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Keywords:

  • Alcohol consumption;
  • attention;
  • binge drinking;
  • BRIEF;
  • executive function;
  • intelligence;
  • low to moderate neurodevelopmental effects;
  • multiple outcome analyses;
  • prenatal exposure;
  • TEACh-5;
  • WPPSI-R

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure of interests
  8. Contribution to authorship
  9. Details of ethics approval
  10. Funding
  11. Acknowledgements
  12. References

Please cite this paper as: Kesmodel U, Bertrand J, Støvring H, Skarpness B, Denny C, Mortensen E, the Lifestyle During Pregnancy Study Group. The effect of different alcohol drinking patterns in early to mid pregnancy on the child’s intelligence, attention, and executive function. BJOG 2012;119:1180–1190.

Objective  To conduct a combined analysis of the estimated effects of maternal average weekly alcohol consumption, and any binge drinking, in early to mid pregnancy on general intelligence, attention, and executive function in 5-year-old children.

Design  Follow-up study.

Setting  Neuropsychological testing in four Danish cities 2003–2008.

Population  A cohort of 1628 women and their children sampled from the Danish National Birth Cohort.

Methods  Participants were sampled based on maternal alcohol consumption during early pregnancy. At age 5 years, the children were tested for general intelligence, attention, and executive function. The three outcomes were analysed together in a multivariate model to obtain joint estimates and P values for the association of alcohol across outcomes. The effects of low to moderate alcohol consumption and binge drinking in early pregnancy were adjusted for a wide range of potential confounding factors.

Main outcome measures  Wechsler Preschool and Primary Scale of Intelligence—Revised (WPPSI-R), the Test of Everyday Attention for Children at Five (TEACh-5), and the Behavior Rating Inventory of Executive Functions (BRIEF) scores.

Results  Multivariate analyses showed no statistically significant effects arising from average weekly alcohol consumption or any binge drinking, either individually or in combination. These results replicate findings from separate analyses of each outcome variable.

Conclusions  The present study contributes comprehensive methodological and statistical approaches that should be incorporated in future studies of low to moderate alcohol consumption and binge drinking during pregnancy. Furthermore, as no safe level of drinking during pregnancy has been established, the most conservative advice for women is not to drink alcohol during pregnancy. However, the present study suggests that small volumes consumed occasionally may not present serious concern.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure of interests
  8. Contribution to authorship
  9. Details of ethics approval
  10. Funding
  11. Acknowledgements
  12. References

High prenatal exposure to alcohol has consistently been associated with adverse effects on neurodevelopment. Areas such as intelligence,1,2 attention,3,4 and executive function5,6 have been found to be particularly vulnerable. Less is known about the effects of low to moderate, weekly average consumption levels. In addition to absolute levels of alcohol exposure in utero, differences in maternal drinking patterns may also impact these areas of functioning in young children.7,8

Individual alcohol consumption may be described by four components: frequency, quantity, variability, and timing.9 During pregnancy, women are usually asked simply how many drinks they drink on average per day,10,11 or per week,12,13 although other variants are also used.9,14 However, a single measure of overall consumption cannot give a sufficiently detailed picture of the pattern of consumption. A recurrent problem in most previous studies on prenatal alcohol exposure is that, with few exceptions, they have obtained only one estimate of consumption at one point in time during pregnancy. Binge drinking,15 or any other measure of variability or peak exposure,16 has only been considered in a very few studies.8

Studies on moderately high alcohol intake during pregnancy have yielded somewhat inconsistent findings, showing sporadic associations with cognitive function. A few studies of children of mothers with an intake of two or three drinks per day have reported lower general intelligence compared with children whose mothers had no intake,17 but several other studies have failed to detect such an association.18 Attention deficits and dysfunctions are among the most commonly reported adverse effects of maternal alcohol consumption during pregnancy, with a few studies showing an association between low levels of prenatal alcohol exposure and attention problems.19 Finally, deficits in executive functioning have been found consistently for children with high levels of prenatal alcohol exposure,20 but no previous studies have investigated associations between low, weekly exposure levels and executive function.

Using data from the Lifestyle During Pregnancy Study (LDPS) of a large cohort of preschool children, recent studies have examined the effects of low to moderate average weekly levels of prenatal alcohol exposure, and any binge drinking, on child IQ,21,22 attention,23 or executive functioning,24 independently, without observing systematic significant effects at less than daily intake levels. However, these three cognitive functions are not independent characteristics of the individual child. By combining multiple outcomes in a single analysis, the results would reflect not only intercorrelations among the three outcomes, but also associations between the combination of outcomes and exposure variables, as well as included covariates such as postnatal factors. Furthermore, in spite of the lack of systematic effects of alcohol exposure observed for individual outcomes, analyses of multiple outcomes might show more consistent and precisely estimated effects of maternal alcohol consumption during pregnancy.

