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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
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)
4 | SHARAPOVA et Al.
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)
Moderate(>1-<6joints/wk)
Heavy(≥6joints/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
Moderate(>1-<6joints/wk)
Heavy(≥6joints/wk)
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)
Moderate(>1-<6joints/wk)
Heavy(≥6joints/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)
Heavy(≥6joints/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)
Heavy(≥6joints/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)
6 | SHARAPOVA 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)
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
Alcohol,tobacco,amphetamines,tranquilisers,heroin,cocaine
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)
Alcohol,tobacco,amphetamines,tranquilisers,heroin,cocaine
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)
Alcohol,tobacco,amphetamines,tranquilisers,heroin,cocaine
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)
Alcohol,tobacco,amphetamines,tranquilisers,heroin,cocaine
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)
8 | SHARAPOVA 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)
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
10 | SHARAPOVA 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.
| 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.
12 | SHARAPOVA et Al.
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
Negativeassociation 4 y OPPS,Fried,1990
Noassociations 4,5and6y Jamaicastudy,Hayes,1991;OPPS,Fried,1992
Verbalscore Noassociations 3 y OPPS,Fried,1990
Negativeassociation 4 y OPPS,Fried,1990
Noassociations 4,5and6y Jamaicastudy,Hayes,1991;OPPS,Fried,1992
Quantitativescore Negativeassociation 3 y OPPS,Fried,1990
Noassociations 4 y OPPS,Fried,1990
Noassociations 4,5and6y Jamaicastudy,Hayes,1991;OPPS,Fried,1992
Perceptualscore Noassociations 3 y OPPS,Fried,1990
Negativeassociation 4 y OPPS,Fried,1990
Noassociations 4,5and6y Jamaicastudy,Hayes,1991;OPPS,Fried,1992
(Continues)
| 13SHARAPOVA et Al.
TABLE 3 (Continued)
Diagnostic instrument Outcomes measured
Reported associations with prenatal marijuana exposure a
Age at assessment
Article (Study, first author, year)
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
Noassociations 4,6and9y Developmentaleffectsofprenatalsubstanceexposurestudy,Bennett,2008
Negativeassociation 6y MHPCD,Goldschmidt,2008
Verbalreasoning Negativeassociation 3 y MHPCD,Day,1994
Noassociations 4,6and9y Developmentaleffectsofprenatalsubstanceexposurestudy,Bennett,2008
Negativeassociation 6y MHPCD,Goldschmidt,2008
Quantitativereasoning Noassociations 3 y MHPCD,Day,1994
Noassociations 4,6and9y Developmentaleffectsofprenatalsubstanceexposurestudy,Bennett,2008
Negativeassociation 6y MHPCD,Goldschmidt,2008
Abstract/visualreasoning Negativeassociation 3 y MHPCD,Day,1994
Noassociations 4,6and9y Developmentaleffectsofprenatalsubstanceexposurestudy,Bennett,2008
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)
14 | SHARAPOVA et Al.
Diagnostic instrument Outcomes measured
Reported associations with prenatal marijuana exposure a
Age at assessment
Article (Study, first author, year)
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
6-9y OPPS,O’Connell,1991
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
Non-significantnegativeassociation
6-9y OPPS,O’Connell,1991
Noassociations 9-12y OPPS,Fried,2000
TABLE 3 (Continued)
(Continues)
| 15SHARAPOVA et Al.
Diagnostic instrument Outcomes measured
Reported associations with prenatal marijuana exposure a
Age at assessment
Article (Study, first author, year)
WideRangeAchievementTest-revised
Reading,arithmetic,spelling Noassociations 6-9y OPPS,O’Connell,1991
Negativeassociation 10 y MHPCD,Goldschmidt,2004
Reading Noassociations 6-9and9-12y
OPPS,O’Connell,1991;Fried,1997
KnoxCubeTest Visualattention,visualmemoryandvisualsequencing
Noassociations 6-9and9-12y
OPPS,O’Connell,1991;Fried,2000
WoodcockReadingMasteryTest
Passagecomprehension Noassociations 6-9and9-12y
OPPS,O’Connell,1991;Fried,1997
BeeryDevelopmentalTestofVisualMotorIntegration
Visualmotorintegration(copygeometricformsintoanotepad)
Nosignificantassociations
6-9y OPPS,O’Connell,1991
Noassociations 9-12y OPPS,Fried,2000
Draw a man Intelligence(scoreisbasedondetail,proportionandcoordination)
Nosignificantassociations
6-9y OPPS,O’Connell,1991
Fingertapping Motorcontrol,speedandlateralcoordination Nosignificantassociations
6-9y OPPS,O’Connell,1991
StroopInterference Teststheabilitytosortandselectivelyreacttoinformation:forexample,word“red”isprintedingreenink.Thechildmustsayloudlythecolourofthetextandnottheword.
Non-significantnegativeassociation
6-9y OPPS,O’Connell,1991
TestofLanguageDevelopment(Primarysyntaxquotientscore)
Abilitytogenerateacceptablesentences Non-significantnegativeassociation
6-9y OPPS,O’Connell,1991
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
Noassociations 9-12y OPPS,Fried,1997
PseudowordTask Readinganddecodingabilities Non-significantnegativeassociationinchildrenwithmoderateexposurecomparedtochildrenwithnoorheavyexposure
9-12y OPPS,Fried,1997
SeashoreRhythmTest Rhythmdiscrimination Noassociations 9-12y OPPS,Fried,1997
TactilePerformanceTask
Motorabilitiesandmotormemory(blind-folded,placewoodenblocksintoproperlyshapedholes)
Noassociations 9-12y OPPS,Fried,1998
TABLE 3 (Continued)
(Continues)
16 | SHARAPOVA et Al.
Diagnostic instrument Outcomes measured
Reported associations with prenatal marijuana exposure a
Age at assessment
Article (Study, first author, year)
WechslerIntelligenceScaleforChildren,3rded.
Full-scaleIQ Noassociations 6-9and9-12y
OPPS,O’Connell,1991;Fried,1997;1998;2000
Information Noassociations 9-12y OPPS,Fried,1997
Non-significantnegativeassociation
9-12y OPPS,Fried,1998
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
OPPS,O’Connell,1991;Fried,1998
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
Noassociations 9-12y OPPS,Fried,2000
PerceptualOrganizationIndex(asummaryindexofpicturecompletion,picturearrangement,blockdesign,andobjectassembly)
Noassociation 6-9and9-12y
OPPS,O’Connell,1991;Fried,1998
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)
| 17SHARAPOVA et Al.
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
Diagnostic instrument Outcomes measured
Reported associations with prenatal marijuana exposure a
Age at assessment
Article (Study, first author, year)
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)
18 | SHARAPOVA et Al.
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
| 19SHARAPOVA et Al.
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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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