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1.  Placental miRNA Expression Profiles Associated with Measures of Infant Neurobehavioral Outcomes 
Pediatric research  2013;74(3):272-278.
A growing body of research suggests that the intrauterine environment influences fetal neurodevelopment by altering the functional placental epigenome. A number of miRNAs are expressed in the placenta, may be sensitive to dysregulation by environmental exposures, and are associated with adverse pregnancy outcomes. Our study aimed to identify relationships between placental miRNA expression and newborn neurobehavior.
We examined the association between the expression of miR-16, miR-21, miR-93, miR-135b, miR-146a, and miR-182 in total RNA from the placentas of 86 term infants as measured by quantitative real-time PCR and newborn neurobehavioral outcomes as assessed using the NICU Network Neurobehavioral Scales (NNNS).
Bivariate analysis revealed that placental miR-16 expression is negatively associated with attention score (p=0.006), while expression of miR-146a and miR-182 are both positively associated with quality of movement score (p=0.016 and p=0.016, respectively). Controlling for potential confounders, high miR-16 expression is significantly associated with reduced attention score (p=0.04), and high miR-146a expression and high miR-182 expression are significantly associated with increased quality of movement score (p=0.04 and p=0.01, respectively).
These results suggest that placental miRNA expression is associated with early neurobehavioral outcomes and miRNAs in the placenta may contribute to the developmental origins of infant neurobehavior.
PMCID: PMC3766495  PMID: 23783433
2.  Co-morbidity of substance use disorder and psychopathology in women who use methamphetamine during pregnancy in the US and New Zealand 
Drug and alcohol dependence  2012;127(1-3):101-107.
Methamphetamine (MA) abuse is a worldwide problem. Little is known about the co-morbidity of substance use disorders (SUD) and other psychiatric disorders of mothers who use MA prenatally. The Infant Development, Environment and Lifestyle (IDEAL) Study is a prospective, investigation of prenatal MA use and child outcome in the United States (US) and New Zealand (NZ). This study examined prenatal MA use and the co-morbidity of SUD and psychiatric disorders at 1-month postpartum.
Mothers who used MA (US = 127, NZ = 97) were compared to a matched comparison group (US = 193, NZ = 110). The Substance Abuse Subtle Screening Inventory-3 was used to measure the probability of a SUD. The Brief Symptom Inventory was used to measure the likelihood of a positive diagnosis of a psychiatric disorder.
In US and NZ, the MA groups had lower SES, increased single parenting, delayed prenatal care, increased polydrug use. In the US only, MA mothers had lower income than the comparison group. MA users were 10 times more likely to have a SUD and twice as likely to meet Brief Symptom Inventory criteria for a diagnosable psychiatric disorder. In NZ, but not the US, MA users were five times more likely have co-morbidity of both. This disparity may be due to higher quantities of prenatal alcohol use associated with increased psychiatric symptoms.
These findings suggest that addressing both substance abuse and psychiatric disorders in mothers who use MA may be required to effectively treat maternal MA use.
PMCID: PMC3498544  PMID: 22789630
Methamphetamine; Maternal Drug Use; Comorbidity; Substance Use Disorder; Psychiatric Disorder
3.  Protective Factors Can Mitigate Behavior Problems After Prenatal Cocaine and Other Drug Exposures 
Pediatrics  2012;130(6):e1479-e1488.
We determined the role of risk and protective factors on the trajectories of behavior problems associated with high prenatal cocaine exposure (PCE)/polydrug exposure.
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).
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.
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.
PMCID: PMC3507246  PMID: 23184114
behavior problems; cumulative risks; prenatal cocaine exposure; protective factors
4.  Neurobehavioral Disinhibition Predicts Initiation of Substance Use in Children with Prenatal Cocaine Exposure 
Drug and alcohol dependence  2012;126(1-2):80-86.
In previous work we (Fisher et al., 2011) examined the emergence of neurobehavioral disinhibition (ND) in adolescents with prenatal substance exposure. We computed ND factor scores at three age points (8/9, 11 and 13/14 years) and found that both prenatal substance exposure and early adversity predicted ND. The purpose of the current study was to determine the association between these ND scores and initiation of substance use between ages 8–16 in this cohort as early initiation of substance use has been related to later substance use disorders. Our hypothesis was that prenatal cocaine exposure predisposes the child to ND, which, in turn, is associated with initiation of substance use by age 16.
