrelationship,thetwodrugsnotofprimary

interestandtheHOMEscale

(a)Foetaldrugexposuremeasurementsdonot

distinguishtimingofexposureoraccountfor

sporadicheavyuseduringpregnancy.(b)Measures

ofhomeenvironmentwerenotstatistically

associatedwithattention-relatedoutcomes,and

otherpostnatalfactorsnotassessedmayinfluence

child’sperformanceonthesetasks.(c)Interaction

betweendrugexposureandparentingand/or

personalityiscurrentlybeinginvestigatedinthis

sample

(Con

tinue

s)

| 5SHARAPOVA et Al.

Aut

hor,

year

St

udy

Sam

ple

size

s (at

fo

llow

- up/

recr

uite

d)

Age

at f

ollo

w- u

pA

naly

ses c

ompa

rison

gro

ups b

y m

ariju

ana

expo

sure

Pren

atal

exp

osur

e to

sub

stan

ces o

ther

than

mar

ijuan

a an

d ot

her c

ovar

iate

s tha

t ana

lyse

s con

trol

led

for

Stud

y bi

ases

and

lim

itatio

ns (r

epor

ted

by th

e au

thor

s and

add

ition

ally

iden

tifie

d by

the

revi

ewer

s)

O’Connell,1991

OPPS

56/56

6-9y

Non-users

Users(>1joint/wk)Reported

range1.5-50joints/wk

(mean=14.4,standard

deviation=15)

Cigarettes,alcohol

Mother’sageatdelivery,mother’seducationlevel,father’s

educationlevel,highestoccupationalstatusofparents,family

income,numberofparentsinthehome,thenumberof

parentsworkingoutsidethehome,thenumberofchildrenin

thefamily,thebirthorderofthesubjectchild,theprincipal

languageofthehome,theprincipallanguageofinstructionin

school,presenceofproblemsinschool,historyofeyeand/or

earinfections,theneedforvisualcorrection,thepresenceof

specialconditionsatthetimeoftestingandHOMEscale

(a)Homeenvironmentmeasuresareviewedas

legitimateoutcomes,ratherthanpotential

confounders.(b)Low-risksamplewhichmay

representaconservativeestimateofdrugeffects.

(c)Potencyofmarijuanapreparationshas

increasedsincetheentranceofpregnantwomenin

thestudy

Fried,1997

OPPS

146/190

9-12y

Infrequent/nouse(≤1joints/

wk)



Cigarettes,alcohol

Familyincome,mother’sageatdelivery,mother’sweight

beforepregnancy,mother’stotalpregnancyweightgain,

averagelevelofparentaleducation,othermaternaldruguse

andprenatalpassivesmokeexposure.Postnatalvariables:sex

ofthechild,thehomeenvironment,themother’spersonality,

child’slevelofdepressionandanxiety,second-handsmoke

exposureofchildandcurrentmaternalsociodemographic

characteristicsandmarijuanauseatthetimeofchild’stesting

(a)Smallnumberofsubjectsinthegroupofchildren

exposedtomoderatemarijuanauselimits

confidenceintheresults

Fried,1998

OPPS

146/190

9-12y

Nouse

Infrequent/moderate(>0-<6

joints/wk)


Cigarettes,alcohol

Familyincome,mother’sageatdelivery,mother’sweight

beforepregnancy,averagelevelofparentaleducation,other

maternaldruguseandprenatalpassivesmokeexposure.

Postnatalvariables:sexofthechild,homeenvironment,

mother’spersonality,child’slevelofdepressionandanxiety,

second-handsmokeexposureofthechild,currentmaternal

sociodemographiccharacteristicsandmarijuanauseatthe

timeofchild’stesting

(a)Somemotherscontinuedtousemarijuanaafter

thepregnancy.(b)Datahadextremeunivariate

outliers(zscore>4):2marijuanaandalcohol,one

nicotinevalue

Fried,2000

OPPS

146/190

9-12y

Nouse

Infrequent/moderate(>0-<6

joints/wk)


Cigarettes,alcohol

Averagelevelofparentaleducation,othermaternaldruguse,

prenatalpassivesmokeexposureandsexofthebaby.

Postnatalvariables:homeenvironment,currentsocio-

economicstatus,child’sgenderandtheenvironmental

tobaccosmokeexposureofthechild

(a)Couldnotcategorisemarijuanauseintothree

levelsduetoinadequatecellsize(delineatedinto

heavyuseandinfrequentormoderateornouse).

(b)Unclearwhetherdeficitsobservedinvisuoper-

ceptualtasksareduetotheperceptualdemandsof

thesetestsorduetooneormorenon-perceptual

requirementsthatarenecessaryfortheir

successfulperformance

TABLE 1 (Continued)

(Con

tinue

s)


Aut

hor,

year

St

udy

Sam

ple

size

s (at

fo

llow

- up/

recr

uite

d)

Age

at f

ollo

w- u

pA

naly

ses c

ompa

rison

gro

ups b

y m

ariju

ana

expo

sure

Pren

atal

exp

osur

e to

sub

stan

ces o

ther

than

mar

ijuan

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d ot

her c

ovar

iate

s tha

t ana

lyse

s con

trol

led

for

Stud

y bi

ases

and

lim

itatio

ns (r

epor

ted

by th

e au

thor

s and

add

ition

ally

iden

tifie

d by

the

revi

ewer

s)

Day,1994

MHPCD

672/763

3 y

Averagedailynumberofjoints

(ranges:0-8.8infirsttrimester,

0-6.5insecondtrimesterand

0-9.4inthirdtrimester)

Alcohol,tobacco,amphetamines,tranquilisers,heroin,cocaine

Maternaleducation,currentworkstatus,familyincome,home

environment,numberanddistanceinagebetweensiblings,

maternallevelsof:depression,anxiety,hostility,self-esteem,

mother’sperceptionofhowdifficultthechildwas

(a)Only55%ofthechildrencompletedthe

quantitativereasoningsubscale.(b)Significant

differencesbetweennon-completionandageat

assessmentwerefound,butnotbyprenatal

marijuanaexposure.(c)Theeffectsreportedare

notclinicallysignificantforanindividual

Leech,1999

MHPCD

608/763

6y

Abstainers

>0to<0.4joint/d

0.4to<1joint/d

≥1joint/d


ChildCharacteristics:ageatassessment,gender,numberof

hospitalisations,numberofillnesses,race

EnvironmentalCharacteristics:HomeScreening

Questionnaire,maleinhousehold,maternalwork/school

status

MaternalCharacteristics:Hostility,lifeevents,maternalage

(a)TheContinuousPerformanceTestvariesacross

studiesintermsofmodality(visual,auditory),type

ofstimulus(colour,letter,number,animal)and

difficultyoftask.Itmaynothavebeendifficult

enough,didnotallowcomparisonofdifferent

typesofcommissionerrorsanddidnotincludea

measureofreactiontime.(b)Allsubjectswere

assessedbyStanford-Binettest,butresultswere

notreportedbymarijuanaexposurestatus

Goldschmidt,

2008

MHPCD

648/763

6y

Abstainers/light/

moderate(≥0and<1joint/d)

Heavy(≥1joint/d)

Alcohol,tobacco,amphetamines,tranquilisers,heroin,cocaine.

