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1.  A Mechanism for the Inhibition of Neural Progenitor Cell Proliferation by Cocaine 
PLoS Medicine  2008;5(6):e117.
Background
Prenatal exposure of the developing brain to cocaine causes morphological and behavioral abnormalities. Recent studies indicate that cocaine-induced proliferation inhibition and/or apoptosis in neural progenitor cells may play a pivotal role in causing these abnormalities. To understand the molecular mechanism through which cocaine inhibits cell proliferation in neural progenitors, we sought to identify the molecules that are responsible for mediating the effect of cocaine on cell cycle regulation.
Methods and Findings
Microarray analysis followed by quantitative real-time reverse transcription PCR was used to screen cocaine-responsive and cell cycle-related genes in a neural progenitor cell line where cocaine exposure caused a robust anti-proliferative effect by interfering with the G1-to-S transition. Cyclin A2, among genes related to the G1-to-S cell cycle transition, was most strongly down-regulated by cocaine. Down-regulation of cyclin A was also found in cocaine-treated human primary neural and A2B5+ progenitor cells, as well as in rat fetal brains exposed to cocaine in utero. Reversing cyclin A down-regulation by gene transfer counteracted the proliferation inhibition caused by cocaine. Further, we found that cocaine-induced accumulation of reactive oxygen species, which involves N-oxidation of cocaine via cytochrome P450, promotes cyclin A down-regulation by causing an endoplasmic reticulum (ER) stress response, as indicated by increased phosphorylation of eIF2α and expression of ATF4. In the developing rat brain, the P450 inhibitor cimetidine counteracted cocaine-induced inhibition of neural progenitor cell proliferation as well as down-regulation of cyclin A.
Conclusions
Our results demonstrate that down-regulation of cyclin A underlies cocaine-induced proliferation inhibition in neural progenitors. The down-regulation of cyclin A is initiated by N-oxidative metabolism of cocaine and consequent ER stress. Inhibition of cocaine N-oxidative metabolism by P450 inhibitors may provide a preventive strategy for counteracting the adverse effects of cocaine on fetal brain development.
Investigating the mechanism of cocaine's effect on fetal brain development, Chun-Ting Lee and colleagues find that down-regulation of cyclin A by a cocaine metabolite inhibits neural proliferation.
Editors' Summary
Background.
Every year, cocaine abuse by mothers during pregnancy exposes thousands of unborn infants (fetuses) to this powerful and addictive stimulant. Maternal cocaine abuse during early pregnancy increases the risk of miscarriage; its use during late pregnancy slows the baby's growth and can trigger premature labor. Babies exposed to cocaine shortly before birth are often irritable and have disturbed sleep patterns. They can also be very sensitive to sound and touch and consequently hard to comfort. These problems usually resolve spontaneously within the first few weeks of life but some permanent birth defects are also associated with frequent cocaine abuse during pregnancy. In particular, babies exposed to cocaine before birth sometimes have small heads—an abnormality that generally indicates a small brain—and, although they usually have normal intelligence, the development of their thinking skills and language is often delayed, and they can have behavioral problems.
Why Was This Study Done?
Exposure to cocaine before birth clearly interferes with some aspects of brain development. More specifically, it reduces the number and position of neurons (the cells that transmit information in the form of electrical impulses around the body) within the brain. All neurons develop from neural progenitor cells, and previous research suggests that cocaine exposure before birth inhibits the proliferation of these cells in the developing brain. It would be useful to understand exactly how cocaine affects neural progenitor cells, because it might then be possible to prevent the drug's adverse effects on brain development. In this study, therefore, the researchers investigate the molecular mechanism that underlies cocaine's effect on neural progenitor cells.
What Did the Researchers Do and Find?
When the researchers investigated the effects of cocaine on AF5 cells (rat neural progenitor cells that grow indefinitely in the laboratory), they found that concentrations of cocaine similar to those measured in fetal brains after maternal drug exposure inhibited the proliferation of AF5 cells by blocking the “G1-to-S transition.” This is a stage that cells have to pass through between each round of cell division (the production of two daughter cells from one parent cell). Next, the researchers showed that cocaine-treated AF5 cells made much less cyclin A2, a protein that controls the G1-to-S transition, than untreated cells. Cocaine also decreased cyclin A2 levels in neural progenitor cells freshly isolated from human fetal brains and in fetal rat brains exposed to the drug while in their mother's womb. Treatment of AF5 cells with a cyclin A2 expression vector (a piece of DNA that directs the production of cyclin A2) counteracted the down-regulation of cyclin A2 and restored AF5 proliferation in the presence of cocaine. Other experiments indicate that the reduction of cyclin A2 by cocaine in AF5 cells involves the accumulation of “reactive oxygen species,” by-products of the breakdown of cocaine by a protein that is a member of a family of proteins called cytochrome P450. Finally, treatment of pregnant rats with cimetidine (which inhibits the action of cytochrome P450) counteracted both the inhibition of neural progenitor cell proliferation and the cyclin A2 down-regulation that cocaine exposure induced in the brains of their unborn pups.
What Do These Findings Mean?
These findings show that the cocaine-induced inhibition of neural progenitor cell proliferation involves, at least in part, interfering with the production (that is, causing down-regulation) of cyclin A2. They also show that this down-regulation is induced by the breakdown of cocaine by cytochrome P450, and that in both a rat cell line and in fetal rats, the cytochrome P450 inhibitor cimetidine (a drug that is already used clinically for stomach problems) can block the adverse effects of cocaine on the proliferation of neural progenitor cells. These findings need to be confirmed in animals more closely related to people than rats, and the long-term effects of cimetidine need to be investigated, in particular its effects on cocaine toxicity. Nevertheless these results raise the possibility that giving cimetidine or other drugs with similar effects to pregnant women who are addicted to cocaine might prevent some of the harm that their drug habit does to their unborn children, although it is not clear whether there is a dosage of cimetidine that might be both safe and adequate for this purpose.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050117.
A PLoS Medicine Perspective article by Steven Hyman further discusses this study
The US National Institute on Drug Abuse provides a fact sheet on cocaine (in English and Spanish)
The UK charity Release provides information and advice to the public and professionals about the law and drugs, including information about cocaine
MedlinePlus also provides a list of links to information about cocaine (in English and Spanish)
The March of Dimes Foundation, a US nonprofit organization for the improvement of child health, provides information about illicit drug use during pregnancy (in English and Spanish)
The Organization of Teratology Information Specialists also provides a fact sheet on cocaine and pregnancy (in English, Spanish, and French)
doi:10.1371/journal.pmed.0050117
PMCID: PMC2504032  PMID: 18593214
2.  Level of Prenatal Cocaine Exposure and Scores on the Bayley Scales of Infant Development: Modifying Effects of Caregiver, Early Intervention, and Birth Weight 
Pediatrics  2002;110(6):1143-1152.
Objectives
The objectives of this study were 1) to assess whether there is an independent association between the level of prenatal cocaine exposure and infants’ developmental test scores after control of potential confounding variables; and 2) if such an association exists, to determine which biological and social variables, individually and in interaction with each other, may modify it.
