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1.  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
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.  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
4.  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
5.  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
6.  Predicting Caregiver-Reported Behavior Problems in Cocaine-Exposed Children at 3 Years 
Predictors of caregiver-reported behavior problems for 3-year-olds with prenatal cocaine exposure (PCE) and matched controls were examined using structural equation modeling. We tested whether PCE had a direct effect on child behavior problems in a model that included other prenatal drug exposure, child sex, caregiver depression, and the quality of the child’s home environment. The sample (N = 256) was drawn from a longitudinal, prospective study of children of (predominantly crack) cocaine-using women and controls matched on race, socioeconomic status, parity, and pregnancy risk. Child Behavior Problems was modeled as a latent variable composed of the 48-item Conners’ Parent Report Scale Conduct Problem and Impulsive-Hyperactive scales and the Eyberg Child Behavior Inventory Intensity scale. Caregiver depression was the only significant predictor of Child Behavior Problems. Mean levels of caregiver self-reported depression and reported child behavior problems did not differ between groups. Mean depression scores were well above the recommended clinical cutoff while mean child behavior problems scores were within normal limits. The model explained 21% of the variance in caregiver-reported child behavior problems in our sample of rural African American, low SES youngsters. Non-maternal caregivers of cocaine-exposed children had significantly lower mean depression scores and mean child behavior problems ratings for 2 of 3 scales used in the study compared to biological mothers of children with PCE and controls. For all groups, much larger proportions of children were rated as having clinically significant behavior problems than would be expected based on the prevalence of behavior problems in the general population.
PMCID: PMC3150578  PMID: 16682870
7.  Prenatal cocaine exposure: The role of cumulative environmental risk and maternal harshness in the development of child internalizing behavior problems in Kindergarten 
This study examined the associations between prenatal exposure to cocaine and other substances and child internalizing behavior problems at Kindergarten. We investigated whether maternal harshness or cumulative environmental risk mediated or moderated this association. Participants consisted of 216 (116 cocaine exposed, 100 non-cocaine exposed) mother-infant dyads participating in an ongoing longitudinal study of prenatal cocaine exposure. Results indicated that, as hypothesized, maternal harshness moderated the association between prenatal cocaine exposure to child internalizing in Kindergarten such that prenatal cocaine exposure increased risk for internalizing problems at high levels of maternal harshness from 7 to 36 months and decreased risk at low levels of harshness. Contrary to hypothesis, the association between prenatal cocaine exposure and child internalizing in Kindergarten was not mediated by maternal harshness or cumulative environmental risk. However, cumulative environmental risk (from 1 month of child age to Kindergarten) was predictive of child internalizing behavior problems at Kindergarten. Results have implications for parenting interventions that may be targeted toward reducing maternal harshness in high risk samples characterized by maternal substance use in pregnancy.
doi:10.1016/j.ntt.2014.04.002
PMCID: PMC4099285  PMID: 24803425
Internalizing Behavior Problems; Maternal Harshness; Cocaine exposure
8.  Prenatal and postnatal cocaine exposure predict teen cocaine use 
Neurotoxicology and teratology  2010;33(1):110-119.
Preclinical studies have identified alterations in cocaine and alcohol self-administration and behavioral responses to pharmacological challenges in adolescent offspring following prenatal exposure. To date, no published human studies have evaluated the relation between prenatal cocaine exposure and postnatal adolescent cocaine use. Human studies of prenatal cocaine-exposed children have also noted an increase in behaviors previously associated with substance use/abuse in teens and young adults, specifically childhood and teen externalizing behaviors, impulsivity, and attention problems. Despite these findings, human research has not addressed prior prenatal exposure as a potential predictor of teen drug use behavior. The purpose of this study was to evaluate the relations between prenatal cocaine exposure and teen cocaine use in a prospective longitudinal cohort (n = 316) that permitted extensive control for child, parent and community risk factors. Logistic regression analyses and Structural Equation Modeling revealed that both prenatal exposure and postnatal parent/caregiver cocaine use were uniquely related to teen use of cocaine at age 14 years. Teen cocaine use was also directly predicted by teen community violence exposure and caregiver negativity, and was indirectly related to teen community drug exposure. These data provide further evidence of the importance of prenatal exposure, family and community factors in the intergenerational transmission of teen/young adult substance abuse/use.
doi:10.1016/j.ntt.2010.06.011
PMCID: PMC4455043  PMID: 20609384
Cocaine; Opiates; Marijuana; Self-report; Biologic sample
9.  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
10.  Protective Factors Can Mitigate Behavior Problems After Prenatal Cocaine and Other Drug Exposures 
Pediatrics  2012;130(6):e1479-e1488.