We studied 386 cocaine exposed and 517 unexposed children followed since birth in a longitudinal study. Five dichotomous variables were computed based on the subject’s report of substance use: alcohol only; tobacco only; marijuana only; illicit substances and any substance.
Cox proportional hazard regression showed that the 8/9 year ND score was related to initiation of alcohol, tobacco, illicit and any substance use but not marijuana use. The trajectory of ND across the three age periods was related to substance use initiation in all five substance use categories. Prenatal cocaine exposure, although initially related to tobacco, marijuana and illicit substance initiation, was no longer significant with ND scores in the models.
Prenatal drug exposure appears to be a risk pathway to ND, which by 8/9 years portends substance use initiation.
PMCID: PMC3439586  PMID: 22608010
neurodevelopmental disinhibition; substance use initiation; prenatal cocaine exposure
5.  Atypical Cry Acoustics in 6-Month-Old Infants at Risk for Autism Spectrum Disorder 
This study examined differences in acoustic characteristics of infant cries in a sample of babies at risk for autism and a low-risk comparison group. Cry samples derived from vocal recordings of 6-month-old infants at risk for autism spectrum disorder (ASD; n = 21) and low-risk infants (n = 18) were subjected to acoustic analyses using analysis software designed for this purpose. Cries were categorized as either pain-related or non-pain-related based on videotape coding. At-risk infants produced pain-related cries with higher and more variable fundamental frequency (F0) than low-risk infants. At-risk infants later classified with ASD at 36 months had among the highest F0 values for both types of cries and produced cries that were more poorly phonated than those of nonautistic infants, reflecting cries that were less likely to be produced in a voiced mode. These results provide preliminary evidence that disruptions in cry acoustics may be part of an atypical vocal signature of autism in early life.
PMCID: PMC3517274  PMID: 22890558
autism; infancy; cry; vocalizations; acoustic analysis
6.  Infant Neurobehavioral Development 
Seminars in perinatology  2011;35(1):8-19.
The trend toward single-room neonatal intensive care units (NICUs) is increasing; however scientific evidence is, at this point, mostly anecdotal. This is a critical time to assess the impact of the single-room NICU on improving medical and neurobehavioral outcomes of the preterm infant. We have developed a theoretical model that may be useful in studying how the change from an open-bay NICU to a single-room NICU could affect infant medical and neurobehavioral outcome. The model identifies mediating factors that are likely to accompany the change to a single-room NICU. These mediating factors include family centered care, developmental care, parenting and family factors, staff behavior and attitudes, and medical practices. Medical outcomes that plan to be measured are sepsis, length of stay, gestational age at discharge, weight gain, illness severity, gestational age at enteral feeding, and necrotizing enterocolitis (NEC). Neurobehavioral outcomes include the NICU Network Neurobehavioral Scale (NNNS) scores, sleep state organization and sleep physiology, infant mother feeding interaction scores, and pain scores. Preliminary findings on the sample of 150 patients in the open-bay NICU showed a “baseline” of effects of family centered care, developmental care, parent satisfaction, maternal depression, and parenting stress on the neurobehavioral outcomes of the newborn. The single-room NICU has the potential to improve the neurobehavioral status of the infant at discharge. Neurobehavioral assessment can assist with early detection and therefore preventative intervention to maximize developmental outcome. We also present an epigenetic model of the potential effects of maternal care on improving infant neurobehavioral status.
PMCID: PMC3168949  PMID: 21255702
preterm; neurobehavior; NNNS; NICU; very-low-birthweight infants; single-room NICU design; epigenetics
7.  Behavioral epigenetics 
Sponsored by the New York Academy of Sciences, the Warren Alpert Medical School of Brown University and the University of Massachusetts Boston, “Behavioral Epigenetics” was held on October 29–30, 2010 at the University of Massachusetts Boston Campus Center, Boston, Massachusetts. This meeting featured speakers and panel discussions exploring the emerging field of behavioral epigenetics, from basic biochemical and cellular mechanisms to the epigenetic modulation of normative development, developmental disorders, and psychopathology. This report provides an overview of the research presented by leading scientists and lively discussion about the future of investigation at the behavioral epigenetic level.