Methods
In a prospective, longitudinal study of 203 urban term infants, 3 cocaine exposure groups were defined by maternal report and infant meconium assay: unexposed, heavier cocaine exposure (> 75th percentile self-reported days of use or meconium benzoylecognine concentration), or lighter cocaine exposure (all others). Examiners, masked to exposure history, tested infants at 6, 12, and 24 months of age with the Bayley Scales of Infant Development.
Results
The final mixed linear regression model included as fixed covariates level of prenatal exposure to cocaine, alcohol, and cigarettes; prenatal marijuana exposure; gestational age and birth weight z score for gestational age; and gender. Age at test, caregiver at time of each test (biological mother, kinship caregiver, unrelated foster caregiver), and any previous child-focused early intervention were included as time-dependent covariates. There were no significant adverse main effects of level of cocaine exposure on Mental Development Index (MDI), Psychomotor Development Index (PDI), or Infant Behavior Record. Child-focused early intervention interacted with level of cocaine exposure such that heavily exposed children who received such intervention showed higher adjusted mean MDI scores than all other groups. Although the sample was born at or near term, there was also a significant interaction of cocaine exposure and gestational age on MDI scores, with those in the heavier exposure group born at slightly lower gestational age having higher mean MDI scores compared with other children born at that gestational age.
There was also a significant interaction on MDI between child’s age and caregiver. At 6 months, the adjusted MDI of children living with a kinship caregiver was 15.5 points lower than that of children living with their biological mother, but this effect was diminished and was no longer significant at 24 months (difference in means: 4.3 points). The adjusted mean MDI of children in unrelated foster care at 6 months was 8.2 points lower than children of biological mothers, whereas it was 7.3 points higher at 24 months.
Early intervention attenuated the age-related decline in PDI scores for all groups. Birth weight < 10th percentile was associated with lower PDI scores for children with heavier cocaine exposure and with lower MDI scores for all groups.
Conclusions
Heavier prenatal cocaine exposure is not an independent risk factor for depressed scores on the Bayley Scales of Infant Development up to 24 months of age when term infants are compared with lighter exposed or unexposed infants of the same demographic background. Cocaine-exposed infants with birth weight below the 10th percentile for gestational age and gender and those placed with kinship caregivers are at increased risk for less optimal developmental outcomes. Pediatric clinicians should refer cocaine-exposed children to the child-focused developmental interventions available for all children at developmental risk.
PMCID: PMC2366173  PMID: 12456912
cocaine; pregnancy; meconium; child development; early intervention; kinship care; foster care
3.  Prenatal Cocaine Exposure and Small-for-Gestational-Age Status: Effects on Growth at 6 Years of age 
Neurotoxicology and teratology  2011;33(5):575-581.
OBJECTIVE
To evaluate the impact of prenatal cocaine exposure and small-for-gestational-age (SGA) status on childhood growth.
STUDY DESIGN
Cocaine exposure was defined by history or meconium metabolites. Hierarchical linear modeling was used to examine cocaine exposure and SGA status on growth, while controlling for exposure to other drugs and alcohol use.
RESULTS
At birth cocaine-exposed infants (n=364) had significantly lower growth parameters compared to non-exposed children (n=771). At 6 years, weight was similar between exposed and unexposed children. SGA infants continued to be growth impaired. There was a significant interaction between prenatal cocaine exposure and SGA status at 6 years. The negative effects of cocaine on weight and height were greater among non-SGA than SGA children (432 vs. 280 gm, and 0.7 and 0.5 cm, respectively) while negative effects of SGA status on weight and height were larger in non-cocaine exposed compared to the exposed children (2.3 kg vs.1.6 kg and 2.2 and 1.0 cm).
CONCLUSIONS
Children exposed to prenatal cocaine were similar in weight to non-exposed children at 6 years of age. Cocaine had an unexplained greater detrimental effect on non-SGA than SGA children. SGA status at birth has an independent detrimental effect on childhood growth.
doi:10.1016/j.ntt.2011.04.003
PMCID: PMC3183411  PMID: 21849244
Prenatal cocaine exposure; small for gestational age; childhood growth
4.  The Effects of Prenatal Cocaine-Exposure on Problem Behavior in Children 4-10 Years 
Neurotoxicology and teratology  2010;32(4):443-451.
Background
Children prenatally exposed to cocaine may be at increased risk for behavioral problems due to disruptions of monaminergically regulated arousal systems and/or environmental conditions.
Objective
To assess behavioral outcomes of cocaine (CE) and non-cocaine exposed (NCE) children, 4 through 10 years old, controlling for other prenatal drug exposures and environmental factors.
Methods
Low socioeconomic status (SES), primarily African-American children (n = 381 (193 (CE), 188 (NCE)) were recruited from birth. Generalized Estimating Equation (GEE) analyses were used to assess the predictive relationship of prenatal cocaine exposure to odds of caregiver reported clinically elevated behavioral problems at 4, 6, 9 and 10 years of age, controlling for confounders.
Results
Prenatal cocaine exposure was associated with increased rates of caregiver reported delinquency (OR=1.93, CI: 1.09-3.42, p<.02). A significant prenatal cocaine exposure by sex interaction was found for delinquency indicating that only females were affected (OR=3.57, CI: 1.67-7.60, p<.001). There was no effect of cocaine on increased odds of other CBCL subscales. Higher prenatal tobacco exposure was associated with increased odds of externalizing symptoms at 4, 9 and 10 years of age. For CE children, those in foster or adoptive care were rated as having more behavior problems than those in biologic mother or relative care. Greater caregiver psychological distress was associated with increased behavioral problems. There were no independent effects of elevated blood lead level on increased behavior problems after control for prenatal drug exposure and other environmental conditions.
Conclusion
Prenatal cocaine and tobacco exposure were associated with greater externalizing behavior after control for multiple prenatal drug exposures, other environmental and caregiving factors and lead exposure from 4 through 10 years of age. Greater caregiver psychological distress negatively affected caregiver ratings of all CBCL domains. Since cocaine and tobacco use during pregnancy and maternal psychological distress have the potential to be altered through prenatal educational, drug treatment and and mental health interventions, they warrant attention in efforts to reduce rates of problem behaviors in children.
doi:10.1016/j.ntt.2010.03.005
PMCID: PMC3586186  PMID: 20227491
behavior; delinquency; prenatal cocaine-exposure; lead exposure; longitudinal
5.  Small for Gestational Age and Higher Birth Weight Predict Childhood Obesity in Preterm Infants 
American journal of perinatology  2010;27(9):721-730.
