It's not your mother's marijuana: effects on maternal-fetal health and the developing child.

Pro-marijuana advocacy efforts exemplified by the "medical" marijuana movement, coupled with the absence of conspicuous public health messages about the potential dangers of marijuana use during pregnancy, could lead to greater use of today's more potent marijuana, which could have significant short- and long-term consequences. This article reviews the current literature regarding the effects of prenatal marijuana use on the pregnant woman and her offspring.

White matter microstructure abnormalities and executive function in adolescents with prenatal cocaine exposure.

Children with prenatal exposure to cocaine are at higher risk for negative behavioral function and attention difficulties, and have demonstrated brain diffusion abnormalities in frontal white matter regions. However, brain regions beyond frontal and callosal areas have not been investigated using diffusion tensor imaging (DTI). DTI data were collected on 42 youth aged 14-16 years; subjects were divided into three groups based on detailed exposure histories: those with prenatal exposure to cocaine but not alcohol (prenatal cocaine exposure (PCE), n=12), prenatal exposure to cocaine and alcohol (cocaine and alcohol exposure (CAE), n=17), and controls (n=13). Tractography was performed and along-tract diffusion parameters were examined for group differences and correlations with executive function measures. In the right arcuate fasciculus and cingulum, the CAE group had higher fractional anisotropy (FA) and/or lower mean diffusivity (MD) than the other two groups. The PCE group demonstrated lower FA in the right arcuate and higher MD in the splenium of the corpus callosum than controls. Diffusion parameters in tracts with group differences correlated with measures of executive function. In conclusion, these diffusion differences in adolescents with prenatal cocaine exposure suggest localized, long-term structural brain alterations that may underlie attention and response-inhibition difficulties.

Prenatal substance abuse: short- and long-term effects on the exposed fetus.

Prenatal substance abuse continues to be a significant problem in this country and poses important health risks for the developing fetus. The primary care pediatrician's role in addressing prenatal substance exposure includes prevention, identification of exposure, recognition of medical issues for the exposed newborn infant, protection of the infant, and follow-up of the exposed infant. This report will provide information for the most common drugs involved in prenatal exposure: nicotine, alcohol, marijuana, opiates, cocaine, and methamphetamine.

Adolescents with prenatal cocaine exposure show subtle alterations in striatal surface morphology and frontal cortical volumes.

BACKGROUND: Published structural neuroimaging studies of prenatal cocaine exposure (PCE) in humans have yielded somewhat inconsistent results, with several studies reporting no significant differences in brain structure between exposed subjects and controls. Here, we sought to clarify some of these discrepancies by applying methodologies that allow for the detection of subtle alterations in brain structure. METHODS: We applied surface-based anatomical modeling methods to magnetic resonance imaging (MRI) data to examine regional changes in the shape and volume of the caudate and putamen in adolescents with prenatal cocaine exposure (n = 40, including 28 exposed participants and 12 unexposed controls, age range 14 to 16 years). We also sought to determine whether changes in regional brain volumes in frontal and subcortical regions occurred in adolescents with PCE compared to control participants. RESULTS: The overall volumes of the caudate and putamen did not significantly differ between PCE participants and controls. However, we found significant (P <0.05, uncorrected) effects of levels of prenatal exposure to cocaine on regional patterns of striatal morphology. Higher levels of prenatal cocaine exposure were associated with expansion of certain striatal subregions and with contraction in others. Volumetric analyses revealed no significant changes in the volume of any subcortical region of interest, but there were subtle group differences in the volumes of some frontal cortical regions, in particular reduced volumes of caudal middle frontal cortices and left lateral orbitofrontal cortex in exposed participants compared to controls. CONCLUSIONS: Prenatal cocaine exposure may lead to subtle and regionally specific patterns of regional dysmorphology in the striatum and volumetric changes in the frontal lobes. The localized and bidirectional nature of effects may explain in part the contradictions in the existing literature.

Early adolescent cocaine use as determined by hair analysis in a prenatal cocaine exposure cohort.

