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The Association of Mild, Moderate, and Binge Prenatal Alcohol Exposure and Child Neuropsychological Outcomes: A Meta-AnalysisTRANSCRIPT
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The Association of Mild, Moderate, and Binge PrenatalAlcohol Exposure and Child Neuropsychological Outcomes:
A Meta-Analysis
Audrey L. Flak, Su Su, Jacquelyn Bertrand, Clark H. Denny, Ulrik S. Kesmodel, andMary E. Cogswell
Background: The objective of this review is to evaluate the literature on the association betweenmild, moderate, and binge prenatal alcohol exposure and child neurodevelopment.
Methods: Meta-analysis with systematic searches of MEDLINE (1970 through August 2012),EMBASE (1988 through August 2012), and PsycINFOâ (1970 through August 2012) and examinationof selected references.
Results: From 1,593 articles, we identified 34 presenting data from cohort studies that met ourinclusion criteria. Information on study population, outcomes, measurement instruments, timing andquantification of alcohol exposure, covariates, and results was abstracted. Outcomes included academicperformance, attention, behavior, cognition, language skills, memory, and visual and motor develop-ment. The quality of each article was assessed by 2 researchers using the Newcastle – Ottawa Scale.
Based on 8 studies of 10,000 children aged 6 months through 14 years, we observed a significant detri-mental association between any binge prenatal alcohol exposure and child cognition (Cohen’s d [astandardized mean difference score] À0.13; 95% confidence interval [CI], À0.21, À0.05). Based on 3high-quality studies of 11,900 children aged 9 months to 5 years, we observed a statistically significantdetrimental association between moderate prenatal alcohol exposure and child behavior (Cohen’s d À0.15; 95% CI, À0.28, À0.03). We observed a significant, albeit small, positive association betweenmild-to-moderate prenatal alcohol exposure and child cognition (Cohen’s d 0.04; 95% CI, 0.00, 0.08),but the association was not significant after post hoc exclusion of 1 large study that assessed mild con-sumption nor was it significant when including only studies that assessed moderate alcohol consump-tion. None of the other completed meta-analyses resulted in statistically significant associationsbetween mild, moderate, or binge prenatal alcohol exposure and child neuropsychological outcomes.
Conclusions: Our findings support previous findings suggesting the detrimental effects of prenatalbinge drinking on child cognition. Prenatal alcohol exposure at levels less than daily drinking might bedetrimentally associated with child behavior. The results of this review highlight the importance of abstaining from binge drinking during pregnancy and provide evidence that there is no known safe
amount of alcohol to consume while pregnant.Key Words: Prenatal Alcohol Exposure, Child Neurodevelopment, Systematic Review,
Meta-Analysis.
I N THE UNITED States, from 1991 through 2005, 54%
of women aged 18 to 44 years reported consuming at least
1 drink of alcohol during the past 30 days. During the same
time period, 12% of pregnant women reported consuming at
least 1 drink of alcohol during the past 30 days (Centers for
Disease Control and Prevention, 2009). Despite the known
consequences of heavy prenatal alcohol exposure (often
defined as ≥1 drink per day) (Bailey and Sokol, 2008; U.S.
Department of Health and Human Services, 2005), including
fetal alcohol syndrome and other fetal alcohol spectrum
disorders (FASDs), the effects of mild-to-moderate (>0 to
6 drinks per week) and binge (usually defined as ≥4 or ≥5
drinks per occasion) prenatal alcohol exposure on neurode-
velopment are inconsistent. Due to the large population of
women of childbearing age in the United States who con-
sume alcohol and the high rates of unintended pregnancy,
even small effects of prenatal alcohol use could have detri-
mental repercussions to overall child neurodevelopment at
the population level (Centers for Disease Control and
Prevention, 2009; U.S. Department of Health and Human
From the Department of Epidemiology (ALF), Rollins School of
Public Health, Emory University, Atlanta, Georgia; Oak Ridge Institute
for Science and Education (ALF, SS), Oak Ridge, Tennessee; National
Center on Birth Defects and Developmental Disabilities (ALF, JB,
CHD), Centers for Disease Control and Prevention, Atlanta, Georgia;
National Center for Immunization and Respiratory Diseases (SS), Cen-ters for Disease Control and Prevention, Atlanta, Georgia; Department of
Epidemiology (USK), School of Public Health, Aarhus University,
Aarhus, Denmark; Department of Obstetrics and Gynecology (USK),
Aarhus University Hospital, Aarhus, Denmark; and National Center forChronic Disease Prevention and Health Promotion (MEC), Centers for
Disease Control and Prevention, Atlanta, Georgia.
Received for publication July 16, 2012; accepted May 15, 2013.Reprint requests: Audrey L. Flak, MPH, Department of Epidemiol-
ogy, Emory University, CNR 3rd Floor, 1518 Clifton Road, Mailstop
1518-002-3BB, Atlanta, GA 30332; Tel.: 404-727-8710; Fax: 404-727-
8737; E-mail: [email protected]
The findings and conclusions in this report are those of the authors and
do not necessarily represent the official position of the Centers for Disease
Control and Prevention.
©Published 2013. This article is a U.S. Government work and is in the public domain in the U.S.A.
DOI: 10.1111/acer.12214
Alcohol Clin Exp Res, Vol **, No *, 2013: pp 1–13 1
ALCOHOLISM: CLINICAL AND EXPERIMENTAL RESEARCH Vol. **, No. *** 2013
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Services, 2000). Neurodevelopment refers to development of
the nervous system that includes a number of functional
domains, such as academic achievement, attention, behavior,
cognition, language development, memory, and motor
development.
In a previous meta-analysis, Testa and colleagues (2003)
found no consistent association between light (<1 drink per
day) and moderate (1 to 1.99 drinks per day) prenatalalcohol consumption and infant mental development. While
their results were not consistent across child ages, they did
find significant associations between both levels of alcohol
consumption and infant mental development in 12- to 13-
month-old children. Testa and colleagues (2003) focused on
general mental development among infants aged 6 to
26 months and did not examine the effects of binge prenatal
alcohol consumption. In a 2007 systematic review, Hender-
son and colleagues (2007) concluded prenatal binge drinking
might be associated with neurodevelopment, but did not
attempt a meta-analysis due to the limited number and heter-
ogeneity of studies. The 4 studies included by this reviewexamined neurodevelopment in children aged 18 months
through 14 years. More recently, in a 2011 systematic review,
Bay and Kesmodel concluded that light levels of prenatal
alcohol exposure (1 to 2 drinks per day) were not associated
with motor dysfunction in individuals aged 3 days through
26 years. Another recent review aimed at informing advice
for pregnant women concluded that recent studies indicate
an association between light and moderate prenatal alcohol
exposure and neurodevelopmental problems (O’Leary and
Bower, 2012). This review summarized the effects of previ-
ously published systematic reviews as well as research studies
in 2009 to 2010, but did not focus on neurodevelopmental
outcomes nor did it include a meta-analysis.
