**2. Methodological Issues and Current Trends in Prevalence and Characteristics of Prenatal Drug Exposure**

Prenatal drug exposure is a major public health concern for mothers and their children. In addition, society bears significant financial costs associated with social and child welfare services utilization [3, 4], neonatal intensive care unit costs, and longer hospital stays after delivery [3–8]. Children with prenatal drug exposure are also more likely to need interven‐ tion services to address medical, developmental, behavioral, academic, and socio-emotional issues [9]. Decades of research have documented the negative impact of prenatal drug exposure on child developmental outcomes including growth, emotion and behavior regula‐ tion, and cognitive function. The impact of prenatal drug exposure on the developing child has also been shown to interact with the quality of the child's environment. Given the complexities related to prenatal drug exposure and the influence of many potential external factors, the prevalence, characteristics, and effects on developmental outcomes can be difficult to assess. Difficulties arise from the dose, timing, and duration of prenatal drug exposure, the use of multiple drugs during pregnancy, methodology limitations in the ability to document prenatal drug exposure, differentiating between delayed and longer-term effects, genetic factors, and variability introduced by environmental experiences including the quality of relationships and the home environment [10]. In addition, methods used to measure prena‐ tal drug exposure are varied, ranging from survey methods (e.g., national surveys) to prenatal interviewing (e.g., longitudinal cohort studies).

The main strategy for dealing with the complexities of research aimed at elucidating the impact and mechanisms of prenatal drug exposure on child development is to use longitudinal

research designs that incorporate measurement of explanatory variables. Pregnant sub‐ stance abusers are not studied based on whether they classify as "recreational" users or addicts. Rather, the timing (first, second, third trimester), dose, and pattern of drug use (continuous vs. binge exposure) are key variables. Among cohort studies, there are differences in sample characteristics that are important for the interpretation of any study results that suggest negative developmental outcomes associated with prenatal drug exposure. For example, some studies focus on "high- dose" exposure (e.g., Seattle Longitudinal Study of Fetal Alcohol Syndrome), whereas other studies focus on the full spectrum of exposures ranging from light-, moderate-, to high-dose exposure (e.g., Pittsburgh Maternal Health Practices and Child Development Project). Most studies have attempted to quantify the pattern of drug expo‐ sure as either continuous (e.g., average number of drinks/day) or binge (e.g., ≥4 drinks/ occasion). Cross-sectional study designs are also used to study clinical populations, captur‐ ing the important characteristics of young children who have been referred for assessment and services.

Current trends suggest that while the prevalence of women using drugs during pregnancy is relatively low, maternal substance use has an impact on many children. Approximately 400,000–440,000 infants, 10–11% of all births, are prenatally exposed to alcohol, tobacco, or illicit drugs [11]. In addition, current trends in prenatal drug exposure suggest shifts in both the prevalence and patterns of maternal substance use that reflect both wide spread knowl‐ edge and perceptions of the impact of drugs of abuse in general, and prenatal drug exposure more specifically. Alcohol and tobacco are the most commonly used drugs during pregnan‐ cy, followed by marijuana, cocaine, and opioids [12]. For all types of prenatal drug exposure, the data show that reported use in pregnant women is lower compared to nonpregnant women in the same age category and that more pregnant women report use in the first trimester compared to second and third trimesters [12]. In general, a greater number of younger pregnant women (ages 18–25) report use compared to older women (ages 26–44) [12].

#### **2.1. Current prevalence estimates of prenatal drug exposure**

current trends in prenatal drug exposure including the prevalence, patterns, and characteris‐ tics of prenatal drug use, including alcohol, tobacco, marijuana, and other illicit drugs. Then, the impact of current neuroimaging methodology on our understanding of the effects of prenatal drug exposure is explored. The review considers examples of how neuroimaging tools have increased our understanding of the often subtle and complex impact of prenatal substance exposure on child brain development and behavior. The impact of prenatal drug exposure is challenging to assess due to characteristics of maternal drug use such as poly‐ drug exposure and differences in the purity and legality of drugs. Developmental outcomes associated with prenatal drug exposure will also be affected by the timing, dose, and pat‐ tern of drug use during pregnancy, and the varying impact of other environmental factors such as maternal health and nutrition, access to prenatal care, and the home environment [1, 2]. For over 40 years, the impact of prenatal drug exposure has been studied in relation to growth, behavior, and cognitive outcomes using both longitudinal and cross-sectional designs, which have provided a depth of understanding. Overall, the most important outcome of decades of research has been that no safe levels of any type of prenatal drug use during pregnancy have been identified. Furthermore, the impact of prenatal drug exposure is often subtle and combined with other environmental risk factors, contributes to poor developmen‐

tal outcomes for young children and adolescents.

194 Recent Advances in Drug Addiction Research and Clinical Applications

**Characteristics of Prenatal Drug Exposure**

interviewing (e.g., longitudinal cohort studies).