BACKGROUND: Preclinical and other research suggest that youth with prenatal cocaine exposure (PCE) may be at high risk for cocaine use due to both altered brain development and exposure to unhealthy environments. METHODS: Participants are early adolescents who were prospectively enrolled in a longitudinal study of PCE prior to or at birth. Hair samples were collected from the youth at ages 10½ and 12½ (N=263). Samples were analyzed for cocaine and its metabolites using ELISA screening with gas chromatography/mass spectroscopy (GC/MS) confirmation of positive samples. Statistical analyses included comparisons between the hair-positive and hair-negative groups on risk and protective factors chosen a priori as well as hierarchical logistical regression analyses to predict membership in the hair-positive group. RESULTS: Hair samples were positive for cocaine use for 14% (n=36) of the tested cohort. Exactly half of the hair-positive preteens had a history of PCE. Group comparisons revealed that hair-negative youth had significantly higher IQ scores at age 10½; the hair-positive youth had greater availability of cigarettes, alcohol, and other drugs in the home; caregivers with more alcohol problems and depressive symptoms; less nurturing home environments; and less positive attachment to their primary caregivers and peers. The caregivers of the hair-positive preteens reported that the youth displayed more externalizing and social problems, and the hair-positive youth endorsed more experimentation with cigarettes, alcohol, and/or other drugs. Mental health problems, peer drug use, exposure to violence, and neighborhood characteristics did not differ between the groups. Regression analyses showed that the availability of drugs in the home had the greatest predictive value for hair-positive group membership while higher IQ, more nurturing home environments, and positive attachment to caregivers or peers exerted some protective effect. CONCLUSION: The results do not support a direct relationship between PCE and early adolescent experimentation with cocaine. Proximal risk and protective factors-those associated with the home environment and preteens' caregivers-were more closely related to early cocaine use than more distal factors such as neighborhood characteristics. Consistent with theories of adolescent problem behavior, the data demonstrate the complexity of predicting pre-adolescent drug use and identify a number of individual and contextual factors that could serve as important foci for intervention.

Executive functioning at ages 5 and 7 years in children with prenatal cocaine exposure.

This prospective longitudinal study evaluated the effect of prenatal cocaine exposure (PCE) on executive functioning in 5- and 7-year-old children. In total, 154 pregnant cocaine users, identified by urine toxicology and structured interviews, were matched to 154 nonusers. Children were assessed by certified masked evaluators, and caregivers were interviewed by experienced staff during home visits. In approximately 90% of the surviving sample tested at ages 5 and 7 years, structural equation modeling demonstrated that an increased head circumference at birth (adjusted for gestation) significantly predicted better performance on executive functioning, and that PCE was indirectly related to executive functioning through its significant negative effect on head circumference at birth. At age 5 years, quality of environment also predicted executive functioning, and the R(2) for the total model was 0.24. At 7 years, caregiver functioning predicted quality of environment, which in turn was positively related to executive functioning, and girls had better executive functioning. The total model at age 7 years accounted for 30% of the variance in executive functioning.

Diffusion tensor imaging of frontal white matter and executive functioning in cocaine-exposed children.

BACKGROUND: Although animal studies have demonstrated frontal white matter and behavioral changes resulting from prenatal cocaine exposure, no human studies have associated neuropsychological deficits in attention and inhibition with brain structure. We used diffusion tensor imaging to investigate frontal white matter integrity and executive functioning in cocaine-exposed children. METHODS: Six direction diffusion tensor images were acquired using a Siemens 3T scanner with a spin-echo echo-planar imaging pulse sequence on right-handed cocaine-exposed (n = 28) and sociodemographically similar non-exposed children (n = 25; mean age: 10.6 years) drawn from a prospective, longitudinal study. Average diffusion and fractional anisotropy were measured in the left and right frontal callosal and frontal projection fibers. Executive functioning was assessed using two well-validated neuropsychological tests (Stroop color-word test and Trail Making Test). RESULTS: Cocaine-exposed children showed significantly higher average diffusion in the left frontal callosal and right frontal projection fibers. Cocaine-exposed children were also significantly slower on a visual-motor set-shifting task with a trend toward lower scores on a verbal inhibition task. Controlling for gender and intelligence, average diffusion in the left frontal callosal fibers was related to prenatal exposure to alcohol and marijuana and an interaction between cocaine and marijuana exposure. Performance on the visual-motor set-shifting task was related to prenatal cocaine exposure and an interaction between cocaine and tobacco exposure. Significant correlations were found between test performance and fractional anisotropy in areas of the frontal white matter. CONCLUSIONS: Prenatal cocaine exposure, alone and in combination with exposure to other drugs, is associated with slightly poorer executive functioning and subtle microstructural changes suggesting less mature development of frontal white matter pathways. The relative contribution of postnatal environmental factors, including characteristics of the caregiving environment and stressors associated with poverty and out-of-home placement, on brain development and behavioral functioning in polydrug-exposed children awaits further research.

