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CORK Bibliography: Child Development after Prenatal Drug Exposure

89 citations. January 2010 to present

Prepared: September 2012

Abbott LC; Winzer-Serhan UH. Smoking during pregnancy: Lessons learned from epidemiological studies and experimental studies using animal models. (review). Critical Reviews in Toxicology 42(4): 279-303, 2012. (229 refs.)

Numerous epidemiological studies in the human population clearly indicate that smoking while pregnant has deleterious effects on fetal development as well as long-term adverse consequences on postnatal development and maturation of several organ systems. Low birth weight, sudden infant death syndrome (SIDS), behavioral disorders including attention deficit hyperactivity disorder (ADHD), externalizing and internalizing behavioral problems and conduct disorders in children have all been linked to prenatal exposure to tobacco smoke. The major pharmacologically active chemical found in tobacco smoke is nicotine, and prenatal exposure to nicotine has been shown to have significant effect on the development of multiple organ systems, including the nervous, respiratory, and cardiovascular systems. In this review, we define mainstream and sidestream smoke, summarize the major classes of compounds found in cigarette smoke, and describe how use of laboratory animal models can be used to assess mechanisms of toxicity and risk in the human population in general. We then discuss the association with smoking during pregnancy and the occurrence of reduced lung function, low birth weight, the incidence of congenital structural malformations, SIDS, ADHD, cognitive impairment, and mood disorders in children, and review pertinent experimental studies using a variety of animal models of developmental nicotine exposure, including, rats, mice, monkeys, lambs, and pigs that have increased our understanding of the pathophysiology of these disorders.

Copyright 2012, Informa HealthCare

Accornero VH; Anthony JC; Morrow CE; Xue L; Mansoor E; Johnson AL et al. Estimated effect of prenatal cocaine exposure on examiner-rated behavior at age 7 years. Neurotoxicology and Teratology 33(3): 370-378, 2011. (69 refs.)

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 status. 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 beta = -0.25; 95% CI = -0.48. -0.02; p = 0.04) but not Sociability (estimated slope beta = 0.03; 95% Cl = -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.

Copyright 2011, Elsevier Science

Akuete K; Oh SS; Thyne S; Rodriguez-Santana JR; Chapela R; Meade K et al. Ethnic variability in persistent asthma after in utero tobacco exposure. Pediatrics 128(3): E623-E630, 2011. (53 refs.)

BACKGROUND: The effects of in utero tobacco smoke exposure on childhood respiratory health have been investigated, and outcomes have been inconsistent. OBJECTIVE: To determine if in utero tobacco smoke exposure is associated with childhood persistent asthma in Mexican, Puerto Rican, and black children. PATIENTS AND METHODS: There were 295 Mexican, Puerto Rican, and black asthmatic children, aged 8 to 16 years, who underwent spirometry, and clinical data were collected from the parents during a standardized interview. The effect of in utero tobacco smoke exposure on the development of persistent asthma and related clinical outcomes was evaluated by logistic regression. RESULTS: Children with persistent asthma had a higher odds of exposure to in utero tobacco smoke, but not current tobacco smoke, than did children with intermittent asthma (odds ratio [OR]: 3.57; P = .029). Tobacco smoke exposure from parents in the first 2 years of life did not alter this association. Furthermore, there were higher odds of in utero tobacco smoke exposure in children experiencing nocturnal symptoms (OR: 2.77; P = .048), daily asthma symptoms (OR: 2.73; P = .046), and emergency department visits (OR: 3.85; P = .015) within the year. CONCLUSIONS: Exposure to tobacco smoke in utero was significantly associated with persistent asthma among Mexican, Puerto Rican, and black children compared with those with intermittent asthma. These results suggest that smoking cessation during pregnancy may lead to a decrease in the incidence of persistent asthma in these populations.

Copyright 2011, American Academy of Pediatrics

Anderko L; Braun J; Auinger P. Contribution of tobacco smoke exposure to learning disabilities. Journal of Obstetric, Gynecologic and Neonatal Nursing 39(1): 111-117, 2010. (34 refs.)

Objective: To investigate the contribution of exposure to prenatal tobacco smoke (PTS) and environmental tobacco smoke (ETS) to parent-reported learning disabilities. Design: A nationally representative, cross-sectional survey conducted in the United States, the National Health and Nutrition Examination Survey (NHANES) 1999 to 2002, was used to explore the association between reported learning disability and exposure to PTS and ETS. Participants: Data were analyzed from 5,420 children ages 4 to 15 years old. Methods: Secondary data analysis was conducted using logistic regression controlling for a number of potential confounders and covariates. Results: Overall, 10.6% of children had a parent-reported learning disability (LD), exceeding previous estimates. Exposure to PTS (odds ratio [OR] = 1.6) and ETS (OR = 1.6) were significantly associated with increased odds for LD in children, with a greater odds noted (OR = 2.6) when exposed to PTS and ETS. Conclusion: Exposure to tobacco smoke significantly increases the odds for children to have a learning disability. Overall, results indicate that if tobacco exposure is causally associated to LD, eliminating exposures could prevent an estimated 750,000 of parent-reported learning disabilities in the United States. Results underscore the need for diligence in the promotion of smoking prevention and cessation efforts.

Copyright 2010, Wiley-Blackwell Publishing

Ayer JG; Belousova E; Harmer JA; David C; Marks GB; Celermajer DS. Maternal cigarette smoking is associated with reduced high-density lipoprotein cholesterol in healthy 8-year-old children. European Heart Journal 32(19): 2446-2453, 2011. (47 refs.)

Aims: Smoking in pregnancy is common. Its effects on lipoprotein levels and arterial structure in childhood are not well characterized. We aimed to determine the effects of maternal smoking in pregnancy on lipoprotein levels and arterial wall thickness in healthy pre-pubertal children. Methods and results A community-based longitudinal study with prospective ascertainment of exposure to smoking in pregnancy and environmental tobacco smoke (ETS) since birth and then lipoprotein and arterial measurements at age 8 years. In 616 newborn infants (gestation >36 weeks and birth weight >2.5 kg) data were collected prospectively by questionnaire on smoking in pregnancy and ETS exposure in childhood. At age 8-years, 405 of the children had measurements of lipoproteins, blood pressure (BP) and carotid intima-media thickness. Children born to mothers who smoked in pregnancy had lower HDL cholesterol [1.32 vs. 1.50 mmol/L, 95% confidence interval (CI) for difference -0.28 to -0.08, P = 0.0005], higher triglycerides (1.36 vs. 1.20 mmol/L, 95% CI for ratio 1.01-1.30, P = 0.04) and higher systolic BP (102.1 vs. 99.9 mmHg, 95% CI for difference 0.6-3.8, P = 0.006). After adjustment for maternal passive smoking, post-natal ETS exposure, gender, breast feeding duration, physical inactivity, and adiposity, smoking in pregnancy remained significantly associated with lower HDL cholesterol (difference -0.22 mmol/L, 95% CI -0.36 to -0.08, P = 0.003) but not with higher systolic BP. Neither smoking in pregnancy nor post-natal ETS exposure was associated with alterations of carotid artery wall thickness. Conclusion Smoking in pregnancy is independently associated with significantly lower HDL cholesterol in healthy 8-year-old children.

Copyright 2011, Oxford University Press

Bakker H; Jaddoe VWV. Cardiovascular and metabolic influences of fetal smoke exposure. (review). European Journal of Epidemiology 26(10): 763-770, 2011. (118 refs.)

Many epidemiological studies showed associations of low birth weight with cardiovascular disease, type 2 diabetes and obesity. The associations seem to be consistent and stronger among subjects with a postnatal catch up growth. It has been suggested that developmental changes in response to adverse fetal exposures might lead to changes in the fetal anatomy and physiology. These adaptations may be beneficial for short term, but may lead to common diseases in adulthood. Maternal smoking during pregnancy is one of the most important adverse fetal exposures in Western countries, and is known to be associated with a 150-200 g lower birth weight. An accumulating body of evidence suggests that maternal smoking during pregnancy might be involved in pathways leading to both low birth weight and common diseases, including cardiovascular disease, type 2 diabetes and obesity, in adulthood. In this review, we discuss epidemiological studies focused on the associations of maternal smoking with fetal growth and development and cardiovascular and metabolic disease in later life. We also discuss potential biological mechanisms, and challenges for future epidemiological studies.

Copyright 2011, Springer

Bjerg A; Hedman L; Perzanowski M; Lundback B; Ronmark E. A strong synergism of low birth weight and prenatal smoking on asthma in schoolchildren. Pediatrics 127(4): E905-E912, 2011. (34 refs.)

BACKGROUND: Prenatal smoke exposure is associated with airway inflammation and asthma in children. It also increases the risk of low birth weight (LBW). LBW is associated with decreased lung function independently of smoking. OBJECTIVE: To study the independent and joint effects of prenatal smoking and LBW on childhood asthma. METHODS: In 1996, all children aged 7 to 8 years in 3 cities in northern Sweden were invited to an International Study of Asthma and Allergy in Childhood questionnaire survey. This study focused on the follow-up of children aged 11 to 12 years, in which 3389 children (96%) participated. A subset of 2121 children underwent skin-prick testing. Self-reported physician-diagnosed asthma has been clinically validated. RESULTS: Mean birth weight was 3360 g in children exposed to prenatal smoking and 3571 g in nonexposed children (P < .001). The association of prenatal smoking with physician-diagnosed asthma was stronger in LBW children (risk ratio: 8.8 [95% confidence interval: 2.1-38]) than in normal birth weight children (risk ratio: 1.3 [95% confidence interval: 1.0-1.8]). LBW alone was not an independent predictor of asthma. These associations were similar in multivariate analysis, and the interaction term LBW x smoking was highly statistically significant. CONCLUSIONS: There was a strong interaction of LBW and prenatal-smoking on the risk of physician-diagnosed asthma, which has not been demonstrated previously. This was consistently seen with adjustment for known risk factors, including allergic sensitization. Plausibly, airway inflammation from prenatal smoke exposure induces obstructive symptoms more easily in the underdeveloped airways of LBW children.

Copyright 2011, American Academy of Pediatrics

Blood-Siegfried J; Rende EK. The long-term effects of prenatal nicotine exposure on neurologic development. Journal of Midwifery & Women's Health 55(2): 143-152, 2010. (81 refs.)

A large body of documented evidence has found that smoking during pregnancy is harmful to both the mother and the fetus. Prenatal exposure to nicotine in various forms alters neurologic development in experimental animals and may increase the risk for neurologic conditions in humans. There is a positive association between maternal smoking and sudden infant death syndrome (SIDS); however, the connection between nicotine addiction, depression, attention disorders, and learning and behavior problems in humans is not straightforward. Nicotine's action on the production and function of neurotransmitters makes it a prime suspect in the pathology of these diseases. Nicotine accentuates neurotransmitter function in adults but desensitizes these functions in prenatally exposed infants and children. This desensitization causes an abnormal response throughout the lifespan. Furthermore, nicotine use by adolescents and adults can alleviate some of the symptoms caused by these neurotransmitter problems while they increase the risk for nicotine addiction. Although nicotine replacement drugs are used by pregnant women, there is no clear indication that they improve outcomes during pregnancy, and they may add to the damage that occurs to the developing neurologic system in the fetus. Understanding the effects of nicotine exposure is important in providing safe care for pregnant women, children, and families and for developing appropriate smoking cessation programs during pregnancy.

Copyright 2010, Elsevier Science

Booij L; Benkelfat C; Leyton M; Vitaro F; Gravel P; Levesque ML et al. Perinatal effects on in vivo measures of human brain serotonin synthesis in adulthood: A 27-year longitudinal study. European Neuropsychopharmacology 22(6): 419-423, 2012. (25 refs.)

There is an increasing evidence that prenatal and early postnatal stressors have life long impacts on physical and mental health problems. Animal studies have shown that this could include enduring changes to brain serotonin neurotransmission. In the present study, we tested whether perinatal adversity in humans has a long-term impact on brain serotonin neurotransmission in adulthood. Twenty-six healthy males, recruited from a 27-year longitudinal study, underwent a positron emission tomography scan with the tracer alpha-[C-11]methyl-L-tryptophan (C-11-AMT), as an index of serotonin synthesis capacity. The trapping constant is taken as a proxy for the regional 5-HT synthesis. Birth complications, especially a delivery where the fetus showed signs of physiological distress, predicted lower C-11-AMT trapping in the hippocampus and medial orbitofrontal cortex. Lower C-11-AMT trapping in the medial orbitofrontal cortex was also predicted by maternal smoking and lower birth weight. There were no effects of childhood or recent adversity. This is the first human study reporting associations between perinatal adversity and adult C-11-AMT trapping in the hippocampus and medial orbitofrontal cortex. The associations suggest that limbic serotonin pathways may be particularly vulnerable to environmental challenges during the period when they undergo the most prominent neurodevelopmental changes. In combination with other risk factors, perinatal stressors may contribute to increased vulnerability for psychiatric disorders in which serotonin plays a major role.

Copyright 2012, Elsevier Science

Breton CV; Byun HM; Wenten M; Pan F; Yang A; Gilliland FD. Prenatal tobacco smoke exposure affects global and gene-specific DNA methylation. American Journal of Respiratory and Critical Care Medicine 180(5): 462-467, 2009. (32 refs.)

Rationale: Prenatal exposure to tobacco smoke increases the risk for diseases later in the child's life that may be mediated through alterations in DNA methylation. Objectives: To demonstrate that differences in DNA methylation patterns occur in children exposed to tobacco smoke and that variation in detoxification genes may alter these associations. Methods: Methylation of DNA repetitive elements, LINE1 and AluYb8, was measured using bisulfite conversion and pyrosequencing in buccal cells of 348 children participating in the Children's Health Study. Gene-specific CpG methylation differences associated with smoke exposure were screened in 272 participants in the Children's Health Study children using an Illumina GoldenGate panel. CpG loci that demonstrated a statistically significant difference in methylation were validated by pyrosequencing. Estimates were standardized across loci using a Z score to enable cross-comparison of results. Measurements and Main Results: DNA methylation patterns were associated with in utero exposure to maternal smoking. Exposed children had significantly lower methylation of AluYb8 (beta, -0.31; P = 0.03). Differences in smoking-related effects on LINE1 methylation were observed in children with the common GSTM1 null genotype. Differential methylation of CpG loci in eight genes was identified through the screen. Two genes, AXL and PTPRO, were validated by pyrosequencing and showed significant increases in methylation of 0.37 (P = 0.005) and 0.34 (P = 0.02) in exposed children. The associations with maternal smoking varied by a common GSTP1 haplotype. Conclusions: Life-long effects of in utero exposures may be mediated through alterations in DNA methylation. Variants in detoxification genes may modulate the effects of in utero exposure through epigenetic mechanisms.

Copyright 2009, American Thoracic Society

Brown CW; Olson HC; Croninger RG. Maternal alcohol consumption during pregnancy and infant social, mental, and motor development. Journal of Early Intervention 32(2): 110-126, 2010. (55 refs.)

Maternal alcohol consumption during pregnancy is a significant social problem associated with developmental difficulties in young children. Child developmental and behavioral characteristics were examined from the 9-month data point of the Early Childhood Longitudinal Studies-Birth Cohort, a prospective nationally representative study. Several findings indicate linear patterns between the amount of prenatal alcohol dosage and sensory regulation, mental, and motor development outcomes. Undesirable social engagement and child interaction were found to be statistically significant at the prenatal alcohol level of one to three drinks per week. Children exposed to four or more drinks per week showed statistically significant and clinically passive behavior on three sensory regulation variables.

Copyright 2010, Council for Exceptional Children

Bruin JE; Gerstein HC; Holloway AC. Long-term consequences of fetal and neonatal nicotine exposure: A critical review. (review). Toxicological Sciences 116(2): 364-374, 2010. (167 refs.)

