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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.  Preadolescent behavior problems after prenatal cocaine exposure: Relationship between teacher and caretaker ratings (Maternal Lifestyle Study) 
Neurotoxicology and teratology  2010;33(1):78-87.
Background
We previously reported an association between prenatal cocaine exposure (PCE) and childhood behavior problems as observed by the parent or caretaker. However, these behavior problems may not manifest in a structured environment, such as a school setting.
Objective
We determined whether there is an association between PCE and school behavior problems and whether ratings of behavior problems from the teacher differ from those noted by the parent or caretaker.
Methods
The Maternal Lifestyle Study, a multicenter study, enrolled 1388 children with and without PCE at one month of age for longitudinal assessment. Teachers masked to prenatal drug exposure status completed the Teacher Report Form (TRF/6-18) when children were 7, 9, and 11 years old. We also administered the Child Behavior Checklist-parent report (CBCL) to the parent/caretaker at same ages and then at 13 years. We performed latent growth curve modeling to determine whether high PCE will predict externalizing, internalizing, total behavior, and attention problems at 7 years of age and whether changes in problems' scores over time differ between those exposed and non-exposed from both teacher and parent report. Besides levels of PCE as predictors, we controlled for the following covariates, namely: site, child characteristics (gender and other prenatal drug exposures), family level influences (maternal age, depression and psychological symptomatology, continuing drug use, exposure to domestic violence, home environment, and socioeconomic status), and community level factors (neighborhood and community violence).
Results
The mean behavior problem T scores from the teacher report were significantly higher than ratings by the parent or caretaker. Latent growth curve modeling revealed a significant relationship between intercepts of problem T scores from teacher and parent ratings; i.e., children that were rated poorly by teachers were also rated poorly by their parent/caretaker or vice versa. After controlling for covariates, we found high PCE to be a significant predictor of with higher externalizing behavior problem T scores from both parent and teacher report at 7 years (p=0.034 and p=0.021, respectively) in comparison to non-PCE children. These differences in scores from either teacher or caregiver were stable through subsequent years or did not change significantly over time. Boys had higher T scores than girls on internalizing and total problems by caretaker report; they also had significantly higher T scores for internalizing, total, and attention problems by teacher ratings; the difference was marginally significant for externalizing behavior (p=0.070). Caretaker postnatal use of tobacco, depression, and community violence were significant predictors of all behavior problems rated by parent/caretaker, while lower scores on the home environment predicted all behavior outcomes by the teacher report.
Conclusions
Children with high PCE are likely to manifest externalizing behavior problems; their behavior problem scores at 7 years from either report of teacher or parent remained higher than scores of non-exposed children on subsequent years. Screening and identification of behavior problems at earlier ages could make possible initiation of intervention, while considering the likely effects of other confounders.
doi:10.1016/j.ntt.2010.06.005
PMCID: PMC3011027  PMID: 20600844
3.  Child behavior problems among cocaine-exposed toddlers: Indirect and interactive effects 
Development and psychopathology  2011;23(2):539-550.
This study examined the role of maternal psychopathology and maternal warmth as mediators of the association between prenatal cocaine and other substance exposure and toddler behavior problems. It was also hypothesized that infant cortisol reactivity and environmental risk may moderate these associations. Participants were 220 caregiver–infant dyads (119 cocaine exposed, 101 not cocaine exposed; 49% boys). Mother–infant dyads were recruited at delivery with assessments at 4–8 weeks and 7, 13, and 18 months of child ages. Results yielded no direct associations between prenatal cocaine/other substance exposure and toddler behavior problems, but significant indirect associations between prenatal cigarette/alcohol exposure and toddler behavior problems at 18 months. With regard to moderation, results indicated an indirect association between prenatal cocaine exposure and toddler behavior problems via lower maternal warmth for children with higher, but not lower, cortisol reactivity at 7 months. Results suggest potential pathways to toddler behavior problems among children at high biological risk.
doi:10.1017/S0954579411000058
PMCID: PMC3695418  PMID: 23786694
4.  Low-Level Prenatal and Postnatal Blood Lead Exposure and Adrenocortical Responses to Acute Stress in Children 
Environmental Health Perspectives  2007;116(2):249-255.