Maternalvariables:cognitiveability,ageatdelivery,ethnicity,

currentlevelofeducation,income,workstatus,maritalstatus,

depression,hostility,socialsupport,numberoflifeevents

Environmentalvariables:totalnumberofpeopleinthe

household,drugandalcoholproblemsofthemaninthe

household,currenthomeenvironment

Childvariables:sex,nutrition,numberofsiblings,poor

speech/vision/hearing,numberofinjuries,hospitalisations

andillnesses

(a)Thesamplewaspredominantlyoflower

socio-economicstatus

Goldschmidt,

2000

MHPCD

636/763

10 y

Firs

t trim

este

r use

rs:

Abstainers

Light/moderate(0-0.89

joints/d)

Heavy(>0.89joints/d)

Seco

nd-/

third

-trim

este

r use

rs:

Nouse

Lightuse(0-0.4joints/d)

Moderate/heavy(>0.4

joints/d)


Maternalvariables:Numberofyearsofeducation,working/

studyingoutsidethehome,monthlyfamilyincome,race/

ethnicity,presenceofhusbandorboyfriendinthehousehold,

depression,hostilityandnumberofreportedlifeevents

Child’senvironmentvariables:cognitivestimulationand

emotionalsupportprovidedbythechild’sfamily,levelof

overtaggressionamongfamilymembers,numberofsiblings,

childinmaternalcustody,gender,age,numberofillnesses,

numberofinjuries

(a)Mothersreported21children(3.3%)taking

medicationforattentionattention-deficit/

hyperactivitydisorder

TABLE 1 (Continued)

(Con

tinue

s)

| 7SHARAPOVA et Al.

Aut

hor,

year

St

udy

Sam

ple

size

s (at

fo

llow

- up/

recr

uite

d)

Age

at f

ollo

w- u

pA

naly

ses c

ompa

rison

gro

ups b

y m

ariju

ana

expo

sure

Pren

atal

exp

osur

e to

sub

stan

ces o

ther

than

mar

ijuan

a an

d ot

her c

ovar

iate

s tha

t ana

lyse

s con

trol

led

for

Stud

y bi

ases

and

lim

itatio

ns (r

epor

ted

by th

e au

thor

s and

add

ition

ally

iden

tifie

d by

the

revi

ewer

s)

Richardson,

2001

MHPCD

636/763

10 y

Nouse

Light(0-0.4joints/d)

Moderate(>0.4-0.89joints/d)

Heavy(>0.89joints/d)


Maternalvariables:education,monthlyfamilyincome,race

Childcharacteristics:

Age,anxiety,gender,cognitivestimulationandemotional

supportprovidedbythechild’sfamily,uncorrectedvision

problems

(a)Magnitudeofmarijuanaeffectswassmalland

limitedtoonlyafewaspectsoffunctioning.(b)

DifficulttocompareContinuousPerformanceTest

measureofinattentiontoparentalreportsof

inattention.(c)Possiblethatmarijuanaeffectson

theseandadditionaldomainsmaybefoundwhen

thechildrenreach14yofage

Goldschmidt,

2004

MHPCD

636/763

10 y

Light/moderate(<1joints/d)

Heavy(≥1joints/d)


Maternalvariables:age,education,familyincome,presenceof

anadultmaleinthehousehold,ethnicity,workingstatus,

depression,hostility,numberoflifeeventsandsupportfrom

friendsandrelatives

Childcharacteristics:homeenvironment,childinmaternal

custody,numberofsiblings,agebetweenoldestandyoungest

child,child’sgender

(a)Variablessuchasmotivation,socialskillsand

parentinvolvementinchild’seducationwerenot

takenintoaccount.(b)Generalisabilityissome-

whatlimitedascohortislowincomeandonly

womenwhohadreceivedprenatalcare

Faden,2000

NMIHS

8285/9953

3 y

Nouse

<1/m

o 1/

mo

2- 3/

mo

1- 2/

wk

>3/wk

Alcohol,tobacco(cocaineusecollectedbuttooraretobe

analysed)

Birthweight,child’sexactageinmonths,child’ssex,mother’s

race,mother’slevelofeducationandmother’sHispanicstatus

(a)Parentalreportandself-reportofmarijuanause

maycausereportingbias.(b)Biasedestimatesof

effectsfromexposure—importantcovariatesleft

outorincorrectlymodelledintheregression

analysis.

Noland,2003

Prenatal

coca

ine

exposurestudy

316/415

4 y

Exposed

Unexposed

No/lightuse

Heavieruse(>5jointsper

wee

k)

Cocaine,alcohol,tobacco

Race,gender,birthmothercharacteristics(age,education,

verbalability,blockdesignandpicturecompletion,SES,

psychiatricsymptomsandmaritalstatus),andcurrent

caregivercharacteristics(education,verbalability,block

designandpicturecompletion,SES,psychiatricsymptoms,

maritalstatusandHOMEinterview)

(a)Prenatalmarijuanaexposureeffectonspeeded

andorganisedrespondingmaynotbeapparent

untilsubsystemdevelopsmorefully.(b)Atypical

levelsofgestationalstressassociatedwithsample

maylimitgeneralisability

Noland,2005

Prenatal

coca

ine

exposurestudy

330/

415

4 y

Exposed

Unexposed

No/lightuse

Heavieruse(>5jointsper

wee

k)

Cocaine,alcohol,tobacco

Gender,AfricanAmericanethnicityofbirthmother,maternal

ageatbirth,parity,prenatalcarevisit(s),maternalyearsof

education,maritalstatus,lowsocio-economicstatus,

biologicalandcurrentcaregivermentalfunctioningvariables

(a)Prenatalsubstanceexposureaccountsforavery

smallpercentofthevarianceinperformance

TABLE 1 (Continued)

(Con

tinue

s)


Aut

hor,

year

St

udy

Sam

ple

size

s (at

fo

llow

- up/

recr

uite

d)

Age

at f

ollo

w- u

pA

naly

ses c

ompa

rison

gro

ups b

y m

ariju

ana

expo

sure

Pren

atal

exp

osur

e to

sub

stan

ces o

ther

than

mar

ijuan

a an

d ot

her c

ovar

iate

s tha

t ana

lyse

s con

trol

led

for

Stud

y bi

ases

and

lim

itatio

ns (r

epor

ted

by th

e au

thor

s and

add

ition

ally

iden

tifie

d by

the

revi

ewer

s)

Bennett,2008

Developmental

effectsof

prenatal

substance

exposurestudy

185/

231

4,6and9y

0joints/d

0.

01- 0

.5/d

0.