Cigarette smoking during pregnancy is associated with numerous obstetrical, fetal, and developmental complications, as well as an increased risk of adverse health consequences in the adult offspring. Nicotine replacement therapy (NRT) has been developed as a pharmacotherapy for smoking cessation and is considered to be a safer alternative for women to smoking during pregnancy. The safety of NRT use during pregnancy has been evaluated in a limited number of short-term human trials, but there is currently no information on the long-term effects of developmental nicotine exposure in humans. However, animal studies suggest that nicotine alone may be a key chemical responsible for many of the long-term effects associated with maternal cigarette smoking on the offspring, such as impaired fertility, type 2 diabetes, obesity, hypertension, neurobehavioral defects, and respiratory dysfunction. This review will examine the long-term effects of fetal and neonatal nicotine exposure on postnatal health.

Copyright 2010, Oxford University Press

Bublitz MH; Stroud LR. Maternal smoking during pregnancy and offspring brain structure and function: Review and agenda for future research. (review). Nicotine & Tobacco Research 14(4): 388-397, 2012. (41 refs.)

Maternal smoking during pregnancy (MSDP) has been associated with long-term neurobehavioral and cognitive deficits in offspring. Animal models demonstrate alterations in brain structure and function following prenatal nicotine exposure. However, few studies have assessed the relationship between MSDP and brain development in humans. Therefore, the aims of this review are (a) to synthesize findings from the small number of human studies investigating effects of MSDP on offspring brain development and (b) to outline an agenda for future research in this nascent area. We searched MEDLINE and Psychinfo databases for human studies of MSDP and offspring brain structure and/or function. Eleven studies meeting our search criteria were identified; 6 studies investigated effects of MSDP on brain structure; 5 examined effects on brain function. Across studies, MSDP was associated with decreased volume/thickness of the cerebellum and corpus callosum, increased auditory brainstem responses, and lack of coordination across brain regions during information and auditory processing. Results from the small number of human studies revealed effects of MSDP on brain structure and function, highlighting potential neural pathways linking MSDP and offspring neurobehavioral and cognitive deficits. Given the limited amount of research in this area, we propose an agenda for future research. Gold standard studies would utilize longitudinal designs, integrated biological and maternal report measures of MSDP, and repeated measures of brain structure/function and neurobehavioral deficits across key developmental periods.

Copyright 2012, Oxford University Press

Buckingham-Howes S; Oberlander SE; Kim EM; Black MM. Prenatal drug exposure and peer victimization in early adolescence: Testing childhood anxiety/depression and aggression as possible mediators. Journal of Developmental And Behavioral Pediatrics 33(5): 416-422, 2012. (38 refs.)

Objective: Children who are prenatally exposed to drugs may be at risk for emotion dysregulation, including childhood anxiety/depression and aggression, potentially increasing their risk for peer victimization. The objectives of this study were to investigate how prenatal drug exposure relates to adolescent peer victimization and the mediating effects of childhood anxiety/depression and aggression. Methods: Seventy-six prenatally drug exposed (PDE) and 38 nonexposed (NE) adolescent-caregiver dyads followed since birth and middle childhood, respectively, participated in an evaluation during adolescence. In middle childhood, caregivers reported on their child's anxiety/depression and aggression, and children reported on violence exposure. In adolescence, caregivers and adolescents responded to a parallel single-item measure of peer victimization. Analyses were conducted using multivariate linear and logistic regression models, adjusting for covariates, including violence exposure. Results: One-third (33.3%, n = 35) of the sample endorsed peer victimization: 40.8% PDE and 17.6% NE, p = .01. In middle childhood, PDE youth had more aggressive behaviors (11.92 vs 7.45, p < .01) and anxiety/depression symptoms (3.43 vs 1.76, p < .01) than NE youth. Anxious/depressed behavior during childhood mediated the association between prenatal drug exposure and adolescent peer victimization. Aggression was not a significant mediator. Conclusions: The consequences of prenatal drug exposure extend into adolescence. Prenatal drug exposure may interfere with emotion regulation, resulting in anxious/depressed behavior during childhood and significantly increasing the risk for peer victimization during adolescence, even in the presence of violence exposure. Strategies to reduce anxious/depressed behavior among children with a history of prenatal drug exposure may reduce adolescent peer victimization.

Copyright 2012, Lippincott, Williams & Wilkins

Buschgens CJM; Swinkels SHN; van Aken MAG; Ormel J; Verhulst FC; Buitelaar JK. Externalizing behaviors in preadolescents: Familial risk to externalizing behaviors, prenatal and perinatal risks, and their interactions. European Child and Adolescent Psychiatry 18(2): 65-74, 2009. (53 refs.)

Background: Accumulating evidence indicates that there is a rich and varied interplay between persons and their environments, which strongly suggests that this involves gene-environment correlations and interactions. We investigated whether familial risk (FR) to externalizing behaviors and prenatal and perinatal risk factors, separately or in interaction with each other, predicted externalizing behaviors. Methods: The subjects were 10- to 12-year-old preadolescents who were taking part in TRAILS, a large prospective population-based cohort study (N=2,230). Regression analyses were used to determine the relative contribution of FR and prenatal and perinatal risks to parent and teacher ratings of inattention, hyperactivity/impulsivity aggression, and delinquency. Results: Regression models explained between 6 and 11% of the variance of externalizing behaviors. We found main effects of FR (vs. no FR), macrosomia (birth weight >4,500 g), maternal prenatal smoking ( MPS), pregnancy and delivery complications (PDCs), and gender that were rather consistent across rater and outcome measures. For some outcome measures, the effect of MPS and PDCs depended on the presence of FR. These included both positive and negative interaction effects. Correlations between FR and prenatal and perinatal risks were significant but rather low. Conclusions: Both main effects and interaction effects of FR and prenatal and perinatal risks contributed to externalizing behaviors in preadolescents, but all effects were of small size. Further research including use of candidate gene polymorphisms is necessary to identify the underlying neurobiological mechanisms of these main and interaction effects.

Copyright 2009, Springer

Chae SM; Covington CY. Biobehavioral outcomes in adolescents and young adults prenatally exposed to cocaine: Evidence from animal models. Biological Research for Nursing 10(4): 318-330, 2009. (83 refs.)

Cocaine has been a popular illicit drug among drugusing pregnant women over the last three decades. Prenatal cocaine exposure (PCE) has significant effects on children's development throughout early childhood. Very few human studies, however, report the effects of PCE on adolescent or early-adult development. As knowledge about early childhood effects in human children was informed by animal studies, this review considers the effects of PCE on behavioral outcomes in adolescent and young adult animals and provides potential guidance for research in human children. Animal models prenatally exposed to cocaine manifest play deficits, decreased social interaction, and increased aggression during competition in adolescence and young adulthood. Altered behavioral adaptation after stress exposure, including hormonal response change, is also evident. Attention deficits are reported in adult offspring with PCE, not only in a novel environment, but also in a final task session, indicating effects of PCE on transition and maintenance of attention. Animal studies support that PCE effects may extend beyond early childhood and continue to adolescence and adulthood. Additionally, some studies highlight that behavioral changes in offspring with PCE born without teratogenesis remain latent and reveal themselves during adulthood when animals are under stress conditions. Based on the evidence from animal models, well-designed human studies are needed to elucidate the effects of PCE on older human children. Research models that combine behavioral measures with stressful challenges may hold potential in discerning a longer term influence 4 PCE.

Copyright 2009, Sage Publications

Chang L; Cloak C; Jiang CS; Farnham S; Tokeshi B; Buchthal S et al. Altered neurometabolites and motor integration in children exposed to methamphetamine in utero. Neuroimage 48(2): 391-397, 2009. (43 refs.)

Methamphetamine (METH) is a neurotoxic drug. This study aimed to evaluate brain metabolite levels and cognitive function in young children with prenatal METH exposure. 101 children ages 3-4 years were evaluated with neuropsychological tests and underwent proton magnetic resonance spectroscopy (H-1-MRS) without sedation. Complete datasets from 49 METH-exposed and 49 controls who completed the neuropsychological test battery, and 38 METH-exposed and 37 controls with high-quality MR spectra are reported here. Despite similar physical characteristics (including head circumference), global cognitive function (on Stanford-Binet), parental education, intelligence, mood, and socioeconomic status, METH-exposed children had higher total creatine (tCr: + 7%, p= 0.003), N-acetyl compounds (NA: + 4.3%, p= 0.004) and glutamate+glutamine (GLX: + 9.6%, p= 0.02) concentrations in the frontal white matter, but lower myoinositol (MI: -7%, p= 0.01) and MI/tCr (-7.5%, p= 0.03) in the thalamus, than control children. The higher frontal white matter NA in the METH-exposed children was due to the higher NA in the METH-exposed girls (+ 10.2%, p= 0.003), but not the boys (+ 0.8%) compared to sex-matched controls. Furthermore, the METH-exposed children had poorer performance on a visual motor integration (VMI) task, which correlated with lower MI in the thalamus (r-0.26, p-0.03). The higher NA, tCr and GLX concentrations suggest higher neuronal density or cellular compactness in the white matter, especially in the girls, whereas the lower MI suggests lower glial content in the thalamus of these METH-expose children. These findings combined with their poorer performance on VMI also suggest accelerated but aberrant neuronal and glial development in these brain regions.

Copyright 2009, Elsevier Science

Chang L; Cloak CC; Jiang CS; Hoo A; Hernandez AB; Ernst TM. Lower glial metabolite levels in brains of young children with prenatal nicotine exposure. Journal of Neuroimmune Pharmacology 7(1, special issue): 243-252, 2012. (38 refs.)

Many pregnant women smoke cigarettes during pregnancy, but the effect of nicotine on the developing human brain is not well understood, especially in young children. This study aims to determine the effects of prenatal nicotine exposure (PNE) on brain metabolite levels in young (3-4 years old) children, using proton magnetic resonance spectroscopy (H-1 MRS). Twenty-six children with PNE and 24 nicotine-unexposed children (controls) were evaluated with a structured examination, a battery of neuropsychological tests, and MRI/H-1 MRS (without sedation). Concentrations of N-acetyl compounds (NA), total creatine (tCR), choline-containing compounds (CHO), myo-inositol (MI), and glutamate+glutamine (GLX) were measured in four brain regions. Children with PNE had similar performance to controls on neuropsychological testing. However, compared to controls, the PNE group had lower MI (repeated measures ANOVA-p=0.03) and tCr levels (repeated measures ANOVA-p=0.003), especially in the basal ganglia of the girls (-19.3%, p=0.01). In contrast, GLX was elevated in the anterior cingulate cortex of the PNE children (+9.4%, p=0.03), and those with the highest GLX levels had the poorest performance on vocabulary (r=-0.67; p<0.001) and visual motor integration (r=-0.53; p=0.01). The amount of prenatal nicotine exposure did not correlate with metabolite concentrations. These findings suggest that PNE may lead to subclinical abnormalities in glial development, especially in the basal ganglia, and regionally specific changes in other neurometabolites. These alterations were not influenced by the amount of nicotine exposure prenatally. However, the effects of PNE on energy metabolism may be sex specific, with greater alterations in girls.

Copyright 2012, Springer

Chiodo LM; da Costa DE; Hannigan JH; Covington CY; Sokol RJ; Janisse J et al. The impact of maternal age on the effects of prenatal alcohol exposure on attention. Alcoholism: Clinical and Experimental Research 34(10): 1813-1821, 2010. (76 refs.)

Background: Prenatal exposure to alcohol has a variety of morphologic and neurobehavioral consequences, yet more than 10% of women continue to drink during pregnancy, placing their offspring at risk for fetal alcohol spectrum disorders (FASD). Identification of at-risk pregnancies has been difficult, in part, because the presence and severity of FASD are influenced by factors beyond the pattern of alcohol consumption. Establishing maternal characteristics, such as maternal age, that increase the risk of FASD is critical for targeted pregnancy intervention. Methods: We examined the moderating effect of maternal age on measures of attention in 462 children from a longitudinal cohort born to women with known alcohol consumption levels (absolute ounces of alcohol per day at conception) who were recruited during pregnancy. Analyses examined the impact of binge drinking, as average ounces of absolute alcohol per drinking day. Smoking and use of cocaine, marijuana, and opiates were also assessed. At 7 years of age, the children completed the Continuous Performance Test, and their teachers completed the Achenbach Teacher Report Form. Results: After controlling for covariates, stepwise multiple regression analyses revealed a negative relation between levels of prenatal binge drinking and several measures of attention. The interaction between alcohol consumption and maternal age was also significant, indicating that the impact of maternal binge drinking during pregnancy on attention was greater among children born to older drinking mothers. Conclusion: These findings are consistent with previous findings that children born to older alcohol-using women have more deleterious effects of prenatal alcohol exposure on other neurobehavioral outcomes.

Copyright 2010, Wiley-Blackwell

Chiriboga CA; Starr D; Kuhn L; Wasserman GA. Prenatal cocaine exposure and prolonged focus attention. Developmental Neuroscience 31(1/2): 149-158, 2009. (66 refs.)

In experimental models, prenatal cocaine exposure has been found to perturb monoaminergic development of systems implicated in modulating attention. To determine whether prenatal cocaine exposure affects infant attention, we assessed visual recognition memory and focused attention during free play. We enrolled at birth 380 infants, 113 cocaine exposed, using multiple biomarkers to assess drug exposure. Behavior was videotaped and coded off-line for sustained looking time (i.e. focused attention), banging and intrusion. Prenatal cocaine exposure was not associated with visual recognition memory, but was significantly associated with longer sustained looking times (average focused attention) at ages 6 months (p = 0.02) and 12 months (p = 0.04) in analyses that adjusted for variables, including maternal intelligence, education, depressive scores and other exposures (alcohol, tobacco and marijuana). Cocaine-exposed infants at age 12 months also spent significantly less time in banging activity (p = 0.02) after adjusting for confounding variables. This finding was not explained through cocaine effects on motor development, neurological findings or time spent in focused attention. Prenatal cocaine exposure was significantly associated with longer periods of sustained looking or focused attention in infancy, a finding that could interpreted as a measure of poor processing efficiency, or alternatively as precocious maturation of attentional systems. Either interpretation has implications for later cognitive development. Lower banging activity among cocaine exposed was not explained through cocaine effects on motor development or neurological findings, suggesting that activity level itself is diminished in these infants. Whether focused attention findings impact long term development awaits further study.

Copyright 2009, Karger

Cohen RT; Raby BA; Van Steen K; Fuhlbrigge AL; Celedon JC; Rosner BA et al. In utero smoke exposure and impaired response to inhaled corticosteroids in children with asthma. Journal of Allergy and Clinical Immunology 126(3): 491-497, 2010. (38 refs.)

Background: Few studies have examined the effects of in utero smoke exposure (IUS) on lung function in children with asthma, and there are no published data on the impact of IUS on treatment outcomes in children with asthma. Objectives: To explore whether IUS exposure is associated with increased airway responsiveness among children with asthma and whether IUS modifies the response to treatment with inhaled corticosteroids (ICSs). Methods: To assess the impact of parent-reported IUS exposure on airway responsiveness in childhood asthma, we performed a repeated-measures analysis of methacholine PC20 data from the Childhood Asthma Management Program, a 4-year, multicenter, randomized, double-masked, placebo-controlled trial of 1041 children age 5 to 12 years comparing the long-term efficacy of ICS with mast cell stabilizing agents or placebo. Results: Although improvement was seen in both groups, children with asthma and IUS exposure had on average 26% less of an improvement in airway responsiveness over time compared with unexposed children (P = .01). Moreover, while children who were not exposed to IUS who received budesonide experienced substantial improvement in PC20 compared with untreated children (1.25-fold increase; 95% CI, 1.03-1.50; P = .02), the beneficial effects of budesonide were attenuated among children with a history of IUS exposure (1.04-fold increase, 95% CI, 0.65-1.68; P = .88). Conclusion: In utero smoke exposure reduces age-related improvements in airway responsiveness among children with asthma. Moreover, IUS appears to blunt the beneficial effects of ICS use on airways responsiveness. These results emphasize the importance of preventing this exposure through smoking cessation counseling efforts with pregnant women.

Copyright 2010, Mosby Co.

Cornelius MD; Day NL. Developmental consequences of prenatal tobacco exposure. Current Opinion in Neurology 22(2): 121-125, 2009. (34 refs.)