Predicting caregiver-reported behavior problems in cocaine-exposed children at 3 years.

Predictors of caregiver-reported behavior problems for 3-year-olds with prenatal cocaine exposure (PCE) and matched controls were examined using structural equation modeling. We tested whether PCE had a direct effect on child behavior problems in a model that included other prenatal drug exposure, child sex, caregiver depression, and the quality of the child's home environment. The sample (N = 256) was drawn from a longitudinal, prospective study of children of (predominantly crack) cocaine-using women and controls matched on race, socioeconomic status, parity, and pregnancy risk. Child Behavior Problems was modeled as a latent variable composed of the 48-item Conners' Parent Report Scale Conduct Problem and Impulsive-Hyperactive scales and the Eyberg Child Behavior Inventory Intensity scale. Caregiver depression was the only significant predictor of Child Behavior Problems. Mean levels of caregiver self-reported depression and reported child behavior problems did not differ between groups. Mean depression scores were well above the recommended clinical cutoff while mean child behavior problems scores were within normal limits. The model explained 21% of the variance in caregiver-reported child behavior problems in our sample of rural African American, low SES youngsters. Non-maternal caregivers of cocaine-exposed children had significantly lower mean depression scores and mean child behavior problems ratings for 2 of 3 scales used in the study compared to biological mothers of children with PCE and controls. For all groups, much larger proportions of children were rated as having clinically significant behavior problems than would be expected based on the prevalence of behavior problems in the general population.

A framework to monitor environment-induced major genes for developmental trajectories: implication for a prenatal cocaine exposure study.

Whether there are specific genes involved in response to different environmental agents and how such genes regulate developmental trajectories during lifetime are of fundamental importance in health, clinical and pharmaceutical research. In this article, we present a novel statistical model for monitoring environment-induced genes of major effects on longitudinal outcomes of a trait. This model is derived within the maximum likelihood framework, incorporated by mathematical aspects of growth and developmental processes. A typical structural model is implemented to approximate time-dependent covariance matrices for the longitudinal trait. This model allows for a number of biologically meaningful hypothesis tests regarding the effects of major genes on overall growth trajectories or particular stages of development. It can be used to test whether and how major genetic effects are expressed differently under altered environmental agents. In a well-designed case-control study, our model has been employed to detect cocaine-dependent genes that affect growth trajectories for head circumference during childhood. The detected gene triggers significant effects on growth curves in both cocaine-exposed (case) and unexposed groups (control), but with different extents. Significant genotype-environment interactions due to this so-called environment-sensitive gene are promising for further studies toward its genomic mapping using polymorphic molecular markers.

Outcome from a prospective, longitudinal study of prenatal cocaine use: preschool development at 3 years of age.

OBJECTIVE: To determine the effects of prenatal cocaine exposure on child development. METHODS: This prospective, longitudinal study recruited 154 pregnant cocaine users who were matched on race, parity, socioeconomic status, and perinatal risk to 154 noncocaine users. Drug use status was determined by maternal history and urine screening. At 3 years of age, the child subjects were assessed by an evaluator blinded to maternal drug use history. During a home visit at age 3, caregiver, family, and home assessments were administered. RESULTS: Structural equation modeling showed a direct effect of the amount of prenatal cocaine exposure on the adjusted birth head circumference which in turn directly affected preschool development. CONCLUSIONS: We could not demonstrate a direct effect of prenatal cocaine exposure on preschool development, a result that is consistent with that of earlier work and now extending findings to age 3. However, cocaine continued to exert an indirect effect on development through its direct effect on the head circumference at birth.

Relative ability of biologic specimens and interviews to detect prenatal cocaine use.

