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Keywords:

  • Prenatal Alcohol Exposure;
  • Child Neurodevelopment;
  • Systematic Review;
  • Meta-Analysis

Abstract

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References
  8. Supporting Information

Background

The objective of this review is to evaluate the literature on the association between mild, 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 PsycINFO® (1970 through August 2012) and examination of selected references.

Results

From 1,593 articles, we identified 34 presenting data from cohort studies that met our inclusion criteria. Information on study population, outcomes, measurement instruments, timing and quantification of alcohol exposure, covariates, and results was abstracted. Outcomes included academic performance, attention, behavior, cognition, language skills, memory, and visual and motor development. 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 detrimental association between any binge prenatal alcohol exposure and child cognition (Cohen's d [a standardized mean difference score] −0.13; 95% confidence interval [CI], −0.21, −0.05). Based on 3 high-quality studies of 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 −0.15; 95% CI, −0.28, −0.03). We observed a significant, albeit small, positive association between mild-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 consumption nor was it significant when including only studies that assessed moderate alcohol consumption. None of the other completed meta-analyses resulted in statistically significant associations between mild, moderate, or binge prenatal alcohol exposure and child neuropsychological outcomes.

Conclusions

Our findings support previous findings suggesting the detrimental effects of prenatal binge drinking on child cognition. Prenatal alcohol exposure at levels less than daily drinking might be detrimentally 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.

In 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 neurodevelopment are inconsistent. Due to the large population of women of childbearing age in the United States who consume alcohol and the high rates of unintended pregnancy, even small effects of prenatal alcohol use could have detrimental repercussions to overall child neurodevelopment at the population level (Centers for Disease Control and Prevention, 2009; U.S. Department of Health and Human 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) prenatal alcohol 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, Henderson 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 heterogeneity of studies. The 4 studies included by this review examined 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 previously 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 appropriate 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 primary 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 prenatal alcohol exposure (>0 to 6 drinks per week) and child neuropsychological outcomes; (ii) examine the evidence for an association between binge prenatal alcohol exposure (usually defined as ≥4 or ≥5 drinks per occasion) and child neuropsychological 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 prenatal binge drinking, we hypothesized that the literature would reveal a detrimental effect on at least some of the neuropsychological outcomes examined.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References
  8. Supporting Information

Search Strategy

We searched 3 databases using OvidSP: MEDLINE (1970 through August 2012), EMBASE (1988 through August 2012), and PsycINFO® (1970 through August 2012). Search strategies included the keywords “alcohol,” “drinking behavior,” and “fetal development,” and a list of outcomes of interest such as “cognition disorders” (see inclusion criteria that follow). Final search results excluded editorials, letters, reviews, and articles in languages other than English. In collaboration with a medical librarian, we modified the search strategies used by Henderson and colleagues (2007) to include mild and moderate alcohol exposure as well as additional terms on neurodevelopment and to exclude terms for outcomes not of interest (e.g., preterm delivery). The final search strategy is provided in Table S1. Bibliographies of included articles and systematic reviews relating to this subject were searched manually for articles missed by electronic searches.

Study Selection

An article was included in this review if it presented data from a cohort or case–control study on the relation between mild, moderate, or binge prenatal alcohol exposure and 1 or more child neuropsychological outcomes (Table 1). These outcomes included cognition, motor skills, language, behavior, vision, hearing, development, 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 3 drinks per week, up to 6 drinks per week, up to 6 drinks per week including some individuals who consumed at least 3 drinks per week, and more than 6 drinks per week, respectively, with 13.7 g of alcohol equaling 1 drink. There are no internationally acknowledged standard definitions of mild, moderate, and heavy alcohol consumption during pregnancy. The categories used in this review were defined by the authors to focus on drinking at less than daily levels and after careful review of exposure categories used in the literature. Binge drinking was defined as 4 or more drinks on 1 occasion (binge drinking defined as 5 or more drinks on 1 occasion were included as a subset; National Institute on Alcohol Abuse and Alcoholism, 2004; Wechsler et al., 1995).