Purpose of review: This paper reviews results from published, in press, and conference proceedings from 2007 and 2008 that link in-utero tobacco exposure to neurodevelopmental outcomes in exposed offspring. Recent findings: Prenatal tobacco exposure (PTE) affected speech processing, levels of irritability and hypertonicity, attention levels, ability to self-regulate, need to be handled, and response to novelty preference in infants. In early childhood, PTE effects were mostly behavioral outcomes including activity and inattention and externalizing behaviors, including conduct disorder and antisocial behavior. In adolescents, PTE predicted increased attention deficit hyperactivity disorder, modulation of the cerebral cortex and white matter structure, and nicotine addiction. Several studies found moderating effects with PTE and genetic susceptibilities including dopamine transporter, serotonergic synaptic function, and monomine oxidase pathways. Other studies suggested that environmental and genetic factors might be more important than the direct teratological effects of PTE. Summary: The majority of studies reviewed were prospective and tobacco exposure was quantified biologically. Most demonstrated a direct association between PTE and neurodevelopmental outcomes. More work is needed to examine multifactorial influences. Effects of PTE on the offspring appear to be moderated by genetic variability, neurobehavioral disinhibition, and sex.

Copyright 2009, Lippincott, Williams & Wilkins

Cornelius MD; Goldschmidt L; De Genna NM; Larkby C. Long-term effects of prenatal cigarette smoke exposure on behavior dysregulation among 14-year-old offspring of teenage mothers. Maternal and Child Health Journal 16(3): 694-705, 2012. (87 refs.)

In this prospective study, we examined the long-term effects of prenatal cigarette smoke exposure (PCSE) on behavioral dysregulation (BD) in the offspring of adolescent mothers. The adolescent mothers (mean age = 16; range = 12-18; 70% African American) were interviewed about their tobacco use during pregnancy. Offspring were followed to age 14 years (n = 318). Indices of BD outcomes included aggression, rule breaking, externalizing, social problems, attention, distractibility and activity. Multiple measures and multiple informants were used for each construct. Regression analyses were conducted to test if PCSE predicted the BD outcomes, adjusting for demographic and maternal psychological characteristics, and for prenatal exposure to other substances. Independent effects of PCSE were found. Exposed offspring had more aggressive, social, and externalizing problems on both the maternal report and the adolescent self-report measures. They were more active, had more attention problems and greater difficulty with distraction and task orientation. Most PCSE effects were found from first trimester exposure and from exposure to as few as 10 cigarettes per day. These results are consistent with previous findings in this cohort when offspring were 6 and 10 years old, demonstrating that the effects of prenatal cigarette smoke exposure can be identified early and persist into adolescence.

Copyright 2012, Springer

D'Onofrio BM; Van Hulle CA; Goodnight JA; Rathouz PJ; Lahey BB. Is maternal smoking during pregnancy a causal environmental risk factor for adolescent antisocial behavior? Testing etiological theories and assumptions. Psychological Medicine 42(7): 1535-1545, 2012. (60 refs.)

Background. Although many studies indicate that maternal smoking during pregnancy (SDP) is correlated with later offspring antisocial behavior (ASB), recent quasi-experimental studies suggest that background familial factors confound the association. The present study sought to test alternative etiological hypotheses using multiple indices of adolescent ASB, comparing differentially exposed siblings, and testing assumptions in the sibling-comparison design. Method. The study examined the association between maternal SDP and adolescent-reported ASB, criminal convictions and membership in a group of individuals with early-starting and chronic ASB among 6066 offspring of women from the National Longitudinal Survey of Youth, a representative sample of women in the USA. The analyses controlled for statistical covariates and examined associations while comparing differentially exposed siblings. Results. At the population level, each additional pack of cigarettes per day predicted greater mean adolescent-reported ASB symptoms [ratio of means 1.15, 95% confidence interval (CI) 1.08-1.22], odds of being in the top 10% of ASB [odds ratio (OR) 1.34, 95% CI 1.10-1.65], hazard of a criminal conviction [hazard ratio (HR) 1.51, 95% CI 1.34-1.68] and odds of chronic ASB (OR 1.57, 95% CI 1.25-1.99). SDP robustly predicted most assessments of ASB while controlling for measured covariates. When siblings exposed to differing levels of SDP were compared, however, all of the associations were attenuated and were not statistically significant : adolescent-reported mean ASB (ratio of means 0.86, 95% CI 0.74-1.01), high ASB (OR 0.67, 95% CI 0.41-1.12), criminal conviction (HR 0.98, 95% CI 0.66-1.44) and chronic ASB (OR 0.80, 95% CI 0.46-1.38). Conclusions. The results strongly suggest that familial factors account for the correlation between SDP and offspring adolescent ASB, rather than a putative causal environmental influence of SDP.

Copyright 2012, Cambridge University Press

Dorea JG. Co-exposure and confounders during neurodevelopment: We need them in the bigger picture of secondhand smoke exposure during pregnancy. (editorial). Environmental Research 111(8): 1332-1333, 2011. (10 refs.)

Eiden RD; Schuetze P; Colder CR; Veira Y. Maternal cocaine use and mother-toddler aggression. Neurotoxicology and Teratology 33(3): 360-369, 2011. (84 refs.)

This study examined the direct and indirect associations between maternal cocaine use during pregnancy and mother-toddler aggression in an interactive context at 2 years of child age. We hypothesized that in addition to direct effects of cocaine exposure on maternal and child aggression, the association between maternal cocaine use and mother-toddler aggression may be indirect via higher maternal psychiatric symptoms, negative affect, or poor infant autonomic regulation at 13 months. Participants consisted of 220 (119 cocaine exposed, 101 non-cocaine exposed) mother-toddler dyads participating in an ongoing longitudinal study of prenatal cocaine exposure. Results indicated that mothers who used cocaine during pregnancy displayed higher levels of aggression toward their toddlers compared to mothers in the control group. Results from model testing indicated significant indirect associations between maternal cocaine use and maternal aggression via higher maternal negative affect as well as lower infant autonomic regulation at 13 months. Although there were no direct associations between cocaine exposure and toddler aggression, there was a significant indirect effect via lower infant autonomic regulation at 13 months. Results highlight the importance of including maternal aggression in predictive models of prenatal cocaine exposure examining child aggression. Results also emphasize the important role of infant regulation as a mechanism partially explaining associations between cocaine exposure and mother-toddler aggression.

Copyright 2011, Elsevier Science

Ekblad M; Gissler M; Lehtonen L; Korkeila J. Relation of prenatal smoking exposure and use of psychotropic medication up to young adulthood. American Journal of Epidemiology 174(6): 681-690, 2011. (33 refs.)

The study objective was to determine the relation of prenatal smoking exposure to the use of psychotropic medication up to young adulthood by using population-based longitudinal register data consisting of all singletons born in Finland from 1987 to 1989 (n = 175,869). Information on maternal smoking was assessed during antenatal care and received from the Finnish Medical Birth Register. Information on the children's psychotropic medication (1994-2007) was received from the Drug Prescription Register, and the children's psychiatric diagnoses related to outpatient (1998-2007) and inpatient (1987-2007) care were derived from the Finnish Hospital Discharge Register. A total of 15.3% (n = 26,083) of the children were exposed to prenatal smoking. The incidence of psychotropic medication use was 8.3% in unexposed children, 11.3% in children exposed to < 10 cigarettes per day (adjusted odds ratio = 1.36, 95% confidence interval: 1.29, 1.43), and 13.6% in children exposed to > 10 cigarettes per day (odds ratio = 1.63, 95% confidence interval: 1.53, 1.74). The exposure was significantly associated with the risk for all medication use and for both single- and multiple-drug consumption even after adjustment (e.g., mothers' severe psychiatric illnesses). These findings show that exposure to smoking during pregnancy is linked to both mild and severe psychiatric morbidity.

Copyright 2011, Oxford University Press

El Marroun H; Hudziak JJ; Tiemeier H; Creemers H; Steegers EAP; Jaddoe VWV et al. Intrauterine cannabis exposure leads to more aggressive behavior and attention problems in 18-month-old girls. Drug and Alcohol Dependence 118(2-3): 470-474, 2011. (25 refs.)

Background: The development of the fetal endocannabinoid receptor system may be vulnerable to maternal cannabis use during pregnancy and may produce long-term consequences in children. In this study, we aimed to determine the relationship between gestational cannabis use and childhood attention problems and aggressive behavior. Methods: Using a large general population birth cohort, we examined the associations between parental prenatal cannabis and tobacco use and childhood behavior problems at 18 months measured using the Child Behavior Checklist in N=4077 children. Substance use was measured in early pregnancy. Results: Linear regression analyses demonstrated that gestational exposure to cannabis is associated with behavioral problems in early childhood but only in girls and only in the area of increased aggressive behavior (B = 2.02; 95% CI: 0.30-3.73; p = 0.02) and attention problems (B = 1.04; 95% CI: 0.46-1.62; p < 0.001). Furthermore, this study showed that long-term (but not short term) tobacco exposure was associated with behavioral problems in girls (B = 1.16; 95% Cl: 0.20-2.12; p = 0.02). There was no association between cannabis use of the father and child behavior problems. Conclusions: Our results suggest that intrauterine exposure to cannabis is associated with an increased risk for aggressive behavior and attention problems as early as 18 months of age in girls, but not boys. Further research is needed to explore the association between prenatal cannabis exposure and child behavior at later ages. Our data support educating future mothers about the risk to their babies should they smoke cannabis during pregnancy.

Copyright 2011, Elsevier Science

Ellingson JM; Rickert ME; Lichtenstein P; Langstrom N; D'Onofrio BM. Disentangling the relationships between maternal smoking during pregnancy and co-occurring risk factors. Psychological Medicine 42(7): 1547-1557, 2012. (64 refs.)

Background. Maternal smoking during pregnancy (SDP) has been studied extensively as a risk factor for adverse offspring outcomes and is known to co-occur with other familial risk factors. Accounting for general familial risk factors has attenuated associations between SDP and adverse offspring outcomes, and identifying these confounds will be crucial to elucidating the relationship between SDP and its psychological correlates. Method. The current study aimed to disentangle the relationship between maternal SDP and co-occurring risk factors (maternal criminal activity, drug problems, teen pregnancy, educational attainment, and cohabitation at childbirth) using a population-based sample of full- (n = 206 313) and half-sister pairs (n = 19 363) from Sweden. Logistic regression models estimated the strength of association between SDP and co-occurring risk factors. Bivariate behavioral genetic models estimated the degree to which associations between SDP and co-occurring risk factors are attributable to genetic and environmental factors. Results. Maternal SDP was associated with an increase in all co-occurring risk factors. Of the variance associated with SDP, 45% was attributed to genetic factors and 53% was attributed to unshared environmental factors. In bivariate models, genetic factors accounted for 21% (non-drug-, non-violence-related crimes) to 35% (drug-related crimes) of the covariance between SDP and co-occurring risk factors. Unshared environmental factors accounted for the remaining covariance. Conclusions. The genetic factors that influence a woman's criminal behavior, substance abuse and her offspring's rearing environment all influence SDP. Therefore, the intergenerational transmission of genes conferring risk for antisocial behavior and substance misuse may influence the associations between maternal SDP and adverse offspring outcomes.

Copyright 2012, Cambridge University Press

Fisher PA; Lester BM; DeGarmo DS; Lagasse LL; Lin H; Shankaran S et al. The combined effects of prenatal drug exposure and early adversity on neurobehavioral disinhibition in childhood and adolescence. Development and Psychopathology 23(3, special issue): 777-788, 2011. (54 refs.)

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 1,073 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.

Copyright 2011, Cambridge University Press

Frye CA; Paris JJ; Osborne DM; Kippin TE. Prenatal stress alters progestogens to mediate susceptibility to sex-typical, stress-sensitive disorders, such as drug abuse: A review. (review). Frontiers in Psychiatry 2: e-52, 2011

Maternal-offspring interactions begin prior to birth. Experiences of the mother during gestation play a powerful role in determining the developmental programming of the central nervous system. In particular, stress during gestation alters developmental programming of the offspring resulting in susceptibility to sex-typical and stress-sensitive neurodevelopmental, neuropsychiatric, and neurodegenerative disorders. However, neither these effects, nor the underlying mechanisms, are well understood. Our hypothesis is that allopregnanolone, during gestation, plays a particularly vital role in mitigating effects of stress on the developing fetus and may mediate, in part, alterations apparent throughout the lifespan. Specifically, altered balance between glucocorticoids and progestogens during critical periods of development (stemming from psychological, immunological, and/or endocrinological stressors during gestation) may permanently influence behavior, brain morphology, and/or neuroendocrine-sensitive processes. 5alpha-reduced progestogens are integral in the developmental programming of sex-typical, stress-sensitive, and/or disorder-relevant phenotypes. Prenatal stress (PNS) may alter these responses and dysregulate allopregnanolone and its normative effects on stress axis function. As an example of a neurodevelopmental, neuropsychiatric, and/or neurodegenerative process, this review focuses on responsiveness to drugs of abuse, which is sensitive to PNS and progestogen milieu. This review explores the notion that allopregnanolone may effect, or be influenced by, PNS, with consequences for neurodevelopmental-, neuropsychiatric-, and/or neurodegenerative- relevant processes, such as addiction.

Copyright 2011, Frontiers Media

Geerts CC; Bots ML; van der Ent CK; Grobbee DE; Uiterwaal CSPM. Parental smoking and vascular damage in their 5-year-old children. Pediatrics 129(1): 45-54, 2012. (42 refs.)

BACKGROUND: The relation between smoke exposure in early life, the prenatal period in particular, and the vascular development of young children is largely unknown. METHODS: Data from the birth cohort participating in the WHISTLER-Cardio study were used to relate the smoking of parents during pregnancy to subsequent vascular properties in their children. In 259 participating children who turned 5 years of age, parental smoking data were updated and children's carotid artery intimamedia thickness (CIMT) and arterial wall distensibility were measured by using ultrasonography. RESULTS: Children of mothers who had smoked throughout pregnancy had 18.8 mu m thicker CIMT (95% confidence interval [CI] 1.1, 36.5, P = .04) and 15% lower distensibility (95% CI -0.3, -0.02, P = .02) after adjustment for child's age, maternal age, gender, and breastfeeding. The associations were not found in children of mothers who had not smoked in pregnancy but had smoked thereafter. The associations were strongest if both parents had smoked during pregnancy, with 27.7 mu m thicker CIMT (95% CI 0.2, 55.3) and 21% lower distensibility (95% CI -0.4, -0.03). CONCLUSION: Exposure of children to parental tobacco smoke during pregnancy affects their arterial structure and function in early life.

Copyright 2012, American Academy of Pediatrics

Ghetau E; Bloor R; Firth AY. Identification of strabismus in children born to mothers misusing substances during pregnancy: A clinical and research challenge. Drugs: Education, Prevention and Policy 16(1): 88-93, 2009. (17 refs.)

Purpose: To increase awareness of the causal relationship between illicit drug use in pregnancy and the occurrence of strabismus in children amongst the relevant professionals and encourage the use of local arrangements for referral, assessment and treatment of this population at risk. Method: A review of the literature regarding the occurrence of strabismus in children of mothers misusing substances and an outline the consequences of strabismus. Results: Children prenatally exposed to the effects of psychoactive substances are at increased risk of neurodevelopmental and neurobehavioural abnormalities; ocular defects are frequently mentioned as some of them. Strabismus, the consequences of which are treatable, is amongst these. Conclusion: Research in this area is challenging, but while more evidence is awaited, current evidence indicates the increased risk of strabismus in this group and recommendations regarding the early detection of, and referral for, this condition are made.

Copyright 2009, Taylor & Francis

Goetzinger KR; Cahill AG; Macones GA; Odibo AO. The relationship between maternal body mass index and tobacco use on small-for-gestational-age infants. American Journal of Perinatology 29(3): 153-158, 2012. (22 refs.)