The LDPS is particularly well suited to address multiple exposure patterns as well as multiple outcomes: participants were prospectively sampled from a homogeneous, low-risk population,25 and were systematically sampled according to the average number of drinks consumed per week as well as the timing of binge drinking during early pregnancy. The study included a comprehensive assessment of multiple domains of child neurodevelopmental functioning, and a broad range of covariates was available.

The specific aim of the present study was to conduct a combined, multiple outcome analysis of the effects of maternal average weekly alcohol consumption and binge drinking in early to mid pregnancy on a combination of outcomes: general intelligence, attention, and executive function in 5-year old children using the large and well-characterised LDPS sample.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure of interests
  8. Contribution to authorship
  9. Details of ethics approval
  10. Funding
  11. Acknowledgements
  12. References

Sample

The LDPS has been described in detail elsewhere, including the sampling frame.26 Briefly, participants were drawn from the Danish National Birth Cohort (DNBC),25 which is a prospective cohort study of 101 042 women and their children. Women in the DNBC were recruited in 1997–2003, at their first antenatal visit to a general practitioner (routinely the first contact with a healthcare practitioner for a pregnant woman). The women participating represent 60% of those invited, and approximately 30% of all pregnant women in Denmark in the period of enrolment.26

Although the focus was on women with low average weekly alcohol consumption (defined in this study as between one and four drinks per week), oversampling was performed for women with moderate and higher levels of alcohol consumption (defined in this study as the consumption of between five and eight drinks or nine drinks or more, per week, respectively), including binge drinking, to ensure an adequate representation in the data.26 Participants who did not drink during pregnancy were included as the unexposed reference group. The sample design and sampling fractions are displayed in Table 1. A total of 3489 women were sampled from the DNBC and invited to participate in the Lifestyle During Pregnancy Study, including 11 twin pregnancies excluded in this study, leaving 3478 sampled for this study. Women sampled on the basis of pre-pregnancy alcohol intake were not included in these analyses (categories 6 and 7 in Table 1, n = 289), leaving 3189 invited women, of whom 1628 were tested. The children in the LDPS were 60–64 months of age (mean age 5.22 years; range 5.00–5.34 years) at follow-up, and 52% of the children were boys.

Table 1.   Maternal drinking patterns and distribution of participants, Lifestyle During Pregnancy Study, Denmark, 2003–2008
Cat.Average numberof drinks/weekBinge drinkingNumber in DNBCNumber sampledSampling fractionNumber tested
Weeks of pregnancy
Before pregnancyIn pregnancy1–23–45–8≥9
1n.a.0NoNoNoNo39 0045790.015257
1an.a.0YesNoNoNo20982030.097113
1bn.a.0NoYesNoNo40062170.054104
1cn.a.0NoNoYesNo14002000.143109
1dn.a.0NoNoNoYes3991980.49694
2n.a.1–4NoNoNoNo26 8513160.012155
2an.a.1–4YesNoNoNo19012030.107113
2bn.a.1–4NoYesNoNo41432150.052120
2cn.a.1–4NoNoYesNo14431990.13893
2dn.a.1–4NoNoNoYes9012050.228114
3an.a.0Yes in at least 219191530.08081
3bn.a.1–8Yes in at least 229051600.05582
   1–23–4≥5    
4n.a.5–8NoNoNo4321480.34379
4an.a.5–8YesNoNo31250.80611
4bn.a.5–8NoYesNo85650.76537
4cn.a.5–8NoNoYes125820.05640
5an.a.≥9NoNoNo20190.95015
5bn.a.≥9Yes in at least 219110.6795
600NoNoNo10 3671440.01469
7≥15n.a.   9741470.15085

Exclusion criteria for the LDPS were the mother’s or child’s inability to speak Danish, impaired hearing or vision of the child to the extent that the test session could not be performed, a child from a multiple pregnancy, and congenital disorders likely to cause mental retardation (e.g. trisomy 21).26

The 5-year follow-up procedures

The mothers sampled were invited to participate in the study by letter approximately 4–6 weeks (mean 5.8 weeks; SD 0.7 weeks) before their child’s fifth birthday. A self-administered questionnaire was mailed to the participating mothers asking about their child’s general postnatal health and development, as well as maternal and paternal postnatal lifestyle characteristics (available on request from the authors).