PMCID: PMC3783959  PMID: 21615751
behavior; epigenetics; chromosome; gene regulation; transcription; methylation
8.  Patterning in Placental 11-B Hydroxysteroid Dehydrogenase Methylation According to Prenatal Socioeconomic Adversity 
PLoS ONE  2013;8(9):e74691.
Prenatal socioeconomic adversity as an intrauterine exposure is associated with a range of perinatal outcomes although the explanatory mechanisms are not well understood. The development of the fetus can be shaped by the intrauterine environment through alterations in the function of the placenta. In the placenta, the HSD11B2 gene encodes the 11-beta hydroxysteroid dehydrogenase enzyme, which is responsible for the inactivation of maternal cortisol thereby protecting the developing fetus from this exposure. This gene is regulated by DNA methylation, and this methylation and the expression it controls has been shown to be susceptible to a variety of stressors from the maternal environment. The association of prenatal socioeconomic adversity and placental HSD11B2 methylation has not been examined. Following a developmental origins of disease framework, prenatal socioeconomic adversity may alter fetal response to the postnatal environment through functional epigenetic alterations in the placenta. Therefore, we hypothesized that prenatal socioeconomic adversity would be associated with less HSD11B2 methylation.
Methods and Findings
We examined the association between DNA methylation of the HSD11B2 promoter region in the placenta of 444 healthy term newborn infants and several markers of prenatal socioeconomic adversity: maternal education, poverty, dwelling crowding, tobacco use and cumulative risk. We also examined whether such associations were sex-specific. We found that infants whose mothers experienced the greatest levels of socioeconomic adversity during pregnancy had the lowest extent of placental HSD11B2 methylation, particularly for males. Associations were maintained for maternal education when adjusting for confounders (p<0.05).
Patterns of HSD11B2 methylation suggest that environmental cues transmitted from the mother during gestation may program the developing fetus’s response to an adverse postnatal environment, potentially via less exposure to cortisol during development. Less methylation of placental HSD11B2 may therefore be adaptive and promote the effective management of stress associated with social adversity in a postnatal environment.
PMCID: PMC3764127  PMID: 24040322
9.  Prenatal Methamphetamine Exposure and Inhibitory Control among Young School-Age Children 
The Journal of pediatrics  2012;161(3):452-459.
To examine the association between prenatal methamphetamine exposure and inhibitory control in 66 month old children followed since birth in the multicenter, longitudinal Infant Development, Environment and Lifestyle Study.
Study design
The sample included 137 children with prenatal methamphetamine exposure and 130 comparison children, matched for race, birth weight, maternal education and type of insurance. Inhibitory control, an executive function related to emotional and cognitive control, was assessed using a computerized Stroop-like task developed for young children. Hierarchical linear modeling tested the relationship between the extent (heavy, some and no use) of prenatal methamphetamine exposure and accuracy and reaction time outcomes, adjusting for prenatal exposure to alcohol, tobacco and marijuana, age, sex, socioeconomic status, caregiver IQ and psychological symptoms, child protective services report of physical or sexual abuse, and site.
In adjusted analyses, heavy prenatal methamphetamine exposure was related to reduced accuracy in both the incongruent and mixed conditions on the Stroop task. Caregiver psychological symptoms and Child Protective Services (CPS) report of physical or sexual abuse were associated with reduced accuracy in the incongruent and mixed, and incongruent conditions, respectively.
Heavy prenatal methamphetamine exposure, along with caregiver psychological distress and child maltreatment, is related to subtle deficits in inhibitory control during the early school-aged years.
PMCID: PMC3392459  PMID: 22424953
Prenatal exposure; Amphetamines; Children; Neuropsychology; Executive Function
10.  An Initial Investigation of Baseline Respiratory Sinus Arrhythmia as a Moderator of Treatment Outcome for Young Children Born Premature with Externalizing Behavior Problems 
Behavior therapy  2012;43(3):652-665.
