1. Introduction

Opioid use amongst reproductive-age women is increasing globally ^[1][2][1,2] and has been associated with infant risk, including neonatal abstinence syndrome (NAS) ^[3][4][5][6][3,4,5,6], low birth weight [7], preterm birth [8], and altered neonatal brain development [9]. Consequently, there has been a five-fold increase in NAS within the last two decades [3]. Infants with NAS burden the healthcare system, with longer length of hospital stay and increased costs [10]. Pregnant women with opioid dependency represent a vulnerable group of women who have a history of family socioeconomic adversity, child custody loss, and many psychiatric, social, and obstetric needs ^[11][12][11,12]. Thus, children with prenatal opioid exposure (POE) face disproportionate risks. In addition to the neonatal concerns related to POE, some evidence indicates that POE may confer neurodevelopmental risk that endures beyond infancy. A meta-analysis of five studies of POE children’s neurobehavior by Baldacchino and colleagues found significant impairments for cognitive, psychomotor, and behavioral outcomes compared to non-exposed controls in infant and preschool children [13]. Furthermore, in a meta-analysis by Monnelly and colleagues, six of seven studies found that children with POE had increased behavioral problems compared to non-exposed controls of children less than 2 years [14].

Most consistently in the literature, POE has been associated with behavioral issues in early childhood, primarily with symptoms of attention-deficit hyperactivity disorder (ADHD) ^{[15][16][17][18][19][20][21][22][23]}[15,16,17,18,19,20,21,22,23]. For instance, in a cohort of children born in Norway, POE predicted elevated levels of inattention and impulsivity at both 2 and 4.5 years compared to non-exposed peers [16]. Similarly, a longitudinal study in New Zealand revealed that children with POE had increased inattention and hyperactivity during preschool years compared to non-exposed controls [15]. However, confounders associated with increased risk for ADHD (e.g., care disruption and prenatal polydrug exposure) were evident in both studies ^[15][16][15,16], thus limiting conclusions about the unique role of POE on ADHD symptoms.

Less is known about whether ADHD symptoms persist into the school-age period. In small cross-sectional studies, POE has been linked with elevated hyperactivity at 8.5 years [22], poorer sustained attention in boys 7–12 years [24], and higher inattention and impulsivity at 8.5 years [21]. Behavioral ranking scores of Swedish children with POE have corresponded to normative ADHD scores, including symptoms of activity, inattention, and combined subscale scores of children, although the sample size was limited to 16 children [17]. Utilizing cutoff scores for ADHD in behavioral scales, a longitudinal study in Israel reported that over half of the children with POE raised in the biological mother’s home had ADHD and a quarter of adopted children with POE had ADHD [20]. These findings also appear to indicate a pathway between POE and ADHD symptoms, where adoptive homes may mitigate but not eliminate long-term risk. In sum, even though the cognitive and motor outcomes of older children with POE have been assessed [25], no studies have reviewed POE and ADHD associations in older children.

2. Prenatal Opioid Exposure and ADHD Childhood Symptoms

Findings indicated that children with POE have higher hyperactivity/impulsivity, inattention, and combined ADHD symptoms compared to non-exposed controls. This positive association was apparent in children 4–14 years of age. Prenatal opioid exposure had the strongest association with hyperactivity/impulsivity, followed by inattention and then ADHD combined scores, although all effect sizes were considered large ^[26][27]. In addition, children with POE appeared to have more ADHD symptoms during school age compared to preschool age. The association of POE and ADHD symptoms seemed to be stronger when compared to healthy control/comparison groups, followed by environmental control/comparison groups.

Existing literature suggest that POE negatively impacts children’s behavioral regulation in preschool and school-age children. While poor behavioral outcomes after POE have been reported [14], findings have been inconsistent or not included studies of older children [13]. Data from seven published studies indicated that behavioral dysregulation is evident across childhood. Furthermore, Existing literature specify on the specific behavioral challenges of hyperactivity/impulsivity and inattention. While previous meta-analyses have examined behavioral outcomes after POE, none have tested ADHD symptoms specifically. Our study suggests that children with POE are more likely to experience hyperactivity/impulsivity, inattention, and combined symptoms. Moreover, while individual studies have documented elevated hyperactivity [22], impulsivity [21], or inattention [24] after POE, few studies have measured all symptoms of ADHD separately and combined.