For this study, we recruited women admitted to our labor and delivery service, enrolling all consenting patients with a history of prenatal cocaine use and the next admission with no recorded use. During the immediate postpartum period, experienced researchers conducted private, structured interviews to obtain details of prenatal cocaine use and to identify a priori exclusion criteria (other illicit drug use, high alcohol use and chronic illnesses and medications). Specific protocols were used to collect amniotic fluid, cord blood, infant urine, meconium and maternal hair. All specimens were analyzed blind with respect to exposure using gas chromatography/mass spectrometry. Of 115 subjects, 46 had one or more biologic specimens positive for cocaine metabolites and five admitted prenatal use, but had negative specimens. Of these 51 identified as users by any method, 38 admitted, 32 were positive for urine, 28 for hair and 25 for meconium. Of the 38 admitters, 87% had positive specimens; of the 77 denying use, 17% were positive. Urine was most frequently positive in identified users, 67% overall and 62% of users who denied. Hair was next, positive in 65% of all users and 50% of users who denied. Of the 13 subjects who denied use but were positive on at least one specimen, four were identified solely by urine, two only by hair and one only by meconium. Self-report identified five users with all negative specimens. Although no one method identified all users, the single method that maximally identified users was detailed history taken by experienced interviewers.

A general model for detecting genetic determinants underlying longitudinal traits with unequally spaced measurements and nonstationary covariance structure.

A mixture model for determining quantitative trait loci (QTL) affecting growth trajectories has been proposed in the literature. In this article, we extend this model to a more general situation in which longitudinal traits for each subject are measured at unequally spaced time intervals, different subjects have different measurement patterns, and the residual correlation within subjects is nonstationary. We derive an EM-simplex hybrid algorithm to estimate the allele frequencies, Hardy-Weinberg disequilibrium, and linkage disequilibrium between QTL in the original population and parameters contained in the growth equation and in the covariance structure. A worked example of head circumference growth in 145 children is used to validate our extended model. A simulation study is performed to examine the statistical properties of the parameter estimation obtained from this example. Finally, we discuss the implications and extensions of our model for detecting QTL that affect growth trajectories.

Mucopolysaccharidosis Type VII presenting with isolated neonatal ascites.

Mucopolysaccharidosis Type VII (MPS VII) is a lysosomal storage disease caused by a deficiency of the enzyme, beta-glucuronidase. MPS VII has a wide variation in phenotypic expression, including presentation in the neonatal period with nonimmune hydrops fetalis. We report a neonate with MPS VII who initially presented with marked isolated ascites not associated with hydrops fetalis. This appears to be a novel finding in patients with MPS VII.

Cocaine exposure and developmental outcome from birth to 6 months.

The theoretical framework for many of the early studies of prenatal cocaine exposure has been rooted in the basic concepts of teratology/developmental toxicology. Few have published longitudinal analyses of the complex interplay between the relative effects of prenatal cocaine exposure and perinatal and environmental factors on development. The purpose of this paper was to use structural equation modeling to describe the direct and indirect effects of prenatal drug exposure on developmental outcome from birth to age 6 months. Key variables considered for study include prenatal drug exposure, perinatal medical characteristics, maternal/caregiver/family characteristics, the home environment, and neurobehavioral outcomes. We prospectively enrolled 154 predominantly crack-using women. A priori exclusion criteria included: <18 years old, major illnesses diagnosed prior to pregnancy, chronic use of legal drugs, and any use of illicit drugs other than cocaine and marijuana. From the pool of noncocaine users, 154 subjects were matched to users on pregnancy risk, parity, race, and socioeconomic status. At the end of each trimester, experienced staff conducted private interviews prompting memory of amount and timing of past drug use. Urine specimens were collected at two unanticipated times; positive screens were confirmed by gas chromatography/mass spectroscopy. Measures analyzed include medical (birth) and developmental (birth, 1 month, 6 months) assessments, all performed by blinded evaluators, as well as caregiver characteristics and environmental factors (birth, 1 month). A series of four theoretical models was tested, one for each time point (birth, 1 month, 6 months) and a longitudinal model spanning birth to 6 months. Key findings include direct effects of prenatal cocaine exposure on development at birth in the birth model and on development at birth and 6 months in the longitudinal model. In addition, indirect effects of prenatal cocaine exposure were identified on development at birth, 1 month, and 6 months, mediated through the prenatal use of alcohol and tobacco and the birth head circumference. Implications of these and other findings, including the advantages and limitations of structural equation modeling, are discussed.