BACKGROUND:
We determined the role of risk and protective factors on the trajectories of behavior problems associated with high prenatal cocaine exposure (PCE)/polydrug exposure.
METHODS:
The Maternal Lifestyle Study enrolled 1388 children with or without PCE, assessed through age 15 years. Because most women using cocaine during pregnancy also used other substances, we analyzed for the effects of 4 categories of prenatal drug exposure: high PCE/other drugs (OD), some PCE/OD, OD/no PCE, and no PCE/no OD. Risks and protective factors at individual, family, and community levels that may be associated with behavior outcomes were entered stepwise into latent growth curve models, then replaced by cumulative risk and protective indexes, and finally by a combination of levels of risk and protective indexes. Main outcome measures were the trajectories of externalizing, internalizing, total behavior, and attention problems scores from the Child Behavior Checklist (parent).
RESULTS:
A total of 1022 (73.6%) children had known outcomes. High PCE/OD significantly predicted externalizing, total, and attention problems when considering the balance between risk and protective indexes. Some PCE/OD predicted externalizing and attention problems. OD/no PCE also predicted behavior outcomes except for internalizing behavior. High level of protective factors was associated with declining trajectories of problem behavior scores over time, independent of drug exposure and risk index scores.
CONCLUSIONS:
High PCE/OD is a significant risk for behavior problems in adolescence; protective factors may attenuate its detrimental effects. Clinical practice and public health policies should consider enhancing protective factors while minimizing risks to improve outcomes of drug-exposed children.
doi:10.1542/peds.2011-3306
PMCID: PMC3507246  PMID: 23184114
behavior problems; cumulative risks; prenatal cocaine exposure; protective factors
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.  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
13.  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
14.  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
15.  Physiological Correlates of Neurobehavioral Disinhibition that Relate to Drug Use and Risky Sexual Behavior in Adolescents with Prenatal Substance Exposure 
Developmental neuroscience  2014;36(0):306-315.
Physiological correlates of behavioral and emotional problems, substance use onset and initiation of risky sexual behavior have not been studied in adolescents with prenatal drug exposure. We studied the concordance between baseline respiratory sinus arrhythmia (RSA) at age 3 and baseline Cortisol levels at age 11. We hypothesized that children who showed concordance between RSA and Cortisol would have lower neurobehavioral disinhibition scores which would in turn predict age of substance use onset and first sexual intercourse. The sample included 860 children aged 16 years participating in the Maternal Lifestyle Study, a multisite longitudinal study of children with prenatal exposure to cocaine and other substances. Structural equation modeling was used to test pathways between prenatal substance exposure, early adversity, baseline RSA, baseline Cortisol, neurobehavioral disinhibition, drug use, and sexual behavior outcomes. Concordance was studied by examining separate male and female models in which there were statistically significant interactions between baseline RSA and Cortisol. Prenatal substance exposure was operationalized as the number of substances to which the child was exposed. An adversity score was computed based on caregiver postnatal substance use, depression and psychological distress, number of caregiver changes, socioeconomic and poverty status, quality of the home environment, and child history of protective service involvement, abuse and neglect. RSA and Cortisol were measured during a baseline period prior to the beginning of a task. Neurobehavioral disinhibition, based on composite scores of behavioral dysregulation and executive dysfunction, substance use and sexual behavior were derived from questionnaires and cognitive tests administered to the child. Findings were sex specific. In females, those with discordance between RSA and Cortisol (high RSA and low Cortisol or low RSA and high Cortisol) had the most executive dysfunction which, in turn, predicted earlier initiation of alcohol by age 16. Among boys, there also existed a significant baseline RSA by baseline Cortisol interaction. Boys with low baseline RSA and high baseline Cortisol had the highest levels of behavioral dysregulation. This increase in behavioral dysregulation was in turn related to initiation of alcohol use by age 16 and lower age of first sexual intercourse. We found sex-specific pathways to the initiation of alcohol use and risky sexual behavior through the combined activity of parasympathetic and neuroendocrine functioning. The study of multiple physiological systems may suggest new pathways to the study of age of onset of substance use and engagement in risky sexual behavior in adolescents.
