Developmental Consequences of Prenatal Substance Use in Children and Adolescents

Abstract

Objective:

Prenatal substance use is increasing and is a major public health concern due to its impact on women's health and child development. Prior studies demonstrate an association between prenatal substance use and deficits in children's physical, cognitive, behavioral, and emotional development. Many studies, however, have significant methodological limitations that hinder our understanding of the impact of substance use on child development. The goal of this review is to describe the risks of prenatal substance use on child development among studies that have overcome major study limitations to inform the development of targeted interventions to improve child health.

Methods:

Studies investigating the relationship between prenatal substance use and its impact on child development are identified. Studies employing a prospective, longitudinal study design with appropriate comparison groups and methods accounting for potentially confounding variables are reviewed.

Results:

Prenatal tobacco or alcohol use has the most well-established adverse impact on child development, including an increased risk for behavioral problems and deficits in academic performance, resulting in significant functional impairment. Prenatal marijuana use is associated with deficits in executive and intellectual functioning among school-age children and adolescents. Prenatal opioid use and child development findings are conflicting, but treatment with opioid agonist therapy for opioid use disorder (e.g., methadone or buprenorphine) does not appear to have a negative impact on child growth, cognition, language abilities, sensory processing, or temperament. Prenatal amphetamine and cocaine use may have a negative impact on child development, but effects, in part, are mediated by childhood environment and adversity.

Conclusions:

Preventative efforts in women's health are needed to reduce substance use and unplanned pregnancies. Early interventions for children exposed to substances are needed as well as interventions targeting the myriad of issues that co-occur with substance use, including poverty, mental health problems, and childhood adversity.

Introduction

In the United States, the prevalence of substance use during pregnancy is increasing. The 2017 National Survey on Drug Use and Health (NSDUH) demonstrates a significant increase in past month illicit substance, tobacco, and alcohol use among pregnant women compared with NSDUH data collected in 2015 and 2016 (Substance Abuse and Mental Health Services Administration 2018). Past month use of tobacco during pregnancy increased from 10.6% in 2016 to 14.7% in 2017. Similarly, past month use of alcohol during pregnancy increased from 8.3% in 2016 to 11.5% in 2017. Over the past 2 years, past month use of illicit substances among pregnant women has increased from 4.7% in 2015 to 8.5% in 2017. The significant increase in illicit drug use appears to be driven by over a twofold increase in the use of marijuana and nearly a twofold increase in opioid use among pregnant women.

Prior studies demonstrate an association between prenatal substance use and a myriad of poor maternal, newborn, and child health outcomes, including prematurity, low birth weight, neonatal abstinence syndrome (Pinto et al. 2010; Quesada et al. 2012; American College of Obstetrics and Gynecologists 2015), and longer-term deficits in children's physical, cognitive, behavioral, and emotional development (Hutchinson et al. 2018). There are, however, significant limitations to prior work particularly as it relates to longer-term outcomes. For example, often studies evaluating the relationship between prenatal substance use and child outcomes are retrospective or cross sectional (Jones et al. 2008). These types of study designs are unable to reliably capture the timing, duration, and amount of substance use during pregnancy or accurately examine substance use throughout the peripartum period (pregnancy and the year postpartum) (Kaltenback et al. 2018).

In addition, self-report assessments of substance use and urine drug screens are the most common methods employed to assess substance use, but these measures often do not reliably detect substance use among pregnant women (Kennedy et al. 2004; Chasnoff et al. 2005; Chang et al. 2011). Furthermore, frequently, studies do not consider the indirect pathways in which substance use can impact families and child development. For example, maternal substance use has been shown to negatively impact mother–infant interactions and bonding (Rossen et al. 2016) as well as relationships with an intimate partner (Mitchell et al. 2001).

Parental substance use also increases the risk of childhood exposure to stress, trauma, and/or violence (Abar et al. 2013; Eze et al. 2016). Exposure to adverse childhood events (ACEs) such as parental conflict, criminality, violence, poverty, mental illness, neglect, or emotional, physical, or sexual abuse is associated with a myriad of poor child developmental outcomes (Hughes et al. 2017), with multiple ACEs frequently co-occurring and demonstrating a harmful dose–response effect on child health and development (Freeman 2014). Data from the longitudinal National Survey of Child and Adolescent Well-Being demonstrate that caregiver substance abuse is significantly associated with ACEs, including caregiver mental health problems, domestic violence, criminality, and neglect.