We sought to determine the association between small for gestational age (SGA), birth weight, and childhood obesity within preterm polysubstance exposed children. We sampled 312 preterm children with 11-year body mass index (BMI; age- and sex-specific) data from the Maternal Lifestyle Study (51% girls, 21.5% SGA, 46% prenatal cocaine, and 55% tobacco exposed). Multinomial regression analyzed the association between 11-year obesity (OBE) and overweight (OW) and SGA, birth weight, first-year growth velocity, diet, and physical activity variables. Overall, 24% were OBE (BMI for age ≥95th percentile) and 16.7% were OW (BMI ≥85th and <95th percentiles). In adjusted analyses, SGA was associated with OW (odds ratio [OR]=3.4, confidence interval [CI] 1.5 to 7.5). Higher birth weight was associated with OBE (OR = 1.8, CI 1.3 to 2.4) and OW (OR=1.4, CI 1.1 to 2.0). Growth velocity was associated with OBE (OR=2.7, CI 1.8 to 4.0) and OW (OR=1.6, CI 1.1 to 2.4). Low exercise was associated with OBE (OR=2.1, CI 1.0 to 4.4) and OW (OR=2.1, CI 1.0 to 4.5). There was no effect of substance exposure on obesity outcomes. Many (41%) of these high-risk preterm 11-year-olds were obese/overweight. Multiple growth-related processes may be involved in obesity risk for preterm children, including fetal programming as indicated by the SGA effect.
doi:10.1055/s-0030-1253555
PMCID: PMC2949419  PMID: 20408111
Childhood obesity; premature birth; infant SGA; birth weight; exercise; prenatal drug exposure
6.  Neurodevelopment of adopted children exposed in utero to cocaine. 
OBJECTIVE: To assess the neurodevelopment of adopted children who had been exposed in utero to cocaine. DESIGN: A case-control observational study. PARTICIPANTS: Twenty-three children aged 14 months to 6.5 years exposed in utero to cocaine and their adoptive mothers, and 23 age-matched control children not exposed to cocaine and their mothers, matched with the adoptive mothers for IQ and socioeconomic status. SETTING: The Motherisk Programme at The Hospital for Sick Children, Toronto, a consultation service for chemical exposure during pregnancy. MAIN OUTCOME MEASURES: Height, weight and head circumference at birth and at follow-up, and achievement on standard tests of cognitive and language development. RESULTS: Compared with the control group, children exposed in utero to cocaine had an 8-fold increased risk for microcephaly (95% confidence interval 1.5 to 42.3); they also had a lower mean birth weight (p = 0.005) and a lower gestational age (p = 0.002). In follow-up the cocaine-exposed children caught up with the control subjects in weight and stature but not in head circumference (mean 31st percentile v. 63rd percentile) (p = 0.001). Although there were no significant differences between the two groups in global IQ, the cocaine-exposed children had significantly lower scores than the control subjects on the Reynell language test for both verbal comprehension (p = 0.003) and expressive language (p = 0.001). CONCLUSIONS: This is the first study to document that intrauterine exposure to cocaine is associated with measurable and clinically significant toxic neurologic effects, independent of postnatal home and environmental confounders. Because women who use cocaine during pregnancy almost invariably smoke cigarettes and often use alcohol, it is impossible to attribute the measured toxic effects to cocaine alone.
PMCID: PMC1337370  PMID: 7954158
7.  Estimated Effect of Prenatal Cocaine Exposure on Examiner-Rated Behavior at Age 7 Years 
Neurotoxicology and teratology  2011;33(3):370-378.
Prenatal cocaine exposure has been linked to increased child behavior difficulties in some studies but not others.
Objective
The primary aim was to estimate the relationship between in utero cocaine exposure and child behavioral functioning at age 7 years with ratings made by blinded examiners during a structured testing session. A second aim was to examine whether caregiver drug use and psychological problems might mediate suspected relationships between prenatal cocaine exposure and aspects of examiner-rated behavior.
Methods
407 children (212 cocaine-exposed, 195 non-exposed) participating in the longitudinal Miami Prenatal Cocaine Study (MPCS) were rated with regard to their behavior during a neuropsychological assessment conducted at age 7 years. Raters were trained research psychometricians blinded to drug exposure. Individual behavioral items were summarized and the cocaine-behavior relationship was estimated within the context of latent variable modeling, using Mplus software.
Results
Two latent variables, Behavioral Regulation and Sociability, were derived via exploratory latent structure analysis with promax rotation. Prenatal cocaine exposure, statistically controlling for child sex, test age, and prenatal exposure to alcohol, tobacco, and marijuana, was associated with Behavioral Regulation (estimated slope ß = -0.25; 95% CI = -0.48, -0.02; p = 0.04) but not Sociability (estimated slope ß = -0.03; 95% CI = -0.26, 0.20; p = 0.79). Neither postnatal drug use by caregivers nor the severity of their psychological problems at age 5 follow-up predicted levels of child Behavioral Regulation or Sociability at age 7 years (p>0.10).
Conclusions
Examiner ratings of child behavior at age 7 revealed less optimal behavioral regulation for prenatally cocaine-exposed compared to non-exposed children, in contrast with what had been previously found from parent-report data. This evidence highlights the potential value of trained observers in assessing behavioral outcomes of children exposed in utero to drugs and other toxicants.
doi:10.1016/j.ntt.2011.02.014
PMCID: PMC3138213  PMID: 21640292
prenatal cocaine exposure; behavior; examiner ratings; caregiver drug use; caregiver psychological functioning; behavioral regulation
8.  Prenatal Cocaine Exposure and Body Mass Index and Blood Pressure at 9 Years of Age 
Journal of hypertension  2010;28(6):1166-1175.
Background
Prenatal cocaine exposure has been linked to intrauterine growth retardation and poor birth outcomes; little is known about the effects on longer-term medical outcomes, such as overweight status and hypertension in childhood. Our objective was to examine the association between prenatal cocaine exposure and body mass index and blood pressure at 9 years of age among children followed prospectively in a multi-site longitudinal study evaluating the impact of maternal lifestyle during pregnancy on childhood outcome.
Design/Methods
This analysis includes 880 children (277 cocaine exposed and 603 with no cocaine exposure) with blood pressure, height, and weight measurements at 9 years of age. Regression analyses were conducted to explore the relationship between prenatal cocaine exposure and body mass index and blood pressure at 9 years of age after controlling for demographics, other drug exposure, birth weight, maternal weight, infant postnatal weight gain, and childhood television viewing, exercise and dietary habits at 9 years. Path analyses were used to further explore these relationships.
Results
At 9 years of age, 15% of the children were pre-hypertensive and 19% were hypertensive; 16% were at risk for overweight status and 21% were overweight. A small percentage of women were exposed to high levels of prenatal cocaine throughout pregnancy. Among children born to these women, a higher body mass index was noted. Path analysis suggested that high cocaine exposure has an indirect effect on systolic and diastolic blood pressure that is mediated through its effect on body mass index.
Conclusion
High levels of in-utero cocaine exposure are a marker for elevated body mass index and blood pressure among children born full term.
PMCID: PMC2874425  PMID: 20486281
Prenatal cocaine exposure; Body mass index; Childhood hypertension; Overweight; Obesity
9.  Expressive and Receptive Language Functioning in Preschool Children With Prenatal Cocaine Exposure 
Journal of pediatric psychology  2004;29(7):543-554.