Table 1. Systematic Review Inclusion and Exclusion Criteria
Inclusion criteria
  1. Cohort or case–control design
  2. 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 and anthropometric measures, congenital anomalies, outcomes at birth, or child or adolescent alcohol and substance abuse
  2. Does not use a standardized scale to measure outcome
  3. Includes children with diagnoses of fetal alcohol syndrome or fetal alcohol effects
  4. Lacks a comparison group of mothers with no alcohol exposure
  5. Focuses primarily on other drug use with alcohol included only as a confounder or adjustment variable
  6. 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 the prenatal period
  8. Alcohol exposure measured as a continuous variable, all exposure categories include women who drink >7 drinks per week, and investigators assume a linear association between alcohol intake and neurodevelopment (also applies if alcohol exposure transformed in the analysis in attempts to compensate for skewness or outliers, or both)
  9. Contains information only on the same cohort and outcome(s) as already included articles

Articles that met the initial inclusion criteria were examined against a list of exclusion criteria (Table 1) such as including children with an explicit diagnosis of an FASD or lack of a comparison group of children with no prenatal alcohol exposure. Individuals with a diagnosed FASD were excluded because current evidence has indicated that these diagnoses are associated with levels of alcohol exposure above the mild-to-moderate level examined in this review and meta-analysis (Bertrand et al., 2004). Our aim was to investigate the neuropsychological effects of prenatal alcohol exposure below levels previously associated with these clinical diagnoses.

Initially, we screened the title and abstract of each identified article using our inclusion criteria and full list of exclusion criteria. An article was excluded with no further review if it clearly did not meet our article requirements. If the abstract contained any indication of relevance to the review, 1 author also screened the full article (Fig. 1).

image

Figure 1. Summary of article review process including primary reasons for article exclusion.

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Data Abstraction

A study researcher trained in epidemiology abstracted data from the articles marked for inclusion using a standard form. Information extracted from articles included study design, population, outcomes, outcome measurement instruments, timing and quantification of alcohol exposure, measured covariates, and results. To assess reliability, about half of the included articles were abstracted by 1 or more additional researchers. The research team collectively 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 development advances and for children with prenatal alcohol exposure, abnormalities in subtle mental health issues or higher-order neurocognition (e.g., executive function) may only emerge or be assessed at older ages. If more than 1 measurement on the same outcome was completed for the same child at the same age, we chose the measurement based on maternal report (over paternal or teacher report). For full data selection criteria, see Table 2. If an article presented results stratified by a characteristic (e.g., child sex) and results could not be combined, then data in each strata were abstracted and included in the meta-analysis.

Table 2. Data Selection Criteria
Data selection criteria applied when: (i) A given outcome was assessed multiple times in the same cohort, or (ii) Multiple cohorts prenatally exposed to alcohol were compared with the same nonexposed cohort
  • 1.
    When a given outcome was assessed by multiple scales or at multiple time points in the same children, the following rules were applied:
    1. Parental assessment was included instead of teacher assessment
    2. Maternal assessment was included instead of paternal assessment
    3. Results measuring the outcome at the oldest age were included
    4. The most standardized, comprehensive measures were included
  • 2.
    When multiple cohorts of children prenatally exposed to alcohol were compared with the same nonexposed cohort, only 1 comparison could be included in each analysis. This prevented including the same control group more than once in a given meta-analysis. The following rules were applied in this situation:
    1. 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 pregnancy were included instead of children whose mothers binge drank 3 times a week during pregnancy)
    2. If the cohorts of exposed children were prenatally exposed to alcohol during different trimesters, the cohort of children with the earliest exposure was included

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., data did not provide a measure of variance). Author-supplied data were included in the meta-analysis. In cases for which authors no longer had access to the data and information was incomplete, the data were excluded from this review.

Outcome Classification

For the purposes of this review, we divided neuropsychological outcomes 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) were examined separately. This grouping prevented instruments measuring different constructs from being included in the same analysis. Two psychologists reviewed each instrument independently and classified them into 1 of these domains. All discrepancies in outcome classification were discussed, and a consensus was reached.

Quality Assessment

The quality of each article meeting the review criteria was assessed 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 assessment of the following potential confounders: socioeconomic status (SES), cigarette smoking, and maternal age and intelligence. We specifically noted whether studies of high quality controlled for SES (i.e., income or education), given the strong associations between SES and both prenatal alcohol use and child neuropsychological outcomes (Bradley and Corwyn, 2002; Centers for Disease Control and Prevention, 2009). Detailed NOS score ratings for each of the papers may be obtained from the authors.