Children with ≥3 ACEs are 4.5–5 times more likely to have internalizing and externalizing behavioral problems (Freeman 2014). Similarly, the Fragile Families and Child Wellbeing Study demonstrates a similar dose–response effect with children with ≥3 ACEs having increased odds of below average language, literacy, and math skills (odds ratio [OR] 1.8), attention problems (OR 3.5), social problems (OR 2.7), and aggression (OR 2.3) (Jimenez 2016). Many studies investigating the relationship between perinatal substance use and child development do not account for ACEs and other important potentially confounding variables that often associate with substance use and can impact child development such as prenatal care, preterm birth, low birth weight, poverty, nutrition, perinatal psychiatric comorbidities, perinatal polysubstance use, family separation, and multiple family placements (Conway et al. 2007; Shah et al. 2012; Kwiatkowski et al. 2018).

Last, a major challenge in this area of research is identifying an appropriate control group. Many studies compare pregnant women who use substances with women who do not use substances and/or have a substance use disorder and find differences between groups (Goldschmidt et al. 2008). However, in some studies, no differences are found between groups when women with substance use disorders who use substances during pregnancy are compared with women with substance use disorders who do not use substances during pregnancy (Marroun et al. 2018). Comparison groups, including women without substance use disorders, do not take into account the disease of addiction and its potential impact on newborn and child development independent of actual substance use (Jones et al. 2008).

As a result of prior study limitations, there are often conflicting findings between studies and major gaps in our current knowledge about the extent to which prenatal substance use impacts early and long-term child development. The goal of this review is to highlight the increasing prevalence of prenatal substance use and describe prior studies that have overcome major study limitations by using a prospective, longitudinal study design, with appropriate comparison groups, and have accounted for important potentially confounding variables that affect child development. We aim to summarize findings from these studies to inform the development of targeted and effective interventions to improve child and adolescent health.

While the focus of this review will be on long-term child outcomes such as cognitive, emotional, or behavioral problems among children and adolescents, it is important to note that prenatal exposure to substances, including tobacco, stimulants, or opioids, is associated with an increased risk of short-term outcomes such as preterm birth and low birth weight (O'Leary et al. 2009; Ion and Bernal 2015), which both have a significant and negative impact on child development.

Independent of substance use, preterm birth or low birthweight is associated with poor academic performance, inattention, and externalizing and internalizing behaviors in school-aged children (Bhutta et al. 2002). In a meta-analysis of 15 case–control studies of school-aged children, a history of lower birth weight or lower gestational age at the time of delivery was significantly associated with lower cognitive test scores, increased externalizing and internalizing behaviors, and attention problems, including a 2.6-fold increased risk for attention-deficit/hyperactivity disorder (Bhutta et al. 2002). Preterm birth has also been associated with a preterm behavioral phenotype, characterized by a triad of inattention, social, and anxiety problems (Villar et al. 2012). While studies among adolescents are sparse, available studies consistently report a three- to fourfold increased risk of a psychiatric disorder in adolescents born preterm compared with their term-born peers (Johnson and Wolke 2013).

Therefore, throughout this review, we will include mention of short-term newborn outcomes as they relate to substance use and child and adolescent health and development.

Tobacco

The untoward effects of maternal smoking on fetal, newborn, and child health and development are well known. Maternal smoking is consistently associated with decreased birth weight (Cnattingius 2004; Salihu and Wilson 2007; Quesada et al. 2012), preterm birth (Salihu and Wilson 2007; Ion and Bernal 2015), infant mortality (Cnattingius 2004; Tikkanen et al. 2006; Salihu and Wilson 2007; Forray 2016), and sudden infant death syndrome (DiFranza et al. 2004). In addition, maternal smoking is associated with respiratory problems, ear infections, behavioral problems, and neurocognitive deficits in children (DiFranza et al. 2004).

Prior studies consistently demonstrate that children exposed to prenatal smoking have higher rates of behavioral problems compared with children without exposure to prenatal smoking (Olds 1997; Eskenazi and Castorina 1999; Ernst et al. 2001; Wakschlag et al. 2002; Weitzman et al. 2002). Several large, prospective longitudinal studies using multiple assessments of child behaviors from multiple sources (i.e., parents, teachers, and investigators) have found prenatal smoking to associate with childhood behavioral problems, including externalizing behaviors, attention-deficit/hyperactivity disorder-like behaviors, and referral to psychiatric care for conduct disorder even after accounting for multiple potentially confounding variables (Hardy and Mellits 1972; Rantakallio et al. 1992; Weitzman et al. 1992; Wakschlag et al. 1997). In addition, studies demonstrate a dose–response relationship, with greater amounts of prenatal smoking associating with a greater likelihood of the child having behavioral problems (Hardy and Mellits 1972; Weitzman et al. 1992).