Objective
To estimate the relationship between severity of prenatal cocaine exposure and expressive and receptive language skills in full-term, African American children at age 3 years.
Methods
Language was assessed at age 3 using the Clinical Evaluation of Language Fundamentals–Preschool (CELF-P). The sample included 424 children (226 cocaine exposed, 198 non–cocaine exposed) who received preschool language assessments at age 3, drawn from a cohort of 476 children enrolled prospectively at birth.
Results
Structural equation modeling was used to regress expressive and receptive language as intercorrelated response variables on level of prenatal cocaine exposure, measured by a latent construct including maternal self-report of cocaine use and maternal/infant urine toxicology assays and infant meconium. Results indicated a .168 SD decrease in expressive language functioning for every unit increase in exposure level (95% CI = −.320, −.015; p = .031) after consideration for fetal growth and gestational age as correlated response variables. Receptive language was more modestly related to prenatal cocaine exposure and was not statistically significant. Results for expressive language remained stable with inclusion of the McCarthy general cognitive index as a response variable (expressive language β = −.173, 95% CI = −.330, −.016; p = .031), and with adjustment for maternal age and prenatal exposures to alcohol, tobacco, and marijuana (expressive language β = −.175, 95% CI = −.347, −.003; p = .046). Additional child and caregiver environmental variables assessed at age 3 were also evaluated in varying statistical models with similar results.
Conclusion
The evidence from this study supports a gradient relationship between increased level of prenatal cocaine exposure and decreased expressive language functioning in preschool-aged cocaine-exposed children.
doi:10.1093/jpepsy/jsh056
PMCID: PMC2653083  PMID: 15347702
prenatal cocaine exposure; language functioning; preschool children; CELF-P
10.  Growth, Development, and Behavior in Early Childhood Following Prenatal Cocaine Exposure 
Context
Despite recent studies that failed to show catastrophic effects of prenatal cocaine exposure, popular attitudes and public policies still reflect the belief that cocaine is a uniquely dangerous teratogen.
Objective
To critically review outcomes in early childhood after prenatal cocaine exposure in 5 domains: physical growth; cognition; language skills; motor skills; and behavior, attention, affect, and neurophysiology.
Data Sources
Search of MEDLINE and Psychological Abstracts from 1984 to October 2000.
Study Selection
Studies selected for detailed review (1) were published in a peerreviewed English-language journal; (2) included a comparison group; (3) recruited samples prospectively in the perinatal period; (4) used masked assessment; and (5) did not include a substantial proportion of subjects exposed in utero to opiates, amphetamines, phencyclidine, or maternal human immunodeficiency virus infection.
Data Extraction
Thirty-six of 74 articles met criteria and were reviewed by 3 authors. Disagreements were resolved by consensus.
Data Synthesis
After controlling for confounders, there was no consistent negative association between prenatal cocaine exposure and physical growth, developmental test scores, or receptive or expressive language. Less optimal motor scores have been found up to age 7 months but not thereafter, and may reflect heavy tobacco exposure. No independent cocaine effects have been shown on standardized parent and teacher reports of child behavior scored by accepted criteria. Experimental paradigms and novel statistical manipulations of standard instruments suggest an association between prenatal cocaine exposure and decreased attentiveness and emotional expressivity, as well as differences on neurophysiologic and attentional/affective findings.
Conclusions
Among children aged 6 years or younger, there is no convincing evidence that prenatal cocaine exposure is associated with developmental toxic effects that are different in severity, scope, or kind from the sequelae of multiple other risk factors. Many findings once thought to be specific effects of in utero cocaine exposure are correlated with other factors, including prenatal exposure to tobacco, marijuana, or alcohol, and the quality of the child’s environment. Further replication is required of preliminary neurologic findings.
PMCID: PMC2504866  PMID: 11268270
11.  Executive Functioning in Preschool-Age Children Prenatally Exposed to Alcohol, Cocaine, and Marijuana 
Background
Reports from clinical and experimental (animal) research converge on the suggestion that prenatal exposure to alcohol, cocaine, or marijuana undermines executive functioning (EF) and its neurological underpinnings. However, large, adequately controlled, prospective studies of alcohol and marijuana effects on EF have reported conflicting findings, and there have been no such studies of cocaine exposure.
Methods
EF was investigated in a cohort (n = 316) of 4-year-old children the majority of whose mothers had used varying combinations of cocaine, alcohol, and marijuana during pregnancy. With use of postpartum maternal report and biological assay, children were assigned to overlapping prenatal cocaine-exposed, alcohol-exposed, and marijuana-exposed groups and to complementary control groups. The postnatal environmental assessment included measures of maternal intellectual and psychosocial functioning, current drug or alcohol use, and home environment.
Results
The children in the alcohol-exposed group had worse tapping-inhibition performance than children in the non–alcohol-exposed group, and this effect persisted when potential confounding environmental variables, other drug variables, and concurrent verbal intelligence were controlled for.
Conclusions
Prenatal alcohol is predictive of decreased EF in early childhood that could not be attributed to environmental factors. The results are discussed in terms of the age and overall high-risk status of the children.
doi:10.1097/01.ALC.0000060525.10536.F6
PMCID: PMC2597170  PMID: 12711927
Alcohol; Inhibition; Frontal; Prenatal; Cocaine
12.  Severity of Prenatal Cocaine Exposure and Child Language Functioning Through Age Seven Years: A Longitudinal Latent Growth Curve Analysis 
Substance use & misuse  2004;39(1):25-59.
The current study estimates the longitudinal effects of severity of prenatal cocaine exposure on language functioning in an urban sample of full-term African-American children (200 cocaine-exposed, 176 noncocaine-exposed) through age 7 years. The Miami Prenatal Cocaine Study sample was enrolled prospectively at birth, with documentation of prenatal drug exposure status through maternal interview and toxicology assays of maternal and infant urine and infant meconium. Language functioning was measured at ages 3 and 5 years using the Clinical Evaluation of Language Fundamentals–Preschool (CELF-P) and at age 7 years using the Core Language Domain of the NEPSY: A Developmental Neuropsychological Assessment. Longitudinal latent growth curve analyses were used to examine two components of language functioning, a more stable aptitude for language performance and a time-varying trajectory of language development, across the three time points and their relationship to varying levels of prenatal cocaine exposure. Severity of prenatal cocaine exposure was characterized using a latent construct combining maternal self-report of cocaine use during pregnancy by trimesters and maternal and infant bioassays, allowing all available information to be taken into account. The association between severity of exposure and language functioning was examined within a model including factors for fetal growth, gestational age, and IQ as intercorrelated response variables and child’s age, gender, and prenatal alcohol, tobacco, and marijuana exposure as covariates. Results indicated that greater severity of prenatal cocaine exposure was associated with greater deficits within the more stable aptitude for language performance (D = −0.071, 95% CI = −0.133, −0.009; p = 0.026). There was no relationship between severity of prenatal cocaine exposure and the time-varying trajectory of language development. The observed cocaine-associated deficit was independent of multiple alternative suspected sources of variation in language performance, including other potential responses to prenatal cocaine exposure, such as child’s intellectual functioning, and other birth and postnatal influences, including language stimulation in the home environment.