doi:10.1159/000365004
PMCID: PMC4476628  PMID: 25033835
Cortisol; Heart rate variability; Adversity; Sex differences; Teenage substance use onset; Behavioral problems; Executive function
16.  Which family factors predict children’s externalizing behaviors following discharge from psychiatric inpatient treatment? 
Objective
Parents’ behavior management practices, parental stress, and family environment are highly pertinent to children’s conduct problems. Preadolescents’ psychiatric hospitalization usually arises because of severe conduct problems, so the relationships of family-related variables to postdischarge functioning warrant investigation. This study examined postdischarge clinical course and select family factors to model outcomes via a) predictors measured at admission, b) predictors measured concurrently with outcome, and c) changes in predictor values from admission through follow-up.
Method
In a prospective follow-up of 107 child psychiatry inpatients, caregivers completed rating scales pertaining to their child’s behavior, parenting practices, parenting stress, caregiver strain, and their own psychological distress at admission and three, six, and 12 months after discharge.
Results
The magnitude of reductions in parenting stress between admission and follow-up bore the strongest relationship to improvements in externalizing behavior. The largest and most sustained decreases in externalizing behavior arose among youngsters whose parents reported high parenting stress at admission and low parenting stress after discharge. By contrast, children whose parents reported low parenting stress at admission and follow-up showed significantly less postdischarge improvement. Parenting stress changes were not attributable to changes in behavioral symptoms. Parenting stress eclipsed relationships between behavior management practices and child outcomes, suggesting that parenting stress might have a mediational role.
Conclusions
High initial parenting stress disposed to better outcomes over the year of follow-up. Consistently low stress predicted less improvement. Higher stress at admission may imply more advantageous parent–child relationships or motivation for subsequent persistence with treatment. Interventions that ameliorate high stress may warrant further study. Low parenting stress might signify disengagement, or, alternatively, that parents of some chronically impaired children become rather inured to fluctuations in behavioral problems. If confirmed, further examination of these and other accounts for a relationship between low parenting stress and suboptimal child outcome seems warranted.
doi:10.1111/j.1469-7610.2006.01651.x
PMCID: PMC2945501  PMID: 17076752
Behavior disorder; family processes; hospitalization; longitudinal studies; outcome; parenting; psychiatric services
17.  Prenatal cocaine exposure and trajectories of externalizing behavior problems in early childhood: Examining the role of maternal negative affect 
Development and psychopathology  2014;26(2):515-528.
This study examined the association between prenatal cocaine exposure (PCE) and developmental trajectories of externalizing behavior problems from 18 to 54 months of child age. A hypothesized indirect association between PCE and externalizing trajectories via maternal negative affect was also examined. Caregiving environmental risk and child sex were evaluated as moderators. This study consisted of 196 mother-child dyads recruited at delivery from local area hospitals (107 cocaine exposed, 89 non-exposed) and assessed at 7 time points across the toddler to preschool periods. Results revealed no direct associations between PCE and externalizing behavior problem trajectories. However, results did indicate that PCE shared a significant indirect relationship with externalizing behavior problem trajectories via higher levels of maternal negative affect. The association between PCE and externalizing problem trajectories was also moderated by caregiving environmental risk such that PCE children in high-risk caregiving environments did not experience the well documented normative decline in externalizing behavior problems beginning at around three years of age. This study suggests potential pathways to externalizing behavior problems among high-risk children.
doi:10.1017/S0954579414000091
PMCID: PMC3981877  PMID: 24622033
Cocaine; Behavior Problems; Prenatal Substance Exposure; Trajectory; Externalizing
18.  The Long-Term Health Consequences of Child Physical Abuse, Emotional Abuse, and Neglect: A Systematic Review and Meta-Analysis 
PLoS Medicine  2012;9(11):e1001349.
