In this study, multiple regression analyses of absolute brain tissue volumes and head size revealed that prenatal exposures to cocaine, alcohol, and cigarettes individually were associated with reductions in HC and CGM and TOT volumes in 10- to 14-year-old children relative to comparison subjects after controlling for age at scan and gender. Importantly, these reductions reached bivariate statistical significance for cocaine, alcohol, and cigarette exposures, individually. Additional analyses of each exposure in which additional adjustment was made for the remaining 3 exposures revealed that the observed trend to reductions in CGM and TOT volumes associated with prenatal cocaine or alcohol exposure persisted but was no longer statistically significant. In distinction, the effects of prenatal cigarette exposure on CGM and TOT retained marginal significance despite such adjustment (P = .08 and .09, respectively). Last, analysis of variance provided evidence of an inverse relationship between the number of substances to which these children were prenatally exposed and the reduction found in CGM, TOT, and HC.
To our knowledge, this is the first volumetric magnetic resonance neuroimaging study to report whole-brain parenchymal volume and CGM volume reductions in older children that may be related to the individual effects of multiple intrauterine exposures, including cocaine. Our data indicate that, in addition to cocaine, prenatal exposures to tobacco and alcohol could play roles individually or in combination with IUCE in the observed brain tissue volume and HC reductions.
These findings are consistent with those of other investigators. Diminished HC has been linked repeatedly to intrauterine exposure. Prenatal cocaine exposure has been associated with reduced HC at birth14,50,51
with both an inverse dosage effect and trimester-specific effects of prenatal cocaine exposure on HC reported.3,52,53
Similarly, maternal cigarette use has been associated with significant reduction of newborn HC.54,55
Finally, prenatal alcohol exposure during pregnancy has been associated with reduced HC both at birth and as late in childhood as 14 years of age56,57
in children who do not manifest physical features of FAS.
The reported reductions of both CGM and TOT volumes are consistent with other observations about brain structure reported with respect to intrauterine exposures to cocaine, alcohol, cigarettes, or marijuana. Use of recently developed quantitative neuroimaging techniques to study the brain structure and function of children with IUCE has been limited. In the parent sample of this study, cranial ultrasonography revealed that neonates who were exposed to higher (top quartile) levels of prenatal cocaine demonstrated more frequent occurrence of caudothalamic groove subependymal hemorrhage than was found in lighter exposed or unexposed newborns after adjustment for a variety of confounding variables, including prenatal exposure to cigarettes, alcohol, and marijuana.36
Other studies using similar samples have shown no such effects.58
Use of MRI morphometry and magnetic resonance spectroscopy to examine the subsequent effect of IUCE on the brain of school-age children showed no morphometric difference between children with and without IUCE; however, frontal WM creatine was elevated by magnetic resonance spectroscopy in children with IUCE.59
Although concomitant exposures to cigarettes or alcohol were recognized in both groups, statistical adjustment for these exposures was not attempted. Another study that sought correlation between cognitive performance and mean diffusivity measured with diffusion tensor imaging found higher mean diffusivity in anterior callosal and right frontal projection fibers and lower scores on executive function measures among children who had IUCE compared with those without such exposure.60
Notably, these investigators found that prenatal exposures to alcohol and marijuana as well as an interaction between prenatal exposures to marijuana and cocaine affected prefrontal WM mean diffusivity. Although we found an association between alcohol exposure and WM volume in the bivariate analysis of this study, we did not find any group differences in WM volume associated with cocaine exposure; however, our data are volumetric and do not include diffusion tensor imaging and spectroscopy data.