doi:10.1081/JA-120027765
PMCID: PMC2634602  PMID: 15002943
Prenatal cocaine exposure; Language performance
13.  Cocaine Exposure and Children's Self-Regulation: Indirect Association via Maternal Harshness 
Objectives: This study examined the association between prenatal cocaine exposure and children’s self-regulation at 3 years of child age. In addition to direct effects of prenatal cocaine exposure on children’s self-regulation, we hypothesized there would be indirect associations between cocaine exposure and self-regulation via higher maternal harshness and poor autonomic regulation in infancy. Methods: The sample consisted of 216 mother–infant dyads recruited at delivery from local area hospitals (116 cocaine-exposed, 100 non-exposed). Infant autonomic regulation was measured at 7 months of age during an anger/frustration task, maternal harshness was coded from observations of mother–toddler interactions at 2 years of age, and children’s self-regulation was measured at 3 years of age using several laboratory paradigms. Results: Contrary to hypotheses, there were no direct associations between maternal cocaine use during pregnancy and children’s self-regulation. However, results from testing our conceptual model including the indirect effects via maternal harshness or infant parasympathetic regulation indicated that this model fit the data well, χ2 (23) = 34.36, p > 0.05, Comparative Fit Index = 0.95, RMSEA = 0.05. Cocaine using mothers displayed higher intensity of harshness toward their toddlers during lab interactions across a variety of tasks at 2 years of age (β = 0.23, p < 0.05), and higher intensity of harshness at 2 years was predictive of lower self-regulation at 3 years (β = −0.36, p < 0.01). Maternal cocaine use was also predictive of a non-adaptive increase in respiratory sinus arrhythmia (RSA) from baseline to the negative affect task, but RSA change in infancy was not predictive of self-regulation at 3 years. Conclusion: Results are supportive of animal models indicating higher aggression among cocaine treated dams, and indicate that higher maternal harshness among cocaine using mothers is predictive of child self-regulatory outcomes in the preschool period.
doi:10.3389/fpsyt.2011.00031
PMCID: PMC3115536  PMID: 21716637
cocaine exposure; self-regulation; maternal harshness; autonomic regulation
14.  Genetic Markers of Adult Obesity Risk Are Associated with Greater Early Infancy Weight Gain and Growth 
PLoS Medicine  2010;7(5):e1000284.
Ken Ong and colleagues genotyped children from the ALSPAC birth cohort and showed an association between greater early infancy gains in weight and length and genetic markers for adult obesity risk.
Background
Genome-wide studies have identified several common genetic variants that are robustly associated with adult obesity risk. Exploration of these genotype associations in children may provide insights into the timing of weight changes leading to adult obesity.
Methods and Findings
Children from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort were genotyped for ten genetic variants previously associated with adult BMI. Eight variants that showed individual associations with childhood BMI (in/near: FTO, MC4R, TMEM18, GNPDA2, KCTD15, NEGR1, BDNF, and ETV5) were used to derive an “obesity-risk-allele score” comprising the total number of risk alleles (range: 2–15 alleles) in each child with complete genotype data (n = 7,146). Repeated measurements of weight, length/height, and body mass index from birth to age 11 years were expressed as standard deviation scores (SDS). Early infancy was defined as birth to age 6 weeks, and early infancy failure to thrive was defined as weight gain between below the 5th centile, adjusted for birth weight. The obesity-risk-allele score showed little association with birth weight (regression coefficient: 0.01 SDS per allele; 95% CI 0.00–0.02), but had an apparently much larger positive effect on early infancy weight gain (0.119 SDS/allele/year; 0.023–0.216) than on subsequent childhood weight gain (0.004 SDS/allele/year; 0.004–0.005). The obesity-risk-allele score was also positively associated with early infancy length gain (0.158 SDS/allele/year; 0.032–0.284) and with reduced risk of early infancy failure to thrive (odds ratio  = 0.92 per allele; 0.86–0.98; p = 0.009).
Conclusions
The use of robust genetic markers identified greater early infancy gains in weight and length as being on the pathway to adult obesity risk in a contemporary birth cohort.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The proportion of overweight and obese children is increasing across the globe. In the US, the Surgeon General estimates that, compared with 1980, twice as many children and three times the number of adolescents are now overweight. Worldwide, 22 million children under five years old are considered by the World Health Organization to be overweight.
Being overweight or obese in childhood is associated with poor physical and mental health. In addition, childhood obesity is considered a major risk factor for adult obesity, which is itself a major risk factor for cancer, heart disease, diabetes, osteoarthritis, and other chronic conditions.
The most commonly used measure of whether an adult is a healthy weight is body mass index (BMI), defined as weight in kilograms/(height in metres)2. However, adult categories of obese (>30) and overweight (>25) BMI are not directly applicable to children, whose BMI naturally varies as they grow. BMI can be used to screen children for being overweight and or obese but a diagnosis requires further information.
Why Was This Study Done?
As the numbers of obese and overweight children increase, a corresponding rise in future numbers of overweight and obese adults is also expected. This in turn is expected to lead to an increasing incidence of poor health. As a result, there is great interest among health professionals in possible pathways between childhood and adult obesity. It has been proposed that certain periods in childhood may be critical for the development of obesity.
In the last few years, ten genetic variants have been found to be more common in overweight or obese adults. Eight of these have also been linked to childhood BMI and/or obesity. The authors wanted to identify the timing of childhood weight changes that may be associated with adult obesity. Knowledge of obesity risk genetic variants gave them an opportunity to do so now, without following a set of children to adulthood.
What Did the Researchers Do and Find?
The authors analysed data gathered from a subset of 7,146 singleton white European children enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC) study, which is investigating associations between genetics, lifestyle, and health outcomes for a group of children in Bristol whose due date of birth fell between April 1991 and December 1992. They used knowledge of the children's genetic makeup to find associations between an obesity risk allele score—a measure of how many of the obesity risk genetic variants a child possessed—and the children's weight, height, BMI, levels of body fat (at nine years old), and rate of weight gain, up to age 11 years.
They found that, at birth, children with a higher obesity risk allele score were not any heavier, but in the immediate postnatal period they were less likely to be in the bottom 5% of the population for weight gain (adjusted for birthweight), often termed “failure to thrive.” At six weeks of age, children with a higher obesity risk allele score tended to be longer and heavier, even allowing for weight at birth.
After six weeks of age, the obesity risk allele score was not associated with any further increase in length/height, but it was associated with a more rapid weight gain between birth and age 11 years. BMI is derived from height and weight measurements, and the association between the obesity risk allele score and BMI was weak between birth and age three-and-a-half years, but after that age the association with BMI increased rapidly. By age nine, children with a higher obesity risk allele score tended to be heavier and taller, with more fat on their bodies.