Background
A few recent studies have demonstrated heightened hypothalamic–pituitary–adrenal (HPA) axis reactivity to acute stress in animals exposed to heavy metal contaminants, particularly lead. However, Pb-induced dysregulation of the HPA axis has not yet been studied in humans.
Objective
In this study, we examined children’s cortisol response to acute stress (the glucocorticoid product of HPA activation) in relation to low-level prenatal and postnatal Pb exposure.
Methods
Children’s prenatal blood Pb levels were determined from cord blood specimens, and postnatal lead levels were abstracted from pediatrician and state records. Children’s adrenocortical responses to an acute stressor were measured using assays of salivary cortisol before and after administration of a standard cold pressor task.
Results
Pb exposure was not associated with initial salivary cortisol levels. After an acute stressor, however, increasing prenatal and postnatal blood Pb levels were independently associated with significantly heightened salivary cortisol responses.
Conclusions
Our results suggest that relatively low prenatal and postnatal blood lead levels—notably those below the 10 μg/dL blood lead level identified by the Centers for Disease Control and Prevention for public health purposes—can alter children’s adrenocortical responses to acute stress. The behavioral and health consequences of this Pb-induced HPA dysregulation in children have yet to be determined.
doi:10.1289/ehp.10391
PMCID: PMC2235205  PMID: 18288326
adrenocortical; children; cortisol; HPA axis; lead; metal pollution; Pb; stress
5.  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
6.  Prenatal Psychobiological Predictors of Anxiety Risk in Preadolescent Children 
Psychoneuroendocrinology  2012;37(8):1224-1233.
Summary
Experimental animal models have demonstrated that one of the primary consequences of prenatal stress is increased fear and anxiety in the offspring. Few prospective human studies have evaluated the consequences of prenatal stress on anxiety during preadolescence. The purpose of this investigation is to determine the consequences of prenatal exposure to both maternal biological stress signals and psychological distress on anxiety in preadolescent children. Participants included 178 mother-child pairs. Maternal psychological distress (general anxiety, perceived stress, depression and pregnancy-specific anxiety) and biological stress signals were evaluated at 19, 25, and 31 gestational weeks. Anxiety was evaluated in the children at 6 to 9 years of age using the Child Behavior Checklist. Analyses revealed that prenatal exposure to elevated maternal cortisol, depression, perceived stress and pregnancy-specific anxiety was associated with increased anxiety in children. These associations remained after considering obstetric, sociodemographic and postnatal maternal psychological distress; factors that could influence child development. When all of the prenatal measures were considered together, cortisol and pregnancy-specific anxiety independently predicted child anxiety. Children exposed to elevated prenatal maternal cortisol and pregnancy-specific anxiety were at an increased risk for developing anxiety problems during the preadolescent period. This project identifies prenatal risk factors associated with lasting consequences for child mental health and raises the possibility that reducing maternal distress during the prenatal period will have long term benefits for child well-being.
doi:10.1016/j.psyneuen.2011.12.016
PMCID: PMC3356791  PMID: 22265195
anxiety; development; fetal programming; prenatal; cortisol; stress; pregnancy
7.  The Association between Prenatal Exposure to Cigarettes and Cortisol Reactivity in 7-Month-Old Infants 
Developmental psychobiology  2008;50(8):819-834.