Child outcome measures and maternal IQ were obtained during a 3-hour assessment at a university or health clinic site.26 Test sites were located in Copenhagen, Aarhus, Odense, and Aalborg to minimise travel distance for all participants. All assessments were administered by ten trained psychologists blinded to the child’s exposure status. Test procedures were standardised in detail. Measures were administered in a fixed order. Reliability across psychologists was assessed periodically, and remained high throughout the collection of data.26 Tester differences were taken into account by the inclusion of an indicator variable in the statistical analyses representing individual testers.

Although psychologists tested the children, mothers were given the Raven IQ test and completed the Behavior Rating Inventory of Executive Function (BRIEF) Parent Form (see below). The BRIEF Teacher Form was mailed to the kindergarten a few weeks before the planned test date. Because of lower participation by teachers, only results for the parents’ BRIEFs are reported in these analyses.

Measures

Exposure variables

Information on alcohol consumption during the index pregnancy was extracted from the first DNBC interview, administered prenatally.27 For women participating in the follow-up, the median time for completing the interview was 17 weeks of gestation (range 7–39 weeks), and 61.6% (n = 1002) completed it between 14 and 20 weeks of gestation. By 20 weeks of gestation, 75% of women had completed the interview. The questions and procedures used have been shown to yield valid (relative to other methods) and reliable information among pregnant Danish women.15,28,29 For the average alcohol intake per week, questions assessed the average number of drinks per week of beer, wine, and spirits that the pregnant woman consumed at the time of the prenatal interview. The definition of a drink followed the definition from the Danish National Board of Health (DNBH), with one standard drink being equal to 12 grams of pure alcohol. The prenatal maternal average alcohol intake was a priori categorised into four groups (0, 1–4, 5–8, and ≥9 drinks/week). Information on episodes of binge drinking was obtained from the same prenatal interviews. Episodes of binge drinking were defined as an intake of five or more drinks on a single occasion. The obtained information also included data on the number of binge episodes as well as the timing (gestational week) of these episodes up until the time of the interview, thus covering nearly the first half of pregnancy. Because the majority of women (69%) reported only one episode of binge drinking, we categorised binge into any versus no binge for this analysis. Some women reported one or more episodes of binge drinking during the early weeks of pregnancy, although their average number of drinks per week at the time of interview was zero. These women were classified accordingly as consuming an average of zero drinks at the time of interview, but with one or more previous binge episodes.

Outcome variables

The LDPS included a comprehensive neuropsychological assessment, which has been described elsewhere.26 This analysis includes a standard clinical intelligence test, a project-developed test of attention, validated with a separate group of Danish preschoolers, and a standard clinical measure of executive function for preschoolers.

Intelligence was assessed with the Wechsler Primary and Preschool Scales of Intelligence—Revised (WPPSI-R),30 which is one of the most widely used standardised tests of intelligence for children aged 3–7 years. The WPPSI-R was the version available in Danish at start of the study. It consists of five verbal subtests and five performance (non-verbal) subtests. from which verbal (VIQ), performance (PIQ), and full-scale (FSIQ) IQs are derived. To reduce the length of the test session, we used a short form including three verbal (arithmetic, information, and vocabulary) and three performance (block design, geometric design, and object assembly) subtests. Standard procedures were used to prorate IQs from the shortened forms of the tests.

As no Danish WPPSI-R norms were available at the time of the study, Swedish norms were used to derive scaled scores and IQs.21

Attention was measured using the recently developed Test of Everyday Attention for Children at Five (TEACh-5).31 The measure is a downward extension for younger children based on the model proposed by Posner and Petersen.32–35 A detailed description of the development of TEACh-5, its validation, and its psychometric properties has been provided elsewhere.31 For the present analyses both selective attention and sustained attention were assessed. Briefly, selective attention was composed of a non-verbal cancellation task plus an auditory task of listening for a specific target among distracters. Sustained attention was composed of an auditory task of counting the number of times a target sound was produced at various rates of presentation, plus a visual motor task of drawing a line as slowly as possible.

The number correct and the log-transformed scores (auditory target identification and drawing a line) were first standardised to a mean of 0 and an SD of 1. The mean of the four standardised scores were then calculated and re-standardised to a mean of 0 and a SD of 1 for use in the statistical analyses.

The BRIEF is an 86-item questionnaire that assesses executive function behaviours in the home, as rated by the mother, and in the day-care environment, as rated by staff. Several aspects of executive functioning are evaluated by the BRIEF, but only data on the three standardised index scores, Behavioral Regulation Index (BRI), Metacognition Index (MI), and Global Executive Composite (GEC),36 are presented in this paper.

A translated version of the BRIEF was used (Hogrefe Psychological Publishers), with minor adjustments for Danish preschool children. No Danish BRIEF norms were available at the time of the study, and consequently we constructed our own Danish norms. A normalising T-score transformation for the observed BRIEF scores was computed, with higher scores indicating more difficulty.37 The BRIEF is a highly reliable instrument: for the two index scores and the overall score, Cronbach′s α, based on the full LDPS sample, was in the range of 0.91–0.96 for the parent version of the questionnaire.

