Maternal Alcohol Consumption, Alcohol Metabolism Genes, and the Risk of Oral Clefts: A Population-Based Case-Control Study in Norway, 1996–2001

Abstract

Alcohol is a well-known teratogen, and previous studies have shown that the risk of oral clefts is increased by heavy maternal alcohol consumption—defined as 5 or more alcoholic drinks per sitting—during the first trimester of pregnancy. However, it is unclear whether genetic variation in maternal alcohol metabolism affects its teratogenicity. For consumption of a given level of alcohol, reduced rates of alcohol metabolism in a mother and fetus could increase the time of exposure of the fetus to higher peak levels of alcohol. The alcohol dehydrogenase 1 C (ADH1C) gene has been identified as a risk factor for cleft lip and palate independent of alcohol consumption. Previous reports have suggested that variants in the ADH1C gene may modify the association between alcohol and clefts by changing the rate of alcohol metabolism. This population-based case-control study investigated the association between oral clefts and maternal alcohol consumption among mothers and infants with ADH1C haplotypes encoding slow or fast alcohol metabolizing phenotypes. The study was conducted in Norway between 1996 and 2001; the study group included 483 Norwegian infants born with oral clefts and their mothers, and the control group was comprised of 503 structurally normal infants and their mothers, randomly selected from other live births. The level of alcohol consumption during the first 3 months of pregnancy was assessed with a self-administered, mailed questionnaire. As compared to abstaining from all alcohol use, consumption of 5 or more alcoholic drinks per sitting (binge drinking) during the first trimester of pregnancy was associated with more than twice the risk of having an infant with an oral cleft; the odds ratio (OR) was 2.6, with a 95% confidence interval (CI) of 1.4 to 4.7. This relationship was present only if either the mother or the infant carried the ADH1C variant associated with reduced alcohol metabolism (OR, 3.0; 95% CI, 1.4–6.8). There was no evidence of a relationship between maternal drinking and risk of fetal clefts if both mother and infant had only the rapid metabolism variant (OR, 0.9; 95% CI, 0.2–4.1). These findings demonstrate that the presence of slow-metabolism variants of alcohol-metabolizing genes in either the mother or fetus can substantially increase the risk of oral clefts in babies of mothers who are binge drinkers during the first trimester of pregnancy. Genetic variations in the capacity of the mother to metabolize alcohol may modify the teratogenic effects of maternal alcohol drinking.