The aim of the current study was to examine the moderating effect of baseline respiratory sinus arrhythmia (RSA) on Parent-Child Interaction Therapy (PCIT), a behavioral parent-training intervention, for young children born premature. In this pilot randomized controlled trial, 28 young children (mean age of 37.79 months), who were born < 37 weeks gestation and presented with elevated externalizing behavior problems, were randomly assigned to an immediate treatment or waitlist control group. RSA, which provides an approximate marker of individual differences in cardiac vagal tone, was measured during a baseline period. Past research has generally shown that higher levels of baseline RSA correlate with various positive psychological states (e.g., empathy, sustained attention), whereas lower levels of baseline RSA correlate with less optimal psychological states (e.g., higher externalizing behavior problems). Results indicated that baseline RSA significantly interacted with treatment condition in predicting changes in child disruptive behavior. Specifically, low levels of baseline RSA were associated with greater improvements in child disruptive behavior following PCIT. While acknowledging the caveats of measuring and interpreting RSA and the need to include a sympathetic-linked cardiac measure in future research, these findings provide preliminary evidence that children with lower capacity for emotion regulation receive even greater treatment gains. Future research should also examine the moderating effect of RSA in larger samples and explore the potential mediating role of RSA on behavioral parenting interventions.
PMCID: PMC3475510  PMID: 22697452
respiratory sinus arrhythmia; emotion regulation; prematurity; behavior problems; behavioral parent training
11.  Impact of maternal substance use during pregnancy on childhood outcome 
The impact of maternal substance abuse is reflected in the 2002–2003 National Survey on Drug Use and Health. Among pregnant women in the 15–44 age group, 4.3%, 18% and 9.8% used illicit drugs, tobacco and alcohol, respectively. Maternal pregnancy complications following substance use include increases in sexually transmitted disorders, placental abruption and HIV-positive status. Effects on the neonate include a decrease in growth parameters and increases in central nervous system and autonomic nervous system signs and in referrals to child protective agencies. In childhood, behavioral and cognitive effects are seen after prenatal cocaine exposure; tobacco and alcohol have separate and specific effects. The ongoing use of alcohol and tobacco by the caretaker affects childhood behavior. Therefore, efforts should be made to prevent and treat behavioral problems as well as to limit the onset of drug use by adolescent children born to women who use drugs during pregnancy.
PMCID: PMC3717561  PMID: 17317350
Alcohol; Child medicine; Cocaine; Neonatal; Neurobehavioral outcome; Polydrug use; Tobacco
12.  Evidence-Based Intervention for Young Children Born Premature: Preliminary Evidence for Associated Changes in Physiological Regulation 
Infant behavior & development  2012;35(3):417-428.
The current study examined whether changes in maternal behaviors following an evidence-based treatment—Parent Child Interaction Therapy (PCIT)—was associated with improvements in cardiac vagal regulation in young children born premature. Participants included 28 young children (mean age = 37.79 months) that were born premature and presented with elevated externalizing behavior problems. To assess cardiac vagal regulation, resting measures of respiratory sinus arrhythmia (RSA) and RSA change (withdrawal or suppression) to a clean-up task were derived pre and post-treatment. Results indicated that an increase in behaviors mothers are taught to use during treatment (i.e., do skills—praise, reflection, and behavioral descriptions) were associated with an improvement in children’s post-treatment RSA suppression levels. The current study illustrates the important role of caregiver behavior in promoting physiological regulation in children born premature.
PMCID: PMC3409342  PMID: 22721742
cardiac vagal regulation; RSA suppression; emotion regulation; prematurity; child; parent training
13.  Long-Term Impact of Maternal Substance Use during Pregnancy and Extrauterine Environmental Adversity: Stress Hormone Levels of Preadolescent Children 
Pediatric research  2011;70(2):213-219.
Prenatal cocaine exposure (PCE) is associated with blunted stress responsivity within the extrauterine environment. This study investigated the association between PCE and diurnal salivary cortisol levels in preadolescent children characterized by high biological and/or social risk (N = 725). Saliva samples were collected at their home. Analyses revealed no group differences in basal evening or morning cortisol levels; however, children with higher degrees of PCE exhibited blunted overnight increases in cortisol, controlling for additional risk factors. Race and caregiver depression were also associated with diurnal cortisol patterns. While repeated PCE may contribute to alterations in the normal or expected stress response later in life, sociodemographic and environmental factors are likewise important in understanding hormone physiology, especially as more time elapses from the PCE. Anticipating the potential long-term medical, developmental, or behavioral effects of an altered ability to mount a normal protective cortisol stress response is essential in optimizing the outcomes of children with PCE.