51- 1

/d

>1/d

Cocaine,alcohol,cigarettes,

opiates,phencyclidine,tranquilisers,amphetamines,

barbiturates

Environmentalrisk,maternalverbalintelligence,genderand

neonatalhealthproblems

(a)Mainfocusofstudywascocaineexposure.(b)

Maternalmarijuanausewasassociatedwith

cocaine,alcoholandtobaccouse.(c)Resultsare

notgeneralisableasstudyenrolledaconvenience

sampleofurban,predominantlyAfricanAmerican

andlowsocio-economicstatuspopulation.(d)

Otherenvironmentalfactorsmayhaveaffected

children’sIQbutwerenotcontrolledforinthis

study

Carmody,2011

Developmental

effectsof

prenatal

substance

exposurestudy

210/

321

6,9and11y

Joints/d(range0.022-0.497)

Cocaine,alcohol,cigarettes,opiates,phencyclidine,tranquilis-

ers,amphetamines,barbiturates

Environmentalrisk,medicalcomplicationsandgender

(a)Mainfocusofstudywascocaineexposure.(b)

Maternalmarijuanausewasassociatedwith

cocaine,alcoholandtobaccouse.(c)Resultsare

notgeneralisableasstudyenrolledaconvenience

sampleofurban,predominantlyAfricanAmerican

andlowsocio-economicstatuspopulation.(d)

Otherenvironmentalfactorsmayhaveaffected

children’sIQbutwerenotcontrolledforinthis

study

Chakraborty,

2015

IDEAL

165/170

4.5

yFrequencyofuse(daysper

wee

k):

<1

1- 4

5-7

Amountofdrug(jointper

occasion):

Light(<1)

Moderate(1-2)

Heavy(>2)

Methamphetamine,nicotine,alcohol

Sex,ethnicity,stereoacuity,visualacuityandverbalIQ

(a)Resultscannotbeextrapolatedbeyondglobal

motionperceptionorinterpretedasmarijuana

havingbeneficialeffectsonfoetaldevelopment.

(b)Averagemotioncoherencethresholdsreported

fornon-drugexposedchildrenareslightlyelevated

(worse)comparedtopreviousstudiesofglobal

motionperceptioninpreschoolchildren.(c)Study

hasasmallsamplesizeinwhichthemajorityof

participantswerepolydrugusers

IDEAL,InfantDevelopment,EnvironmentandLifestylestudy,NewZealand;IQ,Intelligencequotient;MHPCD,MaternalHealthPracticesandChildDevelopmentProject,USA,Pennsylvania;NMIHS,

NationalMaternalandInfantHealthSurvey,USA;OPPS,OttawaPrenatalProspectiveStudy,Canada.

TABLE 1 (Continued)

| 9SHARAPOVA et Al.

wasdefinedasassociationbetweenprenatalmarijuanaexposureand enhanced neuropsychological function (eg, higher score forattention and lower score for impulsivity). High heterogeneityof assessment tools, analytical approaches and reported effectsizesprecludedaquantitativeassessmentofpublicationbiasandmeta-analysis.

3 | RESULTS

Twenty-onearticleswereeligibleforreviewandanalysis (Table1);the review process determined that these articleswere based ondata from 7 distinct longitudinal studies. There were 4 US stud-ies: Maternal Health Practices and Child Development Project(MHPCD;1982-1997) inPennsylvania,astudyofprenatalcocaineexposure in Ohio (1994-2003), a study of developmental effectsof prenatal substance exposure in New Jersey and Pennsylvania(1993-2004) and theNationalMaternal and Infant Health Survey(NMIHS;1988-1991).Theother3studiesincludedweretheOttawaPrenatalProspectiveStudy(OPPS;1978-1995)inCanada;theInfantDevelopment,EnvironmentandLifestyleStudy(IDEAL;2001-2008)inNewZealand;andastudy inJamaica (1983-1990).All thestud-ieswereofhighquality(ranked7-9outofninestars)basedontheNewcastle-OttawaScale(Table2).38

Each of the seven studies utilised a variety of instrumentsto assess children’s neuropsychological outcomes (Table3).Instrumentsvaried fromveryspecific,measuringonlyone func-tion (eg, pegboard testmeasuringmanual dexterity) to complexmultiscale tools assessing intelligence and various cognitive do-mains(eg,Stanford-BinetIntelligenceScalemeasuringintelligencequotient (IQ), memory, visual reasoning, quantitative reasoningand verbal reasoning). Six studies applied one of the commonlyused comprehensive intelligence or academic achievement testsadministeredby trainedprofessionalswhowereblinded to chil-dren’sprenatalhistory.Thetestsincludedthefollowing:WechslerIntelligenceScaleforChildren(WISC)(OPPS,IDEALandprenatalcocaine exposure study);39 the Stanford-Binet Intelligence Test(MHPCDanddevelopmentaleffectsofprenatalsubstanceexpo-surestudies);40theMcCarthyScalesofChildren’sAbilities(OPPS,Jamaica study and prenatal cocaine exposure study);41 and theWideRangeAchievementTest(OPPSandMHPCD).42Onestudy(NMIHS) relied only on parental reports based on the Denver

DevelopmentalScale.43

Most analyses found no associations between prenatal mari-juanaexposureandchildren’soutcomesorfoundassociationsthatwere significant in bivariate analyses but not in adjusted analyses(Table3).Table1 listscomparisongroupsandcovariates thateacharticleusedforadjustedanalyses.

3.1 | Ottawa prenatal prospective study

EightofthearticlesreportedonresultsofOPPS(Tables1-3).Thiswasa longitudinalstudyof theeffectsofprenatalmarijuana,cigarette

andalcoholuseinoffspringinamostlylow-risk,middle-classpopu-lationof theOttawaarea,Ontario,Canada.44-51Recruitment tookplace through advertisement in media and obstetricians’ offices.Analysesofthechildrenatages1and2yearsfoundnoassociationsbetweenprenatalmarijuanaexposureandcognitiveoutcomes,butfound that prenatal marijuana use was associated (P<0.05) withhigher scores on the 1-year-old Primary Composite score of theInfant Behavior Record that assessed interests and attitudes (ie,thatchildrenexposedinuterohadhigherdevelopmentallevelsthanchildrenwhowerenotexposed).44Atages3and4years,McCarthyquantitativescoreswereloweramongchildrenwithheavyprenatalmarijuanaexposurebeforeadjustmentforconfounding,butmoder-atemarijuanaexposurecorrelatedwithsuperiormotorperformanceon the McCarthy test, even after adjustment for confounders.45 Therewerenodifferencesonaseriesofcognitivetasks(eg,mem-ory,verbalandperceptualscores)between5-and6-year-oldchil-drenwithandwithoutprenatalmarijuanaexposure.46,47Forchildrenaged 6-9years, there was no statistically significant relationshipafteradjustmentbetweenprenatalmarijuanaexposureandparen-talratingsofbehaviourproblems,visual-perceptualtasks,languagecomprehensionordistractibility.48Prenatalmarijuanaexposurewasnotassociatedwithdeficitsinreading,languageorpsychometricallydetermined intelligence in children aged 9-11years.49,50 Prenatalmarijuanaexposurewasnegativelyassociatedwithperformanceinvisualproblem-solvingsituationsasmeasuredbyWISCPerceptualOrganization Index in children aged 9-11years.51 The PerceptualOrganization Indexassessesnon-verbal reasoningandhypothesestestingdrawinguponvisual-perceptualskills.