We examined the association between prenatal exposure to cigarettes and adrenocortical responses to stress in 7-month old infants. Cortisol levels were assessed twice prior to and twice following affect-eliciting procedures in 111 (59 exposed and 52 nonexposed) infants. Cortisol reactivity was defined as the difference between the peak poststressor cortical level and the pretask cortisol level. Higher values indicated higher cortisol reactivity. Exposed infants had higher peak cortisol reactivity than non exposed infants. There were no differences in pretask cortisol levels. Maternal hostility mediated the association between cigarette exposure and peak cortisol reactivity. Furthermore, infant gender moderated this association such that exposed boys had significantly higher peak cortisol reactivity than nonexposed infants or exposed girls. These findings provide additional evidence that prenatal cigarette exposure is associated with dysregulation during infancy and that early adverse, non-social experiences may have relatively long-lasting effects on cortisol reactivity in infants.
doi:10.1002/dev.20334
PMCID: PMC2585825  PMID: 18690653
Prenatal Cigarette Exposure; Infant; Stress Responses; HPA Axis; Reactivity; Maternal Hostility; Sex Differences
8.  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
9.  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
10.  Psychobiological Effects of Prenatal Glucocorticoid Exposure in 10-Year-Old-Children 
Background: Prenatal stress seems to have long-lasting effects on biological and psychological processes of the offspring. However, to date, there have been no studies investigating the effects of prenatal glucocorticoid exposure on psychological, endocrine, and autonomic responses to a standardized psychosocial stress test in children. Methods: A sample of 115 healthy, 10-year-old children was examined. The Glucocorticoids + Tocolytics group was characterized by tocolytic treatment of the mothers due to preterm labor (n = 43). In addition, the pregnant women received glucocorticoid treatment in order to accelerate fetal lung maturation in case of preterm birth. The first comparison group (Tocolytics) consisted of children whose mothers also experienced preterm labor, but did not receive glucocorticoid treatment (n = 35). In the second comparison group (CONTROL), children whose mothers had a complication-free pregnancy were assessed (n = 37). Psychological parameters (stress appraisal and mood) using self-report questionnaires as well as salivary cortisol, salivary alpha-amylase, and heart rate were measured during a standardized psychosocial stress test (Trier Social Stress Test for Children). Results: Group comparisons revealed that a subscale of stress appraisal, control expectancies, significantly differed in children who were prenatally exposed to glucocorticoids as compared to both comparison groups (F = 4.889, p = 0.009). Furthermore, significant differences between the groups were revealed for salivary cortisol. With respect to overall stress appraisal and heart rate, trends toward significance were observed between the three groups. Conclusion: At the age of ten, those children who have been exposed to prenatal maternal glucocorticoids show changed psychobiological stress reactivity to a standardized psychosocial stress test as compared to control children.
doi:10.3389/fpsyt.2012.00104
PMCID: PMC3517968  PMID: 23233841
prenatal glucocorticoids; acute psychosocial stress; psychobiological reactivity; HPA axis; children
11.  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
12.  Prenatal Cocaine Exposure, Gender, and Adolescent Stress Response: A Prospective Longitudinal Study 
Neurotoxicology and teratology  2010;32(6):595-604.
Prenatal cocaine exposure is associated with alterations in arousal regulation in response to stress in young children. However, relations between cocaine exposure and stress response in adolescence have not been examined. We examined salivary cortisol, self-reported emotion, heart rate, and blood pressure (BP) responses to the Trier Social Stress Test (TSST) in 49 Prenatally Cocaine and other drug Exposed (PCE) and 33 Non Cocaine Exposed (NCE) adolescents. PCE adolescents had higher cortisol levels before and after stress exposure than NCE adolescents. PCE girls showed an elevated anxiety response to stress (compared to NCE girls) and PCE boys showed a dampened diastolic BP response (compared to NCE boys). Girls showed higher anger response and lower pre-stress systolic BP than boys. Group differences were found controlling for potential confounding variables and were not moderated by caregiver-child relationship quality (although relationship quality predicted HPA-Axis and anxiety response). Findings suggest that prenatal drug exposure is associated with altered stress response in adolescence and that gender moderates this association.
doi:10.1016/j.ntt.2010.08.007
PMCID: PMC2983086  PMID: 20826209
Prenatal cocaine exposure; Stress response; Cortisol; Emotion; Sex differences
13.  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
14.  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
15.  The Maternal Lifestyle Study: Sleep Problems in Children with Prenatal Substance Exposure 
Objective
To examine the relationships between sleep problems and prenatal exposure to cocaine, opiates, marijuana, alcohol, and nicotine in children 1 month to 12 years of age.
