The Role of Genetic Susceptibility for Maternal Alcohol Metabolism in Determining Pregnancy Outcome
Article Outline
The extent to which genetic polymorphisms influence the effect of various environmental agents on fetal development is of increasing interest and importance in human teratology. Studies of hydantoins,1 tobacco smoke,2 and alcohol3 have all provided some evidence that genetic factors play a role in modulating the effects of these agents on fetal development. This in turn raises the possibility of providing more targeted risk counseling for the subset of women exposed to those agents during pregnancy who are at highest risk of abnormal pregnancy outcomes.
In this issue of The Journal, Jacobson et al4 have set forth new evidence that the maternal ADH1B∗3 allele, 1 of 3 alleles at the ADH1B locus, provides protection against some of the effects of prenatal exposure to alcohol for children of black women who drink during pregnancy. Evidence of the biologic plausibility of this association makes their observations that much more compelling.
The ADH1B∗3 allele is unique to black people, occurring with a population frequency of 22%5; black race/ethnicity has been suggested to be a risk factor for fetal alcohol syndrome.6 Based on its kinetic properties, the isoenzyme encoded by the ADH1B∗3 allele rapidly oxidizes alcohol to acetaldehyde thus maintaining a relatively low blood alcohol concentration along with an elevated acetaldehyde level.7 Although Jacobson et al4 argue that the protective effect of the ADH1B∗3 allele is most likely due to more rapid metabolism of alcohol, thus resulting in fetal exposure to a lower peak maternal blood alcohol concentration during a drinking episode, it is also possible that toxicity caused by an elevated acetaldehyde level could result in unpleasant symptoms in the mother, leading to decreased overall quantity of maternal alcohol consumption. Consistent with the latter hypothesis, Jacobson et al4 noted that women lacking an ADH1B∗3 allele on average consumed almost twice as much alcohol at the time of conception as those for whom at least 1 allele was present.
In either case, whether women who possess the allele metabolize alcohol more rapidly or just consume less alcohol, it appears that the most important factor is the peak blood alcohol concentration to which the fetus is exposed. Thus the modifying effect of the ADH1B∗3 allele in risk for the fetus appears to lie in its relationship with peak maternal blood alcohol level. However, to further define the exact mechanism by which the ADH1B∗3 allele provides this apparent protection, a direct comparison between the offspring of women who do and do not possess the allele but who drank similar quantities of alcohol, in similar patterns, and at similar times in pregnancy would be required.
Two additional published studies relating to this issue merit consideration. McCarver et al8 previously demonstrated a protective effect of the maternal ADH1B∗3 allele using birth length, weight, and head circumference and the Mental Developmental Index score of the Bayley Scales of Infant Development at 12 months of age as end points. However, in contrast to Jacobson et al,4 these authors also demonstrated a protective effect of the fetal ADH1B∗3 allele. As an explanation for this, it could be that in the McCarver study, fetal and maternal genotypes were more similar to each other than those in this study, leading to the finding that both were predictive of fetal outcome.
In the second study, Stoler et al9 reported that women who carried the ADH1B∗3 allele and drank alcohol during pregnancy were at higher rather than reduced risk of having an affected baby defined as an effect on growth and physical features but without measures of cognitive performance. However, in contrast to Jacobson et al,4 these authors reported a trend toward higher levels of alcohol consumption, not lower, in women who carried the ADH1B∗3 allele. Although this finding is not supportive of the theory that rapid metabolizers drink less, it is consistent with the concept that, regardless of alcohol-metabolizing enzyme genotype, higher levels of maternal alcohol consumption confer risk.
Criticisms of previous studies addressing this issue have related to lack of a precise and standard definition of maternal alcohol consumption patterns across studies, and a lack of a standard set of criteria for classifying affected versus unaffected children from one study to the other. With regard to the former, too often data on alcohol consumption are reported as number of “drinks” per week averaged over the entire length of gestation, making it impossible to determine whether consumption was spread evenly over the time period or consumed in much higher quantities in binge episodes during certain periods of pregnancy. It is not completely clear how Jacobson et al4 have analyzed alcohol consumption. Although they have collected data on the number of drinking days per week and the number of drinks consumed per occasion, their analysis was ultimately based on number of drinks averaged across the entire pregnancy.
With respect to classification of affected versus unaffected children, the authors used head circumference at birth, the Mental Developmental Index from the Bayley Scales of Infant Development conducted at 13 months of age and a variety of developmental studies performed at 7.5 years of age. To make the classification of affected children more comprehensive and comparable to other studies, it would have been ideal to have included a standardized physical examination of these children to determine if structural features typical of fetal alcohol syndrome were present. However, it is important to emphasize that alcohol is primarily a behavioral teratogen. Although there is a broad spectrum of defects associated with prenatal alcohol exposure, the developing structure most sensitive to alcohol is the brain, and the resulting neurobehavioral abnormalities have the most profound and lasting consequences for affected individuals. Thus, although there has not yet been identified a distinct neurobehavioral phenotype comparable to the structural features that are characteristic of prenatal alcohol exposure, the classification of affected children in this study based on measures of cognitive performance and development seems most relevant from a public health perspective.
The implications of the study by Jacobson et al4 are important. To the extent that these data can be generalized outside the Detroit sample, maternal ADH1B genotype in black women appears to modify the effects of maternal alcohol use on fetal development. As such, this study suggests that some women may be more genetically susceptible than others who drink alcohol during pregnancy, and therefore, what may represent a “safe” level of consumption for some women may result in adverse pregnancy outcome for others. These results support the overall recommendation recently reissued by the U.S. Surgeon General that the optimal approach to alcohol use in pregnancy is abstinence.
References
- . Prenatal prediction of risk of the fetal hydantoin syndrome. N Engl J Med. 1990;322:1567–1572
- Orofacial clefts, parental cigarette smoking, and transforming growth factor-alpha gene variants. Am J Hum Genet. 1996;58:551–561
- . Genetic polymorphisms: impact on the risk of fetal alcohol spectrum disorders. Birth Defects Res A Clin Mol Teratol. 2005;73:195–203
- . Protective effects of the alcohol dehydrogenase-ADH1B allele in African American children exposed to alcohol during pregnancy. J Pediatr. 2006;148:30–37
- . ADH2 gene polymorphisms are determinants of alcohol pharmacokinetics. Alcohol Clin Exp Res. 1995;19:1494–1499
- . An update on incidence of FAS: FAS is not an equal opportunity birth defect. Neurotoxicol Teratol. 1995;17:445–462
- Alcohol dehydrogenase polymorphisms influence alcohol-elimination rates in a male Jewish population. Alcohol Clin Exp Res. 2004;28:10–14
- . Alcohol dehydrogenase-2∗3 allele protects against alcohol-related birth defects among African Americans. JPET. 1997;283:1095–1101
- . Alcohol dehydrogenase 2 genotypes, maternal alcohol use, and infant outcome. J Pediatr. 2002;141:780–785
PII: S0022-3476(05)00905-4
doi:10.1016/j.jpeds.2005.09.023
© 2006 Elsevier Inc. All rights reserved.
