We report that prenatal exposure to both cigarettes and alcohol is related to changes in brain volume. For prenatal exposure to cigarettes, we found a graded pattern, where children with ADHD who had been exposed had the smallest cerebellum volumes, followed by unexposed subjects with ADHD, and the largest volumes in unexposed controls. These results are consistent with separate effects of prenatal exposure and ADHD on cerebellum volume. In controls, a similar effect fell short of statistical significance. For prenatal exposure to alcohol, we found main effects on cerebral volume and cerebral GM and cerebellum, with again the most pronounced graded effect on cerebellum. However, this graded effect was less clear than for cigarette exposure. Together, our results suggest that the neurobiological mechanisms involved in translating prenatal exposure to alcohol or cigarettes into a risk factor for developing ADHD may involve cerebellum.1, 7
One important question that arises from the recent literature on prenatal exposure and ADHD,4, 28, 51, 52, 53, 54, 55
is whether shared genetic effects can explain both the use of cigarettes or alcohol during pregnancy and genetic transmission of ADHD. Although we have no measures to directly address this hypothesis, we did assess the rate of psychiatric morbidity in first-degree relatives of our subjects with ADHD. If G × E correlation or pleiotropy were indeed mediating these effects, we would expect an increase in this rate for prenatally exposed subjects with ADHD. We found no evidence of such an increase. In addition, the staircase pattern of our results for cerebellum volume suggests that both genetic and environmental effects may be affecting the brain phenotype, with prenatally exposed subjects with ADHD taking a ‘double hit'. Finally, we have previously shown that cerebellum volume is reduced in children with ADHD but not in their unaffected siblings, which also suggests that non-familial factors are relevant to this brain region in ADHD.56
Notably, we found no effect of prenatal exposure to alcohol on brain volume in controls. Combined with recent findings that ADHD is more likely to be diagnosed in the children of parents with alcohol dependence,54
this could be taken to suggest that the effect of prenatal alcohol exposure on brain volume is likely to be more genetically mediated than that of cigarette exposure. However, the magnitude of alcohol exposure in our sample was generally low in comparison with the extant literature, suggesting that a dosage effect may also be in play.
The relevance of prenatal factors for adult disease is addressed in the developmental origins of health and disease hypothesis.57, 58
One element of this hypothesis is that in the event of adverse prenatal circumstances, brain tissue may be spared relative to other tissues, such as muscle,59
and general metabolic programming and that this may be evidenced by such factors as body composition later in life.60
In our data, we find no evidence for effects of prenatal exposure to teratogenic substances on body mass index, either at birth or at the time of scanning. This does not seem to support the brain-sparing hypothesis. However, psychiatric phenotypes are increasingly becoming a focus of the developmental origins of health and disease, where epigenetic effects of prenatal exposure have been put forward as a candidate mechanism of action.12, 58
Our data may be consistent with such an interpretation, as they suggest both genetic and environmental effects on the brain.
We repeated all our analyses on a data set matched for BW rather than SES to test whether our results were specific to prenatal nicotine or alcohol exposure or rather more generally related to a suboptimal prenatal environment.12, 61
Although we felt that this analysis was informative enough to pursue, it should be noted its interpretation is complicated by the fact that prenatal exposure to alcohol or nicotine are both related to reduced BW.3, 11
As such, by matching for BW we may in fact be overcorrecting for a variable of interest. In addition, matching for SES may also have provided more ecologically valid control over other factors affecting BW such as maternal nutrition.35
The general pattern of results in the analyses with data matched by BW was similar to that found in the analyses for groups matched by SES. For cigarette exposure, the brain volumes of exposed subjects with ADHD now resembled those of unexposed subjects with ADHD more closely. However, cerebellum GM volume still showed the staircase pattern of results. For alcohol exposure, none of the main effects found for groups matched for SES met significance, although a suggestive trend for cerebellum volume remained. This strengthened our conclusion that, similar to cigarette exposure, the most pronounced effect of alcohol exposure was on the cerebellum. In sum, these analyses show that whereas some of the effects of prenatal exposure to cigarettes and alcohol may be aspecific, there also appears to be a direct effect of exposure on brain volume, in particular on the volume of cerebellum.
There are some further limitations associated with our study. First, it is a naturalistic retrospective study of modest size. Furthermore, retrospective reports of substance use should always be considered with a certain level of caution. However, research has shown that maternal reports on the use of teratogenic substances during pregnancy are generally reliable, especially when dichotomized, as was done here.62
Importantly, it was impossible for us to control for mediating factors such as maternal nutritional status, timing of use and dosage or postnatal developmental environment in a naturalistic study.10, 11
Therefore, we chose to use SES as a primary matching criterion. SES is often correlated with these confounding factors, offering some control over these issues. By repeating all analyses while controlling for BW, we were able to further address the specificity of our findings.
In conclusion, our results show that prenatal exposure to alcohol or nicotine is relevant to the volume of cerebellum. Our results are consistent with separate effects of prenatal exposure and ADHD on cerebellum volume. As such, they suggest that in ADHD, there may be an effect of prenatal exposure per se that cannot be fully explained by pleiotropic genetic effects.