Design
Sleep data was collected by maternal report in a prospective longitudinal follow-up of children participating in the Maternal Lifestyle multisite study.
Setting
Hospital based research centers in Providence, RI, Miami, FL, Detroit, MI, and Memphis, TN
Participants
There were 808 participants: 374 exposed to cocaine and/or opiates; 434 comparison.
Main exposure
Prenatal cocaine, opiate, marijuana, alcohol, and nicotine exposure.
Outcome measure
Sleep problems in early, middle, and late childhood, assessed as composites of maternal report items.
Results
Of the five substances, prenatal nicotine exposure was the only unique predictor of sleep problems (B = .074, R2 Δ = .008, p = .012) with adjustment for covariates including SES, marital status, physical abuse, prenatal medical care, and postnatal cigarette smoke exposure.
Conclusion
Prenatal exposure to nicotine was positively associated with children's sleep problems persisting throughout the first 12 years of life. Targeting this group of children for educational and behavioral efforts to prevent and treat sleep problems is merited given that good sleep may serve as a protective factor for other developmental outcomes.
doi:10.1001/archpediatrics.2010.52
PMCID: PMC2917192  PMID: 20439796
16.  Maternal depression and infant cortisol: influences of timing, comorbidity and treatment 
Background
The current study examines the relationship between maternal depression and infant cortisol concentrations. The potential roles of comorbid maternal anxiety disorders, timing of maternal depression, and maternal treatment with psychotropic medications during pregnancy are addressed.
Methods
Women with 6-month-old infants (105 boys and 84 girls) participated in a laboratory paradigm that included infant saliva collection at six points, noise burst and arm restraint stressor tasks, and a diagnostic interview of the mother.
Results
Lifetime history of maternal depression was associated with increased baseline and mean (average) infant cortisol levels. Comorbidity with anxiety disorder was related to infant cortisol reactivity. Peripartum (prepartum and/or postpartum) maternal depression, rather than a pre-pregnancy history of disorder, was associated with higher infant cortisol reactivity. Prenatal and postnatal exposure to maternal disorder had similar effects, but prenatal maternal psychotropic medication treatment appeared to attenuate infant cortisol increases associated with prenatal maternal disorder exposure.
Conclusions
These data suggest that exposure to maternal depression and anxiety during pregnancy and the postpartum period may increase infant salivary cortisol. This maternal depression–infant cortisol association is independent of the effects of delivery complications, and appears to be modulated by prenatal maternal psychotropic treatment.
doi:10.1111/j.1469-7610.2008.01914.x
PMCID: PMC2719161  PMID: 18492036
Anxiety; cortisol; depression; infant; perinatal; prenatal; psychotropic; stress
17.  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
18.  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
19.  Prenatal Cortisol Exposure Predicts Infant Cortisol Response to Acute Stress 
Developmental psychobiology  2012;55(2):145-155.
Summary
Experimental animal findings suggest that early stress and glucocorticoid exposure may program the function of the Hypothalamic-pituitary-adrenal (HPA) axis in the offspring. The extension of these findings to human development is not yet clear. A prospective longitudinal study was conducted on 125 mothers and their normally developing children. Amniotic fluid was obtained at, on average, 17.2 weeks gestation; infant behavior and cortisol response to a separation-reunion stress was assessed at 17 months. Amniotic fluid cortisol predicted infant cortisol response to separation-reunion stress: infants who were exposed to higher levels of cortisol in utero showed higher pre-stress cortisol values and blunted response to stress exposure. The association was independent of prenatal, obstetric, and socioeconomic factors and child-parent attachment. The findings provide some of the strongest data in humans that HPA axis functioning in the child may be predicted from prenatal cortisol exposure.
doi:10.1002/dev.21007
PMCID: PMC3398188  PMID: 22315044
Prenatal stress; amniotic fluid; cortisol; infant; fetal programming
20.  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
21.  Blunted Cortisol Responses to Stress Signal Social and Behavioral Problems Among Maltreated/Bullied 12-Year-Old Children 
Biological psychiatry  2011;70(11):10.1016/j.biopsych.2011.06.017.
