1. Exposure to Teratogens as a Risk Factor for Psychopathology Chapter 9 Nicole A. Crocker, Susanna L. Fryer, and Sarah N. Mattson

2. INTRODUCTION AND ETIOLOGICAL FORMULATIONS A teratogen is an agent that causes birth defects by altering the course of typical development. Examples of human teratogens exist in several classes of substances including drugs of abuse, prescription medications, environmental contaminants, and diseases. Behavioral teratogenic exposures are diverse and may include structural damage to the developing brain, cognitive impairments, and emotional dysfunction

3. HISTORICAL CONTEXT Not until 1941 that an association between prenatal exposure to the rubella virus and subsequent birth defects was reported in the scientific literature. For the majority of the 20th century alcohol was not recognized as a human teratogen. 1989 the United States Government passed the Alcoholic Beverage Warning Label Act. February 2005, the U.S. Surgeon General issued an updated “Advisory on Alcohol Use and Pregnancy.”

4. TERMINOLOGICAL and CONCEPTUAL ISSUES Fetal Alcohol Syndrome(FAS) is characterized by: Pre- and/or postnatal growth deficiency Dysmorphic facial features Central nervous system (CNS) dysfunction Cognitive deficits and behavioral abnormalities are commonly observed following prenatal alcohol exposure even in the absence of the growth deficiency and facial stigmata required for clinical recognition of FAS.

5. MENTAL HEALTH OUTCOMES IN FASD Disruptive Behavior Disorders The association between prenatal alcohol exposure and disruptive behavior (i.e., ADHD, conduct disorder) appears to be reliable and persistent, and it is evident at relatively low exposure levels. However, whether this association between prenatal alcohol exposure and delinquency is direct—or is mediated by a more proximal linkage between FASD and early-appearing attention/impulse control problems and/or learning difficulties, which themselves predict later conduct problems—is indeterminate (Hinshaw, 1992).

6. MENTAL HEALTH OUTCOMES IN FASD Mood Disorders Elevated rates of depressive disorders have also been noted in children with FASD, based on parent interviews. Prenatal alcohol exposure is a possible etiological factor in increased negative affect and depressive symptoms. However, this association appeared to also be mediated by the quality and nature of mother-child interactions (O'Connor & Paley, 2006). Potential Mediating and Moderating Factors Maternal psychopathology may be a better predictor of internalizing problems in children with FASD but that alcohol exposure is more directly related to externalizing problems (Staroselsky et al., 2009). Delinquency was not directly related to alcohol exposure but to environmental and behavioral variables such as low parental supervision, adolescent life stress, and self-reported drug use.

7. MENTAL HEALTH OUTCOMES IN FASD In terms of family placement, higher rates of delinquent behavior were endorsed by alcohol-exposed adolescents in biological and foster homes versus those in adoptive homes (Schonfeld et al., 2005). Adaptive Dysfunction As alcohol-exposed individuals reached adulthood, their overall adaptive abilities were equivalent to those of a typically developing 7-year-old, with social skills showing the most severe detriment (Streissguth et al., 1991). Socialization and communication skills of children with FASD may be the most affected domain within adaptive function (Crocker et al., 2009).

8. MENTAL HEALTH OUTCOMES IN FASD Psychopathology in Adults With FASD Clinical difficulties associated with prenatal alcohol exposure, such as impulsivity, mood disorder, and substance abuse, place affected individuals at high risk for suicide. 43% of adults with FASD reported suicide threats and 23% reported a history of suicide attempts throughout the lifetime (Streissguth et al., 1996). Possible Mechanisms of Action A multitude of possible mechanisms for causing the pathology associated with FASD have been identified: Oxidative stress, changes in glucose metabolism, mitochondrial damage, abnormal growth factor activity, dysregulation of developmental gene expression, anomalous cell adhesion, and abnormalities in the development and regulation of neurotransmitter systems.

9. Psychopthology RELATED TO OTHER PRENATAL EXPOSURES Nicotine Most commonly reported effects include increases in antisocial or delinquent behavior and ADHD. Other Stimulant Drugs Stimulants may be associated with subtle neurobehavioral alterations. Regarding psychopathology, increased levels of aggressive behavior have been reported in cocaine-exposed children (Bada et al., 2011). Possible Mechanisms of Action Atypical development of monoamine transmission may help to explain the attention and arousal dysfunction observed in prenatal exposure cases to stimulants.

10. psychopthology RELATED TO OTHER PRENATAL EXPOSURES Behavioral effects of prenatal stimulant exposure are less pronounced than those associated with alcohol and nicotine teratogenesis and that environmental factors related to caregivers may be especially important to consider in stimulant exposure cases. Methylmercury and Lead Associated with neurobehavioral deficits, as a result of both developmental and prenatal exposure (Gutter, & Rice, 2002). Some evidence for increased rates of delinquency in children exposed prenatally to lead (Dietrich, Ris, Succop, Berger, & Bornschein, 2001).

11. SYNTHESIS AND FUTURE DIRECTIONS Insufficient data exist to determine conclusively whether associations exist between all known teratogens and psychopathology. The effect of prenatal alcohol exposure on the development of psychiatric symptoms provides clear evidence that teratogenic exposure can increase the risk of developing psychopathology. Future studies might focus on developing a profile of potential mental health problems for exposed individuals, while also distilling factors that may prevent development of mental health problems in these children.