An intergenerational lifespan perspective on the neuroscience of prenatal substance exposure

Highlights

• Prenatal substance exposure impacts neural development, with associated behavioral outcomes spanning multiple domains.

• Neural and behavioral outcomes following prenatal exposure can begin in infancy and persist into adulthood/parenthood.

• The issue of lasting effects of prenatal substance exposure is too often framed as a simple question of biological teratogenicity.

• Substance use may impact parenting behavior in ways that may be additive or obscure the direct teratological effects of prenatal exposure.

• Research in this area has a range of sampling concerns that may limit generalizability and precise longitudinal prediction.

Abstract

Prenatal substance exposure has the potential to impact a variety of domains, with neurobiological effects that last throughout the lifespan. Different substances may impact the brain in both specific and diffuse ways; however, the aberrant neural outcomes following exposure tend to coalesce in three areas: (1) sensorimotor development; (2) arousal, motivation, and reward; and (3) executive functioning, impulse control, and emotion regulation. This manuscript represents a summary and update of a previous review (Morie et al., 2019). We organize this piece by domain and summarize data from published neuroimaging studies that examine the neural correlates of prenatal exposure across developmental stages. While the published neuroimaging literature in the area of prenatal exposure has a range of sampling concerns that may limit generalizability as well as longitudinal prediction, the findings to date do point to domains of interest warranting further study. With this caveat, we synthesize the extant findings to describe ways in which prenatal substance exposure is associated with developmental psychopathology and implicated in potentially aberrant behavioral patterns beginning in infancy and persisting through childhood, adolescence, adulthood, and even parenthood. We also examine how substance abuse may impact parenting behaviors that in turn influences infant and child behavior in ways that may be additive or obscure the direct teratological effects of prenatal exposure. Given this observation, we offer an additional intergenerational lens through which prenatal substance exposure should be studied.

Introduction

Substance use remains a major public health problem in the United States (SAMHSA, 2017), particularly for mothers in the perinatal period, for whom stress, relapse rates, and risk for overdose are considerable concerns (Jones et al., 2017; Rodriguez and Smith, 2019). Many mothers reduce their substance use throughout pregnancy. Yet rates of use and overdose increase sharply after giving birth (i.e., when a mother may become pregnant again) and even exceed rates seen prior to becoming pregnant initially (Massachusetts Department of Public Health, 2017). These figures are concerning given that substance use during and after pregnancy often impacts multiple generations, through direct teratogenic routes and indirect environmental paths, respectively.

Previous reviews have presented details on the effects of prenatal substance exposure from lifespan (Morie et al., 2019), early childhood behavior (Frank et al., 2001), childhood neurobiological (Derauf et al., 2009), and policy (Thompson et al., 2009) perspectives. Here, we summarize neuroimaging studies that describe the potential consequences of prenatal substance exposure on infant, child, adolescent, adult, and parent neurobiology and behavior. This piece represents an update of Morie et al. (2019) that includes studies published since 2018, and presents findings across the lifespan into late adolescence and early adulthood, including as individuals enter parenthood and begin influencing the next generation through their caregiving behaviors. We organize our summary based on the three primary domains in which findings generally coalesce: (1) sensorimotor development; (2) arousal, motivation, and reward; and (3) executive functioning, impulse control, and emotion regulation. Within each domain, we provide an overview of the neural correlates of prenatal substance exposure across the developmental spectrum. Although neuroimaging approaches each have their own strengths and weaknesses (Neil and Smyser, 2018), included in this mini-review are studies that utilize a variety of approaches (e.g., electroencephalography, event-related potentials, functional magnetic resonance imaging, diffusion tensor imaging) to allow for a broad synthesis of the neural outcomes of individuals who were prenatally exposed to substances.

Importantly, while this review is not specifically focused on a methodological critique of each of the published studies cited, we note that there is enormous methodological variability across studies that limit the ability both to combine findings and make broad generalizations. This methodological variability is especially evident in the varying sample sizes, often a challenge in neuroimaging studies generally, and in the varying definitions and quantification of early exposures. Additionally, the older the children and adolescents, the more likely there are significant environmental disruptions in their lives including continued parental drug use, neglect and abuse, repeated episodes of foster care, early initiation of drug use by the adolescent or young adult, and so on. These disruptions have significant developmental impacts making it very difficult if not impossible to parse the relative contributions of early drug exposure along with continued environmental stress. Rarely do the studies included in this review have a sufficiently rigorous assessment of the environmental contributions to their participants' lives and outcomes. Thus, in this review, we offer the summary of reported findings to date not as a methodological endorsement of study rigor but rather as a review of possible “signals” across studies warranting further consideration and additional study refinements.

Two other caveats are important to note. First, we consider substance abuse and its potential teratologic impact more broadly than a focus on specific drugs. There are many reviews regularly updated (see, for example, Duko et al., 2022; Guille and Aujla, 2019; Sharapova et al., 2018; Singer et al., 2020). Here we focus on an addictive process, a disruption of early reward system and stress regulatory biology by a host of different agents (including prenatal environmental stress) and suggest that across exposures, these are key systems being disrupted with ongoing and later implications for normative development as well as increased risk for psychopathology. We recognize that this broader “process” focus may be inadequate for the biological specificity of certain drugs. But we also argue that the question of lasting effects of prenatal and early postnatal exposures to substances of abuse is too often framed as a simple question of biological teratogenicity. This frame obscures the potential long-term impact of disruption in parental stress-reward biology with the attendant impact on parenting behaviors and similar biology in the child. Thus, our broader frame is intended to encourage more discussion around interactive mechanisms for substance abuse and exposure-related developmental disruptions across the lifespan.

Our third and final caveat is around the “lifespan perspective”. Focusing on the individual, this perspective simply means predicting from early to later in life. There are a few published studies from rigorously maintained prenatally exposed cohorts that are beginning to report longitudinal predictions from childhood to late adolescence and early adulthood (See, for example, Scheyer et al., 2019; Singer et al., 2020; Vassoler and Wimmer, 2020). Hopefully, more of these studies will come into the literature over these next five years as these cohorts continue to age and continue to be followed. We also consider a lifespan perspective to be an intergenerational one. With this frame, we consider the impact of substance use on parenting behaviors and how, in turn, that impact continues to influence the child who was also prenatally exposed when that child remains in the care of their biological parent. While studies are just now appearing linking ongoing disruptions in parenting behavior among substance-using adults and their offspring (see, for example, Rutherford and Mayes, 2019;Rutherford et al., 2021), these are still very few given the practical, clinical, and methodological challenges inherent in maintaining substance-using families together. We argue though that many of the disruptions in the three domains suggested in the neuroimaging literature may be as much related to substance-abuse related disruptions in parental care as to the initial prenatal/postnatal exposure. Further, we argue that this impact of parental behavior increases the risk for substance use in their offspring regardless of (or in addition to) the direct biologic exposure; and with this increased risk for substance use in the offspring comes additive risk for the offspring struggling as parents with their children—hence, a lifespan, intergenerational impact.

With these caveats, we turn to the three domains that are most commonly reported on as impacted across different substances of exposure and different chronological/developmental ages.