Rosana Norman and colleagues conduct a systematic review and meta-analysis to assess the relationship between child physical abuse, emotional abuse, and neglect, and subsequent mental and physical health outcomes.
Background
Child sexual abuse is considered a modifiable risk factor for mental disorders across the life course. However the long-term consequences of other forms of child maltreatment have not yet been systematically examined. The aim of this study was to summarise the evidence relating to the possible relationship between child physical abuse, emotional abuse, and neglect, and subsequent mental and physical health outcomes.
Methods and Findings
A systematic review was conducted using the Medline, EMBASE, and PsycINFO electronic databases up to 26 June 2012. Published cohort, cross-sectional, and case-control studies that examined non-sexual child maltreatment as a risk factor for loss of health were included. All meta-analyses were based on quality-effects models. Out of 285 articles assessed for eligibility, 124 studies satisfied the pre-determined inclusion criteria for meta-analysis. Statistically significant associations were observed between physical abuse, emotional abuse, and neglect and depressive disorders (physical abuse [odds ratio (OR) = 1.54; 95% CI 1.16–2.04], emotional abuse [OR = 3.06; 95% CI 2.43–3.85], and neglect [OR = 2.11; 95% CI 1.61–2.77]); drug use (physical abuse [OR = 1.92; 95% CI 1.67–2.20], emotional abuse [OR = 1.41; 95% CI 1.11–1.79], and neglect [OR = 1.36; 95% CI 1.21–1.54]); suicide attempts (physical abuse [OR = 3.40; 95% CI 2.17–5.32], emotional abuse [OR = 3.37; 95% CI 2.44–4.67], and neglect [OR = 1.95; 95% CI 1.13–3.37]); and sexually transmitted infections and risky sexual behaviour (physical abuse [OR = 1.78; 95% CI 1.50–2.10], emotional abuse [OR = 1.75; 95% CI 1.49–2.04], and neglect [OR = 1.57; 95% CI 1.39–1.78]). Evidence for causality was assessed using Bradford Hill criteria. While suggestive evidence exists for a relationship between maltreatment and chronic diseases and lifestyle risk factors, more research is required to confirm these relationships.
Conclusions
This overview of the evidence suggests a causal relationship between non-sexual child maltreatment and a range of mental disorders, drug use, suicide attempts, sexually transmitted infections, and risky sexual behaviour. All forms of child maltreatment should be considered important risks to health with a sizeable impact on major contributors to the burden of disease in all parts of the world. The awareness of the serious long-term consequences of child maltreatment should encourage better identification of those at risk and the development of effective interventions to protect children from violence.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Child maltreatment—the abuse and neglect of children—is a global problem. There are four types of child maltreatment—sexual abuse (the involvement of a child in sexual activity that he or she does not understand, is unable to give consent to, or is not developmentally prepared for), physical abuse (the use of physical force that harms the child's health, survival, development, or dignity), emotional abuse (the failure to provide a supportive environment by, for example, verbally threatening the child), and neglect (the failure to provide for all aspects of the child's well-being). Most child maltreatment is perpetrated by parents or parental guardians, many of whom were maltreated themselves as children. Other risk factors for parents abusing their children include poverty, mental health problems, and alcohol and drug misuse. Although there is considerable uncertainty about the frequency and severity of child maltreatment, according to the World Health Organization (WHO) about 20% of women and 5%–10% of men report being sexually abused as children, and the prevalence of physical abuse in childhood may be 25%–50%.
Why Was This Study Done?
Child maltreatment has a large public health impact. Sometimes this impact is immediate and direct (injuries and deaths), but, more often, it is long-term, affecting emotional development and overall health. For child sexual abuse, the relationship between abuse and mental disorders in adult life is well-established. Exposure to other forms of child maltreatment has also been associated with a wide range of psychological and behavioral problems, but the health consequences of physical abuse, emotional abuse, and neglect have not been systematically examined. A better understanding of the long-term health effects of child maltreatment is needed to inform maltreatment prevention strategies and to improve treatment for children who have been abused or neglected. In this systematic review and meta-analysis, the researchers quantify the association between exposure to physical abuse, emotional abuse, and neglect in childhood and mental health and physical health outcomes in later life. A systematic review uses predefined criteria to identify all the research on a given topic; a meta-analysis is a statistical approach that combines the results of several studies.