3.2 | Maternal health practices and child development project

MHPCD findings were reported in six articles (Tables1-3).52-57 Participants in MHPCD were women of lower socio-economicstatus, recruited from an outpatient prenatal clinic in Pittsburgh,Pennsylvania.Day etal52 found no associations between prenatalmarijuana exposure and the Stanford-Binet Intelligence Test per-formanceatage3years.Goldschmidtetal53foundheavyprenatalmarijuanausestatisticallysignificantlyassociatedwithlowerverbalandquantitativereasoningandwithdecreasedshort-termmemoryat age 6years. Leech etal54 found a statistically significant nega-tiveassociationbetweenprenatalmarijuanaexposureandmeasuresof impulsivityatage6yearsusingacontinuousperformancetask,butapositiveassociation (P<0.05)withattentionusingthissametask. At age 10years, therewere associations (P<0.05) betweenprenatal exposure tomarijuana and child behaviour problems andschoolachievements.Specifically,firstandthird-trimesterexposuretomarijuanawasassociatedwith increasedhyperactivity, inatten-tion and impulsivity, and heavy second and third-trimester expo-surewas associatedwith increased delinquency and externalisingbehaviour problems.55 Associations were reported between first-trimester prenatal marijuana exposure and lower predicted read-ing and spelling scores, and between second trimester exposure


TABLE 2 Newcastle-Ottawascaleassessmentoftheeligiblestudies

# (by study/year of publication)Star categories 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

Study or location Jamaica OPPSa MHPCDa NMIHS OHa NJ/PAa IDEAL

Author, year Hayes, 1991Fried, 1988

Fried, 1990

Fried, 1992

Fried, 1992

O’Connell, 1991 Fried, 1997

Fried, 1998

Fried, 2000

Day, 1994

Leech, 1999

Goldschmidt, 2008

Goldschmidt, 2000

Richardson, 2001

Goldschmidt, 2004

Faden, 2000

Noland, 2003

Noland, 2005

Bennett, 2008

Carmody, 2011

Chakraborty, 2015

1)Representativenessoftheexposedcohort

a)Trulyrepresentativeoftheaveragedemograph-icsinthecommunity

* *

b)Somewhatrepresentativeoftheaveragedemographicsinthecommunity

* *(Rurallowerincome community)

*(Lowerincomepopulation) *(Lowerincome) *(Lowerincomeand education)

c)Selectedgroupofusers,forexamplenurses,volunteers

Volunteersrespondingtoadvertisementofthestudy,low-risksample Volunteers

d)Nodescriptionofthederivationofthecohort

2)Selectionofthenon-exposedcohort

a)Drawnfromthesamecommunityastheexposedcohort

* * * * * * * *

b)Drawnfromadifferentsource

c)Nodescriptionofthederivationofthenon-exposedcohort

3)Ascertainmentofexposure

a)Securerecord(eg,surgicalrecords) * *b * * *

b)Structuredinterview * * * *

c)Writtenself-report

d)Nodescription

4)Demonstrationthatoutcomeofinterestwasnotpresentatstartofstudyc

a)Yes * * * * * * * *

b)No

Comparability

1)Comparabilityofcohortsonthebasisofthedesignoranalysis

a)Studycontrolsfor_exposuretotobacco_ * * * * * * * *

b)Studycontrolsforanyadditionalfactor * * * * * * * *

Outcome

1)Assessmentofoutcome

a)Independentblindassessment * * * * * * * *

b)Recordlinkage *

c)Self-report

d)Nodescription

2)Wasfollow-uplongenoughforoutcomestooccur?

a)Yes * *(5y) *(1-2y) *(3-4y) *(5-6y) *(6y) *(6-9y) *(9-12y) *(9-12y) *(9-12y) *(3y) *(6y) *(6y) *(10y) *(10y) *(10y) *(3y) *(4y) *(4y) *(4-9y) *(6-11y) 8(4.5y)

b)No

3)Adequacyoffollow-upofcohorts

a)Completefollow-up—allsubjectsaccountedfor * *

b)Subjectslosttofollow-upunlikelytointroducebias—smallnumberlost->80%follow-up,ordescriptionprovidedofthoselost(%)

* *(92) *(88) *(80) *(85) *(83) *(83) *(83) *(83) *(80) *(80) *(97)

c)Follow-uprate<80%andnodescriptionofthoselost(%)

71 70 73 67 77 77 77 76 65

d)Nostatement

Totalscore: 8.5 7 7 7 7 8 7 7 7 9 9 9 9 9 9 9 8 9 8 7 7

IDEAL,InfantDevelopment,EnvironmentandLifestylestudy,NewZealand;MHPCD,MaternalHealthPracticesandChildDevelopmentProject, Pennsylvania,USA;NJ/PA,Developmentaleffectsofprenatalsubstanceexposurestudy,NewJersey/Pennsylvania,USA;NMIHS,NationalMaternal andInfantHealthSurvey,USA;OH,Prenatalcocaineexposurestudy,Ohio,USA;OPPS,OttawaPrenatalProspectiveStudy,Canada.0—Article’sstandinginanassessmentcategory,whennostarisawarded.*Articlehasmetrequirementtobeawardedastar(1scorepoint).aWhenallarticlesbelongingtoasinglestudyreceivedsamescore,thecellswerecombinedtosavespace.bStudyhasmettherequirementtobeawardedthestar,however,thisinformationwasnotinthereviewedarticle,andwasfoundinadifferent publicationthatdidnotmeeteligibilitycriteriaforthisreview(.5scorepoint).cAsoutcomeofinterestisaffectedcognitivedevelopment,allarticleswereawardedstarforthisquestionsinceallstudieshadenrolledparticipantsatbirth.

| 11SHARAPOVA et Al.

TABLE 2 Newcastle-Ottawascaleassessmentoftheeligiblestudies

# (by study/year of publication)Star categories 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

Study or location Jamaica OPPSa MHPCDa NMIHS OHa NJ/PAa IDEAL

Author, year Hayes, 1991Fried, 1988

Fried, 1990

Fried, 1992

Fried, 1992

O’Connell, 1991 Fried, 1997

Fried, 1998

Fried, 2000

Day, 1994

Leech, 1999

Goldschmidt, 2008

Goldschmidt, 2000

Richardson, 2001

Goldschmidt, 2004

Faden, 2000

Noland, 2003

Noland, 2005

Bennett, 2008

Carmody, 2011

Chakraborty, 2015

1)Representativenessoftheexposedcohort

a)Trulyrepresentativeoftheaveragedemograph-icsinthecommunity

* *

b)Somewhatrepresentativeoftheaveragedemographicsinthecommunity

* *(Rurallowerincome community)

*(Lowerincomepopulation) *(Lowerincome) *(Lowerincomeand education)

c)Selectedgroupofusers,forexamplenurses,volunteers

Volunteersrespondingtoadvertisementofthestudy,low-risksample Volunteers

d)Nodescriptionofthederivationofthecohort

2)Selectionofthenon-exposedcohort

a)Drawnfromthesamecommunityastheexposedcohort

* * * * * * * *

b)Drawnfromadifferentsource

c)Nodescriptionofthederivationofthenon-exposedcohort

3)Ascertainmentofexposure

a)Securerecord(eg,surgicalrecords) * *b * * *

b)Structuredinterview * * * *

c)Writtenself-report

d)Nodescription

4)Demonstrationthatoutcomeofinterestwasnotpresentatstartofstudyc

a)Yes * * * * * * * *

b)No

Comparability

1)Comparabilityofcohortsonthebasisofthedesignoranalysis

a)Studycontrolsfor_exposuretotobacco_ * * * * * * * *

b)Studycontrolsforanyadditionalfactor * * * * * * * *

Outcome

1)Assessmentofoutcome

a)Independentblindassessment * * * * * * * *

b)Recordlinkage *

c)Self-report

d)Nodescription

2)Wasfollow-uplongenoughforoutcomestooccur?