Covariates

The analysis examined a number of potential confounding factors obtained from the prenatal interview, as well as several collected during the assessments of the 5-year-olds. From the prenatal interview the following covariates were included: parity (0, 1, ≥2); prenatal maternal smoking (yes/no); maternal pre-pregnancy body mass index [BMI; weight in kg/(height in m)2]. From the 5-year follow-up, the following variables were included: length of parental education in years (i.e. the average time in education for the two parents combined, or the length of maternal education if information on the father was unavailable, treated as a continuous measures); marital status (i.e. single either at the prenatal interview or at follow-up, or married or cohabitating at both time points); postnatal parental smoking (yes, if at least one of the parents smoked in the home, or no, if otherwise); child health status [yes, if presence of major medical conditions or regular use of prescription medications that might influence performance during the test (including epilepsy, and syndromes such as neurofibromatosis type 1, congenital toxoplasmosis, and hypothyroidism, and medicines for asthma and allergy, attention deficit hyperactivity disorder, epilepsy, and respiratory conditions) or no, if otherwise]; dichotomised family/home environment index (yes, if presence of two or more of the following seven adverse conditions: living with only one biological parent; changes in primary caregiver; day care for more than 8 hours/day before the age of 3 years; ≥14 days of separation from the parents; breakfast irregularity; maternal depression; and parental alcohol use at the time of follow-up above the maximum recommended level by the DNBH of 14 drinks per week for women and 21 drinks per week for men, or no, if otherwise); measured hearing ability on the day of the test (impaired or not impaired); measured vision ability on the test day (impaired or not impaired).

Maternal IQ was assessed at the follow-up examination using two verbal subtests (Information and Vocabulary): the Wechsler Adult Intelligence Scale (WAIS);37 and the Raven’s Standard Progressive Matrices.38 Raw scores were standardised based on the results from the full sample and weighted equally in a combined score that was re-standardised to an IQ scale with a mean of 100 and an SD of 15.

The age of the mother was obtained directly from the unique Danish personal identification number, as were the gender of the child and the age of the child at testing. Birthweight (g) and gestational age (days) were obtained from the Danish Birth Registry.

Statistical analysis

Missing information

The final set of data had a number of missing values in each outcome variable that ranged from 8 (0.5%) for FSIQ to 249 (15.3%) for TEACh-5, mainly because of motivational factors, not understanding the test instructions, or lacking the ability to perform the test. Among covariates, the number of missing values ranged from 2 (0.1%) for the hearing variable to 33 (2.0%) for maternal pre-pregnancy BMI. As missing values were most frequent in outcome variables, we report the pattern of missing values for these individually, together with an overall measure of the level of missing data for covariates (i.e. whether or not at least one covariate had a missing value), in Table 2.

Table 2.   Pattern of missing values
Number of variables with missing information n Missing information on
WPPSI-RTEACh-5BRIEF*Covariates**
  1. X, full information; O, missing information on one variable within column; n = 1628; Denmark, 2003–2008.

  2. *BRIEF—version for parent.

  3. **At least one covariate with missing information.

01337XXXX
139XXXO
2XXOX
229XOXX
212XOXO
1XOOX
1OXXO
1OOXX
36OOXO
Numerical analytic approach

The primary analysis of this paper is a multivariate analysis of multiple neurodevelopmental outcomes,39 using various measures of alcohol consumption as exposures, and with adjustments for confounding factors. Each child attempted to complete the full battery of tests, and these outcomes were expected to correlate. This correlation across the variance-covariance matrix, in general, can be shown to reduce the standard errors of the estimates of the model parameters over the analyses of single outcomes. The multivariate model can be analysed with standard statistical software, if the data set is complete without any missing values. As both individual covariate values and individual outcome values were missing in our data set, we addressed the missing data problem by using multiple imputation, which yields unbiased estimates if the data are missing at random (MAR).40,41 This is not the case for an analysis based only on individuals with complete information for the relevant variables (complete case analysis). The first step in multiple imputations generates m > 1 complete data sets, where in each data set the missing data have been replaced by imputed values, based on predictive distributions for each missing value. In the second step, each of the completed data sets is analysed by standard methods, and the results from the m analyses are combined to produce a single set of inferences that includes the variability associated with the missing data. We used stata 11 to generate 200 imputed—and hence complete—data sets, which we then subjected to the ordinary multivariate analysis (proc mixed; sas 9.2). A large number of imputed data sets, n = 200, was used, as we included several parameters in some of the analyses. proc mixed was chosen over the xtmixed command in stata because it allowed weighting with sampling fractions and robust variance estimation.