We sought to estimate the association between prepregnancy body mass index (BMI) and small-for-gestational-age (SGA) neonates and to determine if there is a synergistic effect of tobacco use on SGA across all BMI strata. We performed a retrospective cohort study of 65,104 patients seen for second-trimester ultrasound. BMI was categorized into underweight, normal weight, overweight, and obese. SGA was defined as birth weight < 10th percentile and < 5th percentile. Univariable and multivariable logistic regression analyses were used to evaluate the association between BMI and SGA. Stratified analyses and tests for effect modification were performed to evaluate for a potential synergistic effect between tobacco use and abnormal prepregnancy BMI on SGA. After controlling for potential confounders, underweight BMI was associated with an increased risk for SGA < 10th percentile (adjusted odds ratio [aOR] 1.8, 95% confidence interval [Cl] 1.5 to 2.1), while overweight (aOR 0.7, 95% Cl 0.7 to 0.8) and obese BMIs (aOR 0.6, 95% Cl 0.5 to 0.7) were associated with a decreased risk of SGA. There was no effect modification of tobacco use on the risk of SGA across all BMI categories. Although both tobacco and underweight BMI are independently associated with SGA, there was no evidence of synergism. Continued emphasis on both smoking cessation and maintenance of normal prepregnancy BMI remains paramount to decreasing the incidence of SGA.

Copyright 2012, Thieme Medical Publishers

Goldschmidt L; Cornelius MD; Day NL. Prenatal cigarette smoke exposure and early initiation of multiple substance use. Nicotine & Tobacco Research 14(6): 694-702, 2012. (45 refs.)

Earlier studies have shown a relation between prenatal cigarette smoke exposure (PCSE) and offspring initiation of tobacco use. No prior study has examined the association between PCSE and early initiation of multiple substances (EIMS) including marijuana and alcohol in addition to tobacco. We investigated the association between PCSE and multiple substance use during adolescence. Pregnant women attending an urban prenatal clinic were selected to participate in the prospective longitudinal study based on their substance use. This study is based on the 16-year follow-up phase and consists of 579 mother-offspring dyads. The women were of lower socioeconomic status, 54% were Black, and 53% reported smoking cigarettes. 52% of the offspring were female. EIMS is a measure of the number of substances initiated prior to age 16 by the adolescents; it ranged from 0 (no initiation, N = 166) to 3 (all, N = 162). Adolescents exposed to tobacco during first trimester of gestation were 1.4 times more likely to initiate multiple substances by age 16 than the nonexposed group. PCSE was a significant predictor of EIMS after controlling for other prenatal exposures, home environment, and demographic characteristics, using ordinal polytomous logistic regression. Other risk factors of EIMS were maternal and adolescent depression, less strict and less involved parenting, offspring attention problems, and lack of participation in a youth club. There is a significant relation between PCSE and adolescent's EIMS.

Copyright 2012, Oxford University Press

Gorog K; Pattenden S; Antova T; Niciu E; Rudnai P; Scholtens S et al. Maternal smoking during pregnancy and childhood obesity: Results from the CESAR Study. Maternal and Child Health Journal 15(7): 985-992, 2011. (40 refs.)

Childhood obesity is a worldwide public health concern. Recent studies from high income countries have demonstrated associations between maternal smoking during pregnancy and children's excess body weight. We examine associations between maternal smoking during pregnancy and children's overweight or obesity, in six countries in the less affluent Central/Eastern European region. Questionnaire data were analysed, for 8,926 singleton children aged 9-12 years. Country-specific odds ratios for effects of maternal smoking during pregnancy on being overweight, and on obesity, were estimated using logistic regression. Heterogeneity between country-specific results, and mean effects (allowing for heterogeneity) were estimated. Positive associations between maternal smoking and overweight were seen in all countries but Romania. While not individually statistically significant, the mean odds ratio was 1.26 (95% CI 1.03-1.55), with no evidence of between-country heterogeneity. Obese children were few (2.7%), and associations between obesity and maternal smoking during pregnancy were more heterogeneous, with odds ratios ranging from 0.71 (0.32-1.57) in Poland to 5.49 (2.11-14.30) in Slovakia. Between-country heterogeneity was strongly related to average persons-per-room, a possible socioeconomic indicator, with stronger associations where households were less crowded. Estimates of dose-response relationships tended to be small and non-significant, even when pooled. Our results provide evidence of a link between maternal smoking in pregnancy and childhood overweight. Associations with obesity, though strong in some countries, were less consistent. Maternal smoking may confer an addition to a child's potential for obesity, which is more likely to be realised in affluent conditions.

Copyright 2011, Springer

Habek D; Kovacevic M. Adverse pregnancy outcomes and long-term morbidity after early fetal hypokinesia in maternal smoking pregnancies. Archives of Gynecology and Obstetrics 283(3): 491-495, 2011. (33 refs.)

The aim of this study is to evaluate perinatal outcome and subsequent morbidity and neurodevelopment in 10-year-old children with fetal hypokinesia intrauterinely verified by ultrasonography in early pregnancy as a pattern of abnormal fetal behavior due to maternal chronic smoking. This study revealed significant global fetal hypokinesia as well as head and arm hypokinesia in early pregnancy in mothers' chronic smokers (group 3-more than 20 cigarettes a day). This retrospective study was performed in mothers and their 10-year-old children included in the study of the effect of cigarette smoking on fetal movements in early pregnancy. Perinatal outcome was assessed according to maternal data, course, and outcome of pregnancy and delivery. Data on the long-term (10 years) development and morbidity from infancy during childhood until age 10 years were obtained from the children's medical histories and medical rehabilitation records, maternal, and paternal histories. The psycholinguistic development was estimated. In group 3, there was a poor overall perinatal outcome and high rate of the bronchoconstrictive syndrome and recurrent infections, while one case of the sudden infant death syndrome. Poor school performance was recorded in five children, attention-deficit/hyperactivity disorder in four, and autism, dystonia syndrome, social maladaptation, and minimally cerebral disfunction in one child each. Retarded psycholinguistic development was found in seven children, only three of them attending speech therapy (P < 0.05). Fetal hypokinesia in early pregnancy related with maternal smoking was found to correlate with poor perinatal outcome, subsequent morbidity, and developmental impairments in 10-year-old children born to mothers smoking more than 20 cigarettes a day.

Copyright 2011, Springer

Hamilton R; McGlone L; MacKinnon JR; Russell HC; Bradnam MS; Mactier H. Ophthalmic, clinical and visual electrophysiological findings in children born to mothers prescribed substitute methadone in pregnancy. British Journal of Ophthalmology 94(6): 696-700, 2010. (24 refs.)

Background and aims: There are growing concerns regarding visual outcome of infants exposed to opiates (including substitute methadone) and/or benzodiazepines in utero. We describe the combined ophthalmology and visual electrophysiology findings in 20 infants and children who had been exposed to substitute methadone and other drugs of misuse in utero. Methods: This was a descriptive case series of 20 patients, all of whom had been referred to a paediatric visual electrophysiology service because of concerns regarding visual function, and all of whom had been exposed to methadone in utero. All children underwent a full ophthalmic and orthoptic examination as well as visual electrophysiology testing deemed appropriate on an individual basis. A review was undertaken of paediatric case notes and of maternal antenatal urine toxicology. Results: Ophthalmic abnormalities included reduced acuity (95%), nystagmus (70%), delayed visual maturation (50%), strabismus (30%), refractive errors (30%), and cerebral visual impairment (25%). Visual electrophysiology was abnormal in 60%. A quarter of the children had associated neurodevelopmental abnormalities. The majority of children with nystagmus (79%) had been treated for neonatal abstinence syndrome (NAS). Conclusion: Infants born to drug-misusing mothers prescribed methadone in pregnancy are at risk of a range of visual problems, the underlying causes of which are not clear. Those infants with NAS severe enough to receive pharmaceutical treatment may be at particular risk of developing nystagmus. The inclusion of visual electrophysiology in comprehensive visual assessment of children exposed to substance misuse in utero may help clarify the underlying causes by differentiating abnormalities of retinal and cortical origin.

Copyright 2010, BMJ Publishing

Hayatbakhsh MR; Sadasivam S; Mamun AA; Najman JM; Williams GM; O'Callaghan MJ. Maternal smoking during and after pregnancy and lung function in early adulthood: A prospective study. Thorax 64(9): 810-814, 2009. (29 refs.)

Background and aims: There is a paucity of evidence about whether exposure to antenatal smoking impacts on offspring's lung function in early adulthood. This study aimed to examine whether (1) in utero exposure to maternal smoking is related to poorer respiratory functioning in early adulthood; (2) the impact of prenatal smoking is independent of postnatal maternal smoking; and (3) the link between prenatal smoking and a young adult's lung function is explained by the child's birth weight, smoking or history of asthma. Methods: Data were from a 21-year follow-up of mothers and their children recruited into the Mater University of Queensland Study of Pregnancy, a longitudinal prebirth cohort. The study is based on 2409 young adults (1185 males and 1224 females) who had prospective data available on respiratory function at 21 years and maternal smoking during and after pregnancy. A Spirobank G spirometer system was used to measure forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1) and forced expiratory flow between 25% and 75% of FVC (FEF25-75). Results: In utero exposure to maternal smoking was associated with a reduction in FEV1 and FEF25-75 in males (regression coefficient, -0.16; 95% CI, -0.30 to -0.02), after accounting for maternal smoking after pregnancy. At least part of the effect of in utero smoking on young adults' lung function was explained by the child's birth weight and subsequent asthma. Conclusions: Adverse effects of antenatal smoking on development of airway growth may persist into early adulthood. Gender differences noted in this longitudinal cohort need to be explored further.

Copyright 2009, BMJ Publishing

Huijbregts SCJ; van Berkel SR; Swaab-Barneveld H; van Goozen SHM. Neurobiological and behavioral stress reactivity in children prenatally exposed to tobacco. Psychoneuroendocrinology 36(6): 913-918, 2011. (23 refs.)

This study examined neurobiological and behavioral stress reactivity in children who had been prenatally exposed to tobacco. Neurobiological stress reactivity was measured using salivary cortisol and alpha-amylase levels at five different time points throughout a stressful neuropsychological test session, which involved a competition against a videotaped opponent. Participants (mean age: 10.6 years, SD 1.3) were 14 prenatally exposed (PE) children, 9 children with disruptive behavior problems (DBD), and 15 normal controls (NC). For cortisol responses, no significant differences between the three groups were observed. Normal controls, however, had significantly higher alpha-amylase levels than PE-children throughout the test session, and their alpha-amylase levels also increased throughout the session, whereas these remained low and stable for PE-children. Alpha-amylase levels and trajectory of PE-children were similar to those observed for DBD-children. PE-children also showed significantly increased behavioral stress reactivity compared to NC-children, and neurobiological and behavioral stress reactivity were inversely related in PE-children, again similar to what was observed for DBD-children. These results support the hypothesis that prenatal smoking may lead to long-lasting neurobiological and behavioral changes in exposed offspring.

Copyright 2011, Elsevier Science

Iliadou AN; Koupil I; Villamor E; Altman D; Hultman C; Langstrom N et al. Familial factors confound the association between maternal smoking during pregnancy and young adult offspring overweight. International Journal of Epidemiology 39(5): 1193-1202, 2010. (36 refs.)

Methods: In a population-based Swedish cohort comprising 124 203 singleton males born to Nordic mothers between 1983 and 1988, we examined the association between maternal smoking during pregnancy and the risk of overweight in the offspring at age similar to 18 years. We also investigated the association within siblings, controlling for common genes and shared environment. Results: In the cohort analyses, the risk of overweight was increased in sons of smoking mothers compared with sons of non-smokers: adjusted odds ratios 1.41, 95% confidence interval (CI) 1.34-1.49, and 1.56, 95% CI 1.46-1.66, for one to nine cigarettes per day, and > 10 cigarettes per day, respectively. Stratifying for maternal smoking habits across two subsequent male pregnancies, there was an increased risk of overweight for the second son only if the mother was smoking in both male pregnancies. The effect of smoking during pregnancy on the offspring's body mass index was not present when the association was evaluated within full and half sibling pairs. Conclusion: The association between maternal smoking during pregnancy and offspring's risk of overweight appears to be confounded by familial factors.

Copyright 2010, Oxford University Press

Ino T. Maternal smoking during pregnancy and offspring obesity: Meta-analysis. Pediatrics International 52(1): 94-99, 2010. (49 refs.)

Background: Recent reports have suggested that maternal smoking may increase the risk of development of obesity in the unborn child in later life, but relatively few cohort studies have been done on the relationship between maternal smoking during pregnancy and future development of metabolic syndrome. Methods: A systematic review and meta-analysis of observational studies reporting effect estimates and 95% confidence intervals (95%CI) was conducted on the association between maternal smoking during pregnancy and obesity of future offspring. Results: Seventeen papers were identified from 444 English-language papers (key word search: maternal smoking and obesity) in PubMed. All papers showed a positive association between maternal smoking during pregnancy and childhood obesity. The meta-analysis, using the DerSimonian-Laird method, found the association to be statistically significant. In association with maternal smoking during pregnancy and body mass index with more than 95%CI in the offspring aged 3-33 years, the pooled odds ratio calculated from 16 of these 17 studies was 1.64 (95%CI: 1.42-1.90). After adjustment for publication bias, the pooled adjusted odds ratio was 1.52 (95%CI: 1.36-1.70). In addition, confounders of maternal obesity, low social status, low birthweight and not being breast-fed seemed to be risk factors for offspring obesity. Conclusion: Maternal smoking during pregnancy may cause future obesity and metabolic syndrome.

Copyright 2010, Wiley-Blackwell

Ino T; Shibuya T; Saito K; Ohtani T. Effects of maternal smoking during pregnancy on body composition in offspring. Pediatrics International 53(6): 851-857, 2011. (34 refs.)

Background: The aim of the present cross-sectional study was to use objective methods to assess the association between maternal smoking and body composition in offspring. Methods: A total of 2508 grade 4 school children were enrolled; all underwent lifestyle disease and passive smoking screening. Children were classified into four groups according to their urinary cotinine level and maternal smoking status during or before pregnancy. Items measured on lifestyle disease screening were compared among the four groups. Results: Only degree of obesity (DO) and body mass index (BMI) were significantly associated with maternal smoking during pregnancy. The prevalence of both DO > 20% and DO > 30%, and BMI > 22% and BMI > 25% was highest in children of mothers who smoked during pregnancy. These children had a tendency toward shorter height and increased weight although it was not statistically significant. There were no significant differences between maternal smoking status and lipid profile among groups. Confounders such as food, exercise and sleep were able to be eliminated. Conclusion: Maternal smoking during pregnancy may be an independent risk factor of changing body composition in offspring, that is, shorter height and increased weight.

Copyright 2011, Wiley-Blackwell

Jansson LM; DiPietro JA; Elko A; Velez M. Infant autonomic functioning and neonatal abstinence syndrome. Drug and Alcohol Dependence 109(1-3): 198-204, 2010. (50 refs.)

Background: Neonatal abstinence syndrome (NAS) expression is widely variable among affected infants and the reasons for this variability are largely unknown; mechanisms that predispose infants to NAS expression are not understood. It has been postulated that the regulatory problems of prenatally drug exposed infants are manifested in dysfunctional vagal regulation of autonomic processes. The current study examines whether cardiac vagal tone, an indicator of parasympathetic neuroregulation, provides a marker for autonomic dysregulation subsequently expressed as NAS in prenatally opioid-exposed newborns. Methods: Heart period (HP) and cardiac vagal tone (V) were derived from electrocardiogram data collected from 64 methadone-exposed infants on postnatal days 1 and 3. The postpartum NAS course was assessed serially. Results: Infants with lower V on day 1 had significantly higher NAS symptomatology on day 3. Boys had more severe NAS symptoms than girls through the first 4 days of life and, among infants receiving pharmacologic treatment for NAS, boys required longer treatment course and hospitalizations. Greater poly-drug exposure, detected through toxicology screening throughout pregnancy, and cocaine use in particular, were associated with lower V and shorter HP (faster heart rate) in newborns. Multiple regression models accounted for 25-35% of the variance in NAS symptoms and duration of hospitalization in methadone-exposed infants. Significant predictors included infant sex, SSRI/SNRI use, and cigarette smoking. Conclusions: Results support the hypothesis of a biologic vulnerability of autonomic regulatory functioning in methadone-exposed infants and greater male infant vulnerability to maternal methadone use.