What Did the Researchers Do and Find?
The researchers identified 124 studies that investigated the relationship between child physical abuse, emotional abuse, or neglect and various health outcomes. Their meta-analysis of data from these studies provides suggestive evidence that child physical abuse, emotional abuse, and neglect are causally linked to mental and physical health outcomes. For example, emotionally abused individuals had a three-fold higher risk of developing a depressive disorder than non-abused individuals (an odds ratio [OR] of 3.06). Physically abused and neglected individuals also had a higher risk of developing a depressive disorder than non-abused individuals (ORs of 1.54 and 2.11, respectively). Other mental health disorders associated with child physical abuse, emotional abuse, or neglect included anxiety disorders, drug abuse, and suicidal behavior. Individuals who had been non-sexually maltreated as children also had a higher risk of sexually transmitted diseases and/or risky sexual behavior than non-maltreated individuals. Finally, there was weak and inconsistent evidence that child maltreatment increased the risk of chronic diseases and lifestyle risk factors such as smoking.
What Do These Findings Mean?
By providing suggestive evidence of a causal link between non-sexual child maltreatment and mental health disorders, drug use, suicide attempts, and sexually transmitted diseases and risky sexual behavior, these findings contribute to our understanding of the non-injury health impacts of child maltreatment. Although most of the studies included in the meta-analysis were undertaken in high-income countries, the findings suggest that this link occurs in both high- and low-to-middle-income countries. They also suggest that neglect may be as harmful as physical and emotional abuse. However, they need to be interpreted carefully because of the limitations of this meta-analysis, which include the possibility that children who have been abused may share other, unrecognized factors that are actually the cause of their later mental health problems. Importantly, this confirmation that physical abuse, emotional abuse, and neglect in childhood are important risk factors for a range of health problems draws attention to the need to develop evidence-based strategies for preventing child maltreatment both to reduce childhood suffering and to alleviate an important risk factor for later health problems.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001349.
The World Health Organization provides information on child maltreatment and its prevention (in several languages); Preventing Child Maltreatment: A Guide to Taking Action and Generating Evidence is a 2006 report produced by WHO and the International Society for Prevention of Child Abuse and Neglect
The US Centers for Disease Control and Prevention provides information on child maltreatment and links to additional resources
The National Society for the Prevention of Cruelty to Children (NSPCC) is a not-for-profit organization that aims to end all cruelty to children in the UK; Childline is a resource provided by the NSPCC that provides help, information, and support to children who are being abused
The Hideout is a UK-based website that helps children and young people understand domestic abuse
Childhelp is a US not-for-profit organization dedicated to helping victims of child abuse and neglect; its website includes a selection of personal stories about child maltreatment
doi:10.1371/journal.pmed.1001349
PMCID: PMC3507962  PMID: 23209385
19.  Prenatal Methamphetamine Exposure, Home Environment, and Primary Caregiver Risk Factors Predict Child Behavioral Problems at 5 Years 
This study investigated the prospective association between prenatal methamphetamine (MA) exposure and child behavioral problems at 5 years while also examining the home environment at 30 months and several primary caregiver (PC) risk factors. Participants were 97 MA-exposed and 117 comparison children and their PCs enrolled in the Infant Development, Environment and Lifestyle Study. Hypotheses were that child behaviors would be adversely impacted by (a) prenatal MA exposure, (b) home environments that provided less developmental stimulation and emotional responsiveness to the child, and (c) the presence of PC psychological symptoms and other risk factors. Prenatal MA exposure was associated with child externalizing behavioral problems at 5 years. Home environments that were more conducive to meeting children’s developmental and emotional needs were associated with fewer internalizing and externalizing behavioral problems. Independent of prenatal MA exposure, PC parenting stress and psychological symptoms were associated with increased child behavioral problems. Findings suggest prenatal MA exposure may contribute to externalizing behavioral problems in early childhood and the importance of considering possible vulnerabilities related to prenatal MA exposure in the context of the child’s caregiving environment.
doi:10.1111/ajop.12007
PMCID: PMC3721329  PMID: 23330624
infants; children; pregnant women; methamphetamine use; prenatal substance exposure; primary caregiver; caregiving environment; parenting stress
20.  Longitudinal Effects of Prenatal Cocaine Use on Mother-Child Interactions at Ages 3 and 5 
Objective
To assess the effect of maternal prenatal and past-year cocaine use on mother-child interactions across the preschool years.