A systematic review including older children (but not
adults), several functional domains of neurodevelopment,
and various levels of prenatal alcohol exposure with appro-
priate meta-analysis would allow a synthesis of the most
recent research on this topic and quantify summary effects
(Borenstein et al., 2009; Stroup et al., 2000). One of the pri-
mary advantages of a meta-analysis is the improvement in
sample size and statistical power by combining like studies
and outcomes. In addition, it allows for the assessment of
homogeneity of results between different studies and the
evaluation of evidence of publication bias.
The 3 main objectives of this review were to: (i) evaluate
evidence for an association between mild-to-moderate prena-
tal alcohol exposure (>0 to 6 drinks per week) and child neu-
ropsychological outcomes; (ii) examine the evidence for an
association between binge prenatal alcohol exposure (usually
defined as ≥4 or ≥5 drinks per occasion) and child neuropsy-
chological outcomes; and (iii) identify gaps in our knowledge
and directions for further research. We hypothesized that the
literature on mild-to-moderate prenatal alcohol exposure
and child neuropsychological outcomes would not provide a
discernible or consistent effect (positive or negative). For pre-
natal binge drinking, we hypothesized that the literature
would reveal a detrimental effect on at least some of the
neuropsychological outcomes examined.
MATERIALS AND METHODS
Search Strategy
We searched 3 databases using OvidSP: MEDLINE (1970
through August 2012), EMBASE (1988 through August 2012), andPsycINFOâ (1970 through August 2012). Search strategies includedthe keywords “alcohol,” “drinking behavior,” and “fetal develop-ment,” and a list of outcomes of interest such as “cognition disor-ders” (see inclusion criteria that follow). Final search resultsexcluded editorials, letters, reviews, and articles in languages otherthan English. In collaboration with a medical librarian, we modifiedthe search strategies used by Henderson and colleagues (2007) toinclude mild and moderate alcohol exposure as well as additionalterms on neurodevelopment and to exclude terms for outcomes notof interest (e.g., preterm delivery). The final search strategy is pro-vided in Table S1. Bibliographies of included articles and systematicreviews relating to this subject were searched manually for articlesmissed by electronic searches.
Study Selection
An article was included in this review if it presented data from acohort or case – control study on the relation between mild, moder-ate, or binge prenatal alcohol exposure and 1 or more child neuro-psychological outcomes (Table 1). These outcomes includedcognition, motor skills, language, behavior, vision, hearing, devel-opment, information processing, academic achievement, attention,memory, executive function, mental health, social skills, and hand – eye coordination. For the purposes of this review, mild, mild-to-moderate, moderate, and heavy drinking were defined as up to 3drinks per week, up to 6 drinks per week, up to 6 drinks per weekincluding some individuals who consumed at least 3 drinks perweek, and more than 6 drinks per week, respectively, with 13.7 g of alcohol equaling 1 drink. There are no internationally acknowl-
edged standard definitions of mild, moderate, and heavy alcoholconsumption during pregnancy. The categories used in this reviewwere defined by the authors to focus on drinking at less than dailylevels and after careful review of exposure categories used in the lit-erature. Binge drinking was defined as 4 or more drinks on 1 occa-sion (binge drinking defined as 5 or more drinks on 1 occasion wereincluded as a subset; National Institute on Alcohol Abuse andAlcoholism, 2004; Wechsler et al., 1995).
Articles that met the initial inclusion criteria were examinedagainst a list of exclusion criteria (Table 1) such as including chil-dren with an explicit diagnosis of an FASD or lack of a comparisongroup of children with no prenatal alcohol exposure. Individualswith a diagnosed FASD were excluded because current evidence hasindicated that these diagnoses are associated with levels of alcohol
exposure above the mild-to-moderate level examined in this reviewand meta-analysis (Bertrand et al., 2004). Our aim was to investi-gate the neuropsychological effects of prenatal alcohol exposurebelow levels previously associated with these clinical diagnoses.
Initially, we screened the title and abstract of each identified arti-cle using our inclusion criteria and full list of exclusion criteria. Anarticle was excluded with no further review if it clearly did not meetour article requirements. If the abstract contained any indication of relevance to the review, 1 author also screened the full article(Fig. 1).
Data Abstraction
A study researcher trained in epidemiology abstracted datafrom the articles marked for inclusion using a standard form.
2 FLAKET AL.
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Information extracted from articles included study design, popula-tion, outcomes, outcome measurement instruments, timing andquantification of alcohol exposure, measured covariates, andresults. To assess reliability, about half of the included articles wereabstracted by 1 or more additional researchers. The research teamcollectively resolved any discrepancies in screening or abstraction. If articles contained information on the same children and outcomes,the outcome measurement at the participants’ oldest age was
selected. We chose to include outcomes at older ages as in general,clinical issues are more likely to be identified as developmentadvances and for children with prenatal alcohol exposure, abnor-malities in subtle mental health issues or higher-order neurocogni-tion (e.g., executive function) may only emerge or be assessed atolder ages. If more than 1 measurement on the same outcome wascompleted for the same child at the same age, we chose the measure-ment based on maternal report (over paternal or teacher report).For full data selection criteria, see Table 2. If an article presentedresults stratified by a characteristic (e.g., child sex) and results couldnot be combined, then data in each strata were abstracted andincluded in the meta-analysis.
Authors of included articles were contacted for additional data if the data presented on 1 or more associations in their papers were
incomplete and could not be used in the meta-analysis (e.g., datadid not provide a measure of variance). Author-supplied data wereincluded in the meta-analysis. In cases for which authors no longerhad access to the data and information was incomplete, the datawere excluded from this review.
Outcome Classification
For the purposes of this review, we divided neuropsychologicaloutcomes into 8 functional domains: academic performance,attention, behavior, cognition, language and verbal development,memory, executive function, and visual and motor development.Other neurodevelopmental outcomes (e.g., mental health) wereexamined separately. This grouping prevented instruments measur-ing different constructs from being included in the same analysis.
Two psychologists reviewed each instrument independently andclassified them into 1 of these domains. All discrepancies inoutcome classification were discussed, and a consensus was reached.
Quality Assessment
The quality of each article meeting the review criteria wasassessed by 2 authors using an adapted Newcastle – Ottawa Scale
(NOS) for assessing the quality of nonrandomized studies in meta-analyses (Wells et al., 2013). Differences were settled by discussion.The adapted scale is provided in Table 3 and includes an assessmentof the following potential confounders: socioeconomic status (SES),cigarette smoking, and maternal age and intelligence. We specifi-cally noted whether studies of high quality controlled for SES (i.e.,income or education), given the strong associations between SESand both prenatal alcohol use and child neuropsychological out-comes (Bradley and Corwyn, 2002; Centers for Disease Control andPrevention, 2009). Detailed NOS score ratings for each of thepapers may be obtained from the authors.