**2. Methodological Issues and Current Trends in Prevalence and**

Prenatal drug exposure is a major public health concern for mothers and their children. In addition, society bears significant financial costs associated with social and child welfare services utilization [3, 4], neonatal intensive care unit costs, and longer hospital stays after delivery [3–8]. Children with prenatal drug exposure are also more likely to need interven‐ tion services to address medical, developmental, behavioral, academic, and socio-emotional issues [9]. Decades of research have documented the negative impact of prenatal drug exposure on child developmental outcomes including growth, emotion and behavior regula‐ tion, and cognitive function. The impact of prenatal drug exposure on the developing child has also been shown to interact with the quality of the child's environment. Given the complexities related to prenatal drug exposure and the influence of many potential external factors, the prevalence, characteristics, and effects on developmental outcomes can be difficult to assess. Difficulties arise from the dose, timing, and duration of prenatal drug exposure, the use of multiple drugs during pregnancy, methodology limitations in the ability to document prenatal drug exposure, differentiating between delayed and longer-term effects, genetic factors, and variability introduced by environmental experiences including the quality of relationships and the home environment [10]. In addition, methods used to measure prena‐ tal drug exposure are varied, ranging from survey methods (e.g., national surveys) to prenatal

The main strategy for dealing with the complexities of research aimed at elucidating the impact and mechanisms of prenatal drug exposure on child development is to use longitudinal

Recent estimates [12] show that the rates of prenatal alcohol use are approximately 9.4%, of which 2.3% of women report binge drinking and 0.4% report heavy drinking. Higher levels of drinking are reported in the first trimester compared to second and third trimesters. Patterns of alcohol use among pregnant women have changed over time. More recently, pregnant women are reported to drink more heavily and are more likely to develop an alcohol use disorder compared to earlier studies [13]. In addition, women of childbearing age have shown an increase in binge drinking, a trend that has decreased in males over time [14, 15]. Women who binge drink during pregnancy report, on average, 4.6 binge drinking episodes (nonpreg‐ nant women report 3.1 episodes) and the number of drinks consumed, while binge drinking does not differ from nonpregnant drinkers [2]. The Centers for Disease Control reports that medical record analysis shows a rate of 0.3 out of 1000 children ages 7–9 are diagnosed with fetal alcohol syndrome (FAS), while in-person assessments find higher rates (6–9 per 1000 children). Rates of fetal alcohol spectrum disorders are more difficult to ascertain, but community based studies in both the United State and Western Europe suggest that 24–48 per 1000 school children are affected by prenatal alcohol exposure [16, 17].

Reflecting national trends, the NSDUH [12] reports that cigarette use among women has been steadily decreasing from a rate of 30.7% in 2002–2003 to 24.0% in 2012–2013. However, during the same time period, the prevalence rate of cigarette use among pregnant women did not show a similar significant reduction. Eighteen percent of pregnant women reported cigarette use during pregnancy in 2002–2003 compared to 15.4% in 2012–2013. Other studies have shown that efforts to reduce smoking prevalence among female smokers before pregnancy have not been effective; however, efforts targeting pregnant women have met some success as rates have declined during pregnancy and after delivery [18,19].

The most commonly used illicit drug is marijuana, but illicit drug use also includes cocaine, opioids, and amphetamines. Among pregnant women, the rate of any illicit drug use is 5.4% and has not changed significantly since 2010–2011 [12]. Use remains higher in younger women (14.6%, ages 18–25) compared to older women (3.2%, ages 26–44). A high proportion of women are using marijuana illegally and fail to disclose their use to their providers. A recent study showed 81 percent of providers in urban outpatient clinics are asking their pregnant patients about illicit drug use and; of the women surveyed, 11% of women disclosed current use of marijuana, while 34% tested positive for one or more substances with marijuana being the most commonly detected (27%) [20]. Women who use methamphetamine during preg‐ nancy show decreased prevalence and frequency of use from first to third trimester and women who decreased their use were more likely to seek prenatal care during pregnancy [21].

#### **2.2. Maternal and environmental variables**

There are a number of maternal and environmental characteristics that are associated with substance use during pregnancy [22]. Prenatal substance use is associated with younger maternal age [12] and socioeconomic factors such as lower level of education, unemploy‐ ment, and higher levels of poverty [1]. Physical and mental health factors such as the uti‐ lization of health care during pregnancy [23, 24], fear of criminalization and/or stigma [25], higher rates of affective disorders including depression [1], and poly-substance exposure [1] are highly prevalent in pregnant substance users. Women using drugs during pregnancy are also more likely to have had either current and/or childhood exposure to violence and/ or abuse [24]. Domestic violence is also associated with a higher proportion of substance use in women [24, 26].

The complex interactions of social, psychological, and physical variables that are at play in pregnant substance abusers also have an impact on the stability and quality of the child–parent relationship, a significant factor in healthy child development. The care that infants receive from their primary caretaker lays the foundation for the development of behavior and emotion regulation, social skills, and cognitive ability [18, 19, 27, 28], as well as physical and mental health [29, 30]. Substance abusing mothers show decreased responsivity to their infants. For example, opioid abusing mothers show a decreased ability to identify their infant's cues and to respond appropriately to them [31]. Addiction and mental illness, two factors associated with prenatal substance exposure are also associated with difficulty in forming healthy

attachments [32]. The complex interactions of variables associated with prenatal substance exposure is important because the events that occur early in life, both in terms of the quality of relationships and environment, play a significant role in brain development. The impor‐ tant neural connections that support the brain circuitry that underlies emotional, social, and cognitive behavior are established early in life [33].

Prenatal drug exposures, the timing, and quality of other early experiences have a profound impact on child development because of their influence on early brain development. Early life experiences have an impact on the development of brain structure by influencing the timing and pattern of gene expression and the refinement of neural circuitry [34]. Neuroimaging methods that examine the structure and function of the brain have provided access to study the impact of prenatal drug exposure on the developing brain. Methods such as magnetic resonance imaging (MRI), diffusion tensor imaging (DTI), and functional magnetic reso‐ nance imaging (fMRI) are noninvasive allowing for their use in children. Neuroimaging tools have been used to better understand typical patterns of structural and functional develop‐ ment in the brain. This information can be used to examine how prenatal drug exposure affects normal brain development and how it relates to physical and behavioral outcomes.