Similarly, compelling evidence supports the deleterious effect of prenatal alcohol exposure on brain development. Neuropathologic study of brain from children with FAS indicated alcohol-associated derailment of the migrational phase of normal brain development. These findings included microcephaly, widespread leptomeningeal heterotopias, and schizencephaly.61,62
In addition, midline WM abnormalities such as agenesis and dysgenesis of the corpus callosum as well as septo-optic dysplasia have been found on autopsy and in vivo through MRI study.63,64
Volumetric MRI studies of children with prenatal exposure to alcohol including children without stigmata of FAS revealed reduced intracranial vault size; volume reduction of corpus callosum, basal ganglia, and cerebellum; and abnormal ratios of gray matter to WM in temporoparietal regions of brain, persistent even in adolescence.65–72
A growing body of evidence indicates a lasting adverse effect of prenatal exposure to maternal cigarette use. Mammalian studies demonstrated that prenatal exposure to nicotine can upregulate nicotinic cholinergic receptors in developing brain, shortening the proliferative phase of brain development and thereby allowing earlier onset of neuronal differentiation as compared with comparison subjects.73,74
Volumetric MRI study of brain tissue volumes in adult smokers as compared with nonsmokers revealed reduced gray matter volume in prefrontal cortex in both hemispheres and left anterior cingulate.75
Although these findings related to postnatal cigarette exposure could represent effects of chronic smoking, predisposing traits that lead to smoking, or some combination of these factors, they raise the possibility that prenatal cigarette exposure may exert structural consequences on developing brain.
Data are less available regarding the structural consequences of prenatal marijuana exposure on brain development. Wilson et al76
raised the question of developmental sensitivity of brain to marijuana exposure in their volumetric MRI study that demonstrated proportionately less CGM and more WM in children who initiated marijuana use before the age of 17 as compared with those who did not use marijuana or who initiated use after the 17 years of age.
The limitations of this study must be recognized. First, because not all cases had drug screens from both members of each dyad (urine from mothers and urine or meconium from control infants), we cannot exclude the possibility that in addition to those who were reclassified after recruitment because of positive screen results, there were other exposed children misclassified as “controls.” Second, our definition of heavy cocaine exposure (top quartile for this sample, ≥61 days of reported use during pregnancy) differed from the definition used by others in other cohorts to define heavy cocaine use (≥2 times per week throughout pregnancy), and it is, therefore, possible that our inability to detect an effect of heavy exposure on HC or brain tissue volumes in the analysis adjusted for both demographic and other substance exposures may have been attributable to a cohort that was overall less heavily exposed than some other cohorts.77,78
Comparisons across cohorts are difficult because the potency and contamination of illicit substances, such as cocaine, vary across time and by geographic location so that number of days of use can only approximate the actual “dosage” experienced by the fetus. Third, the total number of children studied was small. This small number prohibits determination of interactions among the prenatal exposures that may have affected the outcomes. Furthermore, stratification by gender was not possible. Finally, the sample studied was exclusively African American or African Caribbean and poor; therefore, generalization of these findings to the general population of children in the United States is not possible at this time. It is possible that study of a larger sample would allow effects of individual and combined prenatal exposures on the MRI outcome measures to emerge that are not apparent now.
Our data indicate that prenatal exposures to cocaine, cigarettes, and alcohol may each individually exert an adverse effect on CGM and TOT volumes that can be detected subsequently in children who are 10 to 14 years of age using volumetric MRI. Furthermore, prenatal exposures to these substances in combination may exert deleterious and lasting consequences on brain structure. Prenatal exposure to increasing numbers of substances was associated with significant reduction in TOT, CGM, and HC. Although firm conclusions about the discrete individual effects of prenatal cocaine, alcohol, or cigarettes on brain volume in the children of our small sample cannot be made, these data are consistent with a possible, lasting effect of each and raise concern that exposure to combinations of these 4 substances during the prenatal period may have an enduring effect on brain structure in children.
The clinical implication of these results suggests that prenatal care and counsel of pregnant women not only should include emphasis on the potential lasting consequences on children of use of individual substances (whether legal or illegal) by their pregnant mothers but also should stress that substances such as cocaine, cigarettes, alcohol, and marijuana may produce cumulative effects on brain structure that are detectable at school age. Furthermore, assistance should be offered to reduce use of all of these substances. From a scientific perspective, additional systematic neuroimaging studies of larger samples are needed to clarify the effect of dosage of each substance, threshold of effect, interaction of substances with each other, and potential moderating effects of demographic variables such as age and gender.