a)Yes * *(5y) *(1-2y) *(3-4y) *(5-6y) *(6y) *(6-9y) *(9-12y) *(9-12y) *(9-12y) *(3y) *(6y) *(6y) *(10y) *(10y) *(10y) *(3y) *(4y) *(4y) *(4-9y) *(6-11y) 8(4.5y)

b)No

3)Adequacyoffollow-upofcohorts

a)Completefollow-up—allsubjectsaccountedfor * *

b)Subjectslosttofollow-upunlikelytointroducebias—smallnumberlost->80%follow-up,ordescriptionprovidedofthoselost(%)

* *(92) *(88) *(80) *(85) *(83) *(83) *(83) *(83) *(80) *(80) *(97)

c)Follow-uprate<80%andnodescriptionofthoselost(%)

71 70 73 67 77 77 77 76 65

d)Nostatement

Totalscore: 8.5 7 7 7 7 8 7 7 7 9 9 9 9 9 9 9 8 9 8 7 7

IDEAL,InfantDevelopment,EnvironmentandLifestylestudy,NewZealand;MHPCD,MaternalHealthPracticesandChildDevelopmentProject, Pennsylvania,USA;NJ/PA,Developmentaleffectsofprenatalsubstanceexposurestudy,NewJersey/Pennsylvania,USA;NMIHS,NationalMaternal andInfantHealthSurvey,USA;OH,Prenatalcocaineexposurestudy,Ohio,USA;OPPS,OttawaPrenatalProspectiveStudy,Canada.0—Article’sstandinginanassessmentcategory,whennostarisawarded.*Articlehasmetrequirementtobeawardedastar(1scorepoint).aWhenallarticlesbelongingtoasinglestudyreceivedsamescore,thecellswerecombinedtosavespace.bStudyhasmettherequirementtobeawardedthestar,however,thisinformationwasnotinthereviewedarticle,andwasfoundinadifferent publicationthatdidnotmeeteligibilitycriteriaforthisreview(.5scorepoint).cAsoutcomeofinterestisaffectedcognitivedevelopment,allarticleswereawardedstarforthisquestionsinceallstudieshadenrolledparticipantsatbirth.


TABLE 3 Scopeofdiagnostictestsandoutcomesintheeligiblestudies

Diagnostic instrument Outcomes measured

Reported associations with prenatal marijuana exposure a

Age at assessment

Article (Study, first author, year)

BayleyScaleofInfantDevelopment

MentalDevelopmentIndex:sensory/perceptualabilities,acquisitionofobjectconstancy,memory,learning,problem-solving,vocalisationandbeginningofverbalcommunicationPsychomotorDevelopmentIndex:degreeofbodycontrol,largemusclecoordination,finermanipulatoryskillsofthehandsandfingers,dynamicmovement,posturalimitationandtheabilitytorecogniseobjectsbysenseoftouch(stereognosis)

Nosignificantassociations

1 and 2 y OPPS,Fried,1988

InfantBehaviorRecord PrimaryCognitionCompositeScore:objectorientation,goaldirectedness,attentionspan,reactivityandvocalisation

Positiveassociation 1 y OPPS,Fried,1988

Noresultsreported 2 y OPPS,Fried,1988

ExtraversionScore:socialorientationtotheexaminer,cooperativeness,andgeneralemotionaltoneVisualandauditorysensorysystems

Noassociations 1 and 2 y OPPS,Fried,1988

ReynellDevelopmentalLanguageScale

Comprehension Negativeassociation 2 y OPPS,Fried,1988

Expression Noassociations 2,3and4y OPPS,Fried,1988;1990

DenverDevelopmentalScale

Grossmotordevelopment Negativeassociation 3 y NMIHS,Faden,2000

Adaptivefunctioning,languageandfinemotordevelopment

Noassociations

McCarthyScalesofChildren’sAbilities

GeneralCognitiveIndex(memory,verbaldevelopment,perceptionandquantitativeabilities)

Noassociations 3 y OPPS,Fried,1990

Negativeassociation 4 y OPPS,Fried,1990

Noassociations 4,5and6y Jamaicastudy,Hayes,1991;OPPS,Fried,1992

Motorperformancescore Positiveassociationinmoderatelyexposedchildrencomparedtounexposedandheavilyexposed

3 y OPPS,Fried,1990

Noassociations 4,5and6y OPPS,Fried,1990;1992;Jamaicastudy,Hayes,1991

Memoryscore Noassociations 3 y OPPS,Fried,1990



Verbalscore Noassociations 3 y OPPS,Fried,1990



Quantitativescore Negativeassociation 3 y OPPS,Fried,1990

Noassociations 4 y OPPS,Fried,1990


Perceptualscore Noassociations 3 y OPPS,Fried,1990



(Continues)


TABLE 3 (Continued)



Age at assessment


McCarthyScalesofChildren’sAbilitiessubsetadaptedforusewithchildren3-12yofage,truncated.

Categoryfluency(languagedevelopment) Noassociations 4 y Prenatalcocaineexposurestudy,Noland,2003

Stanford-BinetIntelligenceScale,4Ed

Compositescore(IQ) Negativeassociation 3 y MHPCD,Day,1994

Noassociations 4,6and9y Developmentaleffectsofprenatalsubstanceexposurestudy,Bennett,2008

Notreported 6y MHPCD,Leech,1999

Negativeassociation 6y MHPCD,Goldschmidt,2008

Short-termmemory Negativeassociation 3 y MHPCD,Day,1994



Verbalreasoning Negativeassociation 3 y MHPCD,Day,1994



Quantitativereasoning Noassociations 3 y MHPCD,Day,1994



Abstract/visualreasoning Negativeassociation 3 y MHPCD,Day,1994


Noassociations 6y MHPCD,Goldschmidt,2008

WechslerPreschoolandPrimaryScaleofIntelligence,III

VerbalIQ,attention Notreported 4 y Prenatalcocaineexposurestudy,Noland,2003;2005

Noassociations 4.5 y IDEAL,Chakraborty,2015

FingersequencingtaskadaptedbyWelshforusewithchildren.

Motorplanning Noassociations 4 y Prenatalcocaineexposurestudy,Noland,2003

Pegboardtest Manualdexterityandbimanualcoordination Noassociations 4 y OPPS,Fried,1990

Picturedeletiontaskforpreschoolers-modified(Corkum)

Attention Non-significantnegativeassociation

4 y Prenatalcocaineexposurestudy,Noland,2005

(Continues)




Age at assessment


TactileFormRecognitionTask

Stereognosis Noassociations 4 y OPPS,Fried,1990

TappingInhibition(testoffrontallobefunctioning(Luria)adaptedbyDiamondandTaylorforusewithchildren3.5through7yofage)

Inhibitorycontrol(Abilitytooverridetheirnatural,habitualordominantbehaviouralresponsetoastimulusinordertoimplementmoreadaptivegoal-orientedbehaviours)

Noassociations 4 y Prenatalcocaineexposurestudy,Noland,2003

PeabodyPictureVocabularyTest

Vocabulary Negativeassociation 4 y OPPS,Fried,1990

Noassociations 5,6and9-12y

OPPS,Fried,1992;1997

RandomDotKinematograms

Globalmotorperception(higherlevelprocessinginvisualcortex)

Positiveassociationinchildrenwhowerenotprenatallyexposedtoalcohol.

