John H. Hannigan

Maternal risk factors in fetal alcohol syndrome: Provocative and permissive influences

We present an hypothesis integrating epidemiological, clinical case, and basic biomedical research to explain why only relatively few women who drink alcohol during pregnancy give birth to children with alcohol-related birth defects (ARBDs), in particular, Fetal Alcohol Syndrome (FAS). We argue that specific sociobehavioral risk factors, e.g., low socioeconomic status, are permissive for FAS in that they provide the context for increased vulnerability. We illustrate how these permissive factors are related to biological factors, e.g., decreased antioxidant status, which in conjunction with alcohol, provoke FAS/ARBDs in vulnerable fetuses. We propose an integrative heuristic model hypothesizing that these permissive and provocative factors increase the likelihood of FAS/ARBDs because they potentiate two related mechanisms of alcohol-induced teratogenesis, specifically, maternal/fetal hypoxia and free radical formation.

Effects of Prenatal Alcohol Exposure on the Hippocampus: Spatial Behavior, Electrophysiology, and Neuroanatomy

Prenatal exposure to alcohol can result in fetal alcohol syndrome (FAS), characterized by growth retardation, facial dysmorphologies, and a host of neurobehavioral impairments. Neurobehavioral effects in FAS, and in alcohol‐related neurodevelopmental disorder, include poor learning and memory, attentional deficits, and motor dysfunction. Many of these behavioral deficits can be modeled in rodents. This paper reviews the literature suggesting that many fetal alcohol effects result, at least in part, from teratogenic effects of alcohol on the hippocampus. Neurobehavioral studies show that animals exposed prenatally to alcohol are impaired in many of the same spatial learning and memory tasks sensitive to hippocampal damage, including T‐mazes, the Morris water maze, and the radial arm maze. Direct evidence for hippocampal involvement is provided by neuroanatomical studies of the hippocampus documenting reduced numbers of neurons, lower dendritic spine density on pyramidal neurons, and decreased morphological plasticity after environmental enrichment in rats exposed prenatally to alcohol. Electrophysiological studies also demonstrate changes in synaptic activity in in vitro hippocampal brain slices isolated from prenatal alcohol‐exposed animals. Considered together, these observations demonstrate that prenatal exposure to alcohol can result in abnormal hippocampal development and function. Such studies provide a better understanding of neurological deficits associated with FAS in humans, and may also contribute to the development of strategies to ameliorate the effects of prenatal alcohol exposure on behavior. Hippocampus 2000;10:94–110.

Environmental enrichment and the behavioral effects of prenatal exposure to alcohol in rats

Animals exposed prenatally to alcohol (4 g/kg/day) via maternal peroral intubation or control offspring were reared after weaning either alone in standard steel/wire cages or in groups of eight, for 6 weeks. Rats exposed prenatally to alcohol and reared in isolation had a dysmetric stride length indicative of an ataxic gait. However, following postweaning environmental enrichment, prenatal alcohol-exposed rats showed no evidence of ataxia. In addition, the prenatal alcohol-exposed rats showed the same magnitude of improved Morris maze performance after enrichment as did the control offspring. These preliminary results suggest that postnatal environment can influence the expression of alcohol-related birth defects in rats, that rats exposed prenatally to alcohol can benefit from the effects of enriched postweaning environment and that postnatal factors can attenuate some of the deficits due to prenatal alcohol exposure.

Prenatal cocaine: Quantity of exposure and gender moderation

ABSTRACT. Animal but few human studies have demonstrated gender-influenced differences in outcome related to prenatal cocaine exposure. Pregnant participants in a prospective pregnancy study were interviewed for drug use. Exposure was considered positive if history or laboratory tests were positive. An ordinal measure of exposure was also constructed. Six years later, the child and primary caretaker were tested to assess drug use in the home since birth and teacher-assessed child behavior. Data were complete for 473 children (204 cocaine exposed). Twenty-four of the exposed children (12%) were considered to have persistent pregnancy exposure based on positive urine screen at delivery. Boys with any prenatal cocaine exposure scored significantly higher (more problem behaviors) than nonexposed boys on the hyperactivity item. In contrast, no similar cocaine effect was observed for girls. When cocaine exposure was expressed as the three-level ordinal variable, boys, but not girls, with persistent exposure had more behavior problems (0.5 to 1.0 SD higher). Even after control for important covariates, boys with persistent exposure had more problems in central processing, motor skills, handling abstract concepts, and passivity to the environment. The magnitude of the relations reported in this research were moderate to large. In summary, both gender and the level of exposure had a significant behavioral effect on school-age behavior. In these analyses, the behavior of boys, but not girls, prenatally exposed to cocaine was significantly and negatively affected, and these findings remained after control for covariates, including prenatal alcohol or other illicit drug exposures and postnatal drug use in the home.