Methods
The sample is drawn from the Miami Prenatal Cocaine Study (MPCS), a longitudinal follow-up of prenatal cocaine exposure (PCE) in a large cohort of African-American infants prospectively enrolled at birth. Analyses are based on the 366 children (168 PCE and 198 NCE) in the care of their biological mothers and with completed mother-child interaction measures at the 3- and/or 5-year assessments. Videotaped interactions were coded using a modified Egeland Teaching Task scheme. GLM/GEE models were used to evaluate the effect of PCE on the overall quality of maternal-child interaction, measured by the Egeland total score at both study visits, and on the individual Egeland subscales at the 5-year visit, while adjusting for other suspected influences on interactions.
Results
PCE dyads demonstrated less optimal overall mother-child interactions compared to NCE dyads. The estimated PCE-associated difference did not shift appreciably with statistical adjustment for child sex, child age at exam or other birth covariates. PCE dyads with past-year maternal cocaine use had significantly lower Egeland summary scores compared to children with neither exposure. In subscale analyses, PCE was most strongly associated with greater maternal intrusiveness and boundary dissolution at the 5-year visit.
Conclusions
Prenatal and past-year maternal cocaine use appear to be associated with poorer quality in mother-child interaction during early childhood. These dynamics should be considered when examining the association between prenatal cocaine exposure and child cognitive, behavioral, and academic outcomes.
doi:10.1097/DBP.0b013e31823968ab
PMCID: PMC3252426  PMID: 22157442
prenatal; cocaine; exposure; mother-child; interaction
21.  Mortality after Parental Death in Childhood: A Nationwide Cohort Study from Three Nordic Countries 
PLoS Medicine  2014;11(7):e1001679.
Jiong Li and colleagues examine mortality rates in children who lost a parent before 18 years old compared with those who did not using population-based data from Denmark, Sweden, and Finland.
Please see later in the article for the Editors' Summary
Background
Bereavement by spousal death and child death in adulthood has been shown to lead to an increased risk of mortality. Maternal death in infancy or parental death in early childhood may have an impact on mortality but evidence has been limited to short-term or selected causes of death. Little is known about long-term or cause-specific mortality after parental death in childhood.
Methods and Findings
This cohort study included all persons born in Denmark from 1968 to 2008 (n = 2,789,807) and in Sweden from 1973 to 2006 (n = 3,380,301), and a random sample of 89.3% of all born in Finland from 1987 to 2007 (n = 1,131,905). A total of 189,094 persons were included in the exposed cohort when they lost a parent before 18 years old. Log-linear Poisson regression was used to estimate mortality rate ratio (MRR). Parental death was associated with a 50% increased all-cause mortality (MRR = 1.50, 95% CI 1.43–1.58). The risks were increased for most specific cause groups and the highest MRRs were observed when the cause of child death and the cause of parental death were in the same category. Parental unnatural death was associated with a higher mortality risk (MRR = 1.84, 95% CI 1.71–2.00) than parental natural death (MRR = 1.33, 95% CI 1.24–1.41). The magnitude of the associations varied according to type of death and age at bereavement over different follow-up periods. The main limitation of the study is the lack of data on post-bereavement information on the quality of the parent-child relationship, lifestyles, and common physical environment.
Conclusions
Parental death in childhood or adolescence is associated with increased all-cause mortality into early adulthood. Since an increased mortality reflects both genetic susceptibility and long-term impacts of parental death on health and social well-being, our findings have implications in clinical responses and public health strategies.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
When someone close dies, it is normal to grieve, to mourn the loss of that individual. Initially, people who have lost a loved one often feel numb and disorientated and find it hard to grasp what has happened. Later, people may feel angry or guilty, and may be overwhelmed by feelings of sadness and despair. They may become depressed or anxious and may even feel suicidal. People who are grieving can also have physical reactions to their loss such as sleep problems, changes in appetite, and illness. How long bereavement—the period of grief and mourning after a death—lasts and how badly it affects an individual depends on the relationship between the individual and the deceased person, on whether the death was expected, and on how much support the mourner receives from relatives, friends, and professionals.