4.5 y IDEAL,Chakraborty,2015

ConnersParentQuestionnaire

Impulsivityhyperactivity Non-significantnegativeassociation

6y OPPS,Fried,1992

Noassociations 6-9y OPPS,O’Connell,1991

Hyperactivityindex,learningproblemsandpsychosomaticproblems

Noassociations 6-9y OPPS,O’Connell,1991

Anxiety,conductproblems Non-significantnegativeassociation

6-9y OPPS,O’Connell,1991

GordonDiagnosticSystem

Sustainedattentionandself-control Negativeassociation 6y OPPS,Fried,1992

Impulsivity Negativeassociation 9-12y OPPS,Fried,1998

ContinuousPerformanceTask

Errorsofcommission(impulsivity) Notreported 4 y Prenatalcocaineexposurestudy,Noland,2005

Negativeassociation 6and10y MHPCD,Leech,1999;Richardson,2001

Errorsofomission(inattentiveness) Notreported 4 y Prenatalcocaineexposurestudy,Noland,2005

Positiveassociation 6y MHPCD,Leech,1999

TheSentenceMemoryTest

Immediateauditorymemoryandauditoryattentionforsentences

Noassociations 6y OPPS,Fried,1992

TheTargetTest Visual-spatialmemory Noassociations 6y OPPS,Fried,1992

TheYaleChildStudyCenterAttentionTask

Attentionandinhibitorycontrol Noassociations 6,9,and11 y

Developmentaleffectsofprenatalsubstanceexposurestudy,Carmody,2011

TestofVisual-PerceptualSkills

PerceptualQuotient,VisualDiscrimination,VisualSequentialMemory

Non-significantnegativeassociation


Noassociations 9-12y OPPS,Fried,2000

VisualClosure,VisualFigureGround,VisualFormConstancy,VisualMemoryandVisualSpatialRelations

Noassociations 6-9and9-12y

OPPS,O’Connell,1991;Fried,2000

TrailMakingTest Visualscanning,visuospatialsequencing,attention,mentalflexibilityandmotorfunction




TABLE 3 (Continued)

(Continues)




Age at assessment


WideRangeAchievementTest-revised

Reading,arithmetic,spelling Noassociations 6-9y OPPS,O’Connell,1991

Negativeassociation 10 y MHPCD,Goldschmidt,2004

Reading Noassociations 6-9and9-12y


KnoxCubeTest Visualattention,visualmemoryandvisualsequencing

Noassociations 6-9and9-12y


WoodcockReadingMasteryTest

Passagecomprehension Noassociations 6-9and9-12y


BeeryDevelopmentalTestofVisualMotorIntegration

Visualmotorintegration(copygeometricformsintoanotepad)




Draw a man Intelligence(scoreisbasedondetail,proportionandcoordination)



Fingertapping Motorcontrol,speedandlateralcoordination Nosignificantassociations


StroopInterference Teststheabilitytosortandselectivelyreacttoinformation:forexample,word“red”isprintedingreenink.Thechildmustsayloudlythecolourofthetextandnottheword.



TestofLanguageDevelopment(Primarysyntaxquotientscore)

Abilitytogenerateacceptablesentences Non-significantnegativeassociation


AuditoryWorkingMemory

Workingmemory Non-significantnegativeassociation

9-12y OPPS,Fried,1998

CategoryTest Problem-solvingcapacity Negativeassociation 9-12y OPPS,Fried,1998

FluencyTest Verbalfluency(numberofwordsstartingwith“C”and“P”producedin60sec)

Noassociations 9-12y OPPS,Fried,1997;1998

OralClozeTask AbilitytounderstandthebasicgrammaticalstructureofEnglishbasedonauditoryprocess


PseudowordTask Readinganddecodingabilities Non-significantnegativeassociationinchildrenwithmoderateexposurecomparedtochildrenwithnoorheavyexposure


SeashoreRhythmTest Rhythmdiscrimination Noassociations 9-12y OPPS,Fried,1997

TactilePerformanceTask

Motorabilitiesandmotormemory(blind-folded,placewoodenblocksintoproperlyshapedholes)


TABLE 3 (Continued)

(Continues)




Age at assessment


WechslerIntelligenceScaleforChildren,3rded.

Full-scaleIQ Noassociations 6-9and9-12y

OPPS,O’Connell,1991;Fried,1997;1998;2000

Information Noassociations 9-12y OPPS,Fried,1997



VerbalIQ,VerbalComprehensionIndex Noassociations 6-9and9-12y

OPPS,O’Connell,1991;Fried,1997;1998

Similarities,Vocabulary Noassociations 9-12y OPPS,Fried,1997;1998

PerformanceIQ Noassociations 6-9and9-12y


Arithmetic,ProcessingSpeedIndex Noassociations 9-12y OPPS,Fried,1998

FreedomfromDistractibilityIndex Noassociations 6-9and9-12y

OPPS,O’Connell,1991;Fried,1998;2000

Coding(discriminationandmemoryofvisualsymbols);SymbolSearch(visualscanning)andDigitSpan(memory)

Noassociations 9-12y OPPS,Fried,1998;2000

Comprehension Negativeassociation 9-12y OPPS,Fried,1998

Mazes(rudimentaryplanning) Negativeassociation 9-12y OPPS,Fried,1998


PerceptualOrganizationIndex(asummaryindexofpicturecompletion,picturearrangement,blockdesign,andobjectassembly)

Noassociation 6-9and9-12y


Negativeassociation 9-12y OPPS,Fried,2000

ObjectAssembly Negativeassociation 9-12y OPPS,Fried,1998;2000

BlockDesign Negativeassociation 9-12y OPPS,Fried,1998;2000

PictureArrangement Noassociations 9-12y OPPS,Fried,1998;2000

PictureCompletion Noassociations 9-12y OPPS,Fried,1998;2000

ChildBehaviorChecklist

Attentionproblems Noassociations 10 y MHPCD,Goldschmidt,2000

Severediscrepancybetweenability(Stanford-BinetIntelligenceScale,4ed.)

Underachieving Negativeassociation 10 y MHPCD,Goldschmidt,2004

Swanson,Noland,andPelhamAssessment

Impulsivity,hyperactivity,inattentionsymptoms

Negativeassociation 10 y MHPCD,Goldschmidt,2000

Teacher’sReportForm Attentionproblems Noassociations 10 y MHPCD,Goldschmidt,2000

Teacher’sassessmentofthechildinlanguagearts,history,math,andscience

Educationalperformance Negativeassociation 10 y MHPCD,Goldschmidt,2004

PeabodyIndividualAchievementTest-revised

Readingcomprehension Negativeassociation 10 y MHPCD,Goldschmidt,2004

TABLE 3 (Continued)

(Continues)


anddeficitsinreadingcomprehensionandunderachievement,allatage10years (P < 0.05).56AsimilaranalysisbyRichardsonandcol-leagues57 suggested that prenatalmarijuanaexposurewas associ-atedwithincreasedimpulsivityin10-year-oldsbasedoncontinuousperformancetask.