Statistical Analysis
Measures of effect from binary and correlational data were con-
verted to Cohen’s d values, a standardized mean difference score,using the methods outlined by Borenstein and colleagues (2009).These conversions prevented studies from being excluded from thisreview based on their use of measures of association (such as oddsratios [ORs]). Random effects meta-analyses were completed sepa-rately for each of the neurodevelopmental domains and exposurequantity combinations using Cohen’s d as the summary measure.For each exposure – outcome meta-analysis, a measure of overalleffect and measures of heterogeneity (i.e., Q statistic, I 2) were calcu-lated. A sensitivity analysis based on study quality and a publicationbias assessment using funnel plots and the Egger test were com-pleted (results available from the authors upon request; Egger et al.,1997). Comprehensive Meta-Analysis 2.0 software was used for allmeta-analyses (Borenstein et al., 2005).
RESULTS
Systematic Review Results
Of the 1,593 articles reviewed, data from 34 met all criteria
and were used in meta-analyses (Fig. 1). The majority of
articles were excluded after review of the titles and abstracts
(n = 1,289), with a smaller group excluded after review of the
study methods and data in the full articles (n = 270). The
most common reasons for exclusion were lack of information
on prenatal alcohol exposure quantity (n = 588) and measur-
ing outcomes other than neuropsychological outcomes
(n = 466). Authors were contacted to request additionalinformation on 23 reviewed articles. We obtained the desired
information for 16 of these articles. The authors for the
remaining 7 articles either no longer had access to the desired
information or did not reply to our requests.
Study data on 1 or more of the associations between neuro-
psychological outcomes and mild or moderate prenatal alco-
hol exposure were in 22 articles (Alati et al., 2008; Bay et al.,
2012; Brown et al., 2010; Forrest et al., 1991; Jacobson et al.,
1993a,b, 2011; Kaplan-Estrin et al., 1999; Kelly et al., 2009,
2012; Kesmodel et al., 2012; Larkby et al., 2011; Larroque
et al., 2000; O’Callaghan et al., 2007; O’Leary et al., 2010;
Table 1. Systematic Review Inclusion and Exclusion Criteria
Inclusion criteria1. Cohort or case – control design2. Includes data on the relation between mild, moderate, or binge prenatal
alcohol exposure and at least 1 child neuropsychological outcome of interest
Exclusion criteria
1. Includes only the following outcomes: infant and child growth andanthropometric measures, congenital anomalies, outcomes at birth, orchild or adolescent alcohol and substance abuse
2. Does not use a standardized scale to measure outcome3. Includes children with diagnoses of fetal alcohol syndrome or fetal
alcohol effects4. Lacks a comparison group of mothers with no alcohol exposure5. Focuses primarily on other drug use with alcohol included only as a
confounder or adjustment variable6. Examines only children whose mothers were exposed to alcohol in
combination with other drug exposures (e.g., tobacco, cocaine[i.e., does not include exposure to alcohol alone])
7. “Alcohol abuse” or “alcoholism” is the only exposure during theprenatal period
8. Alcohol exposure measured as a continuous variable, all exposure catego-ries include women who drink >7 drinks per week, and investigatorsassume a linear association between alcohol intake and neurodevelopment
(also applies if alcohol exposure transformed in the analysis in attempts tocompensate for skewness or outliers, or both)
9. Contains information only on the same cohort and outcome(s) asalready included articles
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Parry and Ogston, 1992; Richardson et al., 1995; Robinson
et al., 2010; Rodriguez et al., 2009; Sayal et al., 2007; Sood
et al., 2001; Willford et al., 2006; Table 4). Data on 1 or more
associations between neuropsychological outcomes and
binge prenatal alcohol exposure were in 15 articles (Alati
et al., 2008; Alvik et al., 2011; Bailey et al., 2004; Coles et al.,
2000; Fraser et al., 2012; Goldschmidt et al., 2004; Kesmodel
et al., 2012; Lemola et al., 2009; Nulman et al., 2004;
O’Callaghan et al., 2007; Olsen, 1994; Streissguth et al.,
1989, 1994a,b; Willford et al., 2004; Table 5). The most
common outcomes examined were cognition, behavior, and
visual and motor development (data in 16, 14, and 13 articles,
respectively). Academic development, attention, language,
memory, and executive function each were in 6 or fewer arti-
cles. Outcomes not fitting in these domains, such as mental
health, were in 4 articles. The scarcity of data on these addi-
tional outcomes precluded further analysis of their results.
Study quality scores, assessed using the adapted NOS scale,
ranged from 2 to 8 on an 8-point scale (with 8 representing a
study of the highest quality; Tables 4 and 5). A study earning
Articles pulled from systematic searches (n = 1,835)
MEDLINE 1970-2012 (n = 720)
EMBASE 1988-2012 (n = 815)
PsycINFO® 1970-2012 (n = 300)
Additional articles from bibliographies screened (n = 30)
Articles identified by outside experts (n = 10)
Duplicates excluded (n = 282)
Total nonduplicates (n = 1,593)
Articles excluded after title and abstract review (n = 1,289):
• No prenatal alcohol exposure measure (n = 412)
• No outcome of interest (n = 433)
• No alcohol exposure of interest (e.g. only examined the effect of daily drinking
during pregnancy) (n = 57)
• Not original research (n = 60)
• Only includes children diagnosed with a fetal alcohol spectrum disorder (n = 144)• Not a human study (n = 98)
• Other (e.g. no control group without any alcohol exposure) (n = 85)
Articles retained for full article review (n = 304)
Articles excluded after full article review due to (n = 270):
• No prenatal alcohol exposure measure (n = 48)
• No outcome of interest (n = 33)
• No alcohol exposure of interest (e.g. only examined the effect of daily drinking
during pregnancy) (n = 71)
• Not original research (n = 22)
• No control group without any alcohol exposure (n = 32)
• Primarily focuses on other drug use with alcohol included only as a confounder
or adjustment variable (n = 9)
• Does not include a measure of association that can be included in this review
(n = 4)
• Other (e.g. only includes children diagnosed with fetal alcohol spectrum disorder)
(n = 51)
Articles retained for meta-analysis (n = 34)
Fig. 1. Summary of article review process including primary reasons for article exclusion.
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6 or more points was deemed of “high quality” for the pur-
poses of sensitivity analyses. This cut-point was decided upon
after examining the distribution of quality scores.