Studies investigating the relationship between prenatal smoking and cognitive impairment and school performance have also demonstrated significant associations, but findings are not as consistent as with prenatal smoking and childhood behavioral problems (DiFranza et al. 2004). It is speculated that the inconsistency in study findings may be owing to cross-sectional or retrospective study designs and/or the lack of control for confounding variables (DiFranza et al. 2004). Studies that have overcome these challenges include those that have used sibling analyses and appropriate comparison groups and have examined the dose–response relationship between the amount of prenatal smoking exposure and impact on child outcomes.

Sibling analyses where mothers use substances during one pregnancy, but not another, can be instrumental in accounting for genetic and other environmental factors that might influence child development. Fergusson and Lloyd (1991) conducted a sibling analysis and demonstrated that children of mothers who smoked in one pregnancy performed worse on an intelligence test compared with their siblings who were not exposed to prenatal smoking. Studies utilizing comparison groups of children of women who quit smoking during pregnancy, compared with women who continue smoking during pregnancy, score higher on tests of cognitive ability (Fried and Watkinson 1990). These types of studies help to delineate the effects of substance use while accounting for the disease of addiction and the variables that often co-occur with tobacco use disorder. Last, studies examining the relationship between the amount of prenatal smoking and school achievement demonstrate a dose–response relationship, with mothers smoking more than 10 cigarettes per day having children at risk for academic delays in mathematics, reading, and general academic ability (Olds et al. 1994).

Alcohol

Similar to prenatal tobacco use, alcohol use in pregnancy has the most well-established adverse fetal and child health effects. Heavy alcohol use in pregnancy is associated with a myriad of poor obstetric outcomes, including, but not limited to, low birth weight (Passaro et al. 1996), prematurity (O'Leary et al. 2009), and small for gestational age (Rosett et al. 1983; Mill et al. 1984; Passaro et al. 1996; Whitehead and Lipscomb, 2003).

It is well known that alcohol use in pregnancy is associated with fetal alcohol syndrome (FAS), characterized by growth retardation, characteristic facial features (e.g., small eyes with drooping upper lids, short upturned nose, flattened cheeks, small jaw, thin upper lip, and flattened philtrum), and central nervous system problems (e.g., intellectual disability, hyperactivity, gross or fine motor delayed development, impaired language development, memory problems, impulsivity, learning problems, and seizures) (Pruett et al. 2013). FAS is one of the most common causes of birth defects and preventable causes of intellectual disability with 5000–12,000 new cases in the United States annually (Pruett et al. 2013).

The neurobehavioral sequelae of FAS are well characterized in the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5), and described as a neurodevelopmental disorder associated with prenatal alcohol exposure (ND-PAE) (American Psychiatric Association 2013). The diagnosis of ND-PAE is dependent on three functional domains, including (1) self-regulation of attention, mood, behavior, and impulses; (2) neurocognitive function such as intelligence quotient (IQ), executive functioning, memory, visual–spatial reasoning skills, and ability to learn; and (3) adaptive functioning in communication, daily living skills, motor skills, and social skills. The neurobehavioral sequelae of FAS manifest during childhood and cause significant distress or impairment in multiple areas of functioning. No amount of alcohol use is recommended during pregnancy as evidence for even low to moderate alcohol use in pregnancy is inconclusive (Henderson et al. 2007).

Marijuana

The use of marijuana during pregnancy is increasing (Brown et al. 2017). Past month use of marijuana among pregnant women increased significantly from 3.4% in 2015 to 7.1% in 2017 (Substance Abuse and Mental Health Services Administration 2018). While the majority of pregnant women will decrease their substance use during pregnancy, the prevalence of daily use of marijuana among pregnant women is similar compared with nonpregnant women of reproductive age (Substance Abuse and Mental Health Services Administration 2018). The increasing use and daily use of marijuana during pregnancy parallel the legalization of marijuana and a rising perception that marijuana use is not harmful and may be helpful for pregnancy-related conditions such as nausea or sleep disturbances (Westfall 2004; Jaques et al. 2014).

