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1.  Genes and Environment in Neonatal Intraventricular Hemorrhage 
Seminars in perinatology  2015;39(8):592-603.
Emerging data suggest intraventricular hemorrhage (IVH) of the preterm neonate is a complex disorder with contributions from both the environment and the genome. Environmental analyses suggest factors mediating both cerebral blood flow and angiogenesis contribute to IVH, while candidate gene studies report variants in angiogenesis, inflammation and vascular pathways. Gene-by-environment interactions demonstrate the interaction between the environment and the genome, and a non-replicated genome-wide association study suggests that both environmental and genetic factors contribute to the risk for severe IVH in very low birth weight preterm neonates.
doi:10.1053/j.semperi.2015.09.006
PMCID: PMC4668116  PMID: 26516117
2.  Transactional relations between caregiving stress, executive functioning, and problem behavior from early childhood to early adolescence 
Development and psychopathology  2016;28(3):743-756.
Developmental psychopathologists face the difficult task of identifying the environmental conditions that may contribute to early childhood behavior problems. Highly stressed caregivers can exacerbate behavior problems, while children with behavior problems may make parenting more difficult and increase caregiver stress. Unknown is: (1) how these transactions originate, (2) whether they persist over time to contribute to the development of problem behavior and (3) what role resilience factors, such as child executive functioning, may play in mitigating the development of problem behavior. In the present study, transactional relations between caregiving stress, executive functioning, and behavior problems were examined in a sample of 1,388 children with prenatal drug exposures at three developmental time points: early childhood (birth-age 5), middle childhood (ages 6 to 9), and early adolescence (ages 10 to 13). Transactional relations differed between caregiving stress and internalizing versus externalizing behavior. Targeting executive functioning in evidence-based interventions for children with prenatal substance exposure who present with internalizing problems and treating caregiving psychopathology, depression, and parenting stress in early childhood may be particularly important for children presenting with internalizing behavior.
doi:10.1017/S0954579416000286
PMCID: PMC4955944  PMID: 27427803
3.  Early caregiving stress exposure moderates the relation between respiratory sinus arrhythmia reactivity at 1 month and biobehavioral outcomes at age 3 
Psychophysiology  2016;53(1):83-96.
There is a growing scientific interest in the psychophysiological functioning of children living in low-socioeconomic status (SES) contexts, though this research is complicated by knowledge that physiology–behavior relations often operate differently in these environments among adults. Importantly, such research is made more difficult because SES may be a proxy for a wide range of risk factors including poor caregiving and exposure to parental substance use. We used factor analysis to organize risk-exposure data collected from 827 children—many of whom were raised in low-SES contexts and exposed to substances prenatally—into dissociable components including economic stress, caregiving stress (e.g., stress the caregiver may experience, including parental psychopathology), and postnatal substance exposure. These factors, along with respiratory sinus arrhythmia (RSA) reactivity at age 1 month, were used to predict behavior dysregulation and resting RSA at age 3 years. A significant RSA Reactivity × Caregiving Stress interaction indicated that infants who exhibited high RSA reactivity at 1 month experienced the greatest behavior dysregulation at 3 years, but only when they were exposed to high levels of caregiving stress. Among African Americans, the highest resting RSA at 3 years was found in infants with less RSA reactivity, but only if they also experienced less caregiving stress. Our work is consistent with biological sensitivity to context, adaptive calibration, and allostatic load models, and highlights the importance of studying Physiology × Environment interactions in low-SES contexts for predicting behavior and resting RSA.
doi:10.1111/psyp.12569
PMCID: PMC4944757  PMID: 26681620
Individual differences; Infants/children; Heart rate
4.  Cortisol Reactivity to Social Stress as a Mediator of Early Adversity on Risk and Adaptive Outcomes 
Child development  2014;85(6):2279-2298.