Copyright 2010, Elsevier Science

Kiechl-Kohlendorfer U; Ralser E; Peglow UP; Reiter G; Griesmaier E; Trawoger R. Smoking in pregnancy: A risk factor for adverse neurodevelopmental outcome in preterm infants? Acta Paediatrica 99(7): 1016-1019, 2010. (25 refs.)

Aim: To assess whether smoking in pregnancy influences neurodevelopmental outcome at 2-years of age in preterm infants with a gestational age <32 weeks. Methods: Between January 2003 and December 2005 we prospectively enrolled 181 infants born alive between 23 and 32 weeks of gestation; 142 infants (78.5%) completed the follow-up visit. The association between candidate risk factors and delayed motor or mental development (Bayley Scales of Infant Development II; psychomotor or mental developmental index <85) was analysed by means of logistic regression analysis. Results: Low maternal age, smoking in pregnancy, low gestational age, low birth weight, small for gestational age, chronic lung disease, intracerebral haemorrhage, periventricular leucomalacia, and retinopathy of prematurity (stages 3 and 4) all were associated with an increased risk for delayed development (p < 0.05, each). Smoking in pregnancy, small for gestational age and chronic lung disease maintained significance in a multivariable analysis. Conclusion: Smoking in pregnancy emerged as a risk predictor for adverse neurodevelopmental outcome in our study. Strategies to reduce smoking in pregnancy should be further endorsed.

Copyright 2010, Wiley-Blackwell

Knopik VS. Maternal smoking during pregnancy and child outcomes: Real or spurious effect? (review). Developmental Neuropsychology 34(1): 1-36, 2009. (155 refs.)

Maternal smoking during pregnancy (MSDP) is a major public health concern with clearly established consequences to both mother and newborn (e.g., low birth weight, altered cardiorespiratory responses). MSDP has also been associated with higher rates of a variety of poor cognitive and behavioral outcomes in children, including attention deficit hyperactivity disorder (ADHD), conduct disorder, impaired learning and memory, and cognitive dysfunction. However, the evidence suggesting causal effects of MSDP for these outcomes is muddied in the existing literature due to the frequent inability to separate prenatal exposure effects from other confounding environmental and genetic factors. Carefully designed studies using genetically sensitive strategies can build on current evidence and begin to elucidate the likely complex factors contributing to associations between MSDP and child outcomes.

Copyright 2009, Lawrene Erlbaum

Koshy G; Delpisheh A; Brabin BJ. Dose response association of pregnancy cigarette smoke exposure, childhood stature, overweight and obesity. European Journal of Public Health 21(3): 286-291, 2011. (36 refs.)

Background: The combined dose response effects of pregnancy cigarette smoke exposure on childhood overweight, obesity and short stature have not been reported. Method: A community based cross-sectional survey of 3038 children aged 5-11 years from 15 primary schools in Merseyside, UK. Self-completed parental questionnaires were used for family characteristics, socio-economic status and parental smoking practices. Children were measured for height and weight and z-scores calculated for parental smoking categories. Results: Of 689 (34.0%) mothers who smoked during pregnancy 50.5% smoked ten or more cigarettes daily (heavy smokers). Children of maternal non-smokers had prevalence estimates for overweight, obesity and short stature of 25, 9.6 and 3.2%, respectively. Prevalence estimates were higher in children of mothers who were heavy smokers during pregnancy, 31.5% (P = 0.001), 15.6% (P < 0.001) and 5.5% (P = 0.001), respectively. Mean height for age z-scores was lower among heavy maternal (P < 0.001) and paternal smokers (P < 0.01) compared to non-smokers. Childhood overweight, obesity or short stature were all associated with heavy maternal smoking during pregnancy (all P < 0.001). Mean body mass index (BMI) z-scores were higher in boys of mothers who smoked (P = 0.043). The adjusted odds ratio for short stature in children of heavy maternal smokers was 2.76 (95% CI 1.21-6.33) and 4.28 (1.37-13.37) if both parents were heavy smokers. The adjusted OR for obesity in children of maternal smokers was 1.61(1.19-2.18). The population attributable risk for short stature was 8.8% (1.1-22.7) for heavy maternal smokers. Conclusion: A dose-response association was observed between pregnancy smoking exposure, short stature and obesity.

Copyright 2011, Oxford University Press

Kuja-Halkola R; D'Onofrio BM; Iliadou AN; Langstrom N; Lichtenstein P. Prenatal smoking exposure and offspring stress coping in late adolescence: No causal link. International Journal of Epidemiology 39(6): 1531-1540, 2010. (49 refs.)

Background: In utero exposure to tobacco smoking has been suggested to cause persistent alterations in cognitive functioning. We examined if mothers' smoking during pregnancy (SDP) is associated with long-term impairment in offspring stress coping and the causal mechanism behind a possible link. Methods: We used a large cohort (n = 187 106) of young males in Sweden (mean age = 18.2 years), who underwent a semi-structured psychological assessment in 1997-2006, including an evaluation of stress coping ability, as part of the compulsory military conscript examination. We compared differentially exposed siblings within nuclear families and cousins in extended families and used multilevel structural equation models to disentangle genetic from environmental contributions to the association between SDP and stress coping. Results: SDP and offspring stress coping was moderately strongly associated when comparing unrelated individuals [regression coefficient (b) = -0.38 on a nine-point scale; 95% confidence interval (CI) -0.40 to -0.36, P < 0.0001]. In contrast, it disappeared when siblings were compared (b = 0.11; 95% CI -0.01 to 0.23, P = 0.071). This familial confounding was entirely due to genetic influences. Conclusions: SDP is an established risk factor for pregnancy- and birth-related complications. However, we found no long-term effect of SDP on offspring stress coping. Rather, the observed association was due to familial confounding of genetic origin; women prone to SDP also transmit genes to their children that are associated with poorer coping with stress.

Copyright 2010, Oxford University Press

LaGasse LL; Derauf C; Smith LM; Newman E; Shah R; Neal C et al. Prenatal methamphetamine exposure and childhood behavior problems at 3 and 5 years of age. Pediatrics 129(4): 681-688, 2012. (45 refs.)

Objective: We evaluated behavior problems in children who were prenatally exposed to methamphetamine (MA) at ages 3 and 5 years. Methods: The Infant Development, Environment, and Lifestyle study, a prospective, longitudinal study of prenatal MA exposure and child outcome, enrolled subjects postpartum in Los Angeles, California; Honolulu, Hawaii; Des Moines, Iowa; and Tulsa, Oklahoma. Prenatal exposure was determined by maternal self-report and/or meconium results. Exposed and comparison groups were matched on race, birth weight, public health insurance, and education. Mothers in the comparison group denied use and had a negative meconium screen for amphetamines. Prenatal exposures to tobacco, alcohol, or marijuana occurred in both groups. At ages 3 and 5 years, 330 children (166 exposed and 164 comparison) were assessed for behavior problems by using the caregiver report on the Child Behavior Checklist. General linear mixed models were used to determine the effects of prenatal methamphetamine exposure, including heavy exposure (>= 3 days per week), age, and the interaction of exposure and age on behavior problems with adjustment for other drugs of abuse and environmental risk factors. Results: methamphetamine exposure was associated with increased emotional reactivity and anxious/depressed problems at both ages and externalizing and attention-deficit/hyperactivity disorder problems by age 5 years. Heavy exposure was related to attention problems and withdrawn behavior at both ages. There were no effects of MA on the internalizing or total behavior problems scales. Conclusions: This first report of behavior problems in patients as young as 3 years associated with methamphetamine exposure identifies an important public health problem. Continued follow-up can inform the development of preventive intervention programs.

Copyright 2012, American Academy of Pediatrics

Lee BE; Hong YC; Park H; Ha M; Kim JH; Chang N et al. Secondhand smoke exposure during pregnancy and infantile neurodevelopment. Environmental Research 111(4): 539- 544, 2011. (59 refs.)

During prenatal development, the nervous system may be more susceptible to environmental toxicants, such as secondhand smoke. The authors assessed the effects of prenatal and postnatal secondhand smoke exposure on the neurodevelopment of 6-month infants. The subjects were 414 mother and infant pairs with no medical problems, taken from the Mothers' and Children's Environmental Health study. Prenatal and postnatal exposures to secondhand smoke were determined using maternal self-reports. Examiners, unaware of exposure history, assessed the infants at 6 months of age using the Bayley Scales of Infant Development. Bayley scores were compared for secondhand smoke exposed and unexposed groups after adjusting for potential confounders. Multiple logistic regression analysis was carried out to estimate the risk of developmental delay posed by SHS exposure. The multivariate model included residential area, maternal age, pre-pregnancy body mass index, education, income, infant sex, parity, birth weight, and type of feeding. After adjusting for covariates, secondhand smoke exposure during pregnancy was found to be related to a decrease in mental developmental index score, but not to a decrease in psychomotor developmental index score. In addition, secondhand smoke exposure during pregnancy was found to increase the risk of developmental delay (mental developmental index score 5 85) at 6 months. This study suggests that the infants of non-smoking women exposed to secondhand smoke are at risk of neurodevelopmental delay.

Copyright 2011, Elsevier Science

Lester BM; Padbury JF. Third pathophysiology of prenatal cocaine exposure. (review). Developmental Neuroscience 31(2): 23-25, 2009. (237 refs.)

The pathophysiology of the effects of cocaine on fetal development has been described along 2 major pathways: neurochemical effects and vasoconstrictive effects. Following a summary of these effects, we suggest a 'third pathophysiology' in which altered fetal programming affects the acute and long-term adverse effects of in utero cocaine exposure. We describe how cocaine as a stressor alters the expression of key candidate genes, increasing exposure to catecholamines and fetal cortisol-altering neuroendocrine (hypothalamic-pituitary-adrenal axis) activity, leading to infant behavioral dysregulation, poor behavioral control and emotion regulation during childhood and phenotypes that confer vulnerability to substance use in adolescence. This model is discussed in relation to follow-up studies of the effects of in utero cocaine exposure and maturational changes in brain development.

Copyright 2009, Karger

Levine TP; Lester B; Lagasse L; Shankaran S; Bada HS; Bauer CR et al. Psychopathology and special education enrollment in children with prenatal cocaine exposure. Journal of Developmental And Behavioral Pediatrics 33(5): 377-386, 2012. (61 refs.)

Objective: This study evaluated how enrollment in special education services in 11-year-old children relates to prenatal cocaine exposure (PCE), psychopathology, and other risk factors. Methods: Participants were 498 children enrolled in The Maternal Lifestyle Study, a prospective, longitudinal, multisite study examining outcomes of children with PCE. Logistic regression was used to examine the effect of PCE and psychopathology on enrollment in an individualized education plan (IEP; a designation specific to children with special education needs), with environmental, maternal, and infant medical variables as covariates. Results: PCE, an interaction of PCE and oppositional defiant disorder, child attention-deficit hyperactivity disorder, parent-reported internalizing behaviors, and teacher-reported externalizing behaviors, predicted enrollment in an IEP. Other statistically significant variables in the model were male gender, low birth weight, being small for gestational age, white race, caregiver change, low socioeconomic status, low child intelligence quotient, caregiver depression, and prenatal marijuana exposure. Conclusions: PCE increased the likelihood of receiving an IEP with adjustment for covariates. Psychopathology also predicted this special education outcome, in combination with and independent of prenatal cocaine exposure.

Copyright 2012, Lippincott, Williams & Wilkins

Li L; Zhu GQ; Meng T; Shi JY; Wu J; Xu X et al. Biological and epidemiological evidence of interaction of infant genotypes at Rs7205289 and maternal passive smoking in cleft palate. American Journal of Medical Genetics. Part A 155A(12): 2940-2948, 2011. (49 refs.)

The noncoding SNP rs7205289, located in the microRNA-140 gene has been associated with cleft palate risk. MiR-140 was found to regulate zebrafish palatal development in vivo and its expression level be reduced by environmental smoke exposure in vitro. Therefore, we sought to investigate whether the A allele of rs7205289 and maternal smoke exposure during the first trimester might contribute to cleft palate risk by regulating microRNA-140. We used in situ hybridization to explore the microRNA-140 expression pattern. A luciferase reporting system and Western blot were used to validate the target of microRNA-140. Mouse palatal mesenchymal cells (MPMC) were transfected with microRNA-140 expression vectors, or treated with cigarette smoke extract. In addition, we performed a hospital-based case control study in 169 patients with nonsyndromic cleft palate and 306 unaffected controls. We demonstrated microRNA-140 expression in mouse palatal shelves from embryonic days 12 to 15. Pdgfra was the target of microRNA-140 in MPMC. When these cells were transfected with the minor allele vector or exposed to cigarette smoke extract, they showed a decrease in microRNA-140 expression. Epidemiological analyses showed that infants with CA/AA genotypes and exposed to maternal passive smoking during pregnancy had evidence of synergistic interaction in contributing to cleft palate risk. We concluded that infants with CA/AA genotypes at rs7205289 and maternal passive smoking during the first trimester may synergistically contribute to cleft palate risk by decreasing microRNA-140 during palatal development.

Copyright 2011, Wiley-Blackwell

Mahar I; Bagot RC; Davoli MA; Miksys S; Tyndale RF; Walker CD et al. Developmental hippocampal neuroplasticity in a model of nicotine replacement therapy during pregnancy and breastfeeding. PLoS ONE 7(5): e-article 37219, 2012. (66 refs.)

Rationale: The influence of developmental nicotine exposure on the brain represents an important health topic in light of the popularity of nicotine replacement therapy (NRT) as a smoking cessation method during pregnancy. Objectives: In this study, we used a model of NRT during pregnancy and breastfeeding to explore the consequences of chronic developmental nicotine exposure on cerebral neuroplasticity in the offspring. We focused on two dynamic lifelong phenomena in the dentate gyrus (DG) of the hippocampus that are highly sensitive to the environment: granule cell neurogenesis and long-term potentiation (LTP). Methods: Pregnant rats were implanted with osmotic mini-pumps delivering either nicotine or saline solutions. Plasma nicotine and metabolite levels were measured in dams and offspring. Corticosterone levels, DG neurogenesis (cell proliferation, survival and differentiation) and glutamatergic electrophysiological activity were measured in pups. Results: Juvenile (P15) and adolescent (P41) offspring exposed to nicotine throughout prenatal and postnatal development displayed no significant alteration in DG neurogenesis compared to control offspring. However, NRT-like nicotine exposure significantly increased LTP in the DG of juvenile offspring as measured in vitro from hippocampal slices, suggesting that the mechanisms underlying nicotine-induced LTP enhancement previously described in adult rats are already functional in pups. Conclusions: These results indicate that synaptic plasticity is disrupted in offspring breastfed by dams passively exposed to nicotine in an NRT-like fashion.

Copyright 2012, Public Library of Science

Maritz GS; Harding R. Life-long programming implications of exposure to tobacco smoking and nicotine before and soon after birth: Evidence for altered lung development. International Journal of Environmental Research and Public Health 8(3): 875-898, 2011. (134 refs.)

Tobacco smoking during pregnancy remains common, especially in indigenous communities, and likely contributes to respiratory illness in exposed offspring. It is now well established that components of tobacco smoke, notably nicotine, can affect multiple organs in the fetus and newborn, potentially with life-long consequences. Recent studies have shown that nicotine can permanently affect the developing lung such that its final structure and function are adversely affected; these changes can increase the risk of respiratory illness and accelerate the decline in lung function with age. In this review we discuss the impact of maternal smoking on the lungs and consider the evidence that smoking can have life-long, programming consequences for exposed offspring. Exposure to maternal tobacco smoking and nicotine intake during pregnancy and lactation changes the genetic program that controls the development and aging of the lungs of the offspring. Changes in the conducting airways and alveoli reduce lung function in exposed offspring, rendering the lungs more susceptible to obstructive lung disease and accelerating lung aging. Although it is generally accepted that prevention of maternal smoking during pregnancy and lactation is essential, current knowledge of the effects of nicotine on lung development does not support the use of nicotine replacement therapy in this group.