Meta-Analysis Results
We conducted meta-analyses on all exposure – outcome
associations, with data from 2 or more separate populations
resulting in 21 separate meta-analyses. By exposure quantity,
our meta-analyses were as follows: (i) mild exposure and 4
outcomes (behavior, cognition, language and verbal, and
visual and motor), (ii) moderate exposure and 5 outcomes
(attention, behavior, cognition, language and verbal, and
visual and motor), (iii) mild-to-moderate exposure and 3 out-
comes (behavior, cognition, and visual and motor), and (iv)
binge exposure and 9 outcomes (academic reading perfor-
mance, academic math performance, attention, behavior,
cognition, language and verbal, memory, visual and motor,
and executive function).
When we used data from all studies without accounting
for quality (i.e., NOS scores), we did not find any significant
associations between mild, moderate, or mild-to-moderate
prenatal alcohol exposure and neuropsychological outcomes
(i.e., attention, behavior, cognition, visual and motor devel-
opment, and language skills; Fig. S1 presents all calculated
meta-analyses of mild and moderate alcohol exposure with
nonsignificant results). When meta-analyses were limited to
studies of high quality as determined by NOS scores, 2 of the
observed associations were statistically significant. Based on
3 studies with approximately 11,900 children aged 9 months
to 5 years, we observed a statistically significant detrimental
association between moderate prenatal alcohol exposure and
child behavior (Cohen’s d À0.15; 95% confidence interval
[CI], À0.28, À0.03; p = 0.01; Fig. 2). The associations of all
studies in this subanalysis were in the same direction and
adjusted for SES, but only 1 was statistically significant by
itself. This study, by Brown and colleagues (2010), was con-
ducted among 9-month-old infants and assessed behavior
Table 2. Data Selection Criteria
Data selection criteria applied when: (i) A given outcome was assessedmultiple times in the same cohort, or (ii) Multiple cohorts prenatallyexposed to alcohol were compared with the same nonexposed cohort1. When a given outcome was assessed by multiple scales or at multiple time
points in the same children, the following rules were applied:
a. Parental assessment was included instead of teacher assessment
b. Maternal assessment was included instead of paternal assessmentc. Results measuring the outcome at the oldest age were includedd. The most standardized, comprehensive measures were included
2. When multiple cohorts of children prenatally exposed to alcohol werecompared with the same nonexposed cohort, only 1 comparison could beincluded in each analysis. This prevented including the same controlgroup more than once in a given meta-analysis. The following rules wereapplied in this situation:
a. If the exposed children were all exposed prenatally to binge drinking,the cohort of children with the lightest exposure was included (e.g.,children whose mothers binge drank once a week during pregnancywere included instead of children whose mothers binge drank 3 timesa week during pregnancy)
b. If the cohorts of exposed children were prenatally exposed to alcoholduring different trimesters, the cohort of children with the earliest
exposure was included
Table 3. Adapted Newcastle – Ottawa Quality Assessment Scale: CohortStudies
Maximumpoints
Selection1. Representativeness of the exposed cohort 1
a. The researchers attempted to select participants that
were reasonably representative of the average low,moderate, or binge drinkers in the community(1 point)b. The researchers and the reader have reason
to believe that their participants are reasonablyrepresentative of the average low, moderate, orbinge drinkers in the community(1 point)
c. Either no data on representativeness, or noreason to believe the participants wererepresentative of the average low, moderate,or binge drinkers in the community, orover-sampled heavy drinkers (0 points)
2. Selection of the nonexposed cohort 1a. Drawn from the same community as the
exposed cohort (1 point)b. Drawn from a different source than the
exposed cohort (0 points)
c. No description of the derivation of thenonexposed cohort(0 points)
3. Ascertainment of exposure 1a. Structured interview(1 point)b. Self-administered questionnaire(0 points)c. No description (0 points)
4. Demonstration that outcome of interestwas not present at start of study (omitted)
0
Comparability1. Comparability of cohorts on the basisof the design or analysis
2
a. Study controls for SES (could assess usingproxy measures such as education or income)(1 point)
b. Study controls for any of: cigarette smoking,maternal age, maternal IQ (1 point)
Outcome1. Assessment of outcome 1
a. Independent blind assessment(1 point)b. Not a blind assessment(0 points)c. No description of outcome assessment(0 points)
2. Follow-up long enough for outcomes to occur 1a. Yes (1 point)b. No (0 points)
3. Adequacy of follow-up cohorts 1a. Complete follow-upor subjects lost to follow-up
unlikely to introduce bias:≥70% follow-upand description provided of those lost indicatesthey are comparable to those kept on SES
and prenatal alcohol exposure(1 point)b. Follow-up rate <70% and description of
those lost does not indicate comparability(0 points)c. Does not fall under (a) or (b) or no statement
describing the adequacy of follow-up cohorts(0 points)
Total points possible 8
SES, socioeconomics status.
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T a b l e
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1 s t , 2 n d ,
3 r d
0 . 2
t o 3 9 . 8
4 0 . 0
t o 7 8 . 3
6
K e l l y / 2 0 0 9 ,
U n i t e d K i n g d o m
9 , 4
6 0 ( 7 5 . 9
)
2 0 0 0 t o 2 0 0 2
d
C o g n i t i o n
3 y
1 s t , 2 n d ,
3 r d
≤ 2 7 . 4
≤ 8 2 . 2
6
K e l l y / 2 0 1 0 ,
U n i t e d K i n g d o m
1 1 , 5
1 3 ( 9 3 . 6
)
2 0 0 0 t o 2 0 0 2
d
B e h a v i o r
L a n g u a g e
V i s u a l a n d M o t o r
5 y
1 s t , 2 n d ,
3 r d
≤ 2 7 . 4
≤ 8 2 . 2
6
K e s m o d e l / 2 0 1 2 ,
D e n m a r k
1 , 6
2 8 ( 5 1 . 1
)
2 0 0 3 t o 2 0 0 8
A t t e n t i o n
C o g n i t i o n
O t h e r
5 y
1 s t , 2 n d
1 2 . 0
t o 4 8 . 0
7
L a r k b y / 2 0 1 1 ,
U n i t e d S t a t e s
5 9 2 ( 7 1 . 4
)
1 9 8 2 t o N R
B e h a v i o r
1 6 y
1 s t , 3 r d
≤ 4 2 . 5
5
L a r r o q u e / 2 0 0 0 ,
F r a n c e
1 5 6 ( 4 7 . 9
)
1 9 8 5 t o 1 9 8 6
O t h e r
4 . 5 y
1 s t
1 3 . 7
t o 8 2 . 2
5
O ’ C a l l a g h a n / 2 0 0 7 ,
A u s t r a l i a
5 , 1
3 9 ( 7 1 . 1
) g
3 , 7
3 1 ( 5 1 . 7
) h
1 9 8 1 t o 1 9 8 4
A c a d e m i c
A t t e n t i o n
C o g n i t i o n
1 4 y
1 s t , 3 r d
≤ 4 8 . 0
6
O ’ L e a r y / 2 0 0 9 ,
A u s t r a l i a
1 , 8
9 0 ( 8 5 ) i
1 , 6
2 4 ( 7 3 ) j
1 , 3
5 7 ( 6 1 ) k
1 9 9 5 t o 1 9 9 7
d
A t t e n t i o n
B e h a v i o r
C o g n i t i o n
2 y 5 y 8 y
1 s t , 2 n d ,
3 r d
≤ 7 0
5
P a r r y / 1 9 9 2 ,
S c o t l a n d ,
D e n m a r k ,
G e r m a n y
1 , 3
6 1 ( 6 3 . 9
) l
1 , 3
6 0 ( 6 3 . 8
) m
1 9 8 6 t o 1 9 8 6
n
1 9 8 8 t o 1 9 8 9
o
1 9 8 7 t o 1 9 8 8
p
C o g n i t i o n
V i s u a l a n d M o t o r
1 8 m
N R
≤ 2 9
3 0 t o 5 9
2
R i c h a r d s o n / 1 9 9 5 ,
U n i t e d S t a t e s
6 4 5 ( 8 4 . 5
) q
1 9 8 3 t o 1 9 8 6
C o g n i t i o n
V i s u a l a n d M o t o r
1 8 m
1 s t , 2 n d ,
3 r d
< 3 8 . 4
6
R o b i n s o n / 2 0 1 0 ,
A u s t r a l i a
1 , 9
5 2 ( 6 8 . 1
) i
2 , 1
2 7 ( 7 4 . 2
) j
2 , 0
3 7 ( 7 1 . 0
) k
1 , 9
7 7 ( 6 8 . 9
) r
1 , 7
4 4 ( 6 0 . 8
) s
1 9 8 9 t o 1 9 9 1
d
B e h a v i o r
2 y 5 y 8 y 1 0 y
1 4 y
1 s t
≤ 1 3 . 7
2 7 . 4
t o 8 2 . 2
4
C o n t i n u e d .