PMCID: PMC3686483  PMID: 21546861
14.  Placenta Imprinted Gene Expression Association of Infant Neurobehavior 
The Journal of Pediatrics  2011;160(5):854-860.e2.
To identify links between altered gene imprinting in the placenta and infant neurobehavioral profiles.
Study design
We used qRT-PCR to examine the expression of 22 imprinted candidate genes in a series of 106 term human primary placenta tissues and associated that expression with summary scores from the NICU Network Neurobehavioral Scales performed on the corresponding infants. Clustering of the expression data was used to define distinct classes of expression.
Significant associations were identified between classes of expression and the NICU Network Neurobehavioral Scales quality of movement (P=0.02) and handling (P=0.006) scores. Multivariable regression demonstrated an independent effect of imprinted gene expression profile on these neurobehavioral scores after controlling for confounders.
These results suggest that alterations in imprinted gene expression in the placenta are associated with infant neurodevelopmental outcomes. Our results suggest a role for the placenta and genomic imprinting in the placenta beyond intrauterine growth regulation.
PMCID: PMC3311768  PMID: 22153677
neurodevelopment; epigenetics; fetal programming; trophoblast; mental health
15.  Newborn neurobehavioral patterns are differentially related to prenatal maternal Major Depressive Disorder and Serotonin Reuptake Inhibitor treatment 
Depression and Anxiety  2011;28(11):1008-1019.
Prenatal serotonin reuptake inhibitor (SRI) exposure has been related to adverse newborn neurobehavioral outcomes; however these effects have not been compared to those that may arise from prenatal exposure to maternal major depressive disorder (MDD) without SRI treatment. This study examined potential effects of MDD with and without SRI treatment on newborn neurobehavior.
This was a prospective, naturalistic study. Women were seen at an outpatient research center twice during pregnancy (26–28 and 36–38 weeks gestational age (GA)). Psychiatric diagnoses were assessed using the Structured Clinical Interview for the DSM-IV; medication use was measured with the Timeline Follow-Back instrument. Three groups were established based upon MDD diagnosis and SRI use: Control (N=56), MDD (N=20) or MDD+SRI (N=36). Infants were assessed on a single occasion within 3 weeks of birth with the NICU Network Neurobehavioral Assessment Scale (NNNS). Generalized Linear Modeling was used to examine neurobehavioral outcomes by exposure group and infant age at assessment.
Full-term infants exposed to MDD+SRIs had a lower GA than CON or MDD-exposed infants and, controlling for GA, had lower quality of movement and more central nervous system stress signs. In contrast, MDD-exposed infants had the highest quality of movement scores, while having lower attention scores than CON and MDD+SRI-exposed infants.
MDD+SRI-exposed infants appear to have a different neurobehavioral profile than MDD-exposed infants in the first three weeks after delivery; both groups may have different neurobehavioral profiles with increasing age from birth.
PMCID: PMC3215845  PMID: 21898709
infant; motor quality; central nervous system; depression; pregnancy; treatment
16.  Prenatal Cocaine Exposure and Small-for-Gestational-Age Status: Effects on Growth at 6 Years of age 
Neurotoxicology and teratology  2011;33(5):575-581.
To evaluate the impact of prenatal cocaine exposure and small-for-gestational-age (SGA) status on childhood growth.
Cocaine exposure was defined by history or meconium metabolites. Hierarchical linear modeling was used to examine cocaine exposure and SGA status on growth, while controlling for exposure to other drugs and alcohol use.