Copyright 2011, MDPI AG

McGlone L; Mactier H; Weaver LT. Drug misuse in pregnancy: Losing sight of the baby? Archives of Disease In Childhood 94(9): 708-712, 2009. (66 refs.)

Maternal drug misuse can seriously affect the health of the fetus and newborn infant. The association of maternal drug misuse with prematurity, intrauterine growth restriction (IUGR) and neonatal abstinence syndrome (NAS) is well recognised, and there is growing concern about infant visual development and longer-term neuro-developmental outcome. Drug misuse is associated with changes in the visual system as measured by the visual evoked potential (VEP) in adults and animal models. A recent study has shown abnormal VEPs in newborn infants exposed to methadone in utero, consistent with reports of delayed visual development in this population. Since visual abnormalities and neurodevelopmental abnormalities can be predicted by abnormal VEPs in infancy, it is postulated that the VEP may be a valuable tool in the detection of the adverse effects of maternal drug misuse upon the infant. This review summarises the impact of maternal drug misuse upon the health of the fetus and newborn infant, addresses the specific effects of maternal drug misuse upon the developing visual system and discusses the potential role of the VEP in the assessment of these infants.

Copyright 2009, BMJ Publishing

Minnes S; Lang A; Singer L. Prenatal tobacco, marijuana, stimulant, and opiate exposure: Outcomes and practice implications. Addiction Science & Clinical Practice 6(1): unpaginated, 2011

Abuse of drugs by pregnant women both in the United States and worldwide has raised many questions regarding the effects of prenatal drug exposure on the developing fetus and subsequent child outcomes. Studies using the neurobehavioral teratology model have been undertaken to determine specific prenatal drug effects on cognitive and behavioral development. Here we summarize the findings of studies that have investigated the developmental effects of prenatal exposure to tobacco, marijuana, stimulants, and opiates. These studies consider the timing and amount of prenatal exposure; other drug exposures; maternal characteristics; and other health, nutritional, and environmental factors. We review treatment options for pregnant, substance-dependent women and therapeutic interventions for exposed children.

Public Domain

Minnes S; Singer LT; Kirchner HL; Short E; Lewis B; Satayathum S et al. The effects of prenatal cocaine exposure on problem behavior in children 4-10 years. Neurotoxicology and Teratology 32(4): 443-451, 2010. (58 refs.)

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, Cl: 1.09-3.42, p<0.02). A significant prenatal cocaine exposure by sex interaction was found for delinquency indicating that only females were affected (OR = 3.57, Cl: 1.67-7.60, p<0.001). 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 mental health interventions, they warrant attention in efforts to reduce rates of problem behaviors in children.

Copyright 2010, Elsevier Science

Mongraw-Chaffin ML; Cohn BA; Anglemyer AT; Cohen RD; Christianson RE. Maternal smoking, alcohol, and coffee use during pregnancy and son's risk of testicular cancer. Alcohol 43(3): 241-245, 2009. (38 refs.)

It has been suggested that increased risk for testicular cancer occurring worldwide may be due to exposures during fetal development. Lifestyle or environmental exposures may be the most important predictors of risk. However, few studies have directly examined these exposures prospectively. The Child Health and Development Studies is a 40-year follow-up of 20,530 pregnancies occurring between 1959 and 1967. There were 20 cases of testicular cancer diagnosed through 2003 among sons with a maternal interview in early pregnancy. Cases were matched to three controls on birth year and race. Odds ratios and 95% confidence intervals were calculated with exact conditional logistic regression. Compared to controls, mothers of testicular cancer cases were more likely to drink alcohol (unadjusted odds ratio, 3.2; 95% confidence interval, 0.83-15.48 for above vs. below the median for controls) and less likely to drink coffee (unadjusted odds ratio, 0.19; 95% confidence interval, 0.02-1.02 for above vs. below the median). Case mothers were neither more nor less likely to smoke. Although low power may limit interpretation of negative results, the prospective design minimizes bias. In this cohort, maternal serum testosterone in pregnancy was previously reported to be lower in women who drank alcohol. Because populations with high testicular cancer risk also have lower maternal testosterone, we suggest that testosterone could play a role in explaining the higher risk of son's testicular cancer among mothers who drank alcohol during pregnancy.

Copyright 2009, Elsevier Science

Mook-Kanamori DO; Steegers EAP; Eilers PH; Raat H; Hofman A; Jaddoe VWV. Risk factors and outcomes associated with first-trimester fetal growth restriction. Journal of the American Medical Association 303(6): 527-534, 2010. (32 refs.)

Context: Adverse environmental exposures lead to developmental adaptations in fetal life. The influences of maternal physical characteristics and lifestyle habits on first-trimester fetal adaptations and the postnatal consequences are not known. Objective: To determine the risk factors and outcomes associated with first-trimester growth restriction. Design, Setting, and Participants Prospective evaluation of the associations of maternal physical characteristics and lifestyle habits with first-trimester fetal crown to rump length in 1631 mothers with a known and reliable first day of their last menstrual period and a regular menstrual cycle. Subsequently, we assessed the associations of first-trimester fetal growth restriction with the risks of adverse birth outcomes and postnatal growth acceleration until the age of 2 years. The study was based in Rotterdam, the Netherlands. Mothers were enrolled between 2001 and 2005. Main Outcome Measures: First-trimester fetal growth was measured as fetal crown to rump length by ultrasound between the gestational age of 10 weeks 0 days and 13 weeks 6 days. Main birth outcomes were preterm birth (gestational age <37 weeks), low birth weight (<2500 g), and small size for gestational age (lowest fifth birth centile). Postnatal growth was measured until the age of 2 years. Results: In the multivariate analysis, maternal age was positively associated with first-trimester fetal crown to rump length (difference per maternal year of age, 0.79 mm; 95% confidence interval [CI], 0.41 to 1.18 per standard deviation score increase). Higher diastolic blood pressure and higher hematocrit levels were associated with a shorter crown to rump length (differences, -0.40 mm; 95% CI, -0.74 to -0.06 and -0.52 mm; 95% CI, -0.90 to -0.14 per standard deviation increase, respectively). Compared with mothers who were nonsmokers and optimal users of folic acid supplements, those who both smoked and did not use folic acid supplements had shorter fetal crown to rump lengths (difference, -3.84 mm; 95% CI, -5.71 to -1.98). Compared with normal first-trimester fetal growth, first-trimester growth restriction was associated with increased risks of preterm birth (4.0% vs 7.2%; adjusted odds ratio [OR], 2.12; 95% CI, 1.24 to 3.61), low birth weight (3.5% vs 7.5%; adjusted OR, 2.42; 95% CI, 1.41 to 4.16), and small size for gestational age at birth (4.0% vs 10.6%; adjusted OR, 2.64; 95% CI, 1.64 to 4.25). Each standard deviation decrease in first-trimester fetal crown to rump length was associated with a postnatal growth acceleration until the age of 2 years (standard deviation score increase, 0.139 per 2 years; 95% CI, 0.097 to 0.181). Conclusions Maternal physical characteristics and lifestyle habits were independently associated with early fetal growth. First-trimester fetal growth restriction was associated with an increased risk of adverse birth outcomes and growth acceleration in early childhood.

Copyright 2010, American Medical Association

Morrow CE; Accornero VH; Xue LH; Manjunath S; Culbertson JL; Anthony JC et al. Estimated risk of developing selected DSM-IV disorders among 5-year-old children with prenatal cocaine exposure. Journal of Child and Family Studies 18(3): 356-364, 2009. (49 refs.)

We estimated childhood risk of developing selected DSM-IV Disorders, including Attention-Deficit Hyperactivity Disorder (ADHD), Oppositional Defiant Disorder (ODD), and Separation Anxiety Disorder (SAD), in children with prenatal cocaine exposure (PCE). Children were enrolled prospectively at birth (n = 476) with prenatal drug exposures documented by maternal interview, urine and meconium assays. Study participants included 400 African-American children from the birth cohort, 208 cocaine-exposed (CE) and 192 non-cocaine-exposed (NCE), who attended a 5-year follow-up assessment and whose caregiver completed the Computerized Diagnostic Interview Schedule for Children. Under a generalized linear model (logistic link), Fisher's exact methods were used to estimate the PCE-associated relative risk (RR) of these disorders. Our results indicated a modest but statistically robust elevation of ADHD risk associated with increasing levels of PCE (p < 0.05). Binary comparison of CE versus NCE children indicated no PCE-associated RR. Estimated cumulative incidence proportions among CE children were 2.9% for ADHD (vs 3.1% NCE); 1.4% for SAD (vs 1.6% NCE); and 4.3% for ODD (vs 6.8% NCE). Our findings suggest evidence of increased risk of ADHD (but not ODD or SAD) in relation to an increasing gradient of PCE during gestation.

Copyright 2009, Springer

Motlagh MG; Katsovich L; Thompson N; Lin HQ; Kim YS; Scahill L et al. Severe psychosocial stress and heavy cigarette smoking during pregnancy: An examination of the pre- and perinatal risk factors associated with ADHD and Tourette syndrome. European Journal of Epidemiology 19(10): 755-764, 2010. (62 refs.)

Attention-deficit/hyperactivity disorder (ADHD) is frequently diagnosed in children with Tourette syndrome (TS). The basis for this co-occurrence is uncertain. This study aimed to determine if specific pre- and perinatal risk factors, including heavy maternal smoking and severe psychosocial stress during pregnancy, were associated with one or both disorders, or neither. We compared maternal report data on pre- and perinatal risk factors on 222 children between the ages of 7 and 18 years including 45 individuals with TS alone, 52 individuals with ADHD alone, 60 individuals with condition of comorbid TS + ADHD, and 65 unaffected control children. Pre- and perinatal histories as well as psychiatric assessments were performed using standardized questionnaires and semi-structured interviews with the mothers and children. Logistic regression was used to determine the odds ratio for each variable of interest. Compared to the mothers of unaffected control children, the mothers of children with ADHD alone reported higher rates of heavy smoking (> 10 cigarettes per day) during pregnancy and higher levels of severe psychosocial stress during pregnancy (OR = 13.5, p < 0.01 and OR = 6.8, p < 0.002, respectively). The TS + ADHD and the TS alone patients also had higher rates heavy maternal smoking and high levels of psychosocial stress compared to the control children, but these differences failed to reach statistical significance (heavy smoking: OR = 8.5, p < 0.052, OR = 4.6, p < 0.19, respectively; severe psychosocial stress: OR = 3.1, p < 0.07, OR = 2.6, p < 0.11, respectively). Heavy maternal smoking and severe levels psychosocial stress during pregnancy were independently associated with a diagnosis of ADHD. TS patients also had higher rates of these risk factors, but the ORs failed to reach statistical significance. Efforts are needed to reduce the frequency of these risk factors in high-risk populations. Future studies, using genetically sensitive designs, are also needed to sort out the causal pathways.

Copyright 2010, Springer

Motlagh MG; Sukhodolsky DG; Landeros-Weisenberger A; Katsovich L; Thompson N; Scahill L et al. Adverse effects of heavy prenatal maternal smoking on attentional control in children With ADHD. Journal of Attention Disorders 15(7): 593-603, 2011. (84 refs.)

Objective: Exposure to heavy maternal cigarette smoking in pregnancy and severe maternal psychosocial stress during pregnancy appear to be important risk factors for the development of ADHD. This study aimed to determine whether these perinatal risk factors were associated with neuropsychological deficits commonly seen in ADHD. Method: We examined the effect of these two risk factors on measures of attentional control, motor inhibition, visual-motor integration, and fine motor coordination in a group of 81 children with ADHD, aged from 8 to 18 years. The neuropsychological battery included the Connors' Continuous Performance Test (CPT), the Stroop Color-Word Interference Test, the Beery Visual-Motor Integration Test, and the Purdue Pegboard Test. Results: Heavy maternal smoking during pregnancy was associated with slower reaction times (p < .002), and reaction time variability (p < .007) on the CPT. Conclusions: This study suggests a persistent negative effect of heavy prenatal maternal smoking on attentional control in children with ADHD. Future studies should examine the neurobiological basis and determine the degree to which inherited genetic susceptibility factors contribute to this finding.

Copyright 2011, Sage Publications

Nestler EJ. Drug abuse, addiction and the developing brain. (foreword). Developmental Neuroscience 31(1/2): 6-6, 2009. (0 refs.)

Nomura Y; Marks DJ; Halperin JM. Prenatal exposure to maternal and paternal smoking on attention deficit hyperactivity disorders symptoms and diagnosis in offspring. Journal of Nervous and Mental Disease (9): 672-678, 2010. (52 refs.)

The study examined the effect of maternal and paternal smoking during pregnancy on the child's inattention and hyperactivity/impulsivity symptoms, and the risk for attention deficit hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD). Generalized estimating equations, incorporating data from multiple informants (parents and teachers), was used to evaluate levels of ADHD as a function of parental smoking. The risk for ADHD, ODD, and comorbid ADHD and ODD was evaluated using polytomous logistic regression. We found that maternal, but not paternal, smoking was significantly associated with elevated inattention, hyperactivity/impulsivity, and total ADHD symptoms in children. Children of smoking, relative to nonsmoking, mothers had a significant increased risk for comorbid ADHD and ODD and ADHD, but not ODD. Although father's smoking was not associated with an increased risk, as it strongly influenced mothers' smoking, intervention for both parents may be most effective in preventing the pathway to ADHD-related problems in the children.

Copyright 2010, Lippincott, Williams & Wilkins

O'Callaghan FV; Al Mamun A; O'Callaghan M; Alati R; Williams GM; Najman JM. Is smoking in pregnancy an independent predictor of academic difficulties at 14 years of age? A birth cohort study. Early Human Development 86(2): 71-76, 2010. (35 refs.)

Background. Studies of the effects of maternal smoking during pregnancy have reported inconsistent findings in relation to measures of offspring cognitive functioning Few studies, however, have examined learning outcomes in adolescents, as opposed to IQ Aim To examine the association between maternal smoking during pregnancy and academic performance among adolescent offspring Study design: Population-based birth cohort study. Subjects: 7223 mothers and children were enrolled in the Mater-University of Queensland Study of Pregnancy in Brisbane (Australia) from 1981 to 1984. Analyses were restricted to the 4294 mothers and children for whom all information was reported at 14-year follow-up Outcome measures Reports of academic performance of 14-year-old offspring in English. Science and Mathematics with different patterns of maternal smoking (never smoked, smoked before and/or after pregnancy but not during pregnancy, or smoked during pregnancy) Results. Low academic achievement was more common only in those whose mothers had smoked during pregnancy. Effect sizes were, however, small. The adjusted mean difference in total learning score for smoking before and/or after pregnancy but not during pregnancy, and for smoking during pregnancy were -0.18 (-0 58, 0 22) and -0 40 (-0 69, -0 12). Similarly, the adjusted odds ratios were 0.9 (0.65, 1.24) and 1.35(1 07, 1 70) Conclusion: Maternal smoking during pregnancy is a preventable prenatal risk factor associated with small decrements in offspring academic performance that continue into adolescence.

Copyright 2010, Elsevier Science

Piper BJ; Corbett SM. Executive function profile in the offspring of women that smoked during pregnancy. Nicotine & Tobacco Research 14(2): 191-199, 2012. (58 refs.)