All analyses were weighted by sampling fractions, with robust variance estimation to account for the complex stratified sampling design, and all statistical tests were two-sided and declared significant at a level of 5%. All estimates include 95% confidence intervals. For correlation coefficients we used a bootstrap to estimate their confidence intervals.

Data analyses

Parental education, maternal IQ, prenatal maternal smoking, the child’s gender and age at testing, and tester were considered core confounding factors essential to any model of child neurodevelopment, and were included as covariates in an initial model. The final model included the core confounding factors, and the following a priori potential confounding factors were selected on the basis of previous associations described in the literature: parity; maternal marital status; maternal age; pre-pregnancy BMI; home environment; postnatal parental smoking; health status; and hearing and vision abilities.

Furthermore, potential interactions with binge drinking and average alcohol consumption were assessed for the child’s gender, parental education (being strongly associated with cognitive ability), and maternal smoking during pregnancy (being strongly associated with alcohol use).

The study was approved by the DNBC Board of Directors, the DNBC Steering Committee, the regional Ethics Committee, the Danish Data Protection Agency, and the Institutional Review Board at the Centers for Disease Control and Prevention. Signed informed consent was obtained for the LDPS.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure of interests
  8. Contribution to authorship
  9. Details of ethics approval
  10. Funding
  11. Acknowledgements
  12. References

In this sample, the unadjusted mean maternal age was 30.9 (SD 4.4) years: 50.1% of the mothers were primiparous, 12.1% were single, the length of parental education (median number of years, 10th/90th percentile) was 13.0 years (11.0/16.0), and 31.4% reported smoking during pregnancy.21 Among binge drinkers, 69% reported one episode in early pregnancy; the remainder reported between two and 12 episodes. The median weekly number of alcoholic drinks consumed was one drink for the consumption category of 1–4 drinks, five drinks for women in the consumption category of 5–8 drinks; and ten drinks for women in the consumption category of ≥9 drinks. Among the children, the mean birthweight was 3602 (SD 516) grams, and the median gestational age at birth was 281 days with 10th/90th percentiles of 267/293 days. No substantial or statistically significant differences were observed between participants and non-participants for the alcohol exposure variables and the various covariates.21,22

Table 2 shows the pattern of missing data with respect to the three outcomes and the included covariates. The complete case analysis was based on 1337 mother–child pairs, with complete data on all outcomes and covariates. The imputed data set included 1628 pairs. There was relatively little missing data in this sample. The majority of missing data involved one outcome (n = 231) or one or more covariates (n = 39). Among outcome measures, data for the TEACh-5 were most likely to be missing, and among the covariates data for BMI were most likely to be missing.

Table 3 shows the observed correlations among the three outcomes for the 1337 cases with complete information. The table also presents the partial correlations adjusted for alcohol exposure and core confounding factors for both the complete case analysis and the analysis based on imputation sample. The correlation between IQ and the TEACh-5 mean score was moderately strong, whereas the correlations between these two measures and the BRIEF GEC index were significant, but relatively weak. The latter two correlations were negative because low GEC scores correspond with a better rating of the child’s performance.

Table 3.   Correlation matrices for main outcomes in Denmark, 2003–2008
 WPPSI-RTEACh-5BRIEF (parent)
  1. *Confidence intervals computed by bootstrap.

Observed, pairwise correlation matrix (95% CI), complete case, n = 1337
WPPSI-R  1  
TEACh-50.49 (0.43; 0.55)*  1 
BRIEF (parent)−0.16 (−0.25; −0.08)−0.05 (−0.15; 0.05)1
Correlation matrix, adjusted for alcohol and core confounding factors (95% CI), complete case, n = 1337
WPPSI-R  1  
TEACh-50.44 (0.38; 0.50)  1 
BRIEF (parent)−0.11 (−0.21; −0.02)−0.03 (−0.12; 0.06)1
Correlation matrix, adjusted for alcohol and core confounding factors (95% CI), imputed data set, n = 1628
WPPSI-R  1  
TEACh-50.52 (0.47; 0.58)  1 
BRIEF (parent)−0.17 (−0.25; −0.10)−0.08 (−0.17; 0.01)1

Table 4 shows the results of multivariate analysis for the imputed case analyses of the effects of average consumption and binge drinking. For the unadjusted analysis, the overall multivariate test was clearly not significant (P = 0.44), nor were the separate multivariate tests of average alcohol intake and binge drinking (P = 0.63 and 0.28, respectively). The results of the multivariate analysis were corroborated by the pattern of insignificant results in the unadjusted univariate analyses.