Children chronically exposed to stress early in life are at increased risk for maladaptive outcomes, though the physiological mechanisms driving these effects are unknown. Cortisol reactivity was tested as a mediator of the relation between prenatal substance exposure and/or early adversity on adaptive and maladaptive outcomes. Data were drawn from a prospective longitudinal study of prenatal substance exposure (N = 860). Cortisol reactivity was assessed at age 11. Among African-Americans, prenatal substance exposure exerted an indirect effect through early adversity and cortisol reactivity to predict externalizing behavior, delinquency, and a positive student-teacher relationship at age 11. Decreased cortisol reactivity was related to maladaptive outcomes, and increased cortisol reactivity predicted better executive functioning and a more positive student-teacher relationship.
doi:10.1111/cdev.12316
PMCID: PMC4236260  PMID: 25376131
Prenatal Substance Exposure; Early Adversity; cortisol; problem behavior; delinquency
5.  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
6.  The contributions of early adverse experiences and trajectories of respiratory sinus arrhythmia on the development of neurobehavioral disinhibition among children with prenatal substance exposure 
Development and psychopathology  2014;26(4 0 1):901-916.
Neurobehavioral disinhibition (ND) is a complex condition reflecting a wide range of problems involving difficulties with emotion regulation and behavior control. Respiratory sinus arrhythmia (RSA) is a physiological correlate of emotion regulation that has been studied in a variety of at-risk populations; however, there are no studies of RSA in children with ND. Data were drawn from a prospective longitudinal study of prenatal substance exposure that included 1,073 participants. Baseline RSA and RSA reactivity to an attention-demanding task were assessed at 3, 4, 5, and 6 years. ND was assessed at ages 8/9, 11, and 13/14 years via behavioral dysregulation and executive dysfunction composite measures. Greater exposure to early adversity was related to less RSA reactivity at 3 years, increases in RSA reactivity from ages 3 to 6 years, and increased behavioral dysregulation from ages 8/9 to 13/14. RSA reactivity was examined as a moderator of the association between early adversity and changes in ND. A significant Early Adversity × RSA Reactivity quadratic interaction revealed that children with decelerations in RSA reactivity exhibited increases in behavioral dysregulation, regardless of their exposure to early adversity. However, greater exposure to early adversity was related to greater increases in behavioral dysregulation, but only if children exhibited accelerations in RSA reactivity from ages 3 to 6 years. The results contribute to our understanding of how interactions across multiple levels of analysis contribute to the development of ND.
doi:10.1017/S095457941400056X
PMCID: PMC4447302  PMID: 24909973
7.  Maternal race, demography and health care disparities impact risk for IVH in preterm neonates 
The Journal of pediatrics  2014;164(5):1005-1011.e3.
Objective
To determine whether risk factors associated with Grade (Gr) 2–4 intraventricular hemorrhage (IVH) differs between African ancestry and white subjects.
Study design
Inborn, appropriate for gestational age (GA) infants with birth weights (BW) 500–1250 grams and exposed to >1 dose of antenatal steroids were enrolled in 24 neonatal intensive care units. Cases had Gr 2–4 IVH and controls matched for site, race and BW range had 2 normal ultrasounds read centrally. Multivariate logistic regression modeling identified factors associated with IVH across African ancestry and white race.
Results
Subjects included 579 African ancestry or white race infants with Gr 2–4 IVH and 532 controls. Mothers of African ancestry children were less educated, and white case mothers were more likely to have > 1 prenatal visit and have a multiple gestation (P ≤.01 for all). Increasing GA (P =.01), preeclampsia (P < .001), complete antenatal steroid exposure (P = .02), cesarean delivery (P < .001) and white race (P = .01) were associated with decreased risk for IVH. Chorioamnionitis (P = .01), Apgar< 3 at 5 min (P < .004), surfactant (P < .001) and high frequency ventilation (P < .001) were associated with increased risk for IVH. Among African ancestry infants, having >1 prenatal visit was associated with decreased risk (P = .02). Among white infants, multiple gestation was associated with increased risk (P < .001) and higher maternal education with decreased IVH risk (P < .05).
