Prenatal alcohol exposure and offspring cognition and school performance. A ‘Mendelian randomization’ natural experiment

Abstract

Background There is substantial debate as to whether moderate alcohol use during pregnancy could have subtle but important effects on offspring, by impairing later cognitive function and thus school performance. The authors aimed to investigate the unconfounded effect of moderately increased prenatal alcohol exposure on cognitive/educational performance.Methods We used mother-offspring pairs participating in the Avon Longitudinal Study of Parents and Children (ALSPAC) and performed both conventional observational analyses and Mendelian randomization using an ADH1B variant (rs1229984) associated with reduced alcohol consumption. Women of White European origin with genotype and self-reported prenatal alcohol consumption, whose offspring’s IQ score had been assessed in clinic (N = 4061 pairs) or Key Stage 2 (KS2) academic achievement score was available through linkage to the National Pupil Database (N = 6268), contributed to the analyses.Results Women reporting moderate drinking before and during early pregnancy were relatively affluent compared with women reporting lighter drinking, and their children had higher KS2 and IQ scores. In contrast, children whose mothers’ genotype predisposes to lower consumption or abstinence during early pregnancy had higher KS2 scores (mean difference +1.7, 95% confidence interval +0.4, +3.0) than children of mothers whose genotype predisposed to heavier drinking, after adjustment for population stratification.Conclusions Better offspring cognitive/educational outcomes observed in association with prenatal alcohol exposure presumably reflected residual confounding by factors associated with social position and maternal education. The unconfounded Mendelian randomization estimates suggest a small but potentially important detrimental effect of small increases in prenatal alcohol exposure, at least on educational outcomes.

Association Between Prenatal Alcohol Exposure and Craniofacial Shape of Children at 12 Months of Age

“…Mendelian randomization studies using the Avon Longitudinal Study of Parents and Children predicted different patterns of PAE and variable outcomes in offspring depending on several variants in the alcohol dehydrogenase gene in the mother or child (eg, ADH1B [OMIM 103720], predictive of reduced alcohol consumption and associated with higher academic achievement in offspring). 29,30 Furthermore, regarding the direct role of genes involved in alcohol metabolism in modifying risk, evidence from laboratory studies using ethanolsensitive and ethanol-resistant chickens, mice, and zebra fish provides insight into the multifactorial genetics of ethanol-mediated cell signaling disruption and neural crest apoptosis. 31 We observed that children of mothers who reported feeling the effects of alcohol quickly or very quickly exhibited larger craniofacial differences in most exposure groups.…”

What can be done to lessen morbidity associated with fetal alcohol spectrum disorders?

“…An observational analysis of children's IQ at age 8 and educational achievement at age 11 showed modest improvements in the children born to mothers who had consumed a moderate amount of alcohol during early pregnancy compared with mothers who had abstained, yet the quasi-experimental method using Mendelian randomisation on the same cohort showed that even small levels of alcohol consumption were associated with reduced educational attainment 33. The authors argue that the positive association seen in the observational study reflected residual confounding with factors associated with maternal social position and education.…”

A Bio-Social and Ethical Framework for Understanding Fetal Alcohol Spectrum Disorders

“…Studies of maternal alcohol consumption in OECD countries suggest that women from upper socioeconomic groups are more likely to drink alcohol during pregnancy [24][25][26][27][28][29][30][31][32] but have significantly lower rates of FASD than women in lower socioeconomic groups [23]. One recent study has found that women from more socially disadvantaged backgrounds are more likely to either abstain or binge drink during pregnancy, while those who are from more socially advantaged backgrounds are more likely to drink consistently at low to moderate levels [33]. The relationship between socioeconomic status, ethnicity and alcohol consumption during pregnancy adds further complexity.…”