Adolescent initiation of licit and illicit substance use: Impact of intrauterine exposures and post-natal exposure to violence
Introduction
By definition, women who continue to use licit or illicit psychoactive substances in pregnancy, even at low levels, may be considered to have problem substance use since they are unable to discontinue use in spite of potential adverse consequences to themselves and their children. Children whose parents have a history of problem licit or illicit substance use may themselves be at an elevated risk for becoming substance users and abusers in adolescence and adulthood [34], a risk ascribed both to environmental and genetic factors [53]. However, after acknowledging familial risk including risks of living with substance using parents or parental figures in school age or adolescence, [3], [19] surprisingly little is known about whether there is an association of intrauterine exposures to psychoactive substances, licit or illicit, with the offspring's own age of initiation of substance use.
Substance use and pubertal maturation are linked [51]. The maturing of the brain in adolescence ushers in an epoch when previously undetectable effects of intrauterine insults may manifest and a time of unusual vulnerability to negative effects of the adolescent's own substance use, particularly because of the immaturity of the frontal cortex and subcortical monoaminergic systems [30]. The earlier the initiation of psychoactive substances, the greater the risk of neuropsychological perturbations and of eventual problem substance use [16], [42], [56], [57], [58], [61], [63], and other negative psychosocial outcomes such as incarceration [60].
The animal data on intrauterine substance exposure and later substance use are inconclusive, conflicting, and focus on adult rather than adolescent animals. Animal studies of intrauterine cocaine exposure (IUCE) provide an instructive example. One study [54] suggested that in male mice intrauterine exposure to higher dosages of cocaine increased the probability of the mouse acquiring cocaine self-administration in adulthood, but a second study [32] suggested that the reinforcing efficacy of cocaine was reduced in adult male rats with IUCE. Mice with IUCE, compared to unexposed, also showed reduced cocaine conditioned place-preference for high doses of cocaine, though the a preference for low and medium doses was not altered [22].
Published findings on whether intrauterine exposures affect human offsprings' future licit and illicit substance use are also contradictory and vary with the demographic characteristics of the sample, and document substance use or problem use rather than age at first use. Two studies in a predominantly European American, middle-class United States sample [8], [9] do not report age of alcohol initiation, but suggest that intrauterine alcohol exposure confers incremental risks for offspring to develop alcohol “problems,” but a similar study from Australia [3] found that maternal alcohol use during the youngster's early adolescence, but not the use in pregnancy, predicted adolescent alcohol use. Data from the National Collaborative Perinatal Project (NCPP) [15] suggested that intrauterine tobacco exposure increases the offspring's risk of developing nicotine addiction, a finding replicated in Australia [47]. Gender specific effects were found in a retrospective study of treatment-seeking smokers suggesting intrauterine tobacco exposure was significantly associated with earlier age of tobacco initiation in males and accelerated daily use in females [48]. Intrauterine marijuana exposure has been found to predict offspring's marijuana use at age 14 in a sample which was 50% African American [19]. In the same sample, in contrast to the studies of European American children, it was found that intrauterine tobacco exposure did not predict offspring use once current maternal use was considered. A single study to date in a predominantly African American low income cohort suggests that boys, but not girls, with IUCE were more likely than unexposed peers at age 11 years to engage in high-risk behaviors, including tobacco use [13]. These findings were not replicated in a multi-site multiethnic sample by other researchers [39] where risk behaviors correlated with the child's post-natal violence exposure, but not with history of intrauterine exposures.
Additionally, there is not always a homology between the intrauterine exposure and the substance that is used by the offspring. For example, a longitudinal study following European–Canadian middle-class children reported that intrauterine marijuana exposure appears to predict the offspring's tobacco use [52], and a retrospective study of adopted adults reported that intrauterine alcohol exposure, independent of home environment, may increase the risk of dependence not only on alcohol but on tobacco and other drugs [70].