Conclusion
Risk for IVH differs between African ancestry and white infants and may be attributable to both race and health care disparities.
doi:10.1016/j.jpeds.2014.01.036
PMCID: PMC4095864  PMID: 24589078
preterm infant; intraventricular hemorrhage; race; multiple gestation; prenatal care
8.  Reactivity and Regulation of Motor Responses in Cocaine-Exposed Infants 
Effects of prenatal exposure to cocaine on the reactivity and regulation of the motor system of 825 four-month-old infants enrolled in the Maternal Lifestyle Study were examined. Videotaped assessments of 338 cocaine-exposed (CE) infants and 487 non-exposed comparison infants were coded by examiners masked to exposure status. Exposure status was determined by meconium assay and maternal self-report of prenatal cocaine use. Infants were presented with a series of 17 visual, auditory and tactile stimuli for 30-second each. Intensity and latency of limb movement responses on a subset of items were analyzed to test the following hypotheses: CE infants are more active in general; CE infants exhibit increased movement levels for a larger proportion of time in response to stimulation; the motor systems of CE infants are more reactive to stimulation (e.g., shorter latencies to respond); and CE infants are poorer regulators of the motor system. Results CE infants were not more active in general and data do not indicate a more highly reactive motor system. However, CE infants exhibited increased movement levels for a larger proportion of time in response to stimulation. Additional analysis of movement exhibited during three tactile items found increased movement lability in CE infants and different patterns of responding, suggesting that the effects of prenatal cocaine exposure on the motor system may vary by context. Covariate effects for tobacco, alcohol, and marijuana are also reported.
doi:10.1016/j.ntt.2014.02.005
PMCID: PMC4337232  PMID: 24583252
cocaine; prenatal exposure; motor activity; reactivity; regulation
9.  COMPARISON OF OUTCOMES BETWEEN BLOOD GROUP O AND NON-GROUP O PREMATURE NEONATES RECEIVING RED CELL TRANSFUSIONS 
Background
At some institutions all babies requiring red blood cell (RBC) transfusions in neonatal intensive care units (NICUs) receive group O RBCs. Although transfused O plasma is minimized in packed RBCs, small amounts of residual anti-A, anti-B and anti-A, B in group O packed RBCs may bind to the corresponding A and B antigens of non-group O RBCs, possibly hemolyzing their native RBCs and thereby releasing free hemoglobin theoretically resulting in hypercoagulability and promoting bacterial growth from free iron.
Study Design and Methods
Transfused group O and non- group O premature infants in the University of Kentucky Children’s Hospital NICU database were compared for a number of severity markers to determine if transfused non-group O patients had worse outcomes than those of group O.
Results
724 neonates in this sample of NICU babies received at least one blood component. There were no significant differences between group O and non-group O babies with regard to final disposition or complications.
Conclusions
This reassuring finding validates the longstanding neonatal transfusion practice of using group O packed red cells for NICU babies of all blood groups. However, because a recent study shows increased mortality from NEC in AB neonates receiving only group O RBC and suggests a change in neonatal transfusion practice to ABO group specific red cells, more studies may be warranted
doi:10.1309/AJCPJX94SPZLQLGG
PMCID: PMC4349557  PMID: 24225743
10.  Death or Neurodevelopmental Impairment at 18 To 22 Months in a Randomized Trial of Early Dexamethasone to Prevent Death or Chronic Lung Disease in Extremely Low Birth Weight Infants 
The Journal of pediatrics  2013;164(1):34-39.e2.
Objective
To evaluate the incidence of death or neurodevelopmental impairment (NDI) at 18 to 22 months corrected age in subjects enrolled in a trial of early dexamethasone treatment to prevent death or chronic lung disease in extremely low birth weight infants.
Methods
Evaluation of infants at 18 to 22 months corrected age included anthropomorphic measurements, a standard neurological examination, and the Bayley Scales of Infant Development-II, including the Mental Developmental Index (MDI) and the Psychomotor Developmental Index (PDI). NDI was defined as moderate or severe cerebral palsy, MDI or PDI less than 70, blindness, or hearing impairment.
Results
Death or NDI at 18 to 22 months corrected age was similar in the dexamethasone and placebo groups (65 vs 66 percent, p= 0.99 among those with known outcome). The proportion of survivors with NDI was also similar, as were mean values for weight, length, and head circumference and the proportion of infants with poor growth (50 vs 41 percent, p=0.42 for weight less than 10th percentile). Forty nine percent of infants in the placebo group received treatment with corticosteroid compared to 32% in the dexamethasone group (p=0.02).