Why Was This Study Done?
The loss of a life-partner or of a child is associated with an increased risk of death (mortality), and there is also some evidence that the death of a parent during childhood leads to an increased mortality risk in the short term. However, little is known about the long-term impact on mortality of early parental loss or whether the impact varies with the type of death—a natural death from illness or an unnatural death from external causes such as an accident—or with the specific cause of death. A better understanding of the impact of early bereavement on mortality is needed to ensure that bereaved children receive appropriate health and social support after a parent's death. Here, the researchers undertake a nationwide cohort study in three Nordic countries to investigate long-term and cause-specific mortality after parental death in childhood. A cohort study compares the occurrence of an event (here, death) in a group of individuals who have been exposed to a particular variable (here, early parental loss) with the occurrence of the same event in an unexposed cohort.
What Did the Researchers Do and Find?
The researchers obtained data on everyone born in Denmark from 1968 to 2008 and in Sweden from 1973 to 2006, and on most people born in Finland from 1987 to 2007 (more than 7 million individuals in total) from national registries. They identified 189,094 individuals who had lost a parent between the age of 6 months and 18 years. They then estimated the mortality rate ratio (MRR) associated with parental death during childhood or adolescence by comparing the number of deaths in this exposed cohort (after excluding children who died on the same day as a parent or shortly after from the same cause) and in the unexposed cohort. Compared with the unexposed cohort, the exposed cohort had 50% higher all-cause mortality (MRR = 1.50). The risk of mortality in the exposed cohort was increased for most major categories of cause of death but the highest MRRs were seen when the cause of death in children, adolescents, and young adults during follow-up and the cause of parental death were in the same category. Notably, parental unnatural death was associated with a higher mortality risk (MRR = 1.84) than parental natural death (MRR = 1.33). Finally, the exposed cohort had increased all-cause MRRs well into early adulthood irrespective of child age at parental death, and the magnitude of MRRs differed by child age at parental death and by type of death.
What Do These Findings Mean?
These findings show that in three high-income Nordic countries parental death during childhood and adolescence is associated with an increased risk of all-cause mortality into early adulthood, irrespective of sex and age at bereavement and after accounting for baseline characteristics such as socioeconomic status. Part of this association may be due to “confounding” factors—the people who lost a parent during childhood may have shared other unknown characteristics that increased their risk of death. Because the study was undertaken in high-income countries, these findings are unlikely to be the result of a lack of material or health care needs. Rather, the increased mortality among the exposed group reflects both genetic susceptibility and the long-term impacts of parental death on health and social well-being. Given that increased mortality probably only represents the tip of the iceberg of the adverse effects of early bereavement, these findings highlight the need to provide long-term health and social support to bereaved children.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001679.
The UK National Health Service Choices website provides information about bereavement, including personal stories; it also provides information about children and bereavement and about young people and bereavement, including links to not-for-profit organizations that support children through bereavement
The US National Cancer Institute has detailed information about dealing with bereavement for the public and for health professionals that includes a section on children and grief (in English and Spanish)
The US National Alliance for Grieving Children promotes awareness of the needs of children and teens grieving a death and provides education and resources for anyone who wants to support them
MedlinePlus provides links to other resources about bereavement (in English and Spanish)
doi:10.1371/journal.pmed.1001679
PMCID: PMC4106717  PMID: 25051501
22.  Child Behavior Problems: Role of Cocaine Use, Parenting and Child Exposure to Violence 
Psychology of violence  2014;4(3):266-280.
Objective
Studies examining the association between prenatal cocaine exposure (PCE) and child behavior problems have yielded mixed results, suggesting a need to identify additional mediating and moderating influences. We hypothesized that the relation between PCE and behavior problems at kindergarten would be mediated/moderated by child exposure to violence; and that maternal warmth/sensitivity and harshness would moderate the association between violence exposure and behavior problems.
Methods
Participants consisted of 216 (116 cocaine-exposed, 100 non-cocaine exposed (NCE) mother-child dyads participating in an ongoing longitudinal study of PCE.
