Fetal alcohol exposure has multiple deleterious effects on brain development, and represents a leading known cause of mental retardation. This review of the effects of alcohol exposure on the developing brain evaluates results from human, animal and in vitro studies, but focuses on key research issues, including possible mechanisms of damage. Factors that affect the risk and severity of fetal alcohol damage also are considered.

A binge ethanol exposure paradigm, three consecutive days per week throughout the third trimester at ethanol doses that created blood ethanol concentrations commonly achieved by human ethanol abusers, resulted in changes in maternal and fetal heart rate, changes in blood pressure, hypercapnea, acidemia, and maternal, but not fetal, hypoxemia. We conclude that in an ovine model system, ethanol doses that create blood ethanol concentrations as high as 260 mg/dl do not result in fetal hypoxemia. Remaining issues to address with this model system are whether neurodevelopmental injuries that are associated with maternal ethanol abuse are mediated by a reduction in fetal cerebral blood flow, fetal hypercapnea, or acidemia.

In humans, microcephaly (small head for body size) is a common feature of fetal alcohol syndrome. An analogous measure, termed microencephaly (small brain for body size), can be used for evaluating the detrimental effects of the differential timing of alcohol exposure on brain development in animal model systems. Timed-pregnant rats were exposed to binge-like alcohol during either the first 10 days (first trimester equivalent) or second 10 days of gestation (second trimester equivalent), or the combination of first and second trimesters equivalent for prenatal treatments. Offspring from some of the animals exposed to alcohol during the combined first and second trimesters equivalent were raised artificially from postnatal day (P) 4 through P9 (part of the third trimester equivalent), and also received binge-like alcohol during this period, producing animals that were exposed to alcohol during all three trimesters equivalent. Offspring from untreated dams were also raised artificially and received alcohol only from P4 to P9, thus creating animals that were exposed to alcohol only during part of the third trimester equivalent. All pups were perfused on P10. Appropriate controls (nutritional and normally reared) were used for every alcohol treatment combination. Peak blood alcohol concentrations were not different among the treatment groups for a given sampling time. Significant somatic growth deficits occurred in offspring exposed to alcohol for the equivalent of all three trimesters, compared with offspring exposed to alcohol during other periods. Brain growth in offspring also was significantly affected by the timing of alcohol exposure. The whole brain, forebrain, and cerebellum to body weight ratios of pups exposed to alcohol during the third trimester had more significant brain growth deficits than pups in groups exposed to alcohol during other times of brain development. Although alcohol exposure during the third trimester had a significant detrimental impact on overall brain growth, significant differences in temporal vulnerability were also found for the brainstem to body weight ratios. Offspring of dams exposed to alcohol during the first trimester had the same magnitude of deficit as those exposed to alcohol during the third trimester, and those two groups were significantly deficient compared with the groups exposed to alcohol at other times, suggesting some differential vulnerability of this region to alcohol-induced injury at different times of development. This study is the first thorough examination of microencephaly and gross regional vulnerability of the developing brain as related to temporal factors of alcohol exposure in an animal model system, and the results support and expand on the findings of the available clinical literature. Furthermore, our results substantiate claims that the cessation of alcohol before the third trimester can lessen the severity of some alcohol-related birth deficits.