Table 4.   Mean differences between maternal alcohol intake in pregnancy and the reference group on WPPSI-R* intelligence test, TEACh-5** test of attention, and BRIEF*** test of executive function
    WPPSI-R*TEACh-5**BRIEF (parent)***
Mean difference (95% CI)Mean difference (95% CI)Mean difference (95% CI)
  1. Imputed data set analyses; = 1628; Denmark, 2003–2008.

  2. *Full-scale IQ.

  3. **Mean attention score.

  4. ***GEC index.

  5. ****Average alcohol intake adjusted for binge drinking, and vice versa.

  6. *****Multivariate test of no alcohol effect (average or binge) across the three outcomes.

  7. ******Multivariate test of no average alcohol effect across the three outcomes.

  8. *******Multivariate test of no binge alcohol effect across the three outcomes.

  9. ********Adjusted for parental education, maternal IQ, prenatal maternal smoking, the child’s gender and age at testing, and tester.

  10. *********Adjusted for parental education, maternal IQ, prenatal maternal smoking, the child’s gender and age at testing and tester, parity, maternal marital status, age, BMI, prenatal maternal average number of drinks per week, home environment, postnatal parental smoking, health status, hearing and vision abilities.

    Unadjusted****
  Multivariate test of no alcohol effect: = 0.44*****
Average alcohol intake  Multivariate test of no average alcohol effect: = 0.63******
0 758ReferenceReferenceReference
1–4 6750.84 (−1.30; 2.98)0.02 (−0.14; 0.17)0.81 (−0.76; 2.38)
5–8 175−1.02 (−3.87; 1.82)−0.01 (−0.30; 0.27)0.63 (−2.37; 3.64)
≥9 20−6.71 (−15.07; 1.65)−0.57 (−1.25; 0.10)2.04 (−0.87; 4.95)
Binge drinking  Multivariate test of no binge alcohol effect: = 0.28*******
No 495ReferenceReferenceReference
Yes11331.27 (−0.42; 2.97)0.04 (−0.09; 0.17)0.61 (−0.64; 1.87)
    Adjusted for core confounding factors********
  Multivariate test of no alcohol effect: = 0.80*****
Average alcohol intake  Multivariate test of no average alcohol effect: = 0.65******
0 758ReferenceReferenceReference
1–4 6750.45 (−1.44; 2.33)0.01 (−0.14; 0.17)0.81 (−0.63; 2.24)
5–8 175−0.62 (−3.49; 2.25)−0.00 (−0.27; 0.27)0.09 (−2.56; 2.74)
≥9 20−6.65 (−14.88; 1.59)−0.60 (−1.28; 0.07)0.64 (−2.35; 3.63)
Binge drinking  Multivariate test of no binge alcohol effect: = 0.90*******
No 495ReferenceReferenceReference
Yes11330.32 (−1.13; 1.76)−0.01 (−0.13; 0.12)0.27 (−0.91; 1.44)
    Adjusted for all potential confounding factors*********
  Multivariate test of no alcohol effect: = 0.89*****
Average alcohol intake  Multivariate test of no average alcohol effect: = 0.74******
0 758ReferenceReferenceReference
1–4 6750.59 (−1.27; 2.44)0.04 (−0.11; 0.19)0.89 (−0.54; 2.31)
5–8 175−0.41 (−3.20; 2.37)0.03 (−0.26; 0.31)−0.02 (−2.56; 2.51)
≥9 20−5.53 (−13.87; 2.81)−0.48 (−1.15; 0.19)0.36 (−2.70; 3.42)
Binge drinking  Multivariate test of no binge alcohol effect: = 0.96*******
No 495ReferenceReferenceReference
Yes11330.16 (−1.31; 1.64)−0.01 (−0.14; 0.11)0.17 (−1.01; 1.35)

Neither the unadjusted analysis nor the adjusted analyses showed any significant multivariate tests. For the model adjusting for core confounding factors, the overall test of the effects from alcohol consumption gave P = 0.80, and average alcohol consumption and binge drinking gave P = 0.65 and P = 0.90, respectively. Thus, a very consistent pattern of insignificant effects of both average consumption and binge drinking was observed. The point estimates of the effects were little affected by adjustment for confounding factors. All models showed insignificant negative effects of nine drinks or more per week on WPPSI-R IQ and TEACh-5 attention scores, whereas the effect on BRIEF were mixed for this group.

Linear and quadratic models were fitted to the outcome variables across increased levels of the average number of drinks per week. Neither model was significant (data not shown).

The multivariate tests of the interaction between average consumption and binge drinking were not significant in any of the statistical models (complete case, = 0.60; multiple imputed data, = 0.96). This was also the case for multivariate tests of the potential interaction of gender, parental education, and prenatal smoking with average consumption, and also with binge drinking.