Conclusion
The risk of death or NDI and rate of poor growth were high but similar in the dexamethasone and placebo groups. The lack of a discernible effect of early dexamethasone on neurodevelopmental outcome may be due to frequent clinical corticosteroid use in the placebo group.
doi:10.1016/j.jpeds.2013.07.027
PMCID: PMC4120744  PMID: 23992673
neurodevelopmental outcome; growth; bronchopulmonary dysplasia; cerebral palsy; neonatal follow-up
11.  Perceptual Specialization and Configural Face Processing in Infancy 
Adults’ face processing expertise includes sensitivity to second-order configural information (spatial relations among features, such as distance between eyes). Prior research indicates that infants process this information in female faces. In the current experiments, 9-month-olds discriminated spacing changes in upright human male and monkey faces but not in inverted faces. However, they failed to process matching changes in upright house stimuli. A similar pattern of performance was exhibited by 5-month-olds. Thus, 5- and 9-month-olds exhibited specialization by processing configural information in upright primate faces but not in houses or inverted faces. This finding suggests that, even early in life, infants treat faces in a special manner by responding to changes in configural information more readily in faces than in non-face stimuli. However, previously reported differences in infants’ processing of human versus monkey faces at 9 months of age (but not at younger ages), which have been associated with perceptual narrowing, were not evident in the current study. Thus, perceptual narrowing is not absolute in the sense of loss of the ability to process information from other species’ faces at older ages.
doi:10.1016/j.jecp.2013.07.007
PMCID: PMC3796849  PMID: 23994509
12.  Prenatal Substance Exposure: Neurobiological Organization at One Month 
The Journal of pediatrics  2013;163(4):989-994.e1.
Objective
To examine the autonomic nervous system and neurobehavioral response to a sustained visual attention challenge among 1-month old infants with prenatal substance exposure.
Study design
We measured heart rate (HR), respiratory sinus arrhythmia (RSA), and neurobehavior during sustained visual orientation tasks included in the NICU Network Neurobehavioral Scale (NNNS) in 1,129, 1-month infants with prenatal substance exposure. Four groups were compared: infants with prenatal cocaine and opiate exposure, infants with cocaine exposure, infants with opiate exposure, and infants with exposure to other substances (i.e. alcohol, marijuana, and tobacco).
Results
Infants with prenatal cocaine and opiate exposure had the highest HRs and lowest levels of RSA during a sustained visual attention procedure compared with the other three groups. Infants with prenatal cocaine and opiate exposure had poorer quality of movement and more hypertonicity during the NNNS exam compared with the other three exposure groups. Infants with prenatal cocaine and opiate exposure had more nonoptimal reflexes and stress/abstinence signs compared with infants with prenatal cocaine exposure only and infants with prenatal exposure to alcohol, tobacco, and marijuana.
Conclusions
Problems with arousal regulation were identified among infants with prenatal substance exposure. Autonomic dysregulation has been implicated as a mechanism by which these difficulties occur. Our results suggest that infants with both prenatal cocaine and opiate exposure have the greatest autonomic response to the challenge of a sustained visual attention task, which may place these infants at risk for developing problems associated with physiological and behavioral regulation, a necessary prerequisite for early learning.
doi:10.1016/j.jpeds.2013.04.033
PMCID: PMC3773295  PMID: 23743094
in utero drug exposure; physiology; neurobehavioral
13.  Prenatal Cocaine Exposure and Motor Performance at 4 Months 
OBJECTIVE
The relation between prenatal cocaine exposure and quality of movement was studied at 4 mo using the Posture and Fine Motor Assessment of Infants (PFMAI–I).
METHOD
Posture and fine motor scores of 4-month-old infants exposed to cocaine in utero (n = 370) were compared with an unexposed group (n = 533) within the context of gestational age, medical and demographic characteristics, and level of prenatal substance exposure using the PFMAI–I.
RESULTS
Infants prenatally exposed to cocaine had significantly lower posture scores than infants in the unexposed group. There was no main effect of cocaine exposure on fine motor scores; however, there were independent effects of gestational age at birth on both posture and fine motor scores at 4-mo corrected age.
