Considering Prenatal Alcohol Exposure in a Developmental Origins of Health and Disease Framework.

Effects of prenatal alcohol exposure in humans are impossible to study via controlled experiments; we are limited to observational studies. Although alcohol is considered a teratogen, there is a lack of clarity about the nature of the association between prenatal alcohol exposure, particularly low-level exposure, and offspring development in part because of the potential for unmeasured factors to play a role. In this issue of the Journal, an article by Lees and colleagues (1) leverages data from a large, representative sample, the Adolescent Brain Cognitive Development (ABCD) Study, to examine prenatal alcohol exposure in relation to adolescents’ neurodevelopmental outcomes based on behavioral assessments,maternal reportofpsychopathology, and imagingdata, with multiple statistical methods to control for other variables. However, review of this article in the context of other studies in the broader field studying the developmental origins of health and disease demonstrates that different research approaches addressingdevelopment beginningbefore birth can lead to divergent conclusions and highlights the importance of considering prenatal exposures in concert with other environmental factors. The study by Lees et al. follows a behavioral teratology model, focusing on alcoholwith the goal of isolating its effects by controlling statistically for other potentially confounding variables that could explain child outcomes—an approach that the large sample of nearly 10,000 participants permits. This model dominates prenatal alcohol exposure research, which began in the 1970s when “fetal alcohol syndrome”was first described in a small study of alcoholic mothers whose infant offspring were assessed to determine the consequences of having an alcoholic mother (2). Research has progressed substantially since, beginning with preclinical models establishing high levels of alcohol as teratogenic— although not before guidelines promoting abstinence from alcohol during pregnancy were swiftly implemented and became commonly accepted. In contrast to other neurodevelopmental disorders, fetal alcohol spectrum disorders, theumbrella termfor a rangeof fetal alcohol exposureeffects, including fetal alcohol syndrome, have a unique etiology in that the causal factor (i.e., alcohol) is integral to the diagnosis. The field of the developmental origins of health and disease, which has come to the fore in developmental psychopathology research, centers on the in utero environment as an influential first home (3). During pregnancy, maternal experiences such as life stress, depression, diet, and exposure to toxins are associated with alterations in gestational biology that affect fetal brain development during critical periods, with implications for future risk for compromised neurodevelopmental trajectories (4). Prenatal exposures are not randomly distributed; typically in studies of the developmental origins of health and disease, substantial effort is made to interrogate observational findings, and any causality is asserted with caution because other possibilities (such as confounding effects and selection bias) may explain associations (5). Lees et al., in perhaps the largest study of its kind in the United States, examine cognitive and psychological outcomes, assessed via maternal retrospective selfreport, in adolescents exposed prenatally to alcohol. Alcohol use was infrequent in the sample: of those with complete data, 2,090 (24%)women drank some alcohol before knowing they were pregnant, and 156 (1.8%) of the sample continued to drink at low levels (,7 drinks/week) after pregnancy awareness. Cognitive outcomes in offspring were assessed at ages 8.9–11 years using the fluid intelligence battery from the National InstitutesofHealth (NIH) toolbox, aswell as theRey Auditory Verbal Learning Test; the use of an observer-based, standardized neurocognitive test battery is a notable study strength. Covariate-adjusted comparisons showed that youths prenatally exposed to alcohol exhibited enhanced cognitive functioningcomparedwith thoseborn to abstainers (although, similar to all behavioral outcomes, not of a magnitude that is clinically significant). Examination of a doseresponse relationship revealed an inverted U-shaped association between the number of alcoholic drinks and Flanker Task performance (a measure of inhibitory control); no association was observed with the other NIH toolbox tasks Are we interested in asking what harm might alcohol cause, or what predicts poorer (or enhanced) development? Evidently the framing of the question, and subsequent choice of analytic methods, will lead to different conclusions.