Heavy maternal alcohol consumption during early pregnancy increases the risk of oral clefts, but little is known about how genetic variation in alcohol metabolism affects this association. Variants in the alcohol dehydrogenase 1C (ADH1C) gene may modify the association between alcohol and clefts. In a population-based case-control study carried out in Norway (1996-2001), the authors examined the association between maternal alcohol consumption and risk of oral clefts according to mother and infant ADH1C haplotypes encoding fast or slow alcohol-metabolizing phenotypes. Subjects were 483 infants with oral cleft malformations and 503 control infants and their mothers, randomly selected from all other livebirths taking place during the same period. Mothers who consumed 5 or more alcoholic drinks per sitting during the first trimester of pregnancy had an elevated risk of oral cleft in their offspring (odds ratio (OR) = 2.6, 95% confidence interval (CI): 1.4, 4.7). This increased risk was evident only in mothers or children who carried the ADH1C haplotype associated with reduced alcohol metabolism (OR= 3.0, 95% CI: 1.4, 6.8). There was no evidence of alcohol-related risk when both mother and infant carried only the rapid-metabolism ADH1C variant (OR = 0.9, 95% CI: 0.2, 4.1). The teratogenic effect of alcohol may depend on the genetic capacity of the mother and fetus to metabolize alcohol.
BACKGROUND: Controversies still exist regarding the existence of a 'safe' level of alcohol intake during pregnancy. The aim of this study was to assess the risk of fetal death (spontaneous abortion and stillbirth) according to maternal alcohol consumption in a large Danish pregnancy cohort.
METHODS: A cohort study carried out within the framework of the Danish National Birth Cohort. A total of the 92 719 participants enrolled in the Danish National Birth Cohort who provided information about lifestyle during first trimester of pregnancy were included in the study. Information about average weekly consumption of alcohol during pregnancy, smoking, coffee drinking, occupational status and reproductive history were obtained by means of computer-assisted telephone interviews. Pregnancy outcomes (spontaneous abortion, stillbirth, live birth and other pregnancy outcome) and gestational age at end of pregnancy were obtained through register linkage with the Civil Registration System and the National Discharge Registry. Data were analysed using Cox regression models, taking the varying gestational age at recruitment and time-dependent co-variables into account.
RESULTS: Fifty-five per cent of the participants abstained from alcohol drinking during pregnancy and only 2.2% reported four or more drinks per week. The adjusted hazard ratios for fetal death in first trimester were 1.66 [95% confidence interval (CI) 1.43-1.92] and 2.82 (95% CI 2.27-3.49) for women who reported 2-3½ drinks per week and 4 or more drinks per week, respectively, and 1.57 (95% CI 1.30-1.90) and 1.73 (95% CI 1.24-2.41) for fetal death during pregnancy weeks 13-16. No increased risk was found for fetal death after 16 weeks of pregnancy.
CONCLUSIONS: Even low amounts of alcohol consumption during early pregnancy increased the risk of spontaneous abortion substantially. The results indicate that the fetus is particularly susceptible to alcohol exposure early in pregnancy.
We posit that: (i) light alcohol consumption during pregnancy does not improve the cognitive development of human offspring and (ii) observational study outcomes indicating apparent protective effects arise from residual confounding due to socioeconomic status. Our hypotheses counter emerging hypotheses apparent in the epidemiological literature that light alcohol consumption during pregnancy improves offspring's cognitive development. Determining the plausibility of this proposition is important given its potential to influence women's alcohol consumption behavior during pregnancy. However, given ethical concerns, it is unlikely that a randomized control trial will be conducted to test this hypothesis. The veracity of alcohol's purported positive effect on cognitive development is therefore explored here by comparing research evidence on light alcohol consumption to the evidence for folate and DHA supplementation intake during pregnancy. An alternative approach for further testing this hypothesis in observational studies is also suggested.
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.