Smoking tobacco during pregnancy results in exposure to the fetal neuroteratogen nicotine. The current study evaluated if the offspring of smokers show abnormalities in maternal ratings of executive function, prevalence of Attention Deficit Hyperactivity Disorder (ADHD), and academic performance. A secondary objective was to determine the utility of online data collection. Mothers (N = 357) completed the parent form of the Behavioral Rating Inventory of Executive Function (BRIEF) and provided information about smoking during pregnancy. The internal consistency of the BRIEF when administered electronically was quite satisfactory (Cronbach's alpha = .98). As anticipated, ADHD was more frequently diagnosed in the offspring of women that smoked at least 10 cigarettes/day (odds ratio [OR] = 2.64, 95% CI = 1.22-5.71). Higher (i.e., more problematic) ratings relative to unexposed children (p < .01) were only identified on the total BRIEF score, the Metacognition Index, and on the Initiate, Plan/Organize, and Monitor scales among children exposed to >= 10 cigarettes/day. Nicotine-exposed children were also more likely to perform less well than their classmates in math (OR = 2.78, 95% CI = 1.59-4.87) and reading (OR = 2.00, 95% CI = 1.10-3.63), and these academic effects were independent of maternal education levels. This report provides preliminary evidence that the BRIEF has adequate psychometric properties when administered electronically and that mothers who smoke have offspring with lower executive function proficiency. These findings contribute to a larger literature that indicates that smoking during pregnancy results in adverse reproductive outcomes and, possibly, subtle but enduring deficits in prefrontal function.

Copyright 2012, Oxford University Press

Rahu K; Rahu M; Pullmann H; Allik J. Effect of birth weight, maternal education and prenatal smoking on offspring intelligence at school age. Early Human Development 86(8): 493-497, 2010. (53 refs.)

To examine the combined effect of birth weight, mothers' education and prenatal smoking on psychometrically measured intelligence at school age 1,822 children born in 1992-1999 and attending the first six grades from 45 schools representing all of the fifteen Estonian counties with information on birth weight, gestational age and mother's age, marital status, education, parity and smoking in pregnancy, and intelligence tests were studied. The scores of Raven's Standard Progressive Matrices were related to the birth weight: in the normal range of birth weight (>= 2500 g) every 500 g increase in birth weight was accompanied by around 0.7-point increase in IQ scores. A strong association between birth weight and IQ remained even if gestational age and mother's age, marital status, education, place of residence, parity and smoking during pregnancy have been taken into account. Maternal prenatal smoking was accompanied by a 3.3-point deficit in children's intellectual abilities. Marriage and mother's education had an independent positive correlation with offspring intelligence. We concluded that the statistical effect of birth weight, maternal education and smoking in pregnancy on offspring's IQ scores was remarkable and remained even if other factors have been taken into account.

Copyright 2010, Elsevier Sciences

Robinson M; McLean NJ; Oddy WH; Mattes E; Bulsara M; Li JH et al. Smoking cessation in pregnancy and the risk of child behavioural problems: A longitudinal prospective cohort study. Journal of Epidemiology and Community Health 64(7): 622-629, 2010. (51 refs.)

Background: The aim of this study was to examine the influence of smoking in pregnancy on child and adolescent behavioural development, in comparison with mothers who ceased smoking in the first 18 weeks of pregnancy and with those who never smoked, in a large prospective pregnancy cohort. Methods: The Western Australian Pregnancy Cohort (Raine) Study provided comprehensive data from 2900 pregnancies. Smoking was assessed at 18 weeks gestation, and children were followed up at ages 1, 2, 3, 5, 8, 10 and 14 years. The Child Behaviour Checklist (CBCL) was used to measure problem child behaviour with continuous z-scores and clinical cut points at ages 2, 5, 8, 10 and 14 years. Potential confounders included maternal and family sociodemographic characteristics and alcohol exposure. Results: After adjusting for confounders, children of light smokers who quit smoking by 18 weeks gestation had significantly lower CBCL total z-scores, indicative of better behaviour, than children of women who never smoked, children of heavy smokers who quit and continuing smokers. Maternal smoking during pregnancy resulted in higher CBCL total, internalising and externalising scores and a higher risk of clinically meaningful behaviour problems in children from ages 2 to 14. Conclusion: The maternal decision not to quit smoking, or the inability to quit smoking, during pregnancy appears to be a particularly strong marker for poor behavioural outcomes in children. There is a need for a greater understanding of the psychosocial characteristics associated with the decision and ability to quit smoking in pregnancy.

Copyright 2010, BMJ Publishing

Rose-Jacobs R; Soenksen S; Appugliese DP; Cabral HJ; Richardson MA; Beeghly M et al. Early adolescent executive functioning, intrauterine exposures and own drug use. Neurotoxicology and Teratology 33(3): 379-392, 2011. (116 refs.)

Individual differences in adolescents' executive functioning are often attributed either to intrauterine substance exposure or to adolescents' own substance use, but both predictors typically have not been evaluated simultaneously in the same study. This prospective study evaluated whether intrauterine drug exposures, the adolescents' own substance use, and/or their potential interactions are related to poorer executive functioning after controlling for important contextual variables. Analyses were based on data collected on a sample of 137 predominantly African-American/African Caribbean adolescents from low-income urban backgrounds who were followed since their term birth. Intrauterine substance exposures (cocaine, marijuana, alcohol, and cigarettes) and adolescents' substance use were documented using a combination of biological assays and maternal and adolescent self-report. At 12-14 years of age, examiners masked to intrauterine exposures and current substance use assessed the adolescents using the Delis Kaplan Executive Function System (D-KEFS), an age-referenced instrument evaluating multiple dimensions of executive functioning (EF). Results. of covariate-controlled analyses in this study suggest that when intrauterine substance exposures and young adolescents' substance use variables were in the same analysis models, subtle differences in specific EF outcomes were identifiable in this non-referred sample. While further study with larger samples is indicated, these findings suggest that 1) research on adolescent substance use and intrauterine exposure research should evaluate both predictors simultaneously, 2) subtle neurocognitive effects associated with specific intrauterine drug exposures can be identified during early adolescence, and 3) intrauterine substance exposure effects may differ from those associated with adolescents' own drug use.

Copyright 2011, Elsevier Science

Rose-Jacobs R; Waber D; Beeghly M; Cabral H; Appugleise D; Heeren T et al. Intrauterine cocaine exposure and executive functioning in middle childhood. Neurotoxicology and Teratology 31(3): 159-168, 2009. (89 refs.)

This longitudinal study evaluated whether the level of intrauterine cocaine exposure (IUCE) or the interaction between IUCE and contextual variables was related during middle childhood to executive functioning, as assessed with the Stroop Color-Word and Rey Osterrieth Complex Figure tests. The Stroop Interference score measures verbal inhibitory control while the Rey Osterrieth Organizational score evaluates skills such as planning, Organization and perception. Masked examiners assessed 143 children at 9.5 and I I years of age (74 with IUCE and 69 demographically similar children without IUCE). Level of IUCE (Unexposed; Lighter. and Heavier) was documented by positive postpartum maternal reports and infant meconium assays. In covariate-controlled regressions, level of IUCE was not significantly associated with Stroop Interference or Rey Osterrieth Organization scores. However, in covariate controlled post-hoc tests comparing the Heavier exposed group to the combined Lighter/Unexposed group, children in the Heavier group had significantly Poorer Stroop Interference scores, but there was no significant group difference for Rey Osterrieth Organizational scores. Children's average Organization scores in Unexposed, Lighter, and Heavier exposed groups were well below the test norm means. Results of this study indicate that heavier IUCE may be associated with mild compromise on school-aged children's ability to inhibit prepotent verbal responses.

Copyright 2009, Elsevier Science

Ruckinger S; Beyerlein A; Jacobsen G; von Kries R; Vik T. Growth in utero and body mass index at age 5 years in children of smoking and non-smoking mothers. Early Human Development 86(12): 773-777, 2010. (35 refs.)

Background: High birth weight is associated with overweight later in life, while tobacco exposure in utero is associated with low birth weight, but with later risk of overweight. Aims: To examine whether body mass index (BMI) z-scores of children at age 5 are associated with measurements of mid-abdominal diameter (MAD) in utero comparing smoking and non-smoking mothers. Study Design: Growth in utero was recorded as MAD in mm per days of gestational age (MAD for gestational age) at 17, 25, 33 and 37 weeks of gestation in 561 infants whose mothers participated in a population-based study in Scandinavia (1986-1988). Outcome Measures: The offspring's BMI z-score at 5 years was used as a dependent variable, and MAD for gestational age as well as birth weight divided by gestational age in days were included as explanatory variables in separate linear regression models. Maternal BMI was considered as a potential confounder. Results: At 17 and 25 weeks gestation there were no relevant differences in MAD for gestational age between smokers and non-smokers. At 33 and 37 weeks gestation, children of smoking mothers had less increase in MAD than children of non-smoking mothers. In adjusted models, MAD for gestational age in week 33 and 37 was positively associated with BMI z-score at 5 years of age among children of both smoking and nonsmoking mothers. Conclusions: In this study overweight in children exposed to tobacco smoking in utero was apparently not mediated through foetal growth retardation, followed by enhanced fat accretion after birth.

Copyright 2010, Elsevier Science

Ruckinger S; Rzehak P; Chen CM; Sausenthaler S; Koletzko S; Bauer CP; y Group. Prenatal and postnatal tobacco exposure and behavioral problems in 10-year-old children: Results from the GINI-plus prospective birth cohort atudy. Environmental Health Perspectives 118(1): 150-154, 2010. (34 refs.)

BACKGROUND: Prenatal and postnatal tobacco exposure have been reported to be associated with behavioral problems. However, the magnitude of the association with tobacco exposure at specific periods of exposure is unclear. OBJECTIVE: We assessed the relative risk of behavioral problems in children who had been exposed to tobacco smoke in utero and postnatally. METHODS: We analyzed data from a prospective birth cohort study in two cities in Germany: the German Infant Nutrition Intervention. Our sample included 5,991 children born between 1995 and 1998 as well as their parents. We measured behavioral problems using the Strength and Difficulties Questionnaire (SDQ) at follow-up 10 years after birth. According to prespecified SDQ cutoff values, children were classified as "normal," "borderline," or "abnormal" according to the subscales "emotional symptoms," "conduct problems," "hyperactivity/inattention," "peer-relationship problems," and a total difficulties score. Smoke exposure and further covariates were assessed using parent questionnaires. RESULTS: Compared with children not exposed to tobacco smoke, children exposed both pre- and postnatally to tobacco smoke had twice the estimated risk [95% confidence interval (CI), 1.4-3.1] of being classified as abnormal according to the total difficulties score of the SDQ at 10 years of age. Children who were only prenatally exposed had a 90% higher relative risk (95% CI, 0.9-4.0), whereas children who were only postnatally exposed had a 30% higher relative risk (95% CI, 0.9-1.9). These results could not be explained by confounding by parental education, father's employment, child's time spent in front of computer or television screen, being a single father or mother, or mother's age. CONCLUSIONS: Prenatal exposure to tobacco smoke is associated with behavioral problems in school-age children. Although our findings do not preclude the influence of postnatal exposure, prenatal exposure seems to be more important.

Copyright 2010, US Department of Human Health Sciences

Salo S; Kivisto K; Korja R; Biringen Z; Tupola S; Kahila H et al. Emotional availability, parental self-efficacy beliefs, and child development in caregiver-child relationships with buprenorphine-exposed 3-year-olds. Parenting. Science and Practice 9(3-4): 244-259, 2009. (50 refs.)

Objective. The purpose was to compare emotional availability, maternal self-efficacy beliefs, and child developmental status in caregiver-child relationships with prenatally buprenorphine-exposed and nonexposed 3-year-old children. Design. We compared prenatally buprenorphine-exposed children living either with the biological mother (n = 7) or in foster care (n = 14) to nonexposed participants (n = 13). Emotional availability was coded from videotaped parent-child free-play interactions. Results. After controlling for covariates, buprenorphine-exposed children scored lower on maternal Sensitivity and Nonhostility and child Responsiveness and Involvement as well as lower on the Bayley Cognitive and Language scales than did nonexposed children. As compared to foster mothers, biological mothers scored lower on Sensitivity and Nonhostility and self-efficacy beliefs, and their children scored lower on Responsiveness and the Bayley Cognitive Scale. Regardless of group status, the parenting variables were meaningfully related to child socioemotional variables. Conclusions. Buprenorphine-exposed children experienced more environmental risks in emotional availability and parental self-efficacy and performed worse on the Bayley as compared to nonexposed children.

Copyright 2009, Taylor & Francis

Sarkola T; Gissler M; Kahila H; Autti-Ramo I; Halmesmaki E. Alcohol and substance abuse identified during pregnancy: Maternal morbidity, child morbidity and welfare interventions. Acta Paediatrica 101(7): 784-790, 2012. (26 refs.)

Aim: To study the relations between postnatal maternal morbidity, child morbidity and welfare interventions in families with prenatal alcohol or substance abuse. Methods: A register-based longitudinal retrospective cohort study. The exposed cohort included 638 children born to 524 women followed-up during pregnancy for alcohol or substance abuse 19922001. Non-exposed children (n = 1914) born to control women were matched for maternal age, parity, number of foetuses, month of birth and delivery hospital of the index child. Perinatal and follow-up data of both cohorts were collected from national registers until 2007. Results: Postnatal maternal abuse-related healthcare utilization and use of medication were associated with child out-of-home care. Significant differences were in particular observed in the categories of maternal mental and behavioural disorders caused by psychoactive substance use as well as injury and poisoning. Maternal inpatient care for mental and behavioural disorders peaked at the time of child out-of-home care. Maternal abuse-related healthcare utilization was associated with early child healthcare utilization and use of medication for mental and behavioural disorders. These associations were largely explained by the association with child out-of-home care. Conclusions: Postnatal maternal abuse-related morbidity is associated with significant early child morbidity, use of medication and timing of out-of-home care.

Copyright 2012, Wiley-Blackwell

Schlotz W; Phillips DIW. Fetal origins of mental health: Evidence and mechanisms. (review). Brain, Behavior and Immunity 23(7): 905-916, 2009. (231 refs.)

The concept of fetal programming states that changes in the fetal environment during sensitive periods of organ development may cause long-lasting changes in the structure and functioning of these organs later in life and influence the risk for chronic diseases such as coronary heart disease and type 2 diabetes. Fetal growth is a summary marker of the fetal environment and is reflected by relatively easy-to-obtain measures of size at birth such as birth weight. In the last two decades, a body of evidence emerged linking fetal growth with behavioural and mental health outcomes later in life. Cognitive functioning and behavioural problems in childhood, in particular inattention/hyperactivity, have been shown to be inversely related to fetal growth. Although results are mixed, risk for personality disorders and schizophrenia seems to be linked with fetal growth and adversity, while the evidence for mood disorders is weak. Vulnerability for psychopathology may also be influenced by prenatal adversity. There is evidence for associations of fetal growth with temperament in childhood as well as stress reactivity and distress. The associations of fetal growth with mental health later in life are potentially caused by specific prenatal factors such as maternal smoking, alcohol, toxins/drugs, nutrition, psychosocial stress and infection during pregnancy. The mechanisms likely involve changes in neurodevelopment and in the set point of neuroendocrine systems, and there is evidence that prenatal adversity interacts with genetic and postnatal environmental factors. Future studies should examine the effects of specific prenatal factors and attempt to disentangle genetic and prenatal environmental effects.

Copyright 2009, Academic Press

Sheinkopf SJ; Lester BM; Sanes JN; Eliassen JC; Hutchison ER; Seifer R et al. Functional MRI and response inhibition in children exposed to cocaine in utero. Psychiatric Services 31(1/2): 159-166, 2009. (43 refs.)

This study investigated the potential long-term effects of cocaine exposure on brain functioning using fMRI in school-aged children. The sample included 12 children with prenatal cocaine exposure and 12 non-exposed children (8-9 years old). Groups did not differ on IQ, socioeconomic status, or perinatal risk factors. A response inhibition task was administered during an fMRI scan using a 1.5-T MRI system. Task performance did not differentiate groups, but groups were differentiated by patterns of task-related brain activity. Cocaine-exposed children showed greater activation in the right inferior frontal cortex and caudate during response inhibition, whereas non-exposed children showed greater activations in temporal and occipital regions. These preliminary findings suggest that prenatal cocaine may affect the development of brain systems involved in the regulation of attention and response inhibition.