Results
Results yielded no direct or mediated/moderated association between PCE and child behavior problems, and no significant interaction effects between PCE and parenting quality. However, higher exposure to violence in kindergarten was significantly associated with higher child behavior problems. This association was moderated by maternal warmth/sensitivity and harshness. High maternal warmth/sensitivity buffered the association between violence exposure and behavior problems while high maternal harshness exacerbated this association.
Conclusion
This study highlights the role of violence exposure in the development of behavior problems among high-risk children, and emphasizes the significance of parenting quality in buffering or exacerbating this risk among these children. Implications for prevention include targeting the potential role of maternal warmth/sensitivity as a protective influence among children exposed to violence.
doi:10.1037/a0036157
PMCID: PMC4193800  PMID: 25313345
community and family violence; cocaine exposure; child; behavior problems; parenting
23.  Antecedents and Consequences of Caregiving Structure on Young Mothers and Their Infants 
Maternal and child health journal  2011;15(7):1037-1045.
This study describes the multigenerational caregiving structure of infants born to young women, the prenatal predictors of caregiving structure, and the effects of caregiving structure on the health of young mothers and their infants 6 months postpartum. The sample consisted of 784 young mothers involved in a longitudinal study in two U.S. cities. Women were classified into eight caregiving structure groups based on the mother’s report of herself as a caregiver and her selection of the baby’s father and/or grandparents as caregivers. ANCOVA analyses identified predictors and 6 month postpartum outcomes of caregiving structure. Planned comparisons explored the relationships among caregiving structure groups. A majority of women reported caregiving structures other than herself and the father as caregivers (87.1%). Grandparents were indicated as caregivers by most women (62.2%). Postpartum caregiving groups differed on prenatal social support, self-esteem, attachment avoidance and anxiety, relationship status, and living with the baby’s father. While mother’s self esteem significantly predicted father involvement, there were no differences on predictors between when the mother and father were caregivers, versus when the mother and grandparents were caregivers. Differences existed between groups on mother and child outcomes, including parenting stress, distress, and child dysfunction. Women reported significantly less parenting stress, child dysfunction, and negative child emotions when she and the father were caregivers, versus when she and grandparents were caregivers. The family system and the intergenerational dynamics within a multigenerational caregiving structure are critical to the health and well-being of both mothers and their children.
doi:10.1007/s10995-010-0650-3
PMCID: PMC3061973  PMID: 20680671
Caregiving structure; Adolescent pregnancy; Family systems theory; Parenthood and family development; Grandmothers raising grandchildren
24.  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
25.  Children Who Witness Violence, and Parent Report of Children’s Behavior 
Objectives
To examine how much distress children report in response to violence that they have witnessed and how this is associated with parental reports of children’s behavior.
Methods
As part of a study of in utero exposure to cocaine, children completed the Levonn interview for assessing children’s symptoms of distress in response to witnessing violence. The children’s care givers completed the Exposure to Violence Interview (EVI), a caretaker-report measure of the child’s exposure to violent events during the last 12 months. The EVI was analyzed as a 3-level variable: no exposure, low exposure, and high exposure. The caregivers also completed the Children’s Behavior Checklist (CBCL).
Results
Of 94 six-year-old children, 58% had no exposure to violence, 36% had low exposure to violence, and 6% had high exposure to violence, according to caretaker reports. The children’s median ±SD Levonn score was 64 (SD ± 19.3). The mean (SD ± CBCL total T-score was 53 (SD ± 10.2). In multiple regression analyses with gender, low and high exposure on EVI, Levonn, and prenatal cocaine exposure status as predictors, the Levonn score explained 4.8% of total variance in children’s CBCL internalizing scores, 9.1% of the total variance in CBCL externalizing score, and 12.2% of the total variance in CBCL total score (P = .04, P = .004, and P <.001, respectively).
Conclusions
After accounting for the caretaker’s report of the level of the child’s exposure to violence, the child’s own report significantly increased the amount of variance in predicting child behavior problems with the CBCL. These findings indicate that clinicians and researchers should elicit children’s own accounts of exposure to violence in addition to the caretakers’ when attempting to understand children’s behavior.
PMCID: PMC2366171  PMID: 12144371

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