ADHD symptoms in children with POE may increase as children age, there are a number of considerations. The literature suggests that caregivers of children with POE are more likely to have delayed identification of children’s behavioral problems [23]. Thus, it is possible that the higher association with POE and ADHD symptoms at school age (versus preschool age) may be due to delayed identification of ADHD symptoms by caregivers. Third, the origin of this outcome is uncertain as cumulative biological, social, and environmental risk dynamically interact over time.

For instance, Barker’s Fetal Origins of Adult Disease hypothesis states that human fetuses adapt to conditions in utero, which may program or permanently change fetal structure, affecting health over the life-course ^[27][41]. Accordingly, opioids may program the developing fetus, which then may interact with environmental and social vulnerabilities at later ages. The increased challenges in time may be related to a more complex and demanding social environment [23]. Longitudinal studies assessing ADHD symptoms indicated that children with POE persisted to have higher ADHD symptoms scores than non-exposed counterparts ^[16][18][23][16,18,23]. These studies also provided limited clarification on how factors such as maternal polydrug usage, type, dosing, and timing of opioid exposure, NAS diagnosis, change of caregiver, and SES may contribute to outcomes. Researchers speculate any challenges from the POE are further amplified by environmental, social, and biological risk factors ^[28][42]. Future studies should continue to investigate these relationships.

Although ADHD symptoms may present differently across developmental stages, their burden on individuals is typically chronic throughout the life-course ^[29][43]. Beyond the hallmark symptoms, preschool-aged children with ADHD are likely to have increased conflict with peers and lack of compliance with adults ^[30][44]. During school-age years, children with ADHD may experience a surge of oppositional behavior, academic problems, and conflicts with peers ^[30][44]. By adolescence, a rise in conflict with parents and emergence of high-risk behaviors are observed higher than the general population ^[30][44]. Furthermore, two-thirds of children with ADHD have a comorbid condition ^[31][45]. Thus, children with ADHD face greater adversity and stress compared to peers without ADHD ^[32][46]. If ADHD persists into adulthood, both personal and professional life may be disrupted ^[33][47]. Individuals with ADHD achieve lower educational levels, have higher unemployment rates, and are more likely to experience social relationship challenges than those without ADHD ^[34][33][35][40,47,48].

Children with POE appeared to have more ADHD symptoms when compared to healthy controls instead of environmental controls, indicating that the postnatal rearing environment impacts the association between POE and ADHD symptoms. While the environmental controls face significant challenges similar to children with POE (e.g., low socio-economic status, father with OUD, environmental deprivation, neglect), the effect size among the environmental subgroup remained large ^[26][27], indicating that children with POE represent an exceptionally vulnerable population. This finding should be further explored by future researchers, as there were only two studies in the environmental subgroup analysis. Mothers of children with POE oftentimes have high rates of socio-economic difficulty and comorbid mental health challenges [12]. Many children with POE are at risk of child welfare concerns, with an average of one to two caregiver changes [11]. Children with POE have been removed from parental custody due to maternal substance abuse and mental health issues, child neglect, and maternal imprisonment and physical abuse [11], indicating several adverse childhood experiences. It is well documented that adverse childhood experiences have lasting impacts, including increased mental health problems, risky behaviors, infectious and chronic disease, while lowering education, occupation, and income opportunities ^[36][37][38][49,50,51].

Findings indicate that children with POE are at high risk for ADHD symptoms that persist throughout childhood ^{[15][17][20][21][23][39][40]}[15,17,20,21,23,31,32]. Results suggest that children with POE may benefit from long-term assistance, such as enhanced awareness and surveillance. Future researchers should continue to study long-term behavioral dysregulation after POE. When possible, studies should utilize gold-standard measurements to assess POE, such as urine analysis throughout pregnancy and meconium analysis after birth, as these methods for detecting in utero drug exposure are inexpensive, noninvasive, and will enhance understanding of exposure and outcome relationships ^[41][52]. Longitudinal studies should be carefully designed to properly assess biological, social, and environmental risk factors and report outcome data at each time point to increase the availability of aggregate analyses. Furthermore, researchers should report outcomes and subscale data of rating scales controlling for a host of demographic factors and health-related measures to adequately assess the phenotype of children with POE in relation to ADHD symptoms. Lastly, due to variability in behavioral rating scales, researchers investigating ADHD symptoms should carefully review the literature to ensure rating scales match the psychometric properties of the DSM-IV ADHD diagnosis ^[42][53].