A number of clinical studies have been conducted examining the impact of prenatal marijuana use on obstetric and newborn outcomes, resulting in four systematic reviews and meta-analyses (English et al. 1997; Jaques et al. 2014; Metz and Stickrath 2015; Gunn et al. 2016). While some of these studies include limitations previously mentioned, collectively, these data support an association between prenatal marijuana use and slightly lower birth weights and increased rates of neonatal intensive care unit (NICU) admissions (Mark and Terplan 2017). Importantly, lower birth weight is not characterized as low birth weight and its clinical significance is unclear.

There are several published, prospective cohort studies evaluating long-term child and adolescent outcomes associated with prenatal marijuana use (Fried et al. 2003; Goldschmidt et al. 2008; Marroun et al. 2018). These studies suggest that prenatal marijuana exposure is associated with significant negative effects on executive and intellectual functioning among school-age children and adolescents.

In a large, prospective cohort study, school-age children of lower income women with heavy prenatal marijuana use, defined as use of one or more marijuana cigarettes per day, had significantly lower scores on the Stanford–Binet Intelligence Scale compared with normed data (Goldschmidt et al. 2008). After accounting for maternal IQ, home environment, and social support, heavy marijuana use in the first trimester was associated with lower verbal reasoning. Second trimester heavy marijuana use was associated with deficits in the Stanford–Binet Intelligence Scale composite and short-term memory scores, and second and third trimester heavy marijuana use was associated with lower quantitative scores (Goldschmidt et al. 2008).

Similar findings have also been demonstrated in adolescent populations (Fried et al. 2003). In a prospective, longitudinal cohort study of low-risk middle-income families where prenatal marijuana use and tobacco use were ascertained, marijuana use was negatively associated with tasks that required visual memory, analysis, and integration. While these studies are large, prospective longitudinal studies that employ valid assessments of substance use and intellectual functioning as well as account for some important potentially confounding variables, the comparison groups include normal populations or those with prenatal tobacco use. Without an appropriate control group (e.g., women with regular marijuana use before, but not during, pregnancy), it is possible that intellectual effects are moderated by genetics or other unmeasured environmental factors and not a direct result of prenatal marijuana exposure.

The importance of a comparison group is well illustrated in a recent population-based birth cohort study examining the relationship between prenatal marijuana use and risk of internalizing and externalizing behaviors in children at ∼7–10 years. The study demonstrates an increased risk of externalizing, but not internalizing, behaviors among children with prenatal marijuana exposure. This association, however, is also present among women with marijuana use before and after, but not during, pregnancy as well as paternal use of marijuana. These findings suggest that there is an association between parental marijuana use and externalizing behaviors in children, and the association between prenatal marijuana use and externalizing behaviors may not be due to in utero exposure, but likely due to genetic or other environmental factors that associate with marijuana use in general (Marroun et al. 2018).

Recent work has used functional magnetic resonance imaging (fMRI) to attempt to identify the neuronal basis of impaired executive and intellectual functioning in adolescents with prenatal marijuana exposure (Marroun et al. 2016). In a longitudinal prospective study, 31 young adults (aged 18–22; 16 with prenatal marijuana exposure and 15 with no prenatal marijuana exposure) underwent fMRI while completing four executive functioning tests. Task performance results were similar between groups, but interestingly blood flow and brain activity while completing tasks differed between groups with greater left posterior brain activation in the marijuana-exposed group compared with the nonexposed group (Smith et al. 2016). While the significance of this finding is unclear, demonstration of differences requires further investigation. The legalization of marijuana offers a unique opportunity to prospectively study marijuana exposure in pregnancy, particularly as it relates to timing and amount of exposure and type of marijuana used (Mark and Terplan 2017).

Opioids

According to the Centers for Disease Control and Prevention, the number of pregnant women with opioid use disorder at labor and delivery more than quadrupled from 1999 to 2014 (Haight et al. 2018). In 28 states with available data, the prevalence of opioid use disorder increased from 1.5 per 1000 delivery hospitalizations in 1999 to 6.5 in 2014 (Haight et al. 2018). There are substantial maternal, fetal, and newborn risks associated with opioid use disorder. In addition to the risk of unintentional overdose and death as seen in the general population, prenatal opioid use disorder is associated with considerable maternal, obstetric, fetal, and newborn morbidity and mortality. Opioid use disorder is associated with a 4.6-fold increased risk for maternal death at delivery as well as an increased risk for intrauterine growth restriction, placental abruption, prematurity, blood transfusion, stillbirth, cesarean section, and preeclampsia or eclampsia (Maeda et al. 2014).