Background
Evidence from animal and human studies suggests that early-life stress such as physical maltreatment has long-lasting effects on the hypothalamic-pituitary-adrenal (HPA) axis and is associated with blunted HPA axis reactivity in adulthood. Few studies have investigated whether blunted HPA axis reactivity observed in children exposed to early-life stress signals social, emotional, and behavioral problems.
Methods
Participants were 190 12-year-old children (50.5% males) recruited from the Environmental Risk Longitudinal Twin Study, a nationally representative 1994 to 1995 cohort of families with twins. Cortisol responses to psychosocial stress were measured in maltreated/ bullied (n = 64) and comparison children (n = 126). We ascertained maltreatment and bullying victimization using mothers’ reports and assessed children’s social, emotional, and behavioral problems at ages 5 and 12 using mothers’ and teachers’ reports.
Results
Piecewise multilevel growth curve analyses indicated that maltreated/bullied and comparison children showed distinct cortisol responses to stress. Specifically, maltreated/bullied children had lower cortisol responses than comparison children who exhibited a significant increase. Lower cortisol responses were, in turn, associated with more social and behavioral problems among maltreated/bullied children.
Conclusions
These findings provide support for the influence of childhood harm on blunted HPAaxis reactivity and its potential impacton children’s functioning. Our findings emphasize the need to integrate stress biomarkers in guiding prevention efforts for young victims.
doi:10.1016/j.biopsych.2011.06.017
PMCID: PMC3816750  PMID: 21839988
Behavioral problems; bullying; cortisol; HPA axis; maltreatment; social problems
22.  Influence of Cocaine Dependence and Early Life Stress on Pituitary-Adrenal Axis Responses to CRH and the Trier Social Stressor 
Psychoneuroendocrinology  2010;35(10):1492-1500.
Summary
Long-term changes in the hypothalamic pituitary adrenal (HPA) axis as a result of early life stress could be related to the development of substance use disorders during adulthood. In this study, the neuroendocrine, physiologic (HR), and subjective responses to corticotropin releasing hormone (CRH) and the Trier Social Stress Task (TSST) in individuals with cocaine dependence, with (n=21)/without early life stress (n=21), non-dependent individuals with early life stress (n=22), and a control group were examined (n=21). CRH increased cortisol and ACTH levels in all groups. However, a significant effect of early life stress on ACTH was observed indicating that the increase in ACTH was greatest in subjects with a history of childhood stress. Post-hoc analysis indicated the early life stress/non-cocaine dependent individuals exhibited significantly higher levels of ACTH as compared to the early life stress/cocaine-dependent group. Despite the elevated ACTH response there was no difference between the groups in the cortisol response to CRH. The TSST produced a significant elevation in ACTH and cortisol all study groups. No significant group differences were observed. The subjective stress and peak heart rate responses to the TSST were greatest in cocaine-dependent subjects without early life stress. In response to CRH, subjective stress and craving were positively correlated in cocaine-dependent subjects regardless of early life stress history, while stress and craving following the TSST were correlated only in cocaine-dependent subjects without a history of early life stress. Findings support previous studies demonstrating that subjects with a history of childhood adversity exhibit elevated ACTH and blunted cortisol levels in response to stress. In contrast, HR and subjective stress in response to the TSST were greatest in cocaine-dependent subjects without a history of early life stress, suggesting that childhood adversity may desensitize autonomic and subjective responding to social stress in adults with cocaine-dependence.
doi:10.1016/j.psyneuen.2010.05.001
PMCID: PMC2945624  PMID: 20570051
hypothalamic-pituitary-adrenal (HPA)axis; cocaine dependence; early life stress; trauma; Trier Social Stress Task; corticotropin releasing hormone (CRH); stress
23.  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
24.  Disentangling the effects of genetic, prenatal and parenting influences on children’s cortisol variability 
Stress (Amsterdam, Netherlands)  2013;16(6):607-615.