CONCLUSION
These findings demonstrate independent contributions of prenatal cocaine exposure and prematurity to risk of motor delay and support the validity of the PFMAI–I as a measure of motor competence in early infancy.
doi:10.5014/ajot.2011.001263
PMCID: PMC4144172  PMID: 25170184
child development; cocaine-related disorders; motor skills; posture; prenatal exposure delayed effects
14.  Risk-Taking Behavior among Adolescents with Prenatal Drug Exposure and Extrauterine Environmental Adversity 
Objective
High-risk environments characterized by familial substance use, poverty, inadequate parental monitoring, and violence exposure are associated with an increased propensity for adolescents to engage in risk-taking behaviors (e.g., substance use, sexual behavior, and delinquency). However, additional factors such as drug exposure in utero and deficits in inhibitory control among drug-exposed youth may further influence the likelihood that adolescents in high-risk environments will engage in risk-taking behavior. This study examined the influence of prenatal substance exposure, inhibitory control, and sociodemographic/environmental risk factors on risk-taking behaviors in a large cohort of adolescents with and without prenatal cocaine exposure (PCE).
Method
Risk-taking behavior (delinquency, substance use, and sexual activity) was assessed in 963 adolescents (433 cocaine-exposed, 530 nonexposed) at 15 years of age.
Results
PCE predicted later arrests and early onset of sexual behavior in controlled analyses. Associations were partially mediated, however, by adolescent inhibitory control problems. PCE was not associated with substance use at this age. In addition, male gender, low parental involvement, and violence exposure were associated with greater odds of engaging in risk-taking behavior across the observed domains.
Conclusions
Study findings substantiate concern regarding the association between prenatal substance exposure and related risk factors and the long-term outcomes of exposed youth. Access to the appropriate social, educational, and medical services are essential in preventing and intervening with risk-taking behaviors and the potential consequences (e.g., adverse health outcomes, incarceration), especially among high-risk adolescent youth and their families.
doi:10.1097/01.DBP.0000437726.16588.e2
PMCID: PMC4139145  PMID: 24220515
prenatal drug exposure; cocaine; adolescence; risk-taking behavior
15.  Importance of Stability of Early Living Arrangements on Behavior Outcomes of Children With and Without Prenatal Drug Exposure 
Objective:
We evaluated whether living arrangements of children with or without prenatal drug exposure would be associated with their behavior outcomes and adaptive functioning.
Methods:
1388 children with or without prenatal cocaine or opiate exposure were enrolled in a longitudinal cohort study at one month of age, were seen at intervals, tracked over time for their living situation, and evaluated for behavior problems and adaptive functioning at three years of age. Child Behavior Check List and Vineland Adaptive Behavior Scales (VABS) were administered. Using multiple regression models, we determined the factors that would predict behavior problems and adaptive functioning.
Results:
1,092 children were evaluated. Total and externalizing behavior problems T scores of children in relative care were lower (better) than those in parental; externalizing behavior scores were lower than those in non-relative care (p<0.05). Total behavior problem scores increased 2.3 and 1.3 points respectively with each move/year and each year of Child Protective Services’ involvement. Compared to children in non-relative care, those in parental or relative care had higher (better) scores in the VABS total composite (p<0.023), communication (p<0.045), and daily living (p<0.001). Each caretaker change was associated with a decrease of 2.65 and 2.19 points respectively in communication and daily living scores.
Conclusion:
Children’s living arrangements were significantly associated with childhood behavior problems and adaptive functioning. The instability of living situation was also a significant predictor of these outcomes. While family preservation continues to be the goal of the child welfare system, expediting decision toward permanency remains paramount once children are placed in foster care.
doi:10.1097/DBP.0b013e3181644a79
PMCID: PMC3984541  PMID: 18349707
Prenatal cocaine; prenatal opiate; out-of-home-care; child behavior
16.  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
17.  Neurobehavioral Disinhibition Predicts Initiation of Substance Use in Children with Prenatal Cocaine Exposure 
Drug and alcohol dependence  2012;126(1-2):80-86.
Background
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.
Methods
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.
Results
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.