A well-known consequence of opioid use in pregnancy is newborn opioid withdrawal syndrome (NOWS), formerly known as neonatal abstinence syndrome, with 60% of newborns born to pregnant women with opioid use disorders exhibiting withdrawal following delivery (Patrick et al. 2012). Over the past decade, the incidence of NOWS in the United States has increased ∼400%, from 1.2 per 1000 hospital births in 2000 to 5.8 per 1000 hospital births in 2012.

Two recent reviews examining neurocognitive effects of prenatal opioid exposures report conflicting results. Maguire et al. (2016) suggest that prenatal exposure to opioids is potentially associated with deficits in cognition, psychomotor, and behavioral processes in infants and in young children. In contrast, Behnke and Smith (2013) suggest that prenatal opioid exposure results in long-term effects on child behavior, but not cognition. The differences in study findings may be due to the fact that both reviews include studies with significant methodological limitations. The majority of studies included in these reviews are small cross-sectional or retrospective studies with few controls for important confounding variables (Jones et al. 2015). Furthermore, these reviews include a wide variety of opioid exposures, including treatments for opioid use disorder (e.g., methadone or buprenorphine) (Jones et al. 2010), as well as prescribed or illicit opioids such as heroin. The heterogeneity across studies and types of opioids included likely contribute to conflicting findings.

Importantly, recent work has demonstrated that exposure to treatment for prenatal opioid use disorder, including buprenorphine or methadone, is not associated with cognitive or behavioral problems in young children (Kaltenback et al. 2018). Systematic reviews and meta-analyses as well as a randomized controlled trial comparing short-term obstetric and newborn outcomes among infants exposed to buprenorphine or methadone for the treatment of prenatal opioid use disorder generally support buprenorphine as having a more favorable risk profile (Brogly et al. 2014; Zedler et al. 2016). For example, newborns exposed to buprenorphine, compared with methadone, have a lower risk for preterm birth and have a greater birth weight and larger head circumference (Zedler et al. 2016). In addition, prenatal buprenorphine treatment for opioid use disorder is associated with a lower risk for treatment of NOWS, requiring less medication and a shorter hospital stay, compared with newborns with in utero exposure to methadone (Jones et al. 2010; Brogly et al. 2014).

To our knowledge, to date, there are only two retrospective studies (Whitham et al. 2010, 2015) and one prospective study (Kaltenback et al. 2018) examining developmental outcomes in children exposed in utero to buprenorphine or methadone beyond the first year of life. The prospective study is an extension of the Maternal Opioid Treatment: Human Experimental Research (MOTHER) study, a randomized controlled trial comparing newborn and maternal outcomes among neonates exposed to methadone compared with buprenorphine for the treatment of prenatal opioid use disorder (Jones et al. 2010). A total of 96 children from the MOTHER study were evaluated at 3, 6, 12, 24, and 36 months for a wide range of physical and neurodevelopmental outcomes, including child growth, cognition, language abilities, sensory processing, and temperament. The study also included assessments of maternal health, including perceptions of parenting stress, home environment, and addiction severity.

Overall, the study found no deleterious effects of methadone or buprenorphine on child physical or mental development as well as no differences in child development among those exposed to methadone compared with buprenorphine. Importantly, the study also found that severity of or treatment for NOWS compared with those without NOWS or treatment for NOWS did not impact child development (Kaltenback et al. 2018). These findings are encouraging and provide even further support for the use of buprenorphine or methadone for the treatment of opioid use disorder in pregnancy.

Cocaine

Cocaine is the second most common illicit substance of abuse during pregnancy with 3.4% of pregnant women reporting the use of cocaine in the past month (Center for Behavioral Health Statistics and Quality 2016). There are significant maternal and obstetric risks associated with prenatal cocaine exposure such as premature rupture of membranes, placental abruption, preterm birth, low birth weight, and small for gestational age that are known to impact child outcomes (Dombrowski et al. 1991; Gouin et al. 2011; Smid et al. 2019).