6 FLAKET AL.
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T a b l e
4 . ( C o n t i n u e d )
F i r s t a u t h o r / y e a r , c o u n t r y
S a m p l e s i z e a t f o l l o w - u p
n ( % o f b a s e l i n e )
E n r o l l m e n t p e r i o d
O u t c o m e c a t e g o r i e s
a s s e s s e d a
A g e a t
f o l l o w - u p
P r e n a t a l a l c o h o l e x p o s u r e a s s e s s m e n t b
N O S
s c o r e c
T r i m e s t e r ( s )
a s s e s s e d
M i l d
( g / w k )
M o d e r a t e
( g / w k )
R o d r i g u e z / 2 0 0 9 ,
D e n m a r k ,
F i n l a n d
4 , 9
6 8 ( 6 0 . 3
) t
7 , 8
4 4 ( 7 0 . 4
) u
8 , 5
2 5 ( 9 1 . 1
) v
1 9 9 0 t o 1 9 9 2
t
1 9 8 4 t o 1 9 8 7
u
1 9 8 6 v
A t t e n t i o n
1 0 y t
1 2 y t
1 5 y u
7 t o 8 y v
1 s t , 2 n d ,
3 r d t , u
1 s t , 2 n d v
1 3 . 7
t o 5 4 . 8
5
S a y a l / 2 0 0 7 ,
U n i t e d K i n g d o m
8 , 0
4 6 ( 6 3 . 5
)
1 9 9 1 t o 1 9 9 2
d
B e h a v i o r
8 1 m
1 s t
< 1 3 . 7
5
S o o d / 2 0 0 1 ,
U n i t e d S t a t e s
5 0 6 ( 7 6 . 1
)
1 9 8 9 t o 1 9 9 1
d
B e h a v i o r
6 t o 7 y
1 s t , 2 n d ,
3 r d
< 4 8 . 0
3
W i l l f o r d / 2 0 0 6 ,
U n i t e d S t a t e s
6 1 1 ( 7 3 . 7
)
1 9 8 3 t o 1 9 8 5
C o g n i t i o n
1 0 y
1 s t
< 3 8 . 4
3
g / w k , g r a m s p e r w e e k ; N O S ,
N e w c a s t l e
– O t t a w a S c a l e ; y , y e a r ; m , m o n t h ; N R , n o t r e p o r t e d .
a V i s u a l a n d M o t o r =
V i s u a l a n d M o t o r D
e v e l o p m e n t , A c a d e m i c =
A c a d e m i c P e r f o r m a n c e ,
L a n g u a g e =
L a n g u a g e a n d V e r b a l .
b A l c o h o l E x p o s u r e Q u a n t i fi c a t i o n : A l l a l c o h o l e x p o s u r e c a t e g o r i e s w e r e c o n v e r t e d
t o g r a m s p e r w e e k u s i n g t h e c o n v e r s i o n 1 3 . 7 g a l c o h o l =
0 . 6 o z =
1 d r i n k ( U . S .
C e n t e r s f o r D i s e a s e C o n t r o l
a n d P r e v e n t i o n .
A l c o h o l a n d P u b l i c H e a l t h F A Q s .
h t t p : / / w w w . c
d c . g o v / a l c o h o l / f a q s . h t
m ) . T h e e x p o s u r e c a t e g o r i e s r e p o r t e d b y s
t u d i e s i n g r a m s w e r e k e p t i n t a c t r e g a r d l e s s
o f t h e c o n v e r s i o n s u s e d
b y t h e r e s e a r c h e r s .
A l c o h o l c a t e g o r i e s w e r e r o u n d e d t o t h e n e a r e s t t e n t h .
M i l d e x p o
s u r e : a n y e x p o s u r e u p t o 3 d r i n k s p e r w e e
k ( 4 1 . 1 g / w k ) . M o d e r a t e e x p o s u r e : a n y e x p o s u r e u p t o 6 d r i n k s p e r
w e e k ( 8 2 . 2 g / w k ) w h i c h i n c l u d e d s o m e i n d
i v i d u a l s w i t h e x p o s u r e o f a t l e a s t 3 d r i n k s p
e r w e e k ( 4 1 . 1 g / w k ) . I n t h e e v e n t t h a t a s t u d y h a d m u l t i p l e e x p o s u r e c a t e g o r i e s t h a t fi t t h i s c l a s s i fi c a t i o n ,
t h e c a t -
e g o r y t h a t c o v e r e d t h e l a r g e s t r a n g e w a s c h o s e n .
c N O S Q u a l i t y A s s e s s m e n t S c o r e .
