Protective Effects of the Alcohol Dehydrogenase-ADH1B Allele in Children Exposed to Alcohol During Pregnancy

Abstract

The complete form of fetal alcohol syndrome (FAS) reportedly occurs in only 4% to 10% of children whose mothers drink heavily during pregnancy. Fetal alcohol spectrum disorder includes cases with some alcohol-related problems but not the full syndrome and is thus more common. Vulnerability to alcohol-related neurodevelopmental disorders is influenced by genetic polymorphisms of the class I alcohol dehydrogenase ADH1B, which affects the rate of alcohol metabolism. Expression of one of the 3 possible alleles, ADH1B*3, is associated with relatively rapid alcohol metabolism. This study sought to learn the degree to which the maternal ADH1B*3 allele may moderate the effects of in utero alcohol exposure on fetal growth and a range of cognitive and behavioral outcomes. The study population included 263 black mother-child pairs in whom moderate and heavy drinking were overrepresented. Most study participants were socioeconomically disadvantaged. The Michigan Alcoholism Screening Test (MAST) was administered to all mothers during the first prenatal visit, and blood was obtained for ADH genotyping; the children were genotyped at the 7.5- or 14-year visits. Fetal exposure to alcohol was assessed by interviewing the mothers about preconception drinking at the first prenatal visit and then at each subsequent visit asking about the amount of alcohol ingested daily since the previous visit. The children were evaluated at 6 and 12 months and 7.5 and 14 years of age. Infants were assessed using the Mental Development Index from the Bayley Scales of Infant Development. They also were tested for processing speed, visual reaction time, and complexity of play. At age 7.5 years, the children were tested for working memory by the Digit Span and Arithmetic subtests from the Wechsler Intelligence Scale for Children. The Verbal Fluency subtest of the McCarthy Scales of Children's Abilities served to measure executive function and working memory. The Continuous Performance Test quantified sustained attention. In addition, teachers were asked to assess social competence and behavior problems. Women who continued to drink during pregnancy decreased the frequency from 1.9 to 0.9 days a week, but the number of drinks consumed per occasion decreased only 20%, from 4.5 to 3.6 drinks. One third of the women also used cocaine, one third used marijuana, and almost two thirds smoked cigarettes. The most prominent genotype was homozygosity for the ADH1B*1 allele (64.5%), and the rest were either heterozygous (31.4%) or homozygous (4.6%) for the ADH1B*3 allele. At the time of conception, women who carried at least one copy of the ADH1B*3 allele drank half as much absolute alcohol per day (0.57 vs 0.96 ounces) and drank on fewer days per week (1.82 vs 2.45 days) than those who did not carry the allele. During pregnancy, both women who did and did not carry the ADH1B*3 allele reduced their drinking such that there was no difference between the groups in the amount of alcohol ingested per occasion (0.18 and 0.26 ounces, respectively) or the number of drinking days per week (0.67 and 0.85 days). Children whose mothers lacked the ADH1B*3 allele exhibited adverse effects of alcohol during infancy, scoring poorly on all tests, whereas the adverse effects on children whose mothers carried the ADH1B*3 allele were limited to reduced birth weight and processing speed on the FTII. At age 7.5 years, when focused attention, working memory, and efficiency of information processing were assessed, prenatal drinking was associated with poorer Category Fluency (the ability to monitor information retrieved from long-term memory) only in children whose mothers lacked the ADH1B*3 allele. These children also had poorer teacher ratings for attention, aggressive behavior, and social problems. In contrast, no consistent pattern of increased vulnerability during infancy was evident in children who themselves lacked the ADH1B*3 allele. When assessed at 7.5 years, children who carried at least one ADH1B*3 allele had fewer cognitive problems.