However, the long-term developmental effects of prenatal cocaine exposure are significantly less than initially anticipated. In a very small (n = 23), but influential, study published in the New England Journal of Medicine, authors reported that infants exposed to prenatal cocaine had significant depression of interactive behavior and a poor organizational response to environmental stimuli (Chasnoff et al. 1985). The public concluded from these preliminary findings that cocaine exposure in pregnancy would result in an entire generation of neuro-developmentally disabled children who would overwhelm schools and cost billions, which was later determined to be unfounded. As a result of an initial heightened concern, however, a number of studies have investigated the developmental effects of perinatal cocaine exposure.

Prenatal cocaine exposure has consistently been associated with an increased risk for prematurity and poor fetal growth. In a systematic review, Gouin et al. (2011) found a significant association between cocaine use during pregnancy and preterm birth, low birth weight, and small for gestational age. These findings have been replicated in additional prospective studies (Smith and Santos 2016). A literature review performed by Lambert and Bauer (2012) also demonstrated that infants with prenatal cocaine exposure had lower birth weights and smaller head sizes when compared with noncocaine-exposed infants or infants exposed only to alcohol, tobacco, or marijuana.

What is unclear is whether growth effects persist throughout childhood. In a prospective longitudinal study of 219 fifteen-year-olds, children with first trimester cocaine exposure were significantly smaller at age 15 compared with same-age peers without first trimester exposure (using growth measures of weight, height, and head circumference) even after adjusting for factors such as gender, pubertal development, maternal height, substance use, and several sociodemographic and psychosocial characteristics (Richardson et al. 2015). However, there were no significant associations between second or third trimester cocaine exposure and growth (Richardson et al. 2015), and other studies indicate that growth is only significantly inhibited by heavy cocaine use (Smith and Santos 2016) and that growth differences are typically small or absent by school age (Ackerman et al. 2010).

Studies investigating the longer-term impact of perinatal cocaine exposure on child development have yielded mixed results, with some studies suggesting that prenatal cocaine exposure does not result in long-lasting global cognitive impairments in learning or memory (Richardson et al. 2015) and other studies suggesting difficulties with sustained attention processing in early childhood and poorer problem solving, abstract reasoning, and adolescent-reported delinquent behavior (Richardson 1998; Bandstra et al. 2001). Importantly, however, much of the effect of prenatal cocaine exposure and adolescent-reported delinquent behavior appears to be mediated by exposure to violence in the home (Bandstra et al. 2001). Similarly, initial deficits in language performance of school-aged children with prenatal cocaine exposure were shown to resolve with an enriched environment (Lambert and Bauer 2012), highlighting the importance of environmental influence on child development.

Amphetamines

Recent data from the National Inpatient Sample, a nationally representative sample of hospital discharges in the United States, demonstrate that prenatal amphetamine use is increasing (Admon et al. 2018). In the past 6 years, rates of amphetamine use, and in particular methamphetamine use, have increased twofold from 1.2 cases per 1000 deliveries in 2008–2009 to 2.4 cases per 1000 deliveries in 2014–2015. In some parts of the Unites States, particularly in rural regions, the rate of prenatal amphetamine use is greater than the rate of prenatal opioid use. Nationally, amphetamine use disorders are the third most common reason that pregnant women seek substance use treatment (Substance Abuse and Mental Health Services Administration 2013).

The vasoconstrictive effects of prenatal methamphetamine use are particularly harmful during pregnancy and result in placental dysfunction and increased risk for poor obstetric and newborn outcomes. In comparison with opioid use, prenatal methamphetamine use results in a higher rate of preeclampsia, preterm birth, and severe maternal morbidity and mortality (Admon et al. 2018). Methamphetamine use during pregnancy appears to be associated with preterm birth and low birth weight (Gorman et al. 2014) and has a dose–response relationship with these poor obstetric outcomes (Wright et al. 2015). In a large prospective study that controlled for multiple potentially confounder variables (e.g., tobacco use, other drug use, poverty, and housing status), continuous use of methamphetamine throughout pregnancy was associated with low birth weight and preterm birth.

This association, however, was not established in women who used it at any point during pregnancy. In particular, women who stopped using methamphetamine at any time during pregnancy were found to have improved birth outcomes, including increased gestational age at delivery and higher newborn birth weight, compared with women who continued to use it during pregnancy (Wright et al. 2015). As chronic use of methamphetamine has been linked to maternal chronic hypertension, this may be the potential mechanism influencing fetal growth (Wright et al. 2015).