Conclusion
Prenatal drug exposure appears to be a risk pathway to ND, which by 8/9 years portends substance use initiation.
doi:10.1016/j.drugalcdep.2012.04.014
PMCID: PMC3439586  PMID: 22608010
neurodevelopmental disinhibition; substance use initiation; prenatal cocaine exposure
18.  Autonomic Nervous System Function Following Prenatal Opiate Exposure 
In utero exposure to opiates may affect autonomic functioning of the fetus and newborn. We investigated heart rate variability (HRV) as a measure of autonomic stability in prenatal opiate-exposed neonates (n = 14) and in control term infants (n = 10). Electrocardiographic data during both non-nutritive and nutritive sucking were evaluated for RR intervals, heart rate (HR), standard deviation of the consecutive RR intervals (SDRR), standard deviation of the differences of consecutive RR intervals (SDDRR), and the power spectral densities in low and high frequency bands. In controls, mean HR increased significantly, 143–161 per min (p = 0.002), with a trend toward a decrease in RR intervals from non-nutritive to nutritive sucking; these measures did not change significantly among exposed infants. Compared to controls, exposed infants demonstrated significantly greater HRV or greater mean SDRR and SDDRR during non-nutritive period (p < 0.01), greater mean SDDRR during nutritive sucking (p = 0.02), and higher powers in the low and high frequency bands during nutritive feedings. Our findings suggest that prenatal opiate exposure may be associated with changes in autonomic nervous system (ANS) functioning involving both sympathetic and parasympathetic branches. Future studies are needed to examine the effects of prenatal opiate exposure on ANS function.
doi:10.3389/fped.2013.00027
PMCID: PMC3864192  PMID: 24400273
heart rate variability; autonomic nervous system; prenatal opiate; power spectral analysis; neonatal abstinence syndrome
19.  Impact of maternal substance use during pregnancy on childhood outcome 
Summary
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.
doi:10.1016/j.siny.2007.01.002
PMCID: PMC3717561  PMID: 17317350
Alcohol; Child medicine; Cocaine; Neonatal; Neurobehavioral outcome; Polydrug use; Tobacco
20.  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.
doi:10.1203/PDR.0b013e3182291b13
PMCID: PMC3686483  PMID: 21546861
21.  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
22.  Effects of perinatal oxycodone exposure on the cardiovascular response to acute stress in male rats at weaning and in young adulthood 
Oxycodone (OXY) is one of the most commonly abused opiates during pregnancy. Perinatal opiate exposure (POE) is associated with neurobehavioral and hormone changes. Little is known about the effects of perinatal OXY on the cardiovascular (CV) responses to stress.
Objectives: to determine the effects of POE on: (1) CV responses to acute stress and ability to discriminate using a classical conditioning paradigm; (2) changes in CV response to the paradigm and retention of the ability to discriminate from postnatal day (PD) 40 to young adulthood.
Methods: Pregnant rats were given i.v. OXY or vehicle (CON) daily. OXY and CON males were fitted with BP telemetry units. Offspring were classically conditioned by following a pulsed tone (CS+) with tail shock. A steady tone (CS−) was not followed by shock. BP and HR were recorded during resting periods and conditioning. Changes in BP, HR from composite analysis were compared. The paradigm was repeated on PD 75.
Results: At PD 40, OXY rats had a lower baseline mean BP (OXY: 114.8 ± 1.0 vs. CON: 118.3 ± 1.0 mm Hg; mean ± SEM) but larger amplitude of the conditional BP increase during the stress response (OXY: +3.9 ± 0.4 vs. CON: +1.7 ± 0.4 mm Hg). Both OXY and CON rats were able to discriminate between CS+ and CS−. At PD 75, the effects of OXY on the increased amplitude of the conditional BP had dissipated (CON: +3.4 ± 2.3 vs. OXY: +4.5 ± 1.4 mm Hg). BP responses to the stress and non-stress stimuli did not differ in the OXY group, suggesting that OXY may have decreased the ability of the offspring to discriminate (OXY: CS+: 147.1 ± 1.6, CS−: 145.9 ± 1.6 mm Hg vs. CON: CS+: 155.4 ± 2.7, CS−: 147.8 ± 2.7 mm Hg).