What research with animals is telling us about alcohol-related neurodevelopmental disorder

The substantial advances in understanding fetal alcohol syndrome over the past 20 years were made in large part because of research with animals. This review illustrates recent progress in animal research by focusing primarily on the central nervous system effects of prenatal alcohol exposure. Current findings suggest further progress in understanding consequences, risk factors, mechanisms, prevention and treatment will depend on continued research with animals.

Just Say “I Don't”: Lack of Concordance Between Teen Report and Biological Measures of Drug Use

BACKGROUND: Prevalence estimates of illicit drug use by teens are typically generated from confidential or anonymous self-report. While data comparing teen self-report with biological measures are limited, adult studies identify varying degrees of under-reporting. METHODS: Hair analyses for cocaine, opiates and marijuana were compared to confidential teen self- and parent-reported teen drug use in a longitudinal cohort of >400 high-risk urban teens and parents. RESULTS: Both teens and parents substantially underreported recent teen cocaine and opiate use. However, compared with parents, teens were more likely to deny biomarker-verified cocaine use. Teen specimens (hair) were 52 times more likely to identify cocaine use compared with self-report. Parent hair analyses for cocaine and opiate use were 6.5 times and 5.5 times, respectively, more likely to indicate drug use than were parental self-report. The lack of concordance between self-report and bioassay occurred despite participants knowledge that a “certificate of confidentiality” protected both teen and adult participants, and that the biological specimens would be tested for drugs. CONCLUSIONS: These findings confirm prior reports of adult under-reporting of their own drug use while extending our understanding of teens self-admitted drug use. The lack of concordance between teen self- or parent-reported teen drug use and biomarkers confirm our concerns that both teen- and parent-reported teen drug use is limited, at least for youth in high-risk urban settings. Methods of ascertainment other than self- or parent-report must be considered when health care providers, researchers and public health agencies attempt to estimate teen drug-use prevalence.

Amelioration of fetal alcohol-related neurodevelopmental disorders in rats: exploring pharmacological and environmental treatments

Fetal alcohol syndrome (FAS) and alcohol-related neurodevelopmental disorders (ARNDs) in children are characterized by life-long compromises in learning, memory, and adaptive responses. Until the advent of effective prevention measures, it will remain necessary to seek ways to treat the life-long neurobehavioral consequences of prenatal alcohol exposure. To date, there are no clinical remedies to recommend for either specific or global fetal alcohol effects. This article reviews our basic research in animal models that assesses the potential of global environmental manipulations or specific psychopharmacological treatments to ameliorate the neurobehavioral effects of prenatal exposure to alcohol. Postweaning environmental enrichment can improve behavioral performance and ameliorate or even eliminate deficits in prenatal alcohol-exposed rats, although there is persistent impairment in neuronal plasticity, as indicated by the failure of hippocampal pyramidal cells to increase dendrite spine density. Behavioral and neural responses to CNS stimulants differ in rats exposed prenatally to alcohol, although it is not clear that these shifts in dose-response curves would predict benefit to children. Although the present results may sound a note of optimism for the development of effective treatment strategies for children with FAS or ARNDs, it is important to consider that application of these findings in rodents may not be straightforward. We also need to know the critical features of specific environments that influence brain development, and the limits of pharmacotherapy, as well as critical periods of exposure. Continued study of the beneficial, ameliorative effects of environmental enrichment, rehabilitative training, and of pharmacological therapies in animal models, will remain a valuable source of information for eventually devising treatments specific for children with FAS and ARNDs.