Short- and long-term child outcomes associated with prenatal methamphetamine exposure have been examined in the Infant Development, Environment, and Lifestyle (IDEAL) study (Smith et al. 2015). The IDEAL study is a prospective, longitudinal multisite study designed to examine maternal and child growth and development following prenatal amphetamine exposure. Over 200 infants with in utero exposure to methamphetamine in this study are compared with unexposed matched infants (matched on race, birth weight, maternal education, and type of health insurance as a proxy for socioeconomic status) and assessed for a number of child growth, behavioral, and neurobehavioral outcomes from birth up to 7.5 years. The study also includes a large battery of maternal assessments in an effort to better understand the moderating effects of home environment and maternal characteristics on child development (Smith et al. 2015).

While no neonates in this study demonstrated signs or symptoms consistent with the neonatal abstinence syndrome requiring pharmacological intervention, newborns exposed in utero to heavy methamphetamine use, defined as methamphetamine use more than 3 days per week throughout pregnancy, demonstrated an increased stress response based on the NICU Network Neurobehavioral Scale (Smith et al. 2015). In addition, heavy methamphetamine use was associated with poor inhibitory control and increased risk for impaired executive functioning in children. The study also demonstrated the importance of home environment and found that independent of in utero methamphetamine exposure, children with more responsive home environments to developmental and emotional needs demonstrated a lower risk for internalizing and externalizing behaviors (Smith et al. 2015).

Longer-term effects of prenatal methamphetamine exposure on child development may, in part, be mediated by early childhood adversity. Eze et al. (2016) analyzed data from participants evaluated at 7.5 years in the IDEAL study and found that both prenatal methamphetamine exposure and early childhood adversity strongly associated with increased scores on the externalizing behavior domain of the Childhood Behavior Checklist. In a mediation analysis, investigators demonstrated that over a third of the relationships between prenatal methamphetamine exposure and childhood externalizing behaviors could be explained by early childhood adversity. These findings are consistent with another study demonstrating that prenatal methamphetamine exposure and early childhood adversity associate with behavioral and emotional control issues at 5 years (Abar et al. 2013).

Conclusion

Prenatal tobacco or alcohol use has the most well-established adverse impact on child health and development. Prenatal tobacco use is consistently associated with childhood behavioral problems and potential impairment in academic performance. Prenatal alcohol use resulting in FAS is associated with several neurobehavioral sequelae that manifest during childhood and result in significant distress and impairment in multiple areas of functioning. Prenatal marijuana use is associated with significant negative effects on executive and intellectual functioning among school-age children and adolescents. Prenatal opioid use and child development findings are conflicting, but treatment with opioid agonist therapy for opioid use disorder (e.g., methadone or buprenorphine) does not appear to have a negative impact on child growth, cognition, language abilities, sensory processing, or temperament. Prenatal amphetamine or cocaine use may have a negative impact on child development, but effects, in part, are mediated by childhood environment and adversity.

While half of all pregnancies in the United States are unplanned, more than 80% of pregnancies among women with substance use disorders are unplanned (Heil et al. 2010). Family planning should be discussed with every woman of reproductive age, especially those with a substance use disorder, at every opportunity, including during addiction treatment, primary care, or routine gynecological care. During pregnancy, all women should be screened for substance use throughout pregnancy, and if identified, substance use disorder treatment should be facilitated. Maintaining prenatal care and cutting down substance use or stopping use of substances during pregnancy can improve maternal, newborn, and child outcomes.

Given the increase in prenatal substance use and legalization of marijuana in the United States, it is increasingly important to consider prenatal substance use when evaluating children and adolescents with cognitive or behavioral problems. It is also important to note that birth history, such as preterm birth and low birth weight, appears to impact cognitive test scores, increase externalizing and internalizing behaviors, and associate with attention, social, and anxiety problems. Furthermore, when assessing behavioral problems in children exposed to prenatal substance use, it is important to account for other factors known to increase the risk of childhood behavioral problems and are common among substance using populations, such as maternal mental health, child maltreatment, and family separation, so that appropriate interventions can be implemented.

Clinical Significance

The prevalence of prenatal substance use in the United States is increasing. Prenatal substance use has a negative impact on child development, but issues that co-occur with substance use can be equally as harmful to child development. Disentangling the effects of in utero substance use exposure from those that co-occur with substance use disorders (e.g., poverty, mental health problems, lack of education, and childhood adversity) can help providers construct effective treatment plans that are tailored to individual patients and families.

Footnotes

Disclosures

No competing financial interests exist.

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