Conclusion: POE is associated with subtle alterations in stress CV responses in weanling rats which dissipate when the conditioning is repeated at an early adult age. Although POE effect on the ability to discriminate at weanling age could not be detected, POE may impair retention of this ability in adulthood.
doi:10.3389/fphys.2013.00085
PMCID: PMC3633946  PMID: 23630500
oxycodone; opiate; blood pressure; sympathetic; conditioning; classical
23.  Prenatal Cocaine Exposure and Small-for-Gestational-Age Status: Effects on Growth at 6 Years of age 
Neurotoxicology and teratology  2011;33(5):575-581.
OBJECTIVE
To evaluate the impact of prenatal cocaine exposure and small-for-gestational-age (SGA) status on childhood growth.
STUDY DESIGN
Cocaine exposure was defined by history or meconium metabolites. Hierarchical linear modeling was used to examine cocaine exposure and SGA status on growth, while controlling for exposure to other drugs and alcohol use.
RESULTS
At birth cocaine-exposed infants (n=364) had significantly lower growth parameters compared to non-exposed children (n=771). At 6 years, weight was similar between exposed and unexposed children. SGA infants continued to be growth impaired. There was a significant interaction between prenatal cocaine exposure and SGA status at 6 years. The negative effects of cocaine on weight and height were greater among non-SGA than SGA children (432 vs. 280 gm, and 0.7 and 0.5 cm, respectively) while negative effects of SGA status on weight and height were larger in non-cocaine exposed compared to the exposed children (2.3 kg vs.1.6 kg and 2.2 and 1.0 cm).
CONCLUSIONS
Children exposed to prenatal cocaine were similar in weight to non-exposed children at 6 years of age. Cocaine had an unexplained greater detrimental effect on non-SGA than SGA children. SGA status at birth has an independent detrimental effect on childhood growth.
doi:10.1016/j.ntt.2011.04.003
PMCID: PMC3183411  PMID: 21849244
Prenatal cocaine exposure; small for gestational age; childhood growth
24.  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.
doi:10.1017/S0954579411000290
PMCID: PMC3335443  PMID: 21756431
25.  Maternal Periodontitis Treatment and Child Neurodevelopment at 24 to 28 Months of Age 
Pediatrics  2011;127(5):e1212-e1220.
BACKGROUND:
Some maternal infections are associated with impaired infant cognitive and motor performance. Periodontitis results in frequent bacteremia and elevated serum inflammatory mediators.
OBJECTIVE:
The purpose of this study was to determine if periodontitis treatment in pregnant women affects infant cognitive, motor, or language development.
METHODS:
Children born to women who had participated in a previous trial were assessed between 24 and 28 months of age by using the Bayley Scales of Infant and Toddler Development (Third Edition) and the Preschool Language Scale (Fourth Edition). Information about the pregnancy, neonatal period, and home environment was obtained through chart abstractions, laboratory test results, and questionnaires. We compared infants born to women treated for periodontitis before 21 weeks' gestation (treatment group) or after delivery (controls). In unadjusted and adjusted analyses, associations between change in maternal periodontal condition during pregnancy and neurodevelopment scores were tested by using Student's t tests and linear regression.
RESULTS:
A total of 411 of 791 eligible mother/caregiver-child pairs participated. Thirty-seven participating children (9.0%) were born at <37 weeks' gestation. Infants in the treatment and control groups did not differ significantly for adjusted mean cognitive (90.7 vs 91.4), motor (96.8 vs 97.2), or language (92.2 vs 92.1) scores (all P > .5). Results were similar in adjusted analyses. Children of women who experienced greater improvements in periodontal health had significantly higher motor and cognitive scores (P = .01 and .02, respectively), although the effect was small (∼1-point increase for each SD increase in the periodontal measure).
CONCLUSION:
Nonsurgical periodontitis treatment in pregnant women was not associated with cognitive, motor, or language development in these study children.
doi:10.1542/peds.2010-3129
PMCID: PMC3081189  PMID: 21482606
child neurodevelopment; periodontitis; pregnancy; treatment

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