3.3 | Prenatal cocaine exposure study

Two eligible articles used data from a longitudinal prospectivestudyofthedevelopmentaleffectsofprenatalcocaineexposureconducted inOhio (Tables1-3).58,59 Study participantswere pa-tientsofa largeurbanhospitalwhohadclinical indicationsof il-licitdruguseandhadnoprivatehealthinsurance.Atage4years,therewas no relationship between prenatalmarijuana exposureandperformanceonthetappinginhibitiontest,ameasureofabil-itytoresistactingimpulsively;58however,heavierprenatalmari-juanausewasassociatedwithlowerabilitytomaintainsustainedattention.59

3.4 | Developmental effects of prenatal substance exposure study

Twoarticlesreportedonresultsofthestudyofdevelopmentalef-fects of prenatal substance exposurewith the focus onmaternalcocaineuse.Thisstudyrecruitedwomenfromhospital-basedpre-natalclinicsorhospitalsinTrenton,NJ,orattheMedicalCollegeofPennsylvaniaHospital inPhiladelphia,PA (Tables1-3).60,61Neitherarticle found statistically significant associations between mari-juanaexposureandchildIQ,attentionorimpulsivityatages6,9and11years.60,61

3.5 | Jamaica study

Onearticleexamineddatafromalongitudinalstudyofchildrenborntomothers living inruralareasofJamaicaandhaving lowincome.Thewomenwere recruited through fieldworkwith the assistance

of nurses from the JamaicanMinistry of Health antepartum clin-ics (Tables1-3).62Thisstudydifferedfromtheothersasmarijuanausewas not confounded by use of other substances. In a sampleof 4- and 5-year-olds, Hayes and colleagues62 found no associa-tionbetweenprenatalmarijuanaexposureandMcCarthyScalesofChildren’sAbilities scoresmeasuring IQ,memory, verbal develop-ment,perceptionandquantitativeabilities.

3.6 | National maternal and infant health survey

OnearticlebyFadenandcolleaguesanalyseddatafromNMIHS.63 Thislongitudinalfollow-upsurveywasconductedbytheCentersforDiseaseControl and Prevention. The survey sampled participantsfromlivebirthsoccurringin1988,basedonraceand/orbirthweightstrata, to look at poor pregnancy outcomes.64 Women from the1988 surveywere re-contacted and interviewed in 1991. Faden’sstudydifferedfromtheothersincludedinthisreviewaschildout-comewasdeterminedbyself-reportfromthemothersviadetailedquestionnairesmailed after the birth andwhen the child reachedage3yearsratherthanbydirectassessment(Tables1-3).63Prenatalmarijuana use was associated with increased fear, poorer grossmotordevelopmentandshorterlengthofplayatage3years,whichimpededoverallabilitytogetalongwithpeers.63

3.7 | Infant development, environment and lifestyle (IDEAL) study

IDEAL is a prospective, controlled longitudinal study of prenatalmethamphetamineexposurefrombirthto36months,conductedintheUnitedStatesandNewZealand(Tables1-3).65Independentandhospital-based midwives recruited mothers. Among 4.5-year-oldsfromtheNewZealandstudypopulation,prenatalmarijuanaexpo-surewasfoundtobeassociatedwithimprovedglobalmotionper-ception compared to non-exposed children (P = 0.001).66 Globalmotionperceptionisabilitytorecognisespeedanddirectionofmov-ingobjectsandislinkedtocognitiveskillsandsocialcompetence.67



Age at assessment


WideRangeAssessmentofMemoryandLearning

Designmemory,screeningindex Negativeassociation 10 y MHPCD,Richardson,2001

Storymemory,verballearning Noassociation 10 y MHPCD,Richardson,2001

aNegativeassociationsweredefinedasstatisticallysignificantassociationinanalysesadjustedforpotentialconfoundersbetweenprenatalmarijuanaexposureanddiminishedneuropsychologicalfunction,forexamplelowerscoresonreadingcomprehensionormemory;orhigherscoresonerrors,impulsivity, inattention,orunderachievement (P<0.05), regardlessof thetrimesterofexposure.Positiveassociationsweredefinedasstatisticallysignificantassociations inadjustedanalysesbetweenprenatalmarijuanaexposureandenhancedneuropsychological function, forexamplehigherscoresonreadingcomprehensionormemory;or lowerscoresonerrors, impulsivity, inattention,orunderachievement(P<0.05),regardlessofthetrimesterofexposure.Non-significantnegativeandpositiveassociationsweredefinedas statistically significantnegativeorpositiveassociationsfoundinbivariateanalysesbutnotinadjustedanalyses(P≥0.05).Noassociation—theanalysesdidnotfindassociationsbetweenprenatalmarijuanaexposureandneuropsychologicalfunctionsinbivariateandadjustedanalyses.

TABLE 3 (Continued)


4 | COMMENT

4.1 | Principal findings

Among the21 reportscompleted fromseven longitudinal studies,resultsvariedontheassociationbetweenprenatalmarijuanaexpo-sure and child’s neuropsychological functioning. Several analysesfound statistically significant associations between prenatal mari-juanaexposureandbothdecreasedandincreasedneuropsychologi-calfunctions,whileothersfoundnosignificantassociations.Thesefindingsindicatethatthespecificeffectsofprenatalmarijuanaex-posureremainunclear.However,whilemoreresearchiswarrantedtoclarifythespecificeffectsofprenatalmarijuanaexposure,thereweremore instancesofnegativethanpositiveassociationsamongthearticles,suggestingthatexposuretomarijuanamaybeharmfultoneuropsychologicalfunctioning.18-21

The analyses that found positive associations suggested im-provedaspectsofattentionandperceptiveabilitiesinexposedchil-dren aged1-6years.While the positive findingswere statisticallysignificant,itisimportanttonotethatcognitivetestingonchildrenaged≤5yearsistypicallynotasreliableastestingperformedwhenchildrenareolderandbetterabletocommunicateandunderstandthetaskspresentedtothem.68,69 Incontrast, thesignificantnega-tiveassociationsweremostlydrawn from testingof childrenover6yearsold,andthemajorityofstudieswithoutstatisticallysignifi-cantresultsstillshoweddecreaseinneuropsychologicalfunctions.These results suggest some potential adverse effects of prenatalmarijuanaexposureonattentionandperceptiveabilities,inadditiontodecreasedgeneralcognitive function,memory, impulsecontrol,IQandreadingcomprehensionespeciallyinchildrenaged>6years.

4.2 | Strengths of the study

Whilethemajorityofdataonprenatalmarijuanaexposureandneu-ropsychologicaloutcomes inchildrencomefromonlya few longi-tudinalstudies,theyaremethodologicallysound,withstandardisedoutcomeassessment, andhigh response andparticipant retentionrates.44-63,66,70,71 Each study provides some higher level measureofthemarijuanaexposure:asaveragemarijuanauseperday/week(MHPCD,NMIHSanddevelopmentaleffectsofprenatalexposurestudy) or smoking frequency (OPPS, prenatal cocaine study andIDEAL).Onestudyadditionallyprovidedtimingoftheexposurebytrimesterofpregnancy(MHPCD).Thesemeasuresalloweddistinc-tionofadose-responserelationshipofmarijuanause.Heavymari-juanausehadstrongerassociationsandlargereffectsizescomparedtomoderateandlightuse.45,53,55