At birth cocaine-exposed infants (n=364) had significantly lower growth parameters compared to non-exposed children (n=771). At 6 years, weight was similar between exposed and unexposed children. SGA infants continued to be growth impaired. There was a significant interaction between prenatal cocaine exposure and SGA status at 6 years. The negative effects of cocaine on weight and height were greater among non-SGA than SGA children (432 vs. 280 gm, and 0.7 and 0.5 cm, respectively) while negative effects of SGA status on weight and height were larger in non-cocaine exposed compared to the exposed children (2.3 kg vs.1.6 kg and 2.2 and 1.0 cm).
Children exposed to prenatal cocaine were similar in weight to non-exposed children at 6 years of age. Cocaine had an unexplained greater detrimental effect on non-SGA than SGA children. SGA status at birth has an independent detrimental effect on childhood growth.
PMCID: PMC3183411  PMID: 21849244
Prenatal cocaine exposure; small for gestational age; childhood growth
17.  The Combined Effects of Prenatal Drug Exposure and Early Adversity on Neurobehavioral Disinhibition in Childhood and Adolescence 
Development and Psychopathology  2011;23(3):777-788.
The negative effects of prenatal substance exposure on neurobiological and psychological development and of early adversity are clear, but little is known about their combined effects. In this study, multilevel analyses of the effects of prenatal substance exposure and early adversity on the emergence of neurobehavioral disinhibition in adolescence were conducted. Neurobehavioral disinhibition has previously been observed to occur frequently in multiproblem youth from high-risk backgrounds. In the present study, neurobehavioral disinhibition was assessed via behavioral dysregulation and poor executive function composite measures. Data were drawn from a prospective longitudinal investigation of prenatal substance exposure that included 1073 participants followed from birth through adolescence. The results from latent growth modeling analyses showed mean stability but significant individual differences in behavioral dysregulation and mean decline with individual differences in executive function difficulties. Prior behavioral dysregulation predicted increased executive function difficulties. Prenatal drug use predicted the emergence and growth in neurobehavioral disinhibition across adolescence (directly for behavioral dysregulation and indirectly for executive function difficulties via early adversity and behavioral dysregulation). Prenatal drug use and early adversity exhibited unique effects on growth in behavioral dysregulation; early adversity uniquely predicted executive function difficulties. These results are discussed in terms of implications for theory development, social policy, and prevention science.
PMCID: PMC3335443  PMID: 21756431
18.  Serial Pediatric Symptom Checklist Screening in Children with Prenatal Drug Exposure 
To examine screening results obtained by serial annual behavioral assessment of children with prenatal drug exposure.
The Maternal Lifestyle Study enrolled children with prenatal cocaine exposure (PCE) at birth for longitudinal assessments of developmental, behavioral, and health outcomes. At 8, 9, 10, 11, and 12 years of age, caregivers rated participants on the Pediatric Symptom Checklist (PSC). Serial PSC results were compared to an established broad-based behavioral measure at 9, 11, and 13 years. PSC results were analyzed for 1,081 children who had at least 2 annual screens during the 5-year time span. Most subjects (87%) had 4 or more annual screens rated by the same caregiver (80%). PSC scores (and Positive screens) over time were compared at different time points for those with and without PCE. Covariates, including demographic factors and exposures to certain other substances, were controlled.
Children with PCE had significantly higher scores overall, with more Positive screens for behavior problems than children without PCE. Children with PCE had more externalizing behavior problems. Children exposed to tobacco pre- and post-natally also showed higher PSC scores. Over time, PSC scores differed slightly from the 8-year scores, without clear directional trend. Earlier PSC results predicted later behavioral outcomes.
Findings of increased total PSC scores and Positive PSC screens for behavioral concerns in this group of children with prenatal substance exposure support the growing body of evidence that additional attention to identification of mental health problems may be warranted in this high-risk group.
PMCID: PMC3069136  PMID: 21200328
Behavior disorder; child behavior; mental health; screening; prenatal cocaine exposure; Pediatric Symptom Checklist
19.  Placental 11-Beta Hydroxysteroid Dehydrogenase Methylation Is Associated with Newborn Growth and a Measure of Neurobehavioral Outcome 
PLoS ONE  2012;7(3):e33794.
There is growing evidence that the intrauterine environment can impact the neurodevelopment of the fetus through alterations in the functional epigenome of the placenta. In the placenta, the HSD11B2 gene encoding the 11-beta hydroxysteroid dehydrogenase enzyme, which is responsible for the inactivation of maternal cortisol, is regulated by DNA methylation, and has been shown to be susceptible to stressors from the maternal environment.