Copyright 2009, Karger

Smith LM; Paz MS; LaGasse LL; Derauf C; Newman E; Shah R et al. Maternal depression and prenatal exposure to methamphetamine: Neurodevelopmental findings from the infant development, environment, and lifestyle (ideal) study. Depression and Anxiety 29(6): 515-522, 2012. (48 refs.)

Background: Maternal depression is associated with a higher incidence of behavioral problems in infants, but the effects of maternal depression as early as 1 month are not well characterized. The objective of this study is to determine the neurobehavioral effects of maternal depression on infants exposed and not exposed to methamphetamine (MA) using the NICU Network Neurobehavioral Scale (NNNS). Methods: Four hundred twelve mother-infant pairs were enrolled (MA = 204) and only biological mothers with custody of their child were included in the current analysis. At the 1-month visit (n = 126 MA-exposed; n = 193 MA-unexposed), the Beck Depression Inventory-II (BDI-II) was administered, and the NNNS was administered to the infant. Exposure was identified by self-report and/or gas chromatography/mass spectroscopy confirmation of amphetamine and metabolites in newborn meconium. Unexposed subjects were matched, denied amphetamine use, and had negative meconium screens. General Linear Models tested the effects of maternal depression and prenatal MA exposure on NNNS, with significance accepted at P < .05. Results: The MA group had an increased incidence of depression-positive diagnosis and increased depression scores on the BDI-II. After adjusting for covariates, MA exposure was associated with increased arousal and handling scores, and a decreased ability to self-regulate. Maternal depression was associated with higher autonomic stress and poorer quality of movement. No additional differences were observed in infants whose mothers were both depressed and used MA during pregnancy. Conclusions: Maternal depression is associated with neurodevelopmental patterns of increased stress and decreased quality of movement, suggesting maternal depression influences neurodevelopment in infants as young as 1 month.

Copyright 2012, Wiley-Blackwell

Stavrou EP; Baker DF; Bishop JF. Maternal smoking during pregnancy and childhood cancer in New South Wales: A record linkage investigation. Cancer Causes and Control 20(9): 1551-1558, 2009. (78 refs.)

Following linkage between the NSW Central Cancer Registry (CCR) and the NSW Midwives Data Collection, an investigation of the association between maternal smoking during pregnancy and the risk of childhood cancer in their offspring was undertaken. Children born in NSW between 1994 and 2005, inclusive of 1,045,966 babies, were matched to 948 cancer cases in the CCR. After adjustment for maternal age, gestational age, baby's gender, birth weight, remoteness index, socioeconomic disadvantage and maternal health factors, no association (OR = 0.96, 95% CI 0.81-1.15, p = 0.68) was found with childhood cancer between mothers who smoked (81/100,000) and those who did not smoke during pregnancy (99/100, 000). Maternal smoking was, however, significantly associated with retinoblastoma (OR = 2.20, 95% CI 1.19-4.09, p = 0.01). Association between maternal smoking and preterm birth and low birth weight was significant. Maternal smoking during pregnancy is significantly associated with retinoblastoma and adverse birth outcomes. These results should be highlighted to expectant mothers through antitobacco-smoking campaigns.

Copyright 2009, Springer

Stone KC; High PC; Miller-Loncar CL; LaGasse LL; Lester BM. Longitudinal study of maternal report of sleep problems in children with prenatal exposure to cocaine and other drugs. Behavioral Sleep Medicine 7(4): 196-207, 2009. (47 refs.)

Sleep data were collected by maternal report in a prospective longitudinal follow up of cocaine-exposed and unexposed children. There were 139 participants: 23 with no prenatal drug exposure, 55 exposed to cocaine alone or in combination with other drugs, and 61 exposed to drugs other than cocaine. Characteristics differed between exposure groups including birth size, caretaker changes, maternal socioeconomic status, and postnatal drug use. Compared to those with no drug exposure, children with prenatal drug exposure other than cocaine experienced greater sleep problems (p = .026). Prenatal nicotine exposure was a unique predictor of sleep problems (p = .048). Early sleep problems predicted later sleep problems (all ps < .01). Together, these preliminary findings suggest possible neurotoxic sleep effects that persist over time. Larger studies, however, need to be conducted that better control for potential postnatal confounding factors.

Copyright 2009, Taylor & Francis

Sun YL; Strandberg-Larsen K; Vestergaard M; Christensen J; Andersen AMN; Gronbaek M et al. Binge drinking during pregnancy and risk of seizures in childhood: A study based on the Danish National Birth Cohort. American Journal of Epidemiology 169(3): 313-322, 2009. (41 refs.)

Seizures are often found in children with fetal alcohol syndrome, but it is not known whether binge drinking during pregnancy by nonalcoholic women is associated with an increased risk of seizure disorders in children. The authors conducted a population-based cohort study of 80,526 liveborn singletons in the Danish National Birth Cohort (1996-2002). Information on maternal binge drinking (intake of >= 5 drinks on a single occasion) was collected in 2 computer-assisted telephone interviews during pregnancy. Children were followed for up to 8 years. Information on neonatal seizures, epilepsy, and febrile seizures was retrieved from the Danish National Hospitalital Register. Results showed that exposure to binge drinking episodes during pregnancy was not associated with an increased risk of seizure disorders in children, except for those exposed at 11-16 gestational weeks. These children had a 3.15-fold increased risk of neonatal seizures (95% confidence interval: 1.37, 7.25) and a 1.81-fold increased risk of epilepsy (95% confidence interval: 1.13, 2.90). These findings suggest that maternal binge drinking during a specific time period of pregnancy may be associated with an increased risk of specific seizure disorders in the offspring. The results are exploratory, however, and need to be replicated.

Copyright 2009, Oxford University Press

van den Berg G; van Eijsden M; Vrijkotte TGM; Gemke RJBJ. Educational inequalities in perinatal outcomes: The mediating effect of smoking and environmental tobacco exposure. PLoS ONE 7(5): e-article 37002, 2012. (45 refs.)

Objective: Socioeconomic status (SES) is adversely associated with perinatal outcomes. This association is likely to be mediated by tobacco exposure. However, previous studies were limited to single perinatal outcomes and devoted no attention to environmental tobacco exposure. Therefore, this study aimed firstly to explain the role of maternal smoking in the association between maternal education and preterm birth (PTB), low birth weight (LBW) and small for gestational age (SGA), and secondly to explain whether environmental tobacco smoke mediates these associations further. Study Design: This study was nested in a population-based cohort study in the Netherlands, the Amsterdam Born Children and their Development (ABCD) study. Analyses were done in a sample of 3821 pregnant women of Dutch origin, using logistic regression analysis. Results: Least educated women, who were more often smoking and exposed to environmental tobacco smoke, had a significantly higher risk of PTB (OR 1.95 [95% CI: 1.19-3.20]), LBW (OR 2.41 [95% CI: 1.36-4.27]) and SGA (OR 1.90 [95% CI 1.32-2.74]) than highly educated women. The mediating effect of smoking in the least educated women was 43% for PTB, 55% for LBW and 66% for SGA. Environmental tobacco smoke did not explain these associations further. After adjustment for maternal smoking, the association between lower maternal education and pregnancy outcomes was no longer significant. Conclusions: Smoking explains to a considerable extent the association between lower maternal education and adverse perinatal outcomes. Therefore, tobacco-interventions in lower educated women should be primarily focussed on maternal smoking to reduce PTB, LBW, and SGA. Additional attention to environmental tobacco exposure does not seem to reduce educational inequalities in perinatal outcomes.

Copyright 2012, Public Library of Science

Whitaker TM; Bada HS; Bann CM; Shankaran S; LaGasse L; Lester BM et al. Serial pediatric symptom checklist screening in children with prenatal drug exposure. Journal of Developmental and Behavioral Pediatrics 32(3): 206-215, 2011. (38 refs.)

Objective: To examine screening results obtained by serial annual behavioral assessment of children with prenatal drug exposure. Method: 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 with an established broad-based behavioral measure at 9, 11, and 13 years. PSC results were analyzed for 1081 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. Results: 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 prenatally and postnatally 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. Conclusion: 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.

Copyright 2011, Lippincott, Williams & Wilkins

Wiebe SA; Espy KA; Stopp C; Respass J; Stewart P; Jameson TR et al. Gene-environment interactions across development: Exploring DRD2 genotype and prenatal smoking effects on self-regulation. (review). Developmental Psychology 45(1): 31-44, 2009. (116 refs.)

Genetic factors dynamically interact with both pre- and postnatal environmental influences to shape development. Considerable attention has been devoted to gene-environment interactions (G X E) on important outcomes (A. Caspi & T. E. Moffitt, 2006). It is also important to consider the possibility that these G X E effects may vary across development, particularly for constructs like self-regulation that emerge slowly, depend on brain regions that change qualitatively in different developmental periods, and thus may be manifested differently. To illustrate one approach to exploring such developmental patterns, the relation between variation in the TaqIA polymorphism, related to D-2 dopamine receptor expression and availability, and prenatal exposure to tobacco was examined in two exploratory studies. First, in 4-week-old neonates, genotype-exposure interactions were observed for attention and irritable reactivity, but not for stress dysregulation. Second, in preschool children, genotype was related to Preschool Trail Making Test (K. A. Espy and M. F. Cwik, 2004) task performance on conditions requiring executive control; children with both the Al+ genotype and a history of prenatal tobacco exposure displayed disproportionately poor performance. Despite study limitations, these results illustrate the importance of examining the interplay between genetic and prenatal environmental factors across development.

Copyright 2009, American Psychological Association

Willford JA; Chandler LS; Goldschmidt L; Day NL. Effects of prenatal tobacco, alcohol and marijuana exposure on processing speed, visual-motor coordination, and interhemispheric transfer. Neurotoxicology and Teratology 32(6): 580-588, 2010. (120 refs.)

Deficits in motor control are often reported in children with prenatal alcohol exposure (PAE). Less is known about the effects of prenatal tobacco exposure (PTE) and prenatal marijuana exposure (PME) on motor coordination, and previous studies have not considered whether PTE, PAE, and PME interact to affect motor control. This study investigated the effects of PTE, PAE, and PME as well as current drug use on speed of processing, visual-motor coordination, and interhemispheric transfer in 16-year-old adolescents. Data were collected as part of the Maternal Health Practices and Child Development Project. Adolescents (age 16, n = 320) participating in a longitudinal study of the effects of prenatal substance exposure on developmental outcomes were evaluated in this study. The computerized Bimanual Coordination Test (BCT) was used to assess each domain of function. Other important variables, such as demographics, home environment, and psychological characteristics of the mother and adolescent were also considered in the analyses. There were significant and independent effects of PTE, PAE, and PME on processing speed and interhemispheric transfer of information. PTE and PME were associated with deficits in visual-motor coordination. There were no interactions between PAE. PTE, and PME. Current tobacco use predicted deficits in speed of processing. Current alcohol and marijuana use by the offspring were not associated with any measures of performance on the BCT.

Copyright 2010, Elsevier Science

Wouldes TA; Woodward LJ. Maternal methadone dose during pregnancy and infant clinical outcome. Neurotoxicology and Teratology 32(3): 406-413, 2010. (71 refs.)

In recent decades there has been an increase in the methadone dosages prescribed for opioid dependent women during pregnancy. Using prospective longitudinal data from a cohort of 32 methadone exposed and 42 non-methadone exposed infants, this study examined the relationship between maternal methadone dose during pregnancy and a range of infant clinical outcomes. Of particular interest was the extent to which any observed associations might reflect the direct causal effects of maternal methadone dose and/or the confounding effects of adverse maternal lifestyle factors correlated with methadone use during pregnancy. Findings revealed the presence of clear linear relationships between the mean methadone dose prescribed for mothers during pregnancy and a range of adverse infant clinical outcomes. With increasing maternal methadone dose there was a corresponding increase in infants' risk of being born preterm, being symmetrically smaller, spending longer periods in hospital and the need for treatment for Neonatal Abstinence Syndrome. After due allowance for potentially confounding maternal health and lifestyle factors, maternal methadone dose during pregnancy remained a significant predictor of preterm birth, growth, and the duration of infant hospitalization post delivery. These findings suggest a need to examine more closely the potential impacts of recent trends towards the use of higher methadone dose levels during pregnancy.

Copyright 2010, Elsevier Science

Zabaneh R; Smith LM; LaGasse LL; Derauf C; Newman E; Shah R et al. The effects of prenatal methamphetamine exposure on childhood growth patterns from birth to 3 years of age. American Journal of Perinatology 29(3): 203-210, 2012. (39 refs.)

We examined the effects of prenatal methamphetamine (MA) exposure on growth parameters from birth to age 3 years. The 412 subjects included (n = 204 exposed) were enrolled at birth in the Infant Development, Environment and Lifestyle study, a longitudinal study assessing the effects of prenatal MA exposure on childhood outcomes. Individual models were used to examine the effects of prenatal MA exposure on weight, head circumference, height, and weight-for-length growth trajectories. After adjusting for covariates, height trajectory was lower in the exposed versus the comparison children (p = 0.021) over the first 3 years of life. Both groups increased height on average by 2.27 cm per month by age 3 years. In term subjects, MA exposure was also associated with a lower height trajectory (p = 0.034), with both the exposed and comparison groups gaining 2.25 cm per month by age 3 years. There was no difference in weight, head circumference, or weight-for-length growth trajectories between the comparison and the exposed groups. Children exposed prenatally to MA have a modest decrease in height growth trajectory during the first 3 years of life with no observed difference in weight, head circumference, or weight-for-length trajectories.

Copyright 2012, Thieme Medical Publishing

Zagar RJ; Isbell SA; Busch KG; Hughes JR. An empirical theory of the development of homicide within individuals. (review). Psychological Reports 104(1, Special Issue): 199-245, 2009. (151 refs.)

There have been many attempts to explain violent behavior, identify its causes, and predict its occurrence among youth and adults. Research and theoretical constructions have dealt with such far-ranging aspects as childhood health, peer and parental interactions, neuropsychological function, school and community support, and substance use and dependency. Theories have tended to focus on one or a few of these aspects, but there is an effort by many researchers to converge on an integrated approach, By demonstrating unique risk patterns in random samples of later-homicidal abused infants, children, and youth, violent and homicidal delinquents, and homicidal adults, five studies by Zagar and colleagues provide the best current empirical evidence for a view of the development of delinquency as a process of accumulating risks. These risks begin with prenatal substance exposure and continue with abusive or neglectful parenting, academic failure, court contacts, compromised executive function and resultant poor social functioning. Analysis by sex shows that males' and females' risks are virtually identical. Various theories are evaluated with respect to these empirical risk patterns for development of violence and homicide. A proposal for the necessary elements of a successful, overarching explanatory theory is offered.

Copyright 2009, Ammons Scientific

Zammit S; Thomas K; Thompson A; Horwood J; Menezes P; Gunnell D et al. Maternal tobacco, cannabis and alcohol use during pregnancy and risk of adolescent psychotic symptoms in offspring. British Journal of Psychiatry 195(4): 294-300, 2009. (52 refs.)

Background: Adverse effects of maternal substance use during pregnancy on fetal development may increase risk of psychopathology. Aims To examine whether maternal use of tobacco, cannabis or alcohol during pregnancy increases risk of offspring psychotic symptoms. Method A longitudinal study of 6356 adolescents, age 12, who completed a semi-structured interview for psychotic symptoms in the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort. Results Frequency of maternal tobacco use during pregnancy was associated with increased risk of suspected or definite psychotic symptoms (adjusted odds ratio 1.20, 95% CI 1.05-1.37, P=0.007). Maternal alcohol use showed a non-linear association with psychotic symptoms, with this effect almost exclusively in the offspring of women drinking >21 units weekly. Maternal cannabis use was not associated with psychotic Symptoms. Results for paternal smoking during pregnancy and maternal smoking post-pregnancy lend some support for a causal effect of tobacco exposure in utero on development of psychotic experiences. Conclusions: These findings indicate that risk factors for development of non-clinical psychotic experiences may operate during early development. Future studies of how in utero exposure to tobacco affects cerebral development and function may lead to increased understanding of the pathogenesis of psychotic phenomena.

Copyright 2009, Royal College of Psychiatrists