Supplementary multivariate analyses were conducted with the following outcome variables analysed jointly: VIQ and PIQ; TEACh-5 selective and sustained mean scores; and BRIEF BRI and MI indices. No multivariate tests were significant, and thus these analyses affirmed the results of the main analyses.

The complete data case analysis overall gave the same results as the imputed case, but some of the estimates were slightly different (data not shown). Generally, the results based on the imputed data set were comparable with the results of the complete case analysis, but it is worth noting that most of the P values for the analysis based on the imputed data set were higher than the corresponding P values for the complete case analyses. In WPPSI-R and TEACh-5, the complete data set based on multiple imputation showed larger effect estimates for the group consuming nine or more drinks per week, but also gave wider confidence intervals.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure of interests
  8. Contribution to authorship
  9. Details of ethics approval
  10. Funding
  11. Acknowledgements
  12. References

We found no significant association of low to moderate average weekly alcohol consumption, and any binge drinking, during early to mid pregnancy with the neurodevelopment of children at the age of 5 years. This finding was based on comprehensive methodological and statistical approaches applying multivariate techniques together with state-of-the-art handling of missing values that maximised the chance of detecting a difference between children who had prenatal exposure to alcohol and children who did not. Furthermore, potential findings were investigated across and among the most salient neurodevelopmental outcomes previously associated with prenatal alcohol exposure. To our knowledge, no previous studies on alcohol use during pregnancy have performed such multivariate analyses, analysing several outcomes together within the same model.

Results from this study replicate findings for each individual outcome reported elsewhere,21–24 and also replicate some previous studies that investigated associations between average low to moderate alcohol consumption in the range investigated in this study, or any binge drinking, with individual cognitive outcomes.18,42,43 Furthermore, this study provides important information regarding the lack of interactions between exposure patterns (average intake versus binge drinking) as well as the interactions among outcomes. In addition, this study provides methodological and statistical guidance for future studies of this issue, as it describes a method for analysing both the average weekly consumption of alcohol and binge drinking simultaneously, to investigate possible interactions between these drinking patterns. Finally, this study indicates that multiple outcomes should be included in studies of neurodevelopment, as in utero exposure to alcohol may result in a diverse pattern of cognitive strengths and weaknesses that may only be detected across outcome measures for any particular sample of children.

In addition to these general findings, the results of our analyses also revealed substantially higher unadjusted and adjusted correlations between measures of IQ and the composite attention score than between these cognitive measures and the parent rating of executive functions. The reason for this pattern of correlations may be differing methods of data collection. For IQ and attention the child was tested directly by a trained psychologist. Executive function was assessed by parental observation or interpretation of daily behaviour as related to these cognitive skills. However, all correlations were high enough to make the multiple outcome analyses meaningful. Our data showed a somewhat higher correlation between intelligence and attention scores than is usually observed between measures of these domains,44 but this may reflect the fact that we used a composite (and presumably more reliable) measure of attention.

The strengths of the LDPS data include use of a large prospective cohort, inclusion of a large number of covariates (especially maternal IQ and parental education),18,45 and a sample drawn from a relatively middle-class homogenous population of women. Additionally, the inclusion of multiple exposure patterns allowed for the investigation of possible interactions between these patterns and outcomes. Also, the imputation method allowed for an analysis of the total sample potentially adding to statistical power and diminishing bias. This increased power maximised the opportunity to detect subtle effects and reject the null hypothesis.

Like all studies, limitations were encountered. A null effect always raises the possibility that the study design or measures chosen simply failed to detect a true effect. This is an especially salient point when effects are small or subtle, such as would be expected in this case. Also, because of the many associations between drinking habits and individual and social risk factors for offspring cognitive and behavioural development,46–48 residual confounding is a possibility, despite the broad range of covariates included. However, the analyses presented include outcomes from at least two distinct developmental domains (IQ/attention and executive function), which are unlikely to be associated with exactly the same observed and unobserved confounding factors, and thus the similar results found for all three outcomes substantiate the finding of no significant effects from alcohol. The power to detect the very subtle neurodevelopmental effects under investigation should be considered in this study. Although deviations of half a standard deviation would be the smallest functionally meaningful effect, the small sample sizes at the individual average weekly by binge category levels may have precluded the detection of such subtle effects (especially in the nine or more drinks per week category of consumption).26 We previously calculated the minimum detectable RR in our samples as 1.5, 1.7, and 3.5 for the low (1–4 drinks/week), moderate (5–8 drinks/week), and high (≥9 drinks/week) categories, respectively.