A 14-year retrospective maternal report of alcohol consumption in pregnancy predicts pregnancy and teen outcomes

Detecting patterns of maternal drinking that place fetuses at risk for fetal alcohol spectrum disorders (FASDs) is critical to diagnosis, treatment, and prevention but is challenging because information on antenatal drinking collected during pregnancy is often insufficient or lacking. Although retrospective assessments have been considered less favored by many researchers due to presumed poor reliability, this perception may be inaccurate because of reduced maternal denial and/or distortion. The present study hypothesized that fetal alcohol exposure, as assessed retrospectively during child adolescence, would be related significantly to prior measures of maternal drinking and would predict alcohol-related behavioral problems in teens better than antenatal measures of maternal alcohol consumption. Drinking was assessed during pregnancy, and retrospectively about the same pregnancy, at a 14-year follow-up in 288 African-American women using well-validated semistructured interviews. Regression analysis examined the predictive validity of both drinking assessments on pregnancy outcomes and on teacher-reported teen behavior outcomes. Retrospective maternal self-reported drinking assessed 14 years postpartum was significantly higher than antenatal reports of consumption. Retrospective report identified 10.8 times more women as risk drinkers (≥ one drink per day) than the antenatal report. Antenatal and retrospective reports were moderately correlated and both were correlated with the Michigan Alcoholism Screening Test. Self-reported alcohol consumption during pregnancy based on retrospective report identified significantly more teens exposed prenatally to at-risk alcohol levels than antenatal, in-pregnancy reports. Retrospective report predicted more teen behavior problems (e.g., attention problems and externalizing behaviors) than the antenatal report. Antenatal report predicted younger gestational age at birth and retrospective report predicted smaller birth size; neither predicted teen IQ. These results suggest that if only antenatal, in-pregnancy maternal report is used, then a substantial proportion of children exposed prenatally to risk levels of alcohol might be misclassified. The validity of retrospective assessment of prior drinking during pregnancy as a more effective indicator of prenatal exposure was established by predicting more behavioral problems in teens than antenatal report. Retrospective report can provide valid information about drinking during a prior pregnancy and may facilitate diagnosis and subsequent interventions by educators, social service personnel, and health-care providers, thereby reducing the life-long impact of FASDs.

Animal models of fetal alcohol spectrum disorders: Impact of the social environment

Animal models of fetal alcohol spectrum disorder (FASD) have been used to demonstrate the specificity of alcohols teratogenic effects and some of the underlying changes in the central nervous system (CNS) and, more recently, to explore ways to ameliorate the effects of alcohol. The main point of this review is to highlight research findings from the animal literature which point to the impact of the social context or social behavior on the effect(s) of alcohol exposure during development, and also to point to research questions about the social environment and effects of prenatal alcohol exposure that remain to be answered. Alcohol exposure during early development alters maternal responding to the exposed pup in a variety of ways and the alteration in maternal responding could alter later stress responsivity and adult maternal and social behavior of the exposed offspring. Environmental enrichment and voluntary exercise have been shown to ameliorate some of alcohols impact during development, but the roles of enhanced social interactions in the case of enrichment and of social housing during voluntary exercise need to be more fully delineated. Similarly, the role of social context across the lifespan, such as social housing, social experiences, and contact with siblings, needs further study. Because of findings that alcohol during development alters DNA methylation patterns and that there are alterations in the maternal care of the alcohol-exposed offspring, epigenetic effects and their relationship to social behavior in animal models of FASD are likely to become a fruitful area of research. Because of the simpler social behavior and the short lifespan of rodents, animal models of FASD can be useful in determining how the social context impacts the effects of alcohol exposure during development.

Prenatal and postnatal cocaine exposure predict teen cocaine use

Preclinical studies have identified alterations in cocaine and alcohol self-administration and behavioral responses to pharmacological challenges in adolescent offspring following prenatal exposure. To date, no published human studies have evaluated the relation between prenatal cocaine exposure and postnatal adolescent cocaine use. Human studies of prenatal cocaine-exposed children have also noted an increase in behaviors previously associated with substance use/abuse in teens and young adults, specifically childhood and teen externalizing behaviors, impulsivity, and attention problems. Despite these findings, human research has not addressed prior prenatal exposure as a potential predictor of teen drug use behavior. The purpose of this study was to evaluate the relations between prenatal cocaine exposure and teen cocaine use in a prospective longitudinal cohort (n=316) that permitted extensive control for child, parent and community risk factors. Logistic regression analyses and Structural Equation Modeling revealed that both prenatal exposure and postnatal parent/caregiver cocaine use were uniquely related to teen use of cocaine at age 14 years. Teen cocaine use was also directly predicted by teen community violence exposure and caregiver negativity, and was indirectly related to teen community drug exposure. These data provide further evidence of the importance of prenatal exposure, family and community factors in the intergenerational transmission of teen/young adult substance abuse/use.