What Do These Findings Mean?
The combined obesity allele risk score is associated with higher rates of weight gain and adult obesity, and so the authors conclude that weight gain and growth even in the first few weeks after birth may be the beginning of a pathway of greater adult obesity risk.
A study that tracks a population over time can find associations but it cannot show cause and effect. In addition, only a relatively small proportion (1.7%) of the variation in BMI at nine years of age is explained by the obesity risk allele score.
The authors' method of finding associations between childhood events and adult outcomes via genetic markers of risk of disease as an adult has a significant advantage: the authors did not have to follow the children themselves to adulthood, so their findings are more likely to be relevant to current populations. Despite this, this research does not yield advice for parents how to reduce their children's obesity risk. It does suggest that “failure to thrive” in the first six weeks of life is not simply due to a lack of provision of food by the baby's caregiver but that genetic factors also contribute to early weight gain and growth.
The study looked at the combined obesity risk allele score and the authors did not attempt to identify which individual alleles have greater or weaker associations with weight gain and overweight or obesity. This would require further research based on far larger numbers of babies and children. The findings may also not be relevant to children in other types of setting because of the effects of different nutrition and lifestyles.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000284.
Further information is available on the ALSPAC study
The UK National Health Service and other partners provide guidance on establishing a healthy lifestyle for children and families in their Change4Life programme
The International Obesity Taskforce is a global network of expertise and the advocacy arm of the International Association for the Study of Obesity. It works with the World Health Organization, other NGOs, and stakeholders and provides information on overweight and obesity
The Centers for Disease Control and Prevention (CDC) in the US provide guidance and tips on maintaining a healthy weight, including BMI calculators in both metric and Imperial measurements for both adults and children. They also provide BMI growth charts for boys and girls showing how healthy ranges vary for each sex at with age
The Royal College of Paediatrics and Child Health provides growth charts for weight and length/height from birth to age 4 years that are based on WHO 2006 growth standards and have been adapted for use in the UK
The CDC Web site provides information on overweight and obesity in adults and children, including definitions, causes, and data
The CDC also provide information on the role of genes in causing obesity.
The World Health Organization publishes a fact sheet on obesity, overweight and weight management, including links to childhood overweight and obesity
Wikipedia includes an article on childhood obesity (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1000284
PMCID: PMC2876048  PMID: 20520848
15.  Diffusion Tensor Imaging of Frontal White Matter and Executive Functioning in Cocaine-Exposed Children 
Pediatrics  2006;118(5):2014-2024.
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.
doi:10.1542/peds.2006-0003
PMCID: PMC3166953  PMID: 17079574
prenatal exposure; cocaine infants; neuroimaging; cognitive function; neuropsychology
16.  Impact of Prenatal Cocaine Exposure on Attention and Response Inhibition as Assessed by Continuous Performance Tests 
Objective
This study examined the influence of prenatal cocaine exposure on attention and response inhibition measured by continuous performance tests (CPTs) at ages 5 and 7 years.
Methods
The baseline sample consisted of 253 cocaine-exposed and 223 non–cocaine-exposed children enrolled prospectively at birth and assessed comprehensively through age 7 years in the longitudinal Miami Prenatal Cocaine Study. This report includes a subsample of 415 children (219 cocaine-exposed, 196 non–cocaine-exposed) who completed at least one CPT assessment at ages 5 and/or 7 years. Prenatal cocaine exposure was measured by maternal self-report and maternal and infant bioassays. Deficits in attention and response inhibition are estimated in relation to prenatal cocaine exposure using generalized estimating equations within the general linear model.
Results
Results indicate cocaine-associated increases in omission errors at ages 5 and 7 as well as increases in response times for target tasks (i.e., slower reaction times) and decreased consistency in performance at age 7. There were no demonstrable cocaine-associated deficits in commission errors. Estimates did not change markedly with statistical adjustment for selected prenatal and postnatal covariates.
Conclusion
Evidence supports cocaine-associated deficits in attention processing through age 7 years.
doi:10.1097/01.DBP.0000268560.72580.f9
PMCID: PMC2760335  PMID: 17565286
prenatal cocaine exposure; sustained attention; response inhibition; continuous performance test
17.  Comparing attitudes about legal sanctions and teratogenic effects for cocaine, alcohol, tobacco and caffeine: A randomized, independent samples design 
Background
Establishing more sensible measures to treat cocaine-addicted mothers and their children is essential for improving U.S. drug policy. Favorable post-natal environments have moderated potential deleterious prenatal effects. However, since cocaine is an illicit substance having long been demonized, we hypothesized that attitudes toward prenatal cocaine exposure would be more negative than for licit substances, alcohol, nicotine and caffeine. Further, media portrayals about long-term outcomes were hypothesized to influence viewers' attitudes, measured immediately post-viewing. Reducing popular crack baby stigmas could influence future policy decisions by legislators.
In Study 1, 336 participants were randomly assigned to 1 of 4 conditions describing hypothetical legal sanction scenarios for pregnant women using cocaine, alcohol, nicotine or caffeine. Participants rated legal sanctions against pregnant women who used one of these substances and risk potential for developing children.
In Study 2, 139 participants were randomly assigned to positive, neutral and negative media conditions. Immediately post-viewing, participants rated prenatal cocaine-exposed or non-exposed teens for their academic performance and risk for problems at age18.
Results
Participants in Study 1 imposed significantly greater legal sanctions for cocaine, perceiving prenatal cocaine exposure as more harmful than alcohol, nicotine or caffeine. A one-way ANOVA for independent samples showed significant differences, beyond .0001. Post-hoc Sheffe test illustrated that cocaine was rated differently from other substances.
In Study 2, a one-way ANOVA for independent samples was performed on difference scores for the positive, neutral or negative media conditions about prenatal cocaine exposure. Participants in the neutral and negative media conditions estimated significantly lower grade point averages and more problems for the teen with prenatal cocaine exposure than for the non-exposed teen beyond .0001 alpha level. The positive media program closed estimated grade point average differences and risks of later problems to a non-statistically significant margin, p >.05.
Conclusion
Ratings for prenatal cocaine were more negative than comparable ratings for alcohol, nicotine or caffeine exposure. Stereotypes can be reduced, showing viewers that positive postnatal environments ameliorate potential teratogenic effects of cocaine. Reducing negative stereotypes for crack babies may be a requisite for substantive changes in current policy.
doi:10.1186/1747-597X-1-4
PMCID: PMC1435999  PMID: 16722564
18.  Motor and Cognitive Outcomes Through Three Years Of Age In Children Exposed To Prenatal Methamphetamine 
Neurotoxicology and teratology  2011;33(1):176-184.
Background
Methamphetamine (MA) use among pregnant women is an increasing problem in the United States. The impact of prenatal MA exposure on development in childhood is unknown.
Objective
To examine the effects of prenatal MA exposure on motor and cognitive development in children at 1, 2, and 3 years of age.