In general, information bias, in particular misclassification, is a possibility in studies of alcohol during pregnancy.49 Even so, with several exposure categories, non-differential misclassification arising from under-reporting could be expected to lead to bias away from the null value.49 Compared with other studies, under-reporting in this study may be reduced because we used methods shown to yield valid and reliable information among pregnant Danish women,28,29,50 and because consumption of small volumes of alcohol during pregnancy was generally not considered to be problematic in Denmark during the time of data collection.51,52 As information on alcohol use reflected the time period of the study enrollment, which varied from 7 to 39 weeks of gestation, impact on neurodevelopment may have been diluted if such exposure was sensitive to a specific time period in gestation.

It should be noted that on average the exposure represents the lower tail of the distribution for the average consumption categories, suggesting that these findings speak mostly to levels of less than one drink per day.

Although the 51% participation rate for this study is quite good for studies of this nature, the potential impact of differential participation should be considered. It is reassuring that participants and non-participants did not differ substantially on key covariates, but nonetheless it remains possible that participation may have been associated with both alcohol status and child neurodevelopmental functioning (either positive or negative). Such selection bias could potentially mask an apparent association with maternal alcohol use.

Finally, all studies of neurodevelopment must be considered within the framework of child development. Effects that are detectable at younger ages may or may not be detectable at older ages depending on the specific construct under study. In addition, as children develop, cognition diversifies and environmental factors exert influence, and consequently some effects may only be detectable at older ages.53 The LDPS outcomes were assessed only when the participants were 5 years old, a relatively early stage in the development of intelligence, attention, and executive functioning. However, at least one study of the effects of alcohol on IQ suggested that effects observed in early childhood may be diluted in later childhood and adolescence.54 If this is a general phenomenon, it is unlikely that future follow-ups of our sample will show effects of maternal low to moderate average weekly consumption of alcohol and binge drinking on intelligence, attention, and executive function in offspring. However, it is important that studies of older children be conducted to fully address this possibility.

The lack of significant findings suggests that any effects of low average weekly alcohol consumption or any episodes of binge drinking in the first half of pregnancy on these specific aspects of child neurodevelopment may be small. To date, the scientific literature, including the present study, does not establish a safe level of alcohol consumption during pregnancy. As alcohol is a known teratogen, it remains the most conservative advice for women to abstain from alcohol during pregnancy. However, small quantities consumed occasionally in pregnancy do not appear to pose serious issues for these three areas of neurodevelopment. Despite these findings, additional large-scale studies that further investigate the possible effects that low to moderate alcohol use during pregnancy may have across childhood should be conducted using comprehensive methodological and statistical approaches, similar to those described for this study.

Contribution to authorship

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure of interests
  8. Contribution to authorship
  9. Details of ethics approval
  10. Funding
  11. Acknowledgements
  12. References

USK, JB, ELM, LSB, NIL, TK, and MU all contributed to the design of the Lifestyle During Pregnancy Study. USK, JB, HS, BS, and ELM wrote the first draft of the article in collaboration, and HS and BS were responsible for the statistical analyses. All authors contributed to the interpretation of the results, with critical comments and revisions of the article.

Details of ethics approval

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure of interests
  8. Contribution to authorship
  9. Details of ethics approval
  10. Funding
  11. Acknowledgements
  12. References

The study was approved by the DNBC Board of Directors, the DNBC Steering committee, the regional Ethics Committee, the Danish Data Protection Agency, and the Institutional Review Board at the Centers for Disease Control and Prevention. Signed informed consent was obtained for the LDPS.

Funding

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure of interests
  8. Contribution to authorship
  9. Details of ethics approval
  10. Funding
  11. Acknowledgements
  12. References

This study was supported primarily by the Centers for Disease Control and Prevention (CDC), Atlanta, Georgia, USA. Additional support was obtained from The Danish National Board of Health, the Lundbeck Foundation, Ludvig & Sara Elsass’ Foundation, the Augustinus Foundation, and Aase & Ejnar Danielsen’s Foundation.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure of interests
  8. Contribution to authorship
  9. Details of ethics approval
  10. Funding
  11. Acknowledgements
  12. References

The Danish National Research Foundation has established the Danish Epidemiology Science Centre that initiated and created the Danish National Birth Cohort. The cohort is furthermore a result of a major grant from this foundation. Additional support for the Danish National Birth Cohort is obtained from the Pharmacy Foundation, the Egmont Foundation, the March of Dimes Birth Defects Foundation, the Augustinus Foundation, and the Health Foundation. The authors would like to thank all of the participants for their time and effort, as well as Dr Tom Manly for his contribution to the development of the TEACh-5 test.

References

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  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure of interests
  8. Contribution to authorship
  9. Details of ethics approval
  10. Funding
  11. Acknowledgements
  12. References
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