P o s s i b l e v a l u e s : 1 ( l o w e s t q u a l i t y ) t o 8 ( h i g h e s t q
u a l i t y ) .
d R a n g e o f b i r t h y e a r s i n s t e a d o f e n r o l l m
e n t p e r i o d .
e R o u n d e d t o t h e n e a r e s t 5 0 .
f S u l a i m a n a n d c o l l e a g u e s ( 1 9 8 8 ) .
g A t t e n t i o n a l a n d l e a r n i n g q u e s t i o n n a i r e s
.
h P s y c h o m e t r i c a s s e s s m e n t .
i 2 y e a r s .
j 5 y e a r s .
k 8 y e a r s .
l B a y l e y S c a l e s o f I n f a n t D e v e l o p m e n t : M
e n t a l D e v e l o p m e n t I n d e x .
m B a y l e y S c a l e s o f I n f a n t D e v e l o p m e n t :
P s y c h o m o t o r D e v e l o p m e n t I n d e x .
n D u n d e e [ U K ] c o h o r t ( B o l u m a r , 1 9 9 2 ) .
o O d e n s e [ D e n m a r k ] c o h o r t ( B o l u m a r , 1 9 9 2 ) .
p B e r l i n [ G e r m a n y ] c o h o r t ( B o l u m a r , 1 9 9
2 ) .
q 1 8 m o n t h s .
r 1 0 y e a r s .
s 1 4 y e a r s .
t A a r h u s B i r t h C o h o r t ( A B C ) [ D e n m a r k ] .
u H a b i t s f o r T w o ( H H T ) [ D e n m a r k ] .
v N o r t h e r n F i n l a n d B i r t h C o h o r t ( N F B C ) [ F i n l a n d ] .
<
a n d ≤ g r a m s o f a l c o h o l d o n o t i n c l u d e 0 .
O u t c o m e s a n d a g e s a s s e s s e d b y a r t i c l e s ,
b u t n o t i n c l u d e d i n m e t a - a n a l y s e s , a r e n o t
l i s t e d i n t h i s t a b l e .
PRENATAL ALCOHOLAND CHILD OUTCOMES 7
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using the behavior rating scale of the Bayley Scales of Infant
Development (Bayley, 1993).
In a separate meta-analysis based on 7 studies with NOS
scores of 6 or more including approximately 26,100 children,
we observed a statistically significant, albeit small, beneficial
association between mild-to-moderate prenatal alcohol
exposure and cognition (Cohen’s d 0.04; 95% CI, 0.00, 0.08;
p = 0.03; Fig. 2). None of the associations observed in the
individual studies in this subanalysis were statistically signifi-
cant. Although not statistically significant, the direction of 1
study, by Brown and colleagues (2010), was opposite to the
others and another, by Kelly and colleagues (2009), was cen-
tered at zero among girls, but not boys.
This association between mild-to-moderate prenatal alco-
hol exposure and cognition was of similar magnitude, but no
longer significant in a post hoc analysis considering only the
Table 5. Characteristics of Included Studies that Measured Binge Levels of Prenatal Alcohol Exposure by Article
First author/year, countrySample size at follow-up
n (% of baseline)Enrollment
periodOutcome categories
assessedaAge at
follow-up
Prenatal alcohol exposureassessment
NOSscoreb
Trimester(s)assessed
Binge (drinks/ occasion)
Alati/2008, U nited K ingdom 4,332 ( 32.5) 1991 t o 1992c Cognition 8 y 2nd, 3rd 4+ 6Alvik/2011, Norway 1,303 (69.6) 2000 to 2001 Behavior 6 m 1st 5+ 6Bailey/2004, United States 499 (75.0)d
537 (80.8)e1989 to 1991c Behavior
LanguageVisual and Motor
7 y 1st, 2nd, 3rd 5+f 7
Coles/2000, U nited States 136 (41.7) 1993 t o 1994g BehaviorCognition
Visual and Motor
12 m 1st, 2nd, 3rd 5+ 5
Fraser/2012, Canada 195 (81.3) NR Visual and MotorCognition
6 m 1st, 2nd 5+ 7
Goldschmidt/2004,United States
606 ( 79.4) 1983 t o 1986h AcademicOther
10 y 1st, 2nd, 3rd 4+ 5
Kesmodel/2012, D enmark 1,628 (51.1) 2003 t o 2008 AttentionCognition
Executive Function
5 y 1st, 2nd 5+ 7
Lemola/2009, Switzerland 323 (70.5) NR Behavior 17 m 1st, 2nd, 3rd 4+ 3Nulman/2004, Canada 102 (71.3) 1987 to 1997 Academic
Cognition
LanguageVisual and Motor
Other
≤7 y 1st 5+ 6
O’Callaghan/2007, Australia 5,139 (71.1)i
3,731 (51.7) j1981 to 1 984 Academic
AttentionCognition
14 y 1st, 3rd 5+ 6
Olsen/1994, Denmark 276 (84.2)k
251 (76.5)l1988 to 1 989 Cognition
Visual and Motor18 m3.5 y
1st, 2nd, 3rd 8+ 5
Streissguth/1989,United States
486 (86.0) 1974 to 1975 BehaviorCognitionLanguage
Visual and MotorOther
7.5 y 1st, 2nd 5+ 5
Streissguth/1994a, United States 464 (82.0) 1974 to 1975m Academic 14 y 1st, 2nd 5+ 3Streissguth/1994b, United States 462 (82.0) 1974 to 1975m Attention
Executive Function
Memory
14 y 1st, 2nd 5+ 7
Willford/2004, U nited S tates 580 ( 70.0) 1983 t o 1985n Memory 14 y 1st 4+ 5
NOS, Newcastle – Ottawa Scale; y, year; m, month; NR, not reported.aVisual and Motor = Visual and Motor Development, Academic = Academic Performance, Language = Language and Verbal.bNOS Quality Assessment Score. Possible values: 1 (lowest quality) to 8 (highest quality).cRange of birth years instead of enrollment period.dBehavior.eLanguage and Verbal, Visual and Motor Development.fAt least once every 2 weeks during pregnancy.gDrews and colleagues (2003).hGoldschmidt and colleagues (1996).iAttention, Academic Performance. jCognition.k18 months.l3.5 years.
mStreissguth and colleagues (1981).nWillford and colleagues (2006).Outcomes and ages assessedby articles, but not included in meta-analyses, are notlisted in this table.
8 FLAKET AL.
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6 studies that controlled for SES (excluding a study by Alati
et al. [2008] that accounted for SES in published analyses
including individuals with heavy prenatal alcohol exposure,
but not in published analyses that met our inclusion criteria;
Cohen’s d 0.04; 95% CI, À0.01, 0.09; p = 0.08). The associa-
tion with cognition also was not significant when including
only studies that assessed moderate alcohol consumption
(Fig. S1), even when limiting these studies to those that wereof “high quality.”
When including studies of all quality scores, we observed a
significant detrimental association between binge prenatal
alcohol exposure and child cognition (Cohen’s d À0.13; 95%
CI, À0.21, À0.05; p < 0.01; Fig. 2). This analysis used data
on children aged 6 months to 14 years from 8 studies
(n % 10,000). The results of this meta-analysis were border-
line significant when limited to data from studies of high
quality (n % 9,000, p = 0.054).