Developmental plasticity models hypothesize the role of genetic and prenatal environmental influences on the development of the hypothalamic–pituitary–adrenal (HPA) axis and highlight that genes and the prenatal environment may moderate early postnatal environmental influences on HPA functioning. This article examines the interplay of genetic, prenatal and parenting influences across the first 4.5 years of life on a novel index of children’s cortisol variability. Repeated measures data were obtained from 134 adoption-linked families, adopted children and both their adoptive parents and birth mothers, who participated in a longitudinal, prospective US domestic adoption study. Genetic and prenatal influences moderated associations between inconsistency in overreactive parenting from child age 9 months to 4.5 years and children’s cortisol variability at 4.5 years differently for mothers and fathers. Among children whose birth mothers had high morning cortisol, adoptive fathers’ inconsistent overreactive parenting predicted higher cortisol variability, whereas among children with low birth mother morning cortisol adoptive fathers’ inconsistent overreactive parenting predicted lower cortisol variability. Among children who experienced high levels of prenatal risk, adoptive mothers’ inconsistent overreactive parenting predicted lower cortisol variability and adoptive fathers’ inconsistent overreactive parenting predicted higher cortisol variability, whereas among children who experienced low levels of prenatal risk there were no associations between inconsistent overreactive parenting and children’s cortisol variability. Findings supported developmental plasticity models and uncovered novel developmental, gene × environment and prenatal × environment influences on children’s cortisol functioning.
doi:10.3109/10253890.2013.825766
PMCID: PMC3928628  PMID: 23947477
Adoption; cortisol; fathers; genotype-environment interaction; longitudinal; mothers; parenting
25.  Variation in the Glucocorticoid Receptor Gene at rs41423247 Moderates the Effect of Prenatal Maternal Psychological Symptoms on Child Cortisol Reactivity and Behavior 
Neuropsychopharmacology  2012;37(11):2541-2549.
Prenatal maternal psychopathology affects child development, but some children seem more vulnerable than others. Genetic variance in hypothalamic–pituitary–adrenal axis genes may influence the effect of prenatal maternal psychological symptoms on child emotional and behavioral problems. This hypothesis was tested in the Generation R Study, a population-based cohort from fetal life onward. In total, 1727 children of Northern European descent and their mothers participated in this study and were genotyped for variants in the glucocorticoid receptor (GR) gene (rs6189/rs6190, rs10052957, rs41423247, rs6195, and rs6198) and the FK506-binding protein 5 (FKBP5) gene (rs1360780). Prenatal maternal psychological symptoms were assessed at 20 weeks pregnancy and child behavior was assessed by both parents at 3 years. In a subsample of 331 children, data about cortisol reactivity were available. Based on power calculations, only those genetic variants with sufficient minor allele frequencies (rs41423247, rs10052957, and rs1360780) were included in the interaction analyses. We found that variation in GR at rs41423247 moderates the effect of prenatal maternal psychological symptoms on child emotional and behavioral problems (beta 0.41, SE 0.16, p=0.009). This prenatal interaction effect was independent of mother's genotype and maternal postnatal psychopathology, and not found for prenatal psychological symptoms of the father. Moreover, the interaction between rs41423247 and prenatal psychological symptoms was also associated with decreased child cortisol reactivity (beta −2.30, p-value 0.05). These findings emphasize the potential effect of prenatal gene–environment interaction, and give insight in possible mechanisms accounting for children's individual vulnerability to develop emotional and behavioral problems.
doi:10.1038/npp.2012.118
PMCID: PMC3442349  PMID: 22781842
glucocorticoid receptor gene; prenatal psychological symptom; gene–environment interaction; cortisol reactivity; child emotional and behavioral problem; biological psychiatry; child emotional and behavioral problems; cortisol reactivity; epidemiology; gene–environment interaction; glucocorticoid receptor gene; neuroendocrinology; prenatal psychological symptoms; psychiatry and behavioral sciences

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