Design/Methods
IDEAL enrolled 412 mother-infant pairs at four sites (Tulsa OK, Des Moines IA, Los Angeles CA, and Honolulu HI). MA subjects (n=204) were identified by self-report or GC/MS confirmation of amphetamine and metabolites in infant meconium. Comparison subjects (n=208) were matched (race, birth weight, maternal education, type of insurance), denied amphetamine use, and had a negative meconium screen. Both groups included prenatal alcohol, tobacco and marijuana use, but excluded use of opiates, lysergic acid diethylamide, phencyclidine or cocaine only. The Peabody Developmental Motor Scales (PDMS-2) were administered to the infants at the 1 and 3 year visits. This analysis includes a subsample (n=350) of the IDEAL study with completed 1 and/or 3 year visits (n= 330 and 281, respectively). At each annual visit we also conducted the Bayley Scales of Infant Development (BSID-II) as a general evaluation of mental and motor development. The BSID-II analysis includes a subsample (n=356) of the IDEAL study with completed 1, 2, and/or 3 year visits (n= 331, 288, and 278 respectively). GLM analysis conducted on the PDMS-2 and BSID-II examined the effects of MA exposure and heavy MA exposure (≥3 days of use/week), with and without covariates. Longitudinal analyses were used to examine the effects of MA exposure on changes in motor and cognitive performance over time.
Results
Heavy MA exposure was associated with significantly lower grasping scores than some and no use at 1 year (P = 0.018). In longitudinal analysis, lower grasping scores associated with any MA exposure and heavy exposure persisted to 3 years. There were no effects of MA exposure, including heavy exposure, on the Bayley Mental Development Index (MDI) or Psychomotor Development Index (PDI) at any or across age.
Conclusions
There were no differences in cognition as assessed by the BSID-II between the groups. There was a subtle MA exposure effect on fine motor performance at 1 year with the poorest performance observed in the most heavily exposed children. By 3 years, no differences in fine motor performance were observed. These findings suggest MA exposure has modest motor effects at 1 year that are mostly resolved by 3 years.
doi:10.1016/j.ntt.2010.10.004
PMCID: PMC3033584  PMID: 21256431
prenatal exposure; neurodevelopment; Bayley; Peabody
19.  Neurobehavioral and Developmental Traiectories Associated with Level of Prenatal Cocaine Exposure 
Introduction
In experimental models, prenatal cocaine exposure has been found to perturb GABA and dopamine development. Clinically, abnormalities in tone, posture and state regulation are noted in early infancy but the evolution of these findings over time is not well described. The current study assesses the longitudinal effects of prenatal cocaine exposure in dose-dependent fashion on developmental & behavioral and neurological trajectories over the first 2 years of life.
Methods
Three hundred and eighty infants, 113 cocaine-exposed, were enrolled at birth from an urban hospital from 2000 to 2004. Exposure was determined by maternal interview, segmental hair analyses (RIAH™) in all, and meconium and urine in a subset. Developmental, behavioral and neurological assessments were carried out blind to drug exposure at 6, 12 and 24 months of age in the 306 children who returned in follow-up. Mixed-effects linear modeling (developmental growth curve) assessed change in outcome over time.
Results
The mental developmental growth curve showed a negative slope (2.2 points) in adjusted analyses among cocaine-exposed children over the first 2 years of life. (p=.04), while the slope of the motor development growth curve did not. Adjusting for microcephaly at 6 months diminished the strength of the association between cocaine exposure and mental developmental growth curve (effect modification). Cocaine exposure was marginally associated with behavioral outcomes in adjusted analyses. Total Behavior scores and Orientation/Engagement scores improved with age. At 1 year of age, prenatal cocaine exposure was significantly associated with lower motor development scores. High rates of hypertonia (global and diparesis) identified at the 6-month visit dropped dramatically in the first 2 years of life: cocaine-exposed children showed a more rapid rate of resolution of hypertonia than unexposed children, with hypertonia improving 2.2 times faster among those with heavy cocaine exposure.
Conclusion
We found differences in mental performance over the first 2 years of life associated with prenatal cocaine exposure that was mediated by microcephaly implying that cocaine exerts a sustained teratogenic effect on brain development. Early neurological (hypertonia) and behavioral findings associated with prenatal cocaine exposure improved over time. Hypertonia did not predict long-term development impairments. Conceivably, the transient nature of neurobehavioral manifestations reflects postnatally a tendency towards homeostasis of cocaine-related embryopathic perturbations of GABA and dopaminergic systems.
doi:10.13188/2332-3469.1000015
PMCID: PMC4318507  PMID: 25664330
Perinatal; Cocaine exposure; Behavior; Drug use; Hypertonia; Neurologic; Child development
20.  Children's Cognitive Ability from 4- to 9-Years as a Function of Prenatal Cocaine Exposure, Environmental Risk, and Maternal Verbal Intelligence 
Developmental psychology  2008;44(4):919-928.
This study examined the effects of prenatal cocaine exposure, environmental risk, and maternal verbal intelligence on children's cognitive ability. Gender and age were examined as moderators of potential cocaine exposure effects. The Stanford-Binet IV intelligence test was administered to 231 children (91 cocaine exposed, 140 unexposed) at 4, 6, and 9 years of age. Neonatal medical risk and other prenatal exposures (alcohol, cigarettes, and marijuana) were also examined for their unique effects on child IQ. Mixed models analysis indicated that prenatal cocaine exposure interacted with gender as cocaine exposed boys had lower composite IQ scores. Age of assessment did not moderate this relation, indicating that cocaine exposed boys had lower IQs across this age period. A stimulating home environment and high maternal verbal IQ also predicted higher composite IQ scores. Cocaine exposed boys had lower scores on the Abstract/Visual Reasoning subscale, with trends for lower scores on the Short-term Memory and Verbal Reasoning subscales, as exposure effects were observed across domains. The findings indicate that cocaine exposure continues to place children at risk for mild cognitive deficits into preadolescence. Possible mechanisms for the exposure by gender interaction are discussed.
doi:10.1037/0012-1649.44.4.919
PMCID: PMC2556289  PMID: 18605824
prenatal cocaine exposure; environmental risk; gender differences; intelligence
21.  Prenatal cocaine exposure: An examination of childhood externalizing and internalizing behavior problems at age 7 years 
SUMMARY
Aim
This study examines the relationship between prenatal cocaine exposure and parent-reported child behavior problems at age 7 years.
Methods
Data are from 407 African-American children (210 cocaine-exposed, 197 non-cocaine-exposed) enrolled prospectively at birth in a longitudinal study on the neurodevelopmental consequences of in utero exposure to cocaine. Prenatal cocaine exposure was assessed at delivery through maternal self-report and bioassays (maternal and infant urine and infant meconium). The Achenbach Child Behavior Checklist (CBCL), a measure of childhood externalizing and internalizing behavior problems, was completed by the child’s current primary caregiver during an assessment visit scheduled when the child was seven years old.