Previous studies suggest it is important to perform analyses that evaluate multiple intrauterine exposures in the context of post-natal environmental factors which have also been linked in epidemiologic studies to increased risk of early adolescent substance initiation and later substance use disorders. For example, the retrospective Adverse Childhood Exposures (ACE) study identified parental substance use, parental incarceration, household dysfunction and various forms of exposure to violence as factors likely to increase an individual's own risk of developing a substance use disorder [23].
Conversely, multiple environmental factors in adolescents' lives have been shown potentially to protect against substance abuse. A longitudinal study of urban African American adolescents identified an inverse relationship between having a higher number of protective factors (such as increased religiosity) and drug abuse [49]. An inverse relationship between religiosity and substance use was also identified in a retrospective study of a nationally representative sample of adolescents as part of the National Comorbidity Study [43]. A longitudinal study of adolescents from their senior year of high school through their first year after high school found parental monitoring to be a protective factor decreasing substance abuse as adolescents enter young adulthood [67].
We hypothesize that adolescents who experienced intrauterine cocaine exposure (IUCE) and intrauterine exposures to other substances are more likely, after confound control, to become themselves early initiators of licit and illicit psychoactive substances, compared to demographically similar adolescents without such exposures. Although we are aware that other child level factors such as lower IQ [24] and childhood externalizing behavior and other psychiatric symptoms [6], [11] may be on the causal pathway to substance misuse, we focus on potential familial and environmental confounds rather than these possible mediators, which are addressed only in secondary analyses.
Section snippets
Sample recruitment
The IRB of Boston Medical Center (then called Boston City Hospital) approved this study at inception and yearly thereafter. Prior to initiation of the study a Certificate of Confidentiality was obtained from the federal government to protect researchers from being compelled by subpoena to release data regarding study participants. Soon after delivery, all birth mothers gave informed consent to study participation. If the child changed caregivers, similar informed consent was obtained for each
Sample characteristics
Table 1 summarizes sample characteristics by the level of IUCE. Compared to those with no IUCE, children with IUCE were more likely to experience higher levels of marijuana, alcohol, and tobacco intrauterine exposure, and to be of lower birth weight, but there were no sex differences by level of exposure. Mothers who used cocaine during pregnancy were more likely to be born in the United States, and to be older at the child's birth, but the groups did not differ in education level or in the
Discussion
This is one of only a few published studies in humans which evaluate a possible association between prospectively identified intrauterine exposure to cocaine or marijuana with initiation of adolescent substance use, after considering intrauterine exposure to tobacco and alcohol, and potentially relevant covariates. Consistent with neonatal [64] and adolescent neuropsychological findings [55] in this cohort, there appears to be an ordered relationship after confound control between the heavier
Limitations
The study has a number of limitations including sample size. In a larger sample certain effects that are statistically marginal in our analyses (for example, the association of heavier IUCE with early alcohol initiation) might be more robust and multivariable analysis of initiation of tobacco and illicit substances other than marijuana would be possible. Our sample is also by design quite homogeneous, so findings should not be generalized to adolescents born prematurely, from non Black ethnic
Conclusions
Comprehensive treatment of pregnant women who are struggling with use of any psychoactive substance, whether licit or illicit, should be a clinical and public health priority. Effective prevention of early substance use initiation also requires focus on the post-natal quality of life for impoverished children and adolescents, particularly protection from high levels of exposure to violence, which correlate in this cohort with as great or greater odds of early substance use initiation than
Conflict of interest statement
The authors have no financial, personal, or other relationships with people or organizations that may inappropriately influence the authors' submitted work.
Acknowledgments
This research was supported by the National Institutes on Drug Abuse (NIDA) grant number DA06532 to Dr. Frank and by grant MO1 RR00533 and RR025771 from the National Institutes of Health/National Center for Research Resources, a component of the National Institutes of Health (NIH). This work would not have been completed without the wise guidance and unfailing support of Dr. Vincent Smeriglio to us and all the other longitudinal projects. We are everlastingly grateful to him. We would also like
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