None of the meta-analyses resulting in significant associa-
tions between mild, moderate, or binge prenatal alcohol expo-
sure and neuropsychological outcomes showed any evidenceof heterogeneity (determined by p-value > 0.05 for the Q sta-
tistic) or publication bias(Egger test p-value > 0.05).
All remaining analyses failed to show statistically signifi-
cant associations between binge prenatal alcohol exposure
and neuropsychological outcomes (Fig. S2 presents all calcu-
lated meta-analyses of binge alcohol exposure with nonsig-
nificant results). The majority of these analyses included data
from more than 5 populations and showed no indication of
heterogeneity or publication bias.
DISCUSSION
This meta-analysis is the first we know of to suggest that
moderate prenatal alcohol consumption at levels less than
daily drinking might affect child behavior. The studies used
in our meta-analysis on child behavior examined behavioral
aspects such as social engagement, affect, and conduct. While
in our meta-analysis, there were statistically significant find-
ings showing that moderate levels of alcohol exposure were
associated with behavior, the clinical, or functional signifi-
cance of the results from the original studies varied from
subtle to moderate. However, across these studies, some
children with the lowest levels of moderate prenatal alcohol
exposure demonstrated behaviors of concern, including:
increased demand for attention, behavior regulation prob-
lems, and poorer interactive play skills.
Our systematic review and meta-analyses corroborated
other meta-analyses and systematic reviews and have pro-
vided further evidence for a strong association between binge
prenatal alcohol use and cognition (where binge alcohol use
is defined as drinking 4 or more drinks on 1 occasion). We
observed a robust detrimental association between such
exposure and diverse aspects of cognition in children aged
6 months to 14 years. Among 6 study populations for whom
this relation was assessed, children of mothers who engaged
in binge drinking during pregnancy scored lower on tests of
cognitive ability than children whose mothers did not binge
drink during pregnancy. Our meta-analysis included 5 addi-
tional studies, whose populations were not considered in the
systematic review by Henderson and colleagues (2007).
Importantly, 2 of these studies were conducted among older
children (i.e., aged 8 to 14 years), suggesting associations
observed among younger children extended to older children
as well.In contrast to binge prenatal alcohol exposure, mild-
to-moderate prenatal alcohol exposure was not associated
consistently with cognition, corroborating the meta-analysis
by Testa and colleagues (2003), which also did not find a con-
sistent association between less than daily drinking and men-
tal development at all ages examined (6 to 26 months). Our
analysis expanded on the one by Testa by including children
aged 14 years and younger, as well as data not available in
2003 on more than 20,000 children. The results from this
analysis showed a small, beneficial association between mild-
to-moderate prenatal alcohol exposure and child cognition.
We suspect that this association was due to residual con-founding as the association was no longer significant when
considering only studies that controlled for SES.
We detected no consistent evidence that mild or moderate
prenatal alcohol exposure was associated with attention,
cognition, language skills, and visual or motor development,
or that binge drinking was associated with outcomes other
than cognition. Overall, these results align with our initial
hypotheses that (i) we would not observe a consistent associ-
ation between mild and moderate prenatal alcohol exposure
and child neuropsychological outcomes and (ii) prenatal
binge drinking would be detrimentally associated with at
least some of the outcomes examined. Although 21 meta-
analyses used data from more than 20 studies, the number
of high-quality studies in which investigators controlled for
SES was much lower, suggesting the need for further cohort
studies designed to rule out or at least minimize potential
confounding.
While our results suggest underlying associations between
prenatal alcohol consumption and child neurodevelopment,
there are other explanations to consider. Due to the number
of analyses completed, random effects might have played a
role in these results. In choosing estimates to include in anal-
yses, preference was given to those that accounted for poten-
tial confounders such as SES, maternal intelligence, and
home environment. However, studies were not excluded if
they did not adequately control for those factors. The results
we observed might have been a remnant of some of the
effects of these uncontrolled factors. Various types of selec-
tion were not accounted for, including self-selection by
authors who provided additional data to this analysis com-
pared with those who did not, as well as potential selection
bias within each of the included studies. Additionally, poten-
tial variances in the ways individuals were affected by prena-
tal exposures might have obscured underlying true effects.
That is, for some children, attention might have been
affected adversely, while for other children the same prenatal
PRENATAL ALCOHOLAND CHILD OUTCOMES 9
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exposure levels might have produced an effect on motor
function. Because both of these effects would not be reflected
in an analysis focusing on only 1 of these outcomes, sufficient
statistical power to detect subtle effects might not have been
available. This study also could not account for differences
in drinking patterns and the fact that some individuals may
be more genetically susceptible to the effects of mild and
moderate drinking than others (Lewis et al., 2012). Finally,
the functional domain categories used for this analysis did
not represent mutually exclusive areas of neurodevelopment.