Methodology/Principal Findings
We examined the association between DNA methylation of the HSD11B2 promoter region in the placenta of 185 healthy newborn infants and infant and maternal characteristics, as well as the association between this epigenetic variability and newborn neurobehavioral outcome assessed with the NICU Network Neurobehavioral Scales. Controlling for confounders, HSD11B2 methylation extent is greatest in infants with the lowest birthweights (P = 0.04), and this increasing methylation was associated with reduced scores of quality of movement (P = 0.04).
These results suggest that factors in the intrauterine environment which contribute to birth outcome may be associated with placental methylation of the HSD11B2 gene and that this epigenetic alteration is in turn associated with a prospectively predictive early neurobehavioral outcome, suggesting in some part a mechanism for the developmental origins of infant neurological health.
PMCID: PMC3303854  PMID: 22432047
20.  Prenatal Cocaine Exposure and Childhood Obesity at Nine Years 
Neurotoxicology and teratology  2010;33(2):188-197.
Little is known about the association between prenatal cocaine exposure and obesity. We tested whether prenatal cocaine exposure increases the likelihood of obesity in 561 9-year-old term children from the Maternal Lifestyle Study (MLS). Overall, 21.6% of children met criterion for obesity (body mass index [BMI] ≥ 95th percentile, age and sex-specific). While there was no overall cocaine effect on obesity, multivariate logistic analysis revealed that children exposed to cocaine but not alcohol were 4 times more likely to be obese (OR 4.11, CI 2.04–9.76) than children not exposed to either drug. No increase in obesity prevalence was found in children exposed to alcohol but not cocaine (OR 1.08, CI .59–1.93) or both (OR 1.21, CI 0.66–2.22). Alcohol exposure may attenuate the effect of cocaine exposure on obesity. Increased obesity associated with cocaine but not alcohol exposure was first observed at 7 years. BMI was also elevated from 3 to 9 years in children exposed to cocaine but not alcohol, due to increasing weight but normal height. Prenatal exposure to cocaine may alter the neuroendocrine system and metabolic processes resulting in increased weight gain and childhood obesity.
PMCID: PMC3058125  PMID: 21109003
Prenatal cocaine exposure; prenatal alcohol exposure; childhood obesity; growth; fetal origins
21.  Prenatal methamphetamine exposure and neonatal neurobehavioral outcome in the USA and New Zealand 
Neurotoxicology and teratology  2010;33(1):166-175.
Methamphetamine (MA) use among pregnant women is a world-wide problem, but little is known of its impact on exposed infants.
The prospective, controlled longitudinal Infant Development, Environment and Lifestyle (IDEAL) study of prenatal MA exposure from birth to 36 months was conducted in the US and NZ. The US cohort has 183 exposed and 196 comparison infants; the NZ cohort has 85 exposed and 95 comparison infants. Exposure was determined by self-report and meconium assay with alcohol, marijuana, and tobacco exposures present in both groups. The NICU Neurobehavior Scale (NNNS) was administered within 5 days of life. NNNS summary scores were analyzed for exposure including heavy exposure and frequency of use by trimester and dose-response relationship with the amphetamine analyte.
MA Exposure was associated with poorer quality of movement, more total stress/abstinence, physiological stress, and CNS stress with more nonoptimal reflexes in NZ but not in the USA. Heavy MA exposure was associated with lower arousal and excitability. First trimester MA use predicted more stress and third trimester use more lethargy and hypotonicity. Dose-response effects were observed between amphetamine concentration in meconium and CNS stress.
Across cultures, prenatal MA exposure was associated with a similar neurobehavioral pattern of under arousal, low tone, poorer quality of movement and increased stress.
PMCID: PMC2974956  PMID: 20615464
Prenatal exposure; Methamphetamine; Neurodevelopment; Meconium
22.  Intrauterine Growth of Infants Exposed to Prenatal Methamphetamine: Results from the Infant Development, Environment, and Lifestyle (IDEAL) Study 
The Journal of pediatrics  2010;157(2):337-339.