4.3 | Limitations of the data

However, despite these strengths, all of the studies used in thisreviewweresubjecttoseveral limitations.First,concurrentuseofothersubstanceswaspresentamongstudyparticipants,exceptthesingleJamaicanstudyofparticipantswhousedmarijuanaalmostex-clusively.62,72Tobaccoandalcoholwerethemostfrequent.Prenatal

nicotine exposure is a knowndeterminantof negativehealthout-comesforchildrenandtendstobeasignificantconfounderformari-juana research.69,73 Smoking tobacco during pregnancy can causetissuedamageaffectingfoetalbraindevelopmentandhasbeenas-sociatedwithnegativebehaviouralandcognitiveoutcomesthrough-out the lifetime, including conduct disorder, attention-deficit/hyperactivity disorder, poor academic achievement and cognitiveimpairment.74-77Alcoholusemayalsobea sourceof confoundingin this research, as foetal alcohol spectrumdisorders (FASDs) cancause a variety of physical and cognitive impairments.78 Prenatalalcohol exposure is associated with deficits in memory, attentionspan,verballearning,motorfunctionandaloweroverallIQ.79Theprenatal cocaine exposure study and the developmental effectsofprenatalsubstanceexposurestudyexaminedconcurrentuseofcocaine, and the IDEAL study examinedmethamphetamine. Onlythree articles reported that self-reporteddrugusewas confirmedbytoxicologytests.58,59,61Whileallofthearticlesinthereviewat-temptedtocontrolforothersubstancesuseintheiranalyses,varia-tioninmeasurementsofothersubstanceexposures,suchastobaccouse,may skewoutcomes attributable tomarijuana, and statisticalcontrolsmightnotaccountforallpotentialconfoundingoftheothersubstancessincetheinteractiveeffectsofexposurestodifferentormultiplesubstancesarenotfullyunderstood.

A second limitation is not controlling for postnatal maternalmarijuana use and thus potentiallymixing effects of prenatal andpostnatalexposures.Only6ofthereviewedarticlesexplicitlystatedadjustinganalysesforpostnatalmaternalmarijuanause.49,50,54,55,58,59 Fivemorearticles listedpostnatalmaternalmarijuanauseasapo-tentialconfounderthatdidnotmeetrequirementsforinclusionintofinalanalyticmodels.51-53,56,57However,infutureresearchpostnatalmaternalmarijuanausemightbebetterconceptualisedasamedi-ator rather than a confounder. Temporal and causal relationshipsbetweenprenatalandpostnatalmaternalmarijuanauseprenatallyandneuropsychologicalfunctioninginchildrenareplausibleforme-diationconceptualisation.

A third limitation is the potential for bias arising from sampleselectionandresponse.Forexample,theMHPCDstudyconsistedofmostly low-incomewomen and theOPPS study consisted of alow-risk predominantly middle-class sample. Moreover, with theexceptionofNIMS,nosampleswererepresentativeofthegeneralUSpopulation.Additionally,thepregnanciestookplacewhenrecre-ationalusewasillegalandmedicinalusewasillegalinthelocationsofdatacollection,thuspotentiallyresultinginunder-reporting.

A fourth limitation ispublicationbiasduetopossibleselectivepublicationofresults.Morespecifically,comparabilityofthetestre-sultsislimitedbyseveralfactors,includingthefactthattestswereadministered selectively utilising subscales and adaptations in dif-ferentagegroups,andtestresultswerenotreportedinaconsistentmanner.Moreover,atleastthreestudiesconductedWISC;however,notallpresentedtheresultsofthisparticulartestinassociationwithmarijuanaexposure.PublishingWISCmeasuresfromallormostoftheanalyseswouldhaveallowedforanindividualpatientdata(IPD)meta-analysis. Employing IPD meta-analysis would have enabled


researchers tomore reliably compare individual outcomes of pre-natalmarijuanaexposureacrossthedifferentstudies,independentofthespecificintentofthe21publishedworks.80Finally,wewereunabletoconductaformalassessmentofpublicationbiasduetotheheterogeneityofthedata.However,aswithanysystematicreview,issuesofpublicationbiasmayhave influenced the results and ledto overestimates of effect.Althoughwe allowed for the inclusionofnon-peer-reviewedpapers,nonemet the inclusioncriteria.Theresultsarethusreflectiveofthepublishedliterature.

Finally,thereareadditionalconcernsaboutthereportedgrowingpotencyofmarijuanaandincreasingvarietyofmarijuanaproductsandmodesofadministration thatmaypotentially increase these-verityofdependenceandhavestrongereffectsonthebrain.81-84

4.4 | Interpretation of findings

Wheninterpretingthefindingsofthisreview,itisimportanttonotethatneuropsychologicalfunctioningisamultidimensionalconstruct.The children in our reviewwere tested at awide variety of ages.Testing at different ages changes the tools available to measureability, as younger childrenwill not be able to complete the sametasksthatolderchildrencan.Whiletherearesomeeffectsofpre-natalmarijuana exposure on neuropsychological functions in chil-dren,onehastoexercisecautioninterpretingtheseeffects.Ononehand, thoughcognitive functioneffectsdue toprenatalmarijuanaexposuremaybesmall inmagnitudeandoftenarenotstatisticallysignificant, theymay still have a significant impact on social out-comesforanindividualinlaterlife.85,86Thus,itisimportanttofullyunderstand the risks of exposure in the light of the changing cul-tureandpoliticalclimatesurroundingmarijuana.Ontheotherhand,additionalfactors,includinggenetics,maternalcognitiveabilities,87 medicalconditions,suchaspretermbirthornutritionaldeficits,andenvironmental influences,suchasparenting,preschoolattendanceor leadexposure,mayinfluencethedetectableeffectsofprenatalmarijuanaexposure.56,62

5 | CONCLUSIONS

This systematic review suggests possible negative associationsbetween prenatal marijuana exposure and neuropsychologicalfunctions, suchasattention,memoryand impulsecontrol inolderchildren. However, the available literature shows mixed resultsand does not allow us to confidently exclude other explanations,including confounding and publication bias. More mixed resultswere found for the association with prenatal marijuana exposureandlanguagedevelopment,readingandcompositeIQscores.Morecomplete reportingof the findingsmadebyexistingstudiescouldfacilitatedataaccumulationandmeta-analyses,allowingforamorerobustassessmentoftheseassociations.Morerecentdatacaptur-ingtheeffectsofmarijuanaintheabsenceofpolysubstanceuseandchangingdynamics inusecouldalsobebeneficial.Whiledataare

beginningtoaccumulate,educatingthepublicaboutpotentialdan-gersofmarijuanauseduringpregnancyiswarranted.

ACKNOWLEDG EMENTS

WearegratefultoJoannaTalianoforherinvaluablecontributiontocomposingtheliteraturesearchstrategy,runningliteraturesearchesandkeepingusupdatedonnewpublications.WealsoacknowledgePaulCheh, SaraKennedy andDerrickBeasley for conceptualisingthesystematic reviewandpreparinga foundation for thisproject.WethankKatAsmanforreviewingliteraturetosummarisethestateofthescience.RoshniPatelandAmalJamahaveourgratitudefortheirassistancewithscreeningthousandsoftitlesretrievedbytheliteraturesearches,collectingfull-textarticlesandabstractingdata.WealsowouldliketothankLindaPedersonforhelpingtosortandreviewtitlesandabstractsfromtheliteraturesearch.

ORCID

Saida R. Sharapova http://orcid.org/0000-0002-1097-2204

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SUPPORTING INFORMATION

Additional supporting information may be found online in theSupportingInformationsectionattheendofthearticle.

How to cite this article:SharapovaSR,PhillipsE,SiroccoK,KaminskiJW,LeebRT,RolleI.Effectsofprenatalmarijuanaexposureonneuropsychologicaloutcomesinchildrenaged1-11years:Asystematicreview.Paediatr Perinat Epidemiol. 2018;00:1–21. https://doi.org/10.1111/ppe.12505

https://doi.org/10.1111/ppe.12505

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