Cohen’s d, Cohen’s d,
Reference Weight (%) Random (95% CI) Random (95% CI) Scale Age
Association between moderate prenatal alcohol exposure and child behavior (High Quality)
99.9
38.1
16.4
25.5
19.9
Favors unexposed Favors exposed
0.04 (0.00, 0.08)
0.04 (-0.02, 0.11)
-0.15 (-0.35, 0.04)
0.05 (-0.12, 0.21)
0.08 (-0.06, 0.22)
0.00 (-0.15, 0.15)
0.03 (-0.07, 0.14)
0.06 (-0.01, 0.13)
0.10 (-0.11, 0.31)
Association between mild-to-moderate prenatal alcohol exposure and child cognition (High Quality)
Association between binge prenatal alcohol exposure and child cognition (All estimates)
Heterogeneity: Chi2=1.79, df=3 (P=0.62);I
2=0%
Test for overall effect: Z=-2.49 (P=0.01)
BRS
Elicited Play
SDQ
SDQ
Brown 2010a
Jacobson SW 1993b
Kelly 2010 - Boys
Kelly 2010 - Girls
Combined
9m
12m
5y
5y
-0.25 (-0.45, -0.06)
-0.14 (-0.44, 0.16)
-0.05 (-0.29, 0.19)
-0.11 (-0.38, 0.16)
-0.15 (-0.28, -0.03)
-1.00 0.00 1.00
Heterogeneity: Chi2=4.99, df=7 (P=0.66);I
2=0%
Test for overall effect: Z=2.20 (P=0.03)
WISC-III
MDI
MDI
BSRA
BSRA
WPSSI-R
Raven's
MDI
8y
9m
18m
3y
3y
5y
14y
18m
0.00 1.00
Favors unexposed Favors exposed
-1.00
Alati 2008
Brown 2010a
Forrest 1991
Kelly 2009 - Boys
Kelly 2009 - Girls
Kesmodel 2012
O'Callaghan 2007
Richardson 1995b
Combined
33.6
3.6
4.8
7.6
6.2
12.9
28.0
3.3
100.0
Heterogeneity: Chi2=11.11, df=7 (P=0.13);I
2=37%
Test for overall effect: Z=-3.02 (P=0.003)
Combined
Alati 2008
Coles 2000
Fraser 2012
Kesmodel 2012
Nulman 2004
O'Callaghan 2007
Olsen 1994c
Streissguth 1989d
100.1
25.7
3.6
6.3
24.3
1.9
19.5
6.3
12.5
-0.13 (-0.21, -0.05)
-0.16 (-0.26, -0.06)
-0.23 (-0.65, 0.20)
0.02 (-0.29, 0.33)
0.01 (-0.09, 0.12)
-0.28 (-0.87, 0.32)
-0.19 (-0.32, -0.05)
-0.14 (-0.45, 0.17)
-0.27 (-0.47, -0.08)
WISC-III
MDI
FTII - NP
WPPSI-R
McCarthy GCI
Raven's
MDI
WISC-R
8y
12m
6m
5y
7y
14y
18m
7.5y
0.00 1.00
Favors unexposed Favors exposed
-1.00
Fig. 2. Meta-analysis results for the associations between: (1) moderate prenatal alcohol exposure and child behavior, (2) mild-to-moderate prenatalalcohol exposure and child cognition, and (3) binge prenatal alcohol exposure and child cognition. CI, confidence interval; SDQ, Strengths and DifficultiesQuestionnaire; MDI, Bayley Scales of Infant Development: Mental Development Index; WISC, Wechsler Intelligence Scale for Children (III = Third UKEdition; R = Revised); BRS, Behavior Rating Scale Social Engagement Subscale, Bayley Scales of Infant Development, Second Edition; BSRA, BrackenSchool Readiness Assessment; Elicited Play, Complexity of Play Test — Elicited Play Level; McCarthy GCI, McCarthy Scales of Children’s Abilities: Gen-eral Cognitive Index; Raven’s, Raven’s Standard Progressive Matrices Test; WPPSI-R, Wechsler Preschool and Primary Scale of Intelligence — Revised;FTII-NP, FTII Novelty Preference aSample size and standard error obtained from author. bMean, standard deviation, and sample size obtained fromauthor. cUsed standard deviation calculated from other articles using this scale. dUsed approximate sample sizes and standard deviation of the overallgroup.
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Measures used to assess 1 area almost always evaluate
related areas; for example, measures of behavior frequently
also assess aspects of attention. This overlap might have
diluted effects when single measures or domains were
analyzed.
The primary strengths of this analysis were the longitudi-
nal design of included studies and the systematic search and
review process. The longitudinal design of studies allowedfor examination of temporal associations between the expo-
sures and outcomes of interest. Our systematic review of the
literature, followed by screening articles using explicit
inclusion criteria, aided us in capturing articles published in
English relevant to this topic. Published data from studies
were supplemented by additional information gained by
contacting study authors.
The primary limitation of this review was the inconsistency
of the methodologies of the included studies. Alcohol con-
sumption was measured via self-report during different
trimesters. Studies such as that by Robinson and colleagues
(2010) focused on exposure during the first trimester, whilestudies such as the one by Kelly and colleagues (2009) were
concerned with any exposure during the entire prenatal per-
iod. This variation raises concerns about aggregating the
results of these studies, particularly because timing is an
important determinant of the effects of prenatal alcohol
exposure (at least with respect to short-term adverse out-
comes). While self-report is the best available method to
obtain information about alcohol consumption, there con-
tinue to be concerns that reporting might be affected by the
time interval between consumption and recall, the mode of
data collection (Ekholm et al., 2011; Kesmodel and Fryden-
berg, 2004), and social stigma against drinking during preg-
nancy. In regard to outcome assessment, the
neuropsychological outcomes we considered were measured
using different scales on children ranging in age from
6 months to 15 years. Meta-analysis is a beneficial tool for
summarizing study results, but can be affected by methodo-
logical study heterogeneity, as well as assumptions when con-
verting between measures of effect. These effects can be
particularly worrisome when including individuals of a wide
age range to examine such a complex area as neurodevelop-
ment. An additional limitation of this review is the potential
bias introduced by exclusion of articles not in English and
exclusion of results from unpublished studies.
This review highlights the importance of abstaining from
binge drinking during pregnancy. It provides evidence that
there is no known safe amount of alcohol to consume while
pregnant. Effects of prenatal alcohol exposure on neurode-
velopment might start at levels <1 drink a day during the
prenatal period, and drinking at this level may have substan-
tial implications for public health at the population level.
Research is needed in this field to develop better methods for
prenatal alcohol exposure assessment. Future studies using
such assessment methods and standardized quantifications
of exposure will aid us in combining results from multiple
studies. Such studies also should control for important
potential confounders, such as SES and parental intelligence,
to differentiate between the effects of prenatal alcohol expo-
sure and other potential determinants of neuropsychological
outcomes. Studies that use more sophisticated measures of
neurodevelopment and assess domains omitted from previ-
ous studies, such as mental health and executive function,
are particularly important. As more studies on the neurode-
velopment of children with mild, moderate, and binge prena-tal alcohol exposure that incorporate these modifications are
available, periodic systematic reviews and meta-analyses will
make important contributions to this field.
ACKNOWLEDGMENTS
The authors thank Camille Smith, MS, EdS for her work
on outcome classifications for this study and Gail Bang,
MLIS for her development and completion of the systematic
searches. This research was supported in part by an appoint-
ment to the Research Participation Program at the Centers
for Disease Control and Prevention (CDC) administered bythe Oak Ridge Institute for Science and Education through
an interagency agreement between the U.S. Department of
Energy and CDC.
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SUPPORTING INFORMATION
Additional Supporting Information may be found in the
online version of this article:
Table S1. Detailed Systematic Search Criteria.
Fig. S1. Meta-analysis results for the associations
between: (1) moderate prenatal alcohol exposure and child
attention, (2) mild prenatal alcohol exposure and child behav-
ior, (3) mild prenatal alcohol exposure and child cognition,
(4) moderate prenatal alcohol exposure and child cognition,
(5) mild prenatal alcohol exposure and child language and
verbal development, (6) moderate prenatal alcohol exposureand child language and verbal development, (7) mild prena-
tal alcohol exposure and child visual and motor develop-
ment, (8) moderate prenatal alcohol exposure and child
visual and motor development.
Fig. S2. Meta-analysis results for the associations between
binge prenatal alcohol consumption and: (1) academic math
performance, (2) academic reading performance, (3) atten-
tion, (4) behavior, (5) executive function, (6) language and
verbal development, (7) visual and motor development.
PRENATAL ALCOHOLAND CHILD OUTCOMES 13