Table 3. Adapted Newcastle–Ottawa Quality Assessment Scale: Cohort Studies
 Maximum points
  1. SES, socioeconomics status.

Selection
1. Representativeness of the exposed cohort 1
  1. The researchers attempted to select participants that were reasonably representative of the average low, moderate, or binge drinkers in the community (1 point)
  2. The researchers and the reader have reason to believe that their participants are reasonably representative of the average low, moderate, or binge drinkers in the community (1 point)
  3. Either no data on representativeness, or no reason to believe the participants were representative of the average low, moderate, or binge drinkers in the community, or over-sampled heavy drinkers (0 points)
 
2. Selection of the nonexposed cohort 1
  1. Drawn from the same community as the exposed cohort (1 point)
  2. Drawn from a different source than the exposed cohort (0 points)
  3. No description of the derivation of the nonexposed cohort (0 points)
 
3. Ascertainment of exposure 1
  1. Structured interview (1 point)
  2. Self-administered questionnaire (0 points)
  3. No description (0 points)
 
4. Demonstration that outcome of interest was not present at start of study (omitted) 0
Comparability
1. Comparability of cohorts on the basis of the design or analysis 2
  1. Study controls for SES (could assess using proxy measures such as education or income) (1 point)
  2. Study controls for any of: cigarette smoking, maternal age, maternal IQ (1 point)
 
Outcome
1. Assessment of outcome 1
  1. Independent blind assessment (1 point)
  2. Not a blind assessment (0 points)
  3. No description of outcome assessment (0 points)
 
2. Follow-up long enough for outcomes to occur 1
  1. Yes (1 point)
  2. No (0 points)
 
3. Adequacy of follow-up cohorts 1
  1. Complete follow-up or subjects lost to follow-up unlikely to introduce bias: ≥70% follow-up and description provided of those lost indicates they are comparable to those kept on SES and prenatal alcohol exposure (1 point)
  2. Follow-up rate <70% and description of those lost does not indicate comparability (0 points)
  3. Does not fall under (a) or (b) or no statement describing the adequacy of follow-up cohorts (0 points)
 
Total points possible8

Statistical Analysis

Measures of effect from binary and correlational data were converted 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 this review based on their use of measures of association (such as odds ratios [ORs]). Random effects meta-analyses were completed separately for each of the neurodevelopmental domains and exposure quantity combinations using Cohen's d as the summary measure. For each exposure–outcome meta-analysis, a measure of overall effect and measures of heterogeneity (i.e., Q statistic, I2) were calculated. A sensitivity analysis based on study quality and a publication bias assessment using funnel plots and the Egger test were completed (results available from the authors upon request; Egger et al., 1997). Comprehensive Meta-Analysis 2.0 software was used for all meta-analyses (Borenstein et al., 2005).

Results

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References
  8. Supporting Information

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 measuring outcomes other than neuropsychological outcomes (n = 466). Authors were contacted to request additional information 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 neuropsychological outcomes and mild or moderate prenatal alcohol 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; 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 articles. Outcomes not fitting in these domains, such as mental health, were in 4 articles. The scarcity of data on these additional outcomes precluded further analysis of their results.

Table 4. Characteristics of Included Studies that Measured Mild or Moderate Levels of Prenatal Alcohol Exposure by Article
First author/year, countrySample size at follow-up n (% of baseline)Enrollment periodOutcome categories assessedaAge at follow-upPrenatal alcohol exposure assessmentbNOS scorec
Trimester(s) assessedMild (g/wk)Moderate (g/wk)
  1. g/wk, grams per week; NOS, Newcastle–Ottawa Scale; y, year; m, month; NR, not reported.

  2. a

    Visual and Motor = Visual and Motor Development, Academic = Academic Performance, Language = Language and Verbal.

  3. b

    Alcohol Exposure Quantification: All alcohol exposure categories were converted to grams per week using the conversion 13.7 g alcohol = 0.6 oz = 1 drink (U.S. Centers for Disease Control and Prevention. Alcohol and Public Health FAQs. http://www.cdc.gov/alcohol/faqs.htm). The exposure categories reported by studies in grams were kept intact regardless of the conversions used by the researchers. Alcohol categories were rounded to the nearest tenth. Mild exposure: any exposure up to 3 drinks per week (41.1 g/wk). Moderate exposure: any exposure up to 6 drinks per week (82.2 g/wk) which included some individuals with exposure of at least 3 drinks per week (41.1 g/wk). In the event that a study had multiple exposure categories that fit this classification, the category that covered the largest range was chosen.