Previous studies suggest prenatal methamphetamine (MA) exposure inhibits fetal growth. We examined neonatal growth effects of prenatal MA exposure in a prospective cohort study. After adjusting for covariates, exposed neonates had a higher incidence of being small for gestational age (SGA) than unexposed neonates.
PMCID: PMC3018351  PMID: 20570284
drug; amphetamine; antenatal; small for gestational age
23.  Prenatal Cocaine Exposure Alters Cortisol Stress Reactivity in 11 Year Old Children 
The Journal of pediatrics  2010;157(2):288-295.e1.
Determine the association between prenatal cocaine exposure and postnatal environmental adversity on salivary cortisol stress reactivity in school aged children.
Study design
Subjects included 743 11 year old children (n=320 cocaine exposed; 423 comparison) followed since birth in a longitudinal prospective multisite study. Saliva samples were collected to measure cortisol at baseline and after a standardized procedure to induce psychological stress. Children were divided into those who showed an increase in cortisol from baseline to post stress and those who showed a decrease or blunted cortisol response. Covariates measured included site, birthweight, maternal pre and postnatal use of alcohol, tobacco or marijuana, social class, changes in caretakers, maternal depression and psychological symptoms, domestic and community violence, child abuse and quality of the home.
With adjustment for confounding variables, cortisol reactivity to stress was more likely to be blunted in children with prenatal cocaine exposure. Cocaine exposed children exposed to domestic violence showed the strongest effects.
The combination of prenatal cocaine exposure and an adverse postnatal environment could down regulate the hypothalamic-pituitary-adrenal axis (HPA) resulting in the blunted cortisol response to stress possibly increasing risk for later psychopathology and adult disease.
PMCID: PMC3121327  PMID: 20400094
prenatal cocaine exposure; cortisol reactivity; environmental adversity
24.  New Meconium Biomarkers of Prenatal Methamphetamine Exposure Increase Identification of Affected Neonates 
Clinical chemistry  2010;56(5):856-860.
Prenatal methamphetamine (MAMP) exposure is poorly reflected in neonatal meconium. Often, maternal self-reported MAMP use is not corroborated by positive results in amphetamines immunoassays of meconium, and even if initial test results are positive, they frequently are not confirmed for MAMP or amphetamine (AMP) by chromatographic analysis. The presence of the MAMP metabolites p-hydroxymethamphetamine (pOHMAMP), p-hydroxyamphetamine (pOHAMP), and norephedrine (NOREPH) in meconium may improve the identification of MAMP- and AMP-exposed neonates.
Immunoassay-positive and -negative meconium samples were subjected to liquid chromatography–tandem mass spectrometric reanalysis for these recently identified metabolites.
pOHAMP and NOREPH were detected only when MAMP and/or AMP were present and thus do not appear to be promising biomarkers of prenatal MAMP exposure. pOHMAMP, in contrast, identified 6 additional neonates whose mothers reported MAMP exposure, yet had a meconium sample screened as negative; pOHMAMP was more likely to be present if maternal MAMP use continued into the third trimester. Although the pOHMAMP results for meconium samples corroborated the maternal self-reports, the confirmation rate for positive meconium screening results did not improve with the inclusion of these new biomarkers.
pOHMAMP identified additional MAMP-exposed neonates; therefore, MAMP, AMP, and pOHMAMP should be included in meconium chromatographic analyses. To maximize the identification of MAMP-exposed children requires improvement in immunoassay screening tests to reduce false-negative and false-positive results. Additional research will help clarify which AMP-related compounds, if any, contribute to unconfirmed positive results in screening tests. Furthermore, nonamphetamine compounds endogenous to the complex meconium matrix also may cross-react, making chromatographic confirmation of screening results essential.
PMCID: PMC2883877  PMID: 20185623
25.  The Maternal Lifestyle Study: Sleep Problems in Children with Prenatal Substance Exposure 
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.
Sleep data was collected by maternal report in a prospective longitudinal follow-up of children participating in the Maternal Lifestyle multisite study.
Hospital based research centers in Providence, RI, Miami, FL, Detroit, MI, and Memphis, TN
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.
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.
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.
PMCID: PMC2917192  PMID: 20439796

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