Results
Structural equation and GLM/GEE models disclosed no association linking prenatal cocaine exposure status or level of cocaine exposure to child behavior (CBCL Externalizing and Internalizing scores or the eight CBCL sub-scale scores).
Conclusions
This evidence, based on standardized ratings by the current primary caregiver, fails to support hypothesized cocaine-associated behavioral problems in school-aged children with in utero cocaine exposure. A next step in this line of research is to secure standardized ratings from other informants (e.g., teachers, youth self-report).
PMCID: PMC2641031  PMID: 16584100
cocaine; prenatal exposure; child behavior
22.  Assessing Latent Effects of Prenatal Cocaine Exposure on Growth and Risk of Cardiometabolic Disease in Late Adolescence: Design and Methods 
Prenatal cocaine exposure has been linked to neurocognitive and developmental outcomes throughout childhood. The cardiovascular toxicity of cocaine is also markedly increased in pregnancy, but it is unknown whether this toxicity affects anthropometric growth and the development of cardiometabolic disease risk factors in the offspring across the lifespan. During the early 1990s, the Miami Prenatal Cocaine Study enrolled a cohort of 476 African American children (253 cocaine-exposed, 223 non-cocaine-exposed) and their biological mothers at delivery in a prospective, longitudinal study. The MPCS has collected 12 prior waves of multidomain data on over 400 infants and their mothers/alternate caregivers through mid-adolescence and is now embarking on an additional wave of data collection at ages 18-19 years. We describe here the analytical methods for examining the relationship between prenatal cocaine exposure, anthropometric growth, and cardiometabolic disease risk factors in late adolescence in this minority, urban cohort. Findings from this investigation should inform both the fields of substance use and cardiovascular research about subsequent risks of cocaine ingestion during pregnancy in offspring.
doi:10.1155/2012/467918
PMCID: PMC3529470  PMID: 23304172
23.  Prenatal Cocaine Exposure Alters Cortisol Stress Reactivity in 11 Year Old Children 
The Journal of pediatrics  2010;157(2):288-295.e1.
Objective
Determine the association between prenatal cocaine exposure and postnatal environmental adversity on salivary cortisol stress reactivity in school aged children.
Study design
Subjects included 743 11 year old children (n=320 cocaine exposed; 423 comparison) followed since birth in a longitudinal prospective multisite study. Saliva samples were collected to measure cortisol at baseline and after a standardized procedure to induce psychological stress. Children were divided into those who showed an increase in cortisol from baseline to post stress and those who showed a decrease or blunted cortisol response. Covariates measured included site, birthweight, maternal pre and postnatal use of alcohol, tobacco or marijuana, social class, changes in caretakers, maternal depression and psychological symptoms, domestic and community violence, child abuse and quality of the home.
Results
With adjustment for confounding variables, cortisol reactivity to stress was more likely to be blunted in children with prenatal cocaine exposure. Cocaine exposed children exposed to domestic violence showed the strongest effects.
Conclusion
The combination of prenatal cocaine exposure and an adverse postnatal environment could down regulate the hypothalamic-pituitary-adrenal axis (HPA) resulting in the blunted cortisol response to stress possibly increasing risk for later psychopathology and adult disease.
doi:10.1016/j.jpeds.2010.02.039
PMCID: PMC3121327  PMID: 20400094
prenatal cocaine exposure; cortisol reactivity; environmental adversity
24.  Psychopathology and Special Education Enrollment in Children with Prenatal Cocaine Exposure 
Objective
This study evaluated how enrollment in special education services in 11 year old children relates to prenatal cocaine exposure, psychopathology, and other risk factors.
Method
Participants were 498 children enrolled in The Maternal Lifestyle Study, a prospective, longitudinal, multisite study examining outcomes of children with prenatal cocaine exposure. Logistic regression was used to examine the effect of prenatal cocaine exposure and psychopathology on enrollment in an individualized education plan (a designation specific to children with special education needs), with environmental, maternal, and infant medical variables as covariates.
Results
Prenatal cocaine exposure, an interaction of prenatal cocaine exposure and Oppositional Defiant Disorder, child Attention Deficit Hyperactivity Disorder, parent-reported internalizing behaviors, and teacher-reported externalizing behaviors, predicted enrollment in an individualized education plan. Other statistically significant variables in the model were male gender, low birth weight, being small for gestational age, white race, caregiver change, low socio-economic status, low child intelligence quotient, caregiver depression, and prenatal marijuana exposure.
Conclusions
Prenatal cocaine exposure increased the likelihood of receiving an individualized education plan with adjustment for covariates. Psychopathology also predicted this special education outcome, in combination with and independent of prenatal cocaine exposure.
doi:10.1097/DBP.0b013e3182560cd9
PMCID: PMC3400535  PMID: 22487696
cocaine; special education; behavior; prenatal substance exposure
25.  Volumetric MRI Study of Brain in Children With Intrauterine Exposure to Cocaine, Alcohol, Tobacco, and Marijuana 
Pediatrics  2008;121(4):741-750.
OBJECTIVE
The objective of this study was to use volumetric MRI to study brain volumes in 10- to 14-year-old children with and without intrauterine exposure to cocaine, alcohol, cigarettes, or marijuana.
METHODS
Volumetric MRI was performed on 35 children (mean age: 12.3 years; 14 with intrauterine exposure to cocaine, 21 with no intrauterine exposure to cocaine) to determine the effect of prenatal drug exposure on volumes of cortical gray matter; white matter; subcortical gray matter; cerebrospinal fluid; and total parenchymal volume. Head circumference was also obtained. Analyses of each individual substance were adjusted for demographic characteristics and the remaining 3 prenatal substance exposures.
RESULTS
Regression analyses adjusted for demographic characteristics showed that children with intrauterine exposure to cocaine had lower mean cortical gray matter and total parenchymal volumes and smaller mean head circumference than comparison children. After adjustment for other prenatal exposures, these volumes remained smaller but lost statistical significance. Similar analyses conducted for prenatal ethanol exposure adjusted for demographics showed significant reduction in mean cortical gray matter; total parenchymal volumes; and head circumference, which remained smaller but lost statistical significance after adjustment for the remaining 3 exposures. Notably, prenatal cigarette exposure was associated with significant reductions in cortical gray matter and total parenchymal volumes and head circumference after adjustment for demographics that retained marginal significance after adjustment for the other 3 exposures. Finally, as the number of exposures to prenatal substances grew, cortical gray matter and total parenchymal volumes and head circumference declined significantly with smallest measures found among children exposed to all 4.
CONCLUSIONS
These data suggest that intrauterine exposures to cocaine, alcohol, and cigarettes are individually related to reduced head circumference; cortical gray matter; and total parenchymal volumes as measured by MRI at school age. Adjustment for other substance exposures precludes determination of statistically significant individual substance effect on brain volume in this small sample; however, these substances may act cumulatively during gestation to exert lasting effects on brain size and volume.
doi:10.1542/peds.2007-1399
PMCID: PMC2562785  PMID: 18381539
pregnancy; illicit substance; MRI; children; brain

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