  4. c

    NOS Quality Assessment Score. Possible values: 1 (lowest quality) to 8 (highest quality).

  5. d

    Range of birth years instead of enrollment period.

  6. e

    Rounded to the nearest 50.

  7. f

    Sulaiman and colleagues (1988).

  8. g

    Attentional and learning questionnaires.

  9. h

    Psychometric assessment.

  10. i

    2 years.

  11. j

    5 years.

  12. k

    8 years.

  13. l

    Bayley Scales of Infant Development: Mental Development Index.

  14. m

    Bayley Scales of Infant Development: Psychomotor Development Index.

  15. n

    Dundee [UK] cohort (Bolumar, 1992).

  16. o

    Odense [Denmark] cohort (Bolumar, 1992).

  17. p

    Berlin [Germany] cohort (Bolumar, 1992).

  18. q

    18 months.

  19. r

    10 years.

  20. s

    14 years.

  21. t

    Aarhus Birth Cohort (ABC) [Denmark].

  22. u

    Habits for Two (HHT) [Denmark].

  23. v

    Northern Finland Birth Cohort (NFBC) [Finland].

  24. < and ≤grams of alcohol do not include 0. Outcomes and ages assessed by articles, but not included in meta-analyses, are not listed in this table.

Alati/2008, United Kingdom4,332 (32.5)1991 to 1992dCognition8 y1st<13.7 6
Bay/2012, Denmark685 (86.9)2003 to 2008Visual and Motor5 y1st, 2nd 12.0 to 48.08
Brown/2010, United States10,500e (NR)2001d

Behavior

Cognition

Visual and Motor

9 m3rd<13.713.7 to 41.16
Forrest/1991, Scotland592 (70.0)1985 to 1986

Cognition

Visual and Motor

18 m1st, 2ndf 1.0 to 49.07
Jacobson/1993a, United States382 (NR)NRCognition13 m1st, 2nd, 3rd 0.2 to 78.35
Jacobson/2011, United States262 (NR)1986 to 1989Attention7.5 y1st, 2nd, 3rd 1.6 to 78.33
Jacobson/1993b, United States310 (76.9)1986 to 1989Behavior

6.5 m

12 m

1st, 2nd, 3rd 0.2 to 78.37
Kaplan-Estrin/1999, United States92 (24.1)NRVisual and Motor26 m1st, 2nd, 3rd0.2 to 39.840.0 to 78.36
Kelly/2009, United Kingdom9,460 (75.9)2000 to 2002dCognition3 y1st, 2nd, 3rd≤27.4≤82.26
Kelly/2010, United Kingdom11,513 (93.6)2000 to 2002d

Behavior

Language

Visual and Motor

5 y1st, 2nd, 3rd≤27.4≤82.26
Kesmodel/2012, Denmark1,628 (51.1)2003 to 2008

Attention

Cognition

Other

5 y1st, 2nd 12.0 to 48.07
Larkby/2011, United States592 (71.4)1982 to NRBehavior16 y1st, 3rd ≤42.55
Larroque/2000, France156 (47.9)1985 to 1986Other4.5 y1st 13.7 to 82.25
O'Callaghan/2007, Australia

5,139 (71.1)g

3,731 (51.7)h

1981 to 1984

Academic

Attention

Cognition

14 y1st, 3rd ≤48.06
O'Leary/2009, Australia

1,890 (85)i

1,624 (73)j

1,357 (61)k

1995 to 1997d

Attention

Behavior

Cognition

2 y

5 y

8 y

1st, 2nd, 3rd ≤705
Parry/1992, Scotland, Denmark, Germany

1,361 (63.9)l

1,360 (63.8)m

1986 to 1986n

1988 to 1989o

1987 to 1988p

Cognition

Visual and Motor

18 mNR≤2930 to 592
Richardson/1995, United States645 (84.5)q1983 to 1986

Cognition

Visual and Motor

18 m1st, 2nd, 3rd<38.4 6
Robinson/2010, Australia

1,952 (68.1)i

2,127 (74.2)j

2,037 (71.0)k

1,977 (68.9)r

1,744 (60.8)s

1989 to 1991dBehavior

2 y

5 y

8 y

10 y

14 y

1st≤13.727.4 to 82.24
Rodriguez/2009, Denmark, Finland

4,968 (60.3)t

7,844 (70.4)u

8,525 (91.1)v

1990 to 1992t

1984 to 1987u

1986v

Attention

10 yt

12 yt

15 yu

7 to 8 yv

1st, 2nd, 3rdt,u

1st, 2ndv

 13.7 to 54.85
Sayal/2007, United Kingdom8,046 (63.5)1991 to 1992dBehavior81 m1st<13.7 5
Sood/2001, United States506 (76.1)1989 to 1991dBehavior6 to 7 y1st, 2nd, 3rd <48.03
Willford/2006, United States611 (73.7)1983 to 1985Cognition10 y1st<38.4 3
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-upPrenatal alcohol exposure assessmentNOS scoreb
Trimester(s) assessedBinge (drinks/occasion)
  1. NOS, Newcastle–Ottawa Scale; y, year; m, month; NR, not reported.

  2. a

    Visual and Motor = Visual and Motor Development, Academic = Academic Performance, Language = Language and Verbal.

  3. b

    NOS Quality Assessment Score. Possible values: 1 (lowest quality) to 8 (highest quality).

  4. c

    Range of birth years instead of enrollment period.

  5. d

    Behavior.

  6. e

    Language and Verbal, Visual and Motor Development.

  7. f

    At least once every 2 weeks during pregnancy.

  8. g

    Drews and colleagues (2003).

  9. h

    Goldschmidt and colleagues (1996).

  10. i

    Attention, Academic Performance.

  11. j

    Cognition.

  12. k

    18 months.

  13. l

    3.5 years.

  14. m

    Streissguth and colleagues (1981).

  15. n

    Willford and colleagues (2006).

  16. Outcomes and ages assessed by articles, but not included in meta-analyses, are not listed in this table.

Alati/2008, United Kingdom4,332 (32.5)1991 to 1992cCognition8 y2nd, 3rd4+6
Alvik/2011, Norway1,303 (69.6)2000 to 2001Behavior6 m1st5+6
Bailey/2004, United States

499 (75.0)d

537 (80.8)e

1989 to 1991c

Behavior

Language

Visual and Motor

7 y1st, 2nd, 3rd5+f7
Coles/2000, United States136 (41.7)1993 to 1994g

Behavior

Cognition

Visual and Motor

12 m1st, 2nd, 3rd5+5
Fraser/2012, Canada195 (81.3)NR

Visual and Motor

Cognition

6 m1st, 2nd5+7
Goldschmidt/2004, United States606 (79.4)1983 to 1986h

Academic

Other

10 y1st, 2nd, 3rd4+5
Kesmodel/2012, Denmark1,628 (51.1)2003 to 2008

Attention

Cognition

Executive Function

5 y1st, 2nd5+7
Lemola/2009, Switzerland323 (70.5)NRBehavior17 m1st, 2nd, 3rd4+3
Nulman/2004, Canada102 (71.3)1987 to 1997

Academic

Cognition

Language

Visual and Motor

Other

≤7 y1st5+6
O'Callaghan/2007, Australia

5,139 (71.1)i

3,731 (51.7)j

1981 to 1984

Academic

Attention

Cognition

14 y1st, 3rd5+6
Olsen/1994, Denmark

276 (84.2)k

251 (76.5)l

1988 to 1989

Cognition

Visual and Motor

18 m

3.5 y

1st, 2nd, 3rd8+5
Streissguth/1989, United States486 (86.0)1974 to 1975

Behavior

Cognition

Language

Visual and Motor

Other

7.5 y1st, 2nd5+5
Streissguth/1994a, United States464 (82.0)1974 to 1975mAcademic14 y1st, 2nd5+3
Streissguth/1994b, United States462 (82.0)1974 to 1975m

Attention

Executive Function

Memory

14 y1st, 2nd5+7
Willford/2004, United States580 (70.0)1983 to 1985nMemory14 y1st4+5

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 6 or more points was deemed of “high quality” for the purposes 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 outcomes (behavior, cognition, and visual and motor), and (iv) binge exposure and 9 outcomes (academic reading performance, 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 development, 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 −0.15; 95% confidence interval [CI], −0.28, −0.03; = 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 conducted among 9-month-old infants and assessed behavior using the behavior rating scale of the Bayley Scales of Infant Development (Bayley, 1993).

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Figure 2. Meta-analysis results for the associations between: (1) moderate prenatal alcohol exposure and child behavior, (2) mild-to-moderate prenatal alcohol exposure and child cognition, and (3) binge prenatal alcohol exposure and child cognition. CI, confidence interval; SDQ, Strengths and Difficulties Questionnaire; MDI, Bayley Scales of Infant Development: Mental Development Index; WISC, Wechsler Intelligence Scale for Children (III = Third UK Edition; R = Revised); BRS, Behavior Rating Scale Social Engagement Subscale, Bayley Scales of Infant Development, Second Edition; BSRA, Bracken School Readiness Assessment; Elicited Play, Complexity of Play Test—Elicited Play Level; McCarthy GCI, McCarthy Scales of Children's Abilities: General 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 from author. cUsed standard deviation calculated from other articles using this scale. dUsed approximate sample sizes and standard deviation of the overall group.

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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; = 0.03; Fig. 2). None of the associations observed in the individual studies in this subanalysis were statistically significant. 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 centered at zero among girls, but not boys.

This association between mild-to-moderate prenatal alcohol exposure and cognition was of similar magnitude, but no longer significant in a post hoc analysis considering only the 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, −0.01, 0.09; = 0.08). The association 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 were of “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 −0.13; 95% CI, −0.21, −0.05; < 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 borderline significant when limited to data from studies of high quality (n & 9,000, p = 0.054).

None of the meta-analyses resulting in significant associations between mild, moderate, or binge prenatal alcohol exposure and neuropsychological outcomes showed any evidence of heterogeneity (determined by p-value > 0.05 for the Q statistic) or publication bias (Egger test p-value > 0.05).

All remaining analyses failed to show statistically significant associations between binge prenatal alcohol exposure and neuropsychological outcomes (Fig. S2 presents all calculated meta-analyses of binge alcohol exposure with nonsignificant results). The majority of these analyses included data from more than 5 populations and showed no indication of heterogeneity or publication bias.

Discussion

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References
  8. Supporting Information

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 findings showing that moderate levels of alcohol exposure were associated with behavior, the clinical, or functional significance 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 problems, and poorer interactive play skills.

Our systematic review and meta-analyses corroborated other meta-analyses and systematic reviews and have provided 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 additional 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 consistent association between less than daily drinking and mental 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 confounding 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 association 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 analyses, preference was given to those that accounted for potential 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 selection were not accounted for, including self-selection by authors who provided additional data to this analysis compared with those who did not, as well as potential selection bias within each of the included studies. Additionally, potential variances in the ways individuals were affected by prenatal 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 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. 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 longitudinal design of included studies and the systematic search and review process. The longitudinal design of studies allowed for examination of temporal associations between the exposures 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 consumption was measured via self-report during different trimesters. Studies such as that by Robinson and colleagues (2010) focused on exposure during the first trimester, while studies such as the one by Kelly and colleagues (2009) were concerned with any exposure during the entire prenatal period. 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 outcomes). While self-report is the best available method to obtain information about alcohol consumption, there continue 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 Frydenberg, 2004), and social stigma against drinking during pregnancy. 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 methodological study heterogeneity, as well as assumptions when converting 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 neurodevelopment. 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 neurodevelopment might start at levels <1 drink a day during the prenatal period, and drinking at this level may have substantial 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 exposure and other potential determinants of neuropsychological outcomes. Studies that use more sophisticated measures of neurodevelopment and assess domains omitted from previous studies, such as mental health and executive function, are particularly important. As more studies on the neurodevelopment of children with mild, moderate, and binge prenatal alcohol exposure that incorporate these modifications are available, periodic systematic reviews and meta-analyses will make important contributions to this field.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References
  8. Supporting Information

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 appointment to the Research Participation Program at the Centers for Disease Control and Prevention (CDC) administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and CDC.

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  6. Acknowledgments
  7. References
  8. Supporting Information
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Supporting Information

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References
  8. Supporting Information
FilenameFormatSizeDescription
acer12214-sup-0001-Supplement.docxWord document692K

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 behavior, (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 exposure and child language and verbal development, (7) mild prenatal alcohol exposure and child visual and motor development, (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) attention, (4) behavior, (5) executive function, (